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Sample records for antithrombins

  1. Antithrombin, an Important Inhibitor in Blood Clots.

    Science.gov (United States)

    Zhu, Ying; Cong, Qing-Wei; Liu, Yue; Wan, Chun-Ling; Yu, Tao; He, Guang; He, Lin; Cai, Lei; Chou, Kuo-Chen

    2016-01-01

    Blood coagulation is healthy and lifesaving because it can stop bleeding. It can, however, be a troublemaker as well, causing serious medical problems including heart attack and stroke. Body has complex blood coagulation cascade to modulate the blood clots. In the environment of plasma, the blood coagulation cascade is regulated by antithrombin, which is deemed one of the most important serine protease inhibitors. It inhibits thrombin; it can inhibit factors IXa and Xa as well. Interestingly, its inhibitory ability will be significantly increased with the existence of heparin. In this minireview paper, we are to summarize the structural features of antithrombin, as well as its heparin binding modes and anti-coagulation mechanisms, in hopes that the discussion and analysis presented in this paper can stimulate new strategies to find more effective approaches or compounds to modulate the antithrombin. PMID:26411319

  2. Antithrombin III for critically ill patients

    DEFF Research Database (Denmark)

    Afshari, Arash; Wetterslev, Jørn; Brok, Jesper Sune;

    2008-01-01

    Critical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ...

  3. Recombinant human antithrombin III: rhATIII.

    Science.gov (United States)

    2004-01-01

    GTC Biotherapeutics (formerly Genzyme Transgenics Corporation) is developing a transgenic form of antithrombin III known as recombinant human antithrombin III [rhATIII]. It is produced by inserting human DNA into the cells of goats so that the targeted protein is excreted in the milk of the female offspring. The transgenic goats have been cloned in collaboration with the Louisiana State University Agriculture Center. GTC Biotherapeutics is conducting clinical trials of rhATIII in coagulation disorders. rhATIII is believed to be both safer and more cost-effective than the currently available plasma-derived product. rhATIII is also being investigated in cancer and acute lung injury. Genzyme Transgenics Corporation, originally a subsidiary of Genzyme Corporation, changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation. GTC Biotherapeutics is seeking partners for the commercialisation of rhATIII. Restructuring of GTC Biotherapeutics to support its commercialisation programmes was announced in February 2004. Genzyme Transgenics Corporation was developing rhATIII in association with Genzyme General (Genzyme Corporation) in the ATIII LLC joint venture, but in November 2000 a letter of intent was signed for the reacquisition of the rights by Genzyme Transgenics Corporation. It was announced in February 2001 that this reacquisition was not going to be completed and that the development of rhATIII was to continue with ATIII LLC. However, in July 2001, Genzyme Transgenics Corporation reacquired all the rights in the transgenic antithrombin III programme. SMI Genzyme Ltd, a joint venture between Sumitomo Metal Industries, Japan, and Genzyme Transgenics Corporation, USA, was set up to fund development of transgenic antithrombin III in Asia. However, in October 2000, Genzyme Transgenics Corporation reacquired, from Sumitomo Metal Industries, the rights to its technology for production of medicines from milk in 18 Asian countries

  4. Sulfated cellulose thin films with antithrombin affinity

    Directory of Open Access Journals (Sweden)

    2009-11-01

    Full Text Available Cellulose thin films were chemically modified by in situ sulfation to produce surfaces with anticoagulant characteristics. Two celluloses differing in their degree of polymerization (DP: CEL I (DP 215–240 and CEL II (DP 1300–1400 were tethered to maleic anhydride copolymer (MA layers and subsequently exposed to SO3•NMe3 solutions at elevated temperature. The impact of the resulting sulfation on the physicochemical properties of the cellulose films was investigated with respect to film thickness, atomic composition, wettability and roughness. The sulfation was optimized to gain a maximal surface concentration of sulfate groups. The scavenging of antithrombin (AT by the surfaces was determined to conclude on their potential anticoagulant properties.

  5. Antithrombin III and the nephrotic syndrome.

    Science.gov (United States)

    Jørgensen, K A; Stoffersen, E

    1979-05-01

    Plasma and urinary antithrombin III (AT-III) was measured in 15 cases of nephrotic syndrome. Plasma AT-III correlated well with serum albumin, but poorly with proteinuria, whereas urinary AT-III correlated well to proteinuria. The plasma AT-III level had a mean similar to 25 healthy controls, but the range was significantly wider. A case with nephrotic syndrome and left renal vein thrombosis is reported. The urinary output of AT-III rose and the plasma level fell with the activity of the disease. Although AT-III and albumin have similar molecule weight, their renal clearance was found to be different. It is suggested that urinary loss of AT-III plays a role in the hypercoagulable state sometimes found in the nephrotic syndrome.

  6. 21 CFR 864.7060 - Antithrombin III assay.

    Science.gov (United States)

    2010-04-01

    ... level of antithrombin III (a substance which acts with the anticoagulant heparin to prevent coagulation). This determination is used to monitor the administration of heparin in the treatment of thrombosis....

  7. Cloning, Characterization and Anti-Inflammatory Properties of Bothrops jararaca Snake Antithrombin.

    Science.gov (United States)

    Morais-Zani, Karen de; Grego, Kathleen F; Torquato, Ricardo J S; Silva, Caroline S; Tanaka, Aparecida S; Tanaka-Azevedo, Anita M

    2015-01-01

    Antithrombin inhibits blood coagulation through the interaction with serine proteases in both intrinsic and extrinsic pathways. In addition, antithrombin also shows anti-inflammatory properties, which are independent of its effects on coagulation. This work shows for the first time the cloning and sequencing of antithrombin from a snake species. This predicted protein is composed by 430 amino acids and presents about 64.5% sequence identity to human antithrombin. Biacore experiments revealed that the binding affinity of Bothrops jararaca snake antithrombin to heparin was ~30 times higher than that of human antithrombin. Furthermore, Bothrops jararaca antithrombin is more effective in preventing acute inflammation induced by carrageenan when compared to human antithrombin. Hence, the results showed herein suggest that Bothrops jararaca antithrombin can play a key role in the control of acute inflammation and that this molecule might be used as a pharmacological tool and as a prototype for drug development. PMID:25687119

  8. Inherited antithrombin deficiency and end stage renal disease.

    Science.gov (United States)

    Hara, Tomohiko; Naito, Katsusuke

    2005-11-01

    Antithrombin is a potent inhibitor of the coagulant effect of thrombin. In the latter half of 20th century, many families have been described in which an autosomaly dominant inherited antithrombin deficiency has caused severe venous thromboembolic disease in successive generations. The important complication is severe venoocclusive disease by deep venous thrombus. Some inherited antithrombin deficient patients developed renal failure because of fibrin deposition in the kidney glomeruli or renal vein thrombus, and therefore the need for replacement therapy for end stage renal disease (ESRD). Although an inherited antithrombin deficiency with renal failure is rare, prevention against renal failure in such patients, and their renal replacement therapy for ESRD are important. Proteinuria decreases plasma antithrombin level leading to more severe hyper-coagulation state. Therefore early in renal disease, it may be prudent for adaptation of anti-coagulation therapy even if recurrent thrombosis has not occurred. All replacement therapy (hemodialysis, transplantation or peritoneal dialysis) for ESRD are available for such thrombophilic disorders. Anticoagulation agents working without aggravation of antithrombin effects (Argatroban, Nafamostat mesilate etc.) are useful for hemodialysis. The renal allograft recipients with thrombophilia seem to be at risk of developing an acute rejection or other vascular event. Peritoneal dialysis is potentially a good adaptation for such thrombophilic disorders. However which therapy has the best mortality and morbidity outcomes is not clear. Physicians and Surgeons must pay attention to the coagulation state and thrombophilia in ESRD patients, give strong consideration for adequate anti-coagulation therapy and review the best renal replacement modality for each patient.

  9. [Antithrombin resistance: a new mechanism of inherited thrombophilia].

    Science.gov (United States)

    Kojima, Tetsuhito; Takagi, Akira; Murata, Moe; Takagi, Yuki

    2015-06-01

    Venous thromboembolism is a multifactorial disease resulting from complex interactions among genetic and environmental factors. To date, numerous genetic defects have been found in families with hereditary thrombophilia, but there may still be many undiscovered causative gene mutations. We investigated a possible causative gene defect in a large Japanese family with inherited thrombophilia, and found a novel missense mutation in the prothrombin gene (p.Arg596Leu) resulting in a variant prothrombin (prothrombin Yukuhashi). The mutant prothrombin had moderately lower activity than wild type prothrombin in clotting assays, but formation of the thrombin-antithrombin (TAT) complex was substantially impaired resulting in prolonged thrombin activity. A thrombin generation assay revealed that the peak activity of the mutant prothrombin was fairly low, but its inactivation was extremely slow in reconstituted plasma. The Leu596 substitution caused a gain-of-function mutation in the prothrombin gene, resulting in resistance to antithrombin and susceptibility to thrombosis. We also showed the effects of the prothrombin Yukuhashi mutation on the thrombomodulin-protein C anticoagulation system, recent development of a laboratory test detecting antithrombin resistance in plasma, and another antithrombin resistant mutation found in other thrombophilia families. PMID:26256872

  10. Inherited antithrombin deficiency and anabolic steroids: a risky combination.

    Science.gov (United States)

    Choe, Hannah; Elfil, Mohamed; DeSancho, Maria T

    2016-09-01

    A 20-year-old male with asymptomatic inherited type 1 antithrombin deficiency and a family history of thrombosis started injecting himself with testosterone 250 mg intramuscularly twice weekly for 5 weeks. He presented to the hospital with progressive dyspnea on exertion, chest pain and hemoptysis. Workup revealed bilateral submassive pulmonary embolism and proximal right lower extremity deep vein thrombosis. He was treated with intravenous (IV) unfractionated heparin and underwent catheter-directed thrombolysis with alteplase to the main pulmonary arteries. Postprocedure, he remained on IV alteplase infusion for 24 h and unfractionated heparin in the intensive care unit. Concomitantly he received plasma-derived antithrombin concentrate. He was transitioned to subcutaneous enoxaparin twice daily and discharged from the hospital on oral rivaroxaban 15 mg twice a day. This case highlights the heightened thrombogenic effect of anabolic steroids in the setting of underlying thrombophilia especially in younger subjects. PMID:26588446

  11. Generation of Humanized Mouse Models with Focus on Antithrombin Deficiency

    DEFF Research Database (Denmark)

    Jensen, Astrid Bøgh

    2015-01-01

    transgene. The CRISPR/Cas9 system is a relatively new and innovative method for targeted mutagenesis. The Cas9 nuclease introduces a double stranded break in the DNA, which can be repaired through homologous recombination of a targeting vector. A mutated Cas9n (Cas9 nickase) has been designed, which only...... gene by the murine antithrombin regulatory sequences, I designed a targeted mutagenesis using the CRISPR/Cas9 system which conserves the 5’UTR of the murine antithrombin gene. With the CRISPR/Cas9 I achieved targeting efficiency for heterozygous integrations of about 80%, which correlated well with our...... preliminary CRISPR/Cas9 experiments targeting the Rosa26 locus. However, when targeting the Rosa26 locus, using the CRISPR/Cas9n system I only observed 65% targeting efficiency for heterozygous integration which correlates well with the requirement for two nicks created by the mutated Cas9n. Others have shown...

  12. Interaction of antithrombin III with preadsorbed albumin-heparin conjugates

    OpenAIRE

    Hennink, W.E.; Ebert, C.D.; Kim, S. W.; Breemhaar, W.; Bantjes, A.; Feijen, J.

    1984-01-01

    The adsorption of antithrombin III (AT III) onto polystyrene surfaces preadsorbed with albumin or albuminheparin conjugates was studied using a two step enzyme immuno assay. When AT III-buffer solutions were used, the highest adsorption values were measured on high affinity albumin-heparin conjugate pretreated surfaces. Less AT III adsorption was found on nonfractionated albumin-heparin conjugate preadsorbed surfaces. AT III adsorption could also be detected on low affinity conjugate and albu...

  13. Portal vein thrombosis treated using danaparoid sodium and antithrombin III.

    Science.gov (United States)

    Uchiyama, T; Hirokazu, Takahashi; Hosono, K; Endo, H; Akiyama, T; Yoneda, K; Inamori, M; Abe, Y; Kubota, K; Saito, S; Nakajima, A

    2010-01-01

    A 45-year-old man under treatment for liver cirrhosis (LC) due to chronic hepatitis C and hemophilia A was seen in our emergency room because of a 10-kg weight gain in the previous week due to ascites. Portal vein thrombosis (PVT) was detected with computer tomography (CT) and ultrasonographic (US). Danaparoid sodium (DS) and antithrombin III (AT III) were administrated and doppler US images showed improvement of portal venous blood flow. DS or AT III may be safe and alternative therapies for PVT. PMID:20422871

  14. Identification of Regulatory Mutations in SERPINC1 Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency

    Science.gov (United States)

    Toderici, Mara; de la Morena-Barrio, María Eugenia; Padilla, José; Miñano, Antonia; Antón, Ana Isabel; Iniesta, Juan Antonio; Herranz, María Teresa; Fernández, Nuria; Vicente, Vicente; Corral, Javier

    2016-01-01

    Antithrombin is a crucial anticoagulant serpin whose even moderate deficiency significantly increases the risk of thrombosis. Most cases with antithrombin deficiency carried genetic defects affecting exons or flanking regions of SERPINC1.We aimed to identify regulatory mutations inSERPINC1 through sequencing the promoter, intron 1 and 2 of this gene in 23 patients with antithrombin deficiency but without known genetic defects. Three cases with moderate antithrombin deficiency (63–78%) carried potential regulatory mutations. One located 200 bp before the initiation ATG and two in intron 1. These mutations disrupted two out of five potential vitamin D receptor elements (VDRE) identified in SERPINC1 with different software. One genetic defect, c.42-1060_-1057dupTTGA, was a new low prevalent polymorphism (MAF: 0.01) with functional consequences on plasma antithrombin levels. The relevance of the vitamin D pathway on the regulation of SERPINC1 was confirmed in a cell model. Incubation of HepG2 with paricalcitol, a vitamin D analog, increased dose-dependently the levels of SERPINC1transcripts and antithrombin released to the conditioned medium. This study shows further evidence of the transcriptional regulation of SERPINC1 by vitamin D and first describes the functional and pathological relevance of mutations affecting VDRE of this gene. Our study opens new perspectives in the search of new genetic defects involved in antithrombin deficiency and the risk of thrombosis as well as in the design of new antithrombotic treatments. PMID:27003919

  15. Antithrombin gene Arg197Stop mutation-associated venous sinus thrombosis in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    Ang Li; Dexin Wang; Qiming Xue; Baoen Wang; Tianhui Liu; Zhandong Liu; Jimei Li; Chunling Zhang; Jun Chen; Jinmei Sun; YanfeiHan; Lili Wang

    2011-01-01

    This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation from C to T on locus 6431 in exon 3B of the antithrombin gene was observed,leading to an arginine (CGA) to stop codon (TGA) change in the protein. This is the first report of this mutation in China. Ineffective heparin therapy in the propositus patient is associated with a lack of heparin binding sites after antithrombin gene mutation. Characteristic low intracranial pressure in the acute phase might be specific to this patient with cerebral venous sinus thrombosis.

  16. [Discovery and prospects of a novel thrombophilia: antithrombin resistance].

    Science.gov (United States)

    Takagi, Yuki; Kojima, Tetsuhito

    2014-07-01

    Pathogenesis of venous thromboembolism (VTE) known to be complex and multifactorial process involves the interaction of acquired factors and genetic predisposing conditions. Deficiency of natural anticoagulant factors such as antithrombin (AT), protein C and protein S increases the risk of a VTE. Recently, we have reported novel mechanism of hereditary thrombosis in a Japanese family, in which AT resistance was associated with a missense mutation (p.Arg596Leu) in the prothrombin gene named prothrombin Yukuhashi. The mutant thrombin showed a low clotting activity, but a severely impaired inactivation by AT, resulting in a susceptibility to thrombosis. We have developed a new laboratory test to evaluate AT resistance in plasma. Prothrombin mutation causing AT resistance has found in Caucasian, not only in Japanese. PMID:25163329

  17. Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis.

    Science.gov (United States)

    Wiedermann, Christian J

    2006-02-01

    In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin--administered even at low doses--with the therapeutic effects of antithrombin, and has confirmed--at the level of cellular mechanisms--a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies. PMID:16542481

  18. Antithrombin Ⅲ injection via the portal vein suppresses liver damage

    Institute of Scientific and Technical Information of China (English)

    Masavuki Mivazaki; Kazuhiro Kotoh; Ryoichi Takayanagi; Masaki Kato; Masatake Tanaka; Kosuke Tanaka; Shinichiro Takao; Motoyuki Kohjima; Tetsuhide Ito; Munechika Enjoji; Makoto Nakamuta

    2012-01-01

    AIM:To investigate the effects of antithrombin Ⅲ (AT Ⅲ) injection via the portal vein in acute liver failure.METHODS:Thirty rats were intraperitoneally challenged with lipopolysaccharide (LPS) and D-galactosamine (GaiN) and divided into three groups:a control group; a group injected with AT Ⅲ via the tail vein; and a group injected with AT Ⅲ via the portal vein.AT Ⅲ (50U/kg body weight) was administrated 1 h after challenge with LPS and GAIN.Serum levels of inflammatory cytokines and fibrin degradation products,hepatic fibrin deposition,and hepatic mRNA expression of hypoxiarelated genes were analyzed.RESULTS:Serum levels of alanine aminotransferase,tumor necrosis factor-o and interleukin-6 decreased significantly following portal vein AT Ⅲ injection compared with tail vein injection,and control rats.Portal vein AT Ⅲ injection reduced liver cell destruction and decreased hepatic fibrin deposition.This treatment also significantly reduced hepatic mRNA expression of lactate dehydrogenase and heme oxygenase-1.CONCLUSION:A clinically acceptable dose of AT Ⅲ injection into the portal vein suppressed liver damage,probably through its enhanced anticoagulant and antiinflammatory activities.

  19. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.

    Science.gov (United States)

    Tagami, Takashi; Matsui, Hiroki; Fushimi, Kiyohide; Yasunaga, Hideo

    2015-08-31

    The effectiveness of supplemental dose antithrombin administration (1,500 to 3,000 IU/ day) for patients with sepsis-associated disseminated intravascular coagulation (DIC), especially sepsis due to abdominal origin, remains uncertain. This was a retrospective cohort study of patients with mechanically ventilated septic shock and DIC after emergency surgery for perforation of the lower intestinal tract using a nationwide administrative database, Japanese Diagnosis Procedure Combination inpatient database. A total of 2,164 patients treated at 612 hospitals during the 33-month study period between 2010 and 2013 were divided into an antithrombin group (n=1,021) and a control group (n=1,143), from which 518 propensity score-matched pairs were generated. Although there was no significant 28-day mortality difference between the two groups in the unmatched groups (control vs antithrombin: 25.7 vs 22.9 %; difference, 2.8 %; 95 % confidence interval [CI], -0.8-6.4), a significant difference existed between the two groups in propensity-score weighted groups (26.3 vs 21.7 %; difference, 4.6 %; 95 % CI, 2.0-7.1) and propensity-score matched groups (27.6 vs 19.9 %; difference, 7.7 %; 95 % CI, 2.5-12.9). Logistic regression analyses showed a significant association between antithrombin use and lower 28-day mortality in propensity-matched groups (odds ratio, 0.65; 95 % CI, 0.49-0.87). Analysis using the hospital antithrombin-prescribing rate as an instrumental variable showed that receipt of antithrombin was associated with a 6.5 % (95 % CI, 0.05-13.0) reduction in 28-day mortality. Supplemental dose of antithrombin administration may be associated with reduced 28-day mortality in sepsis-associated DIC patients after emergency laparotomy for intestinal perforation.

  20. Relationship between renal histology and plasma antithrombin III activity in women with early onset preeclampsia.

    Science.gov (United States)

    Weiner, C P; Bonsib, S M

    1990-04-01

    Renal biopsy was performed in 12 women with the clinical diagnosis of severe, early-onset preeclampsia at the time of cesarean delivery for the express purpose of aiding future counseling on the risk of recurrence. The mean gestation at delivery was 30 +/- 3 weeks. The mean birthweight was 1090 +/- 505 gm. Four women (33%) were multiparous. Antithrombin III activity was determined immediately prior to delivery unrelated to clinical care and as part of other protocols. The biopsy was performed without difficulty in each, although the sample was inadequate in one patient. The clinical diagnosis of preeclampsia was confirmed in nine (82%). However, three of the nine had underlying renal disease, as did the two women without histologic evidence of preeclampsia (42% of the total). Correlations between laboratory parameters with the histopathologic diagnoses were sought. Neither uric acid, creatinine, blood urea nitrogen, platelet count, or 24-hour urinary protein measurements aided the differentiation of the various subgroups. Antithrombin III activity in women with biopsy-supported preeclampsia (77% +/- 12%) was significantly lower than that in women without histologic evidence of preeclampsia (116% +/- 8%). Antithrombin III activity correctly predicted biopsy findings in at least 9 of 11 (82%). These preliminary findings confirm the high frequency of underlying disease in women with early-onset preeclampsia. Although low antithrombin III activity does not differentiate between "pure" preeclampsia and superimposed disease, a normal antithrombin III activity is reassuring and more consistent with a nonpreeclamptic renal complication than with preeclampsia.

  1. Change of Coagulation Factor Ⅷ and Antithrombin Ⅲ Activity in Bank-Stored Blood

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Coagulation factor Ⅷ and antithrombin Ⅲ activity were detected in 15 health donors. It was found that antithrombin Ⅲ activity decreased obviously 12 h after blood drawing. It lost 56 % of the activity at the 3rd day, and 70 % of the activity at the 7th day. FⅧ:c showed no obvious change after 24 h, until the 3rd day. It lost 40 %-60 % of the activity after 36 h and was reduced to the 30 % of the original activity at the 5th day. Our results suggested that at the 3rd day coagulation factor Ⅷ of bank-stored blood can be used to replenish antithrombin Ⅲ, while bank-stored blood in one day can be used to replenish FⅧ.

  2. Molecular basis of antithrombin deficiency in four Japanese patients with antithrombin gene abnormalities including two novel mutations.

    Science.gov (United States)

    Kyotani, Mayu; Okumura, Kaoru; Takagi, Akira; Murate, Takashi; Yamamoto, Koji; Matsushita, Tadashi; Sugimura, Motoi; Kanayama, Naohiro; Kobayashi, Takao; Saito, Hidehiko; Kojima, Tetsuhito

    2007-08-01

    We analyzed the antithrombin (AT) gene in four unrelated Japanese patients with an AT deficiency, and individually identified four distinct mutations in the heterozygous state. There were two novel mutations, 2417delT leading to a frameshift with a premature termination at amino acid -3 (FS-3Stop) and C2640T resulting in a missense mutation (Ala59Val). Previously reported mutations, T5342C (Ser116Pro) and T72C (Met-32Thr), were also found in the other two patients. To understand the molecular basis responsible for the AT deficiency in these patients, in vitro expression experiments were performed using HEK293 cells transfected with either wild type or respective mutant AT expression vector. We found that -3Stop-AT and -32Thr-AT were not secreted into the culture media, whereas 116Pro-AT and 59Val-AT were secreted normally. We further studied the heparin cofactor activity and the binding to heparin of each recombinant AT molecule. Ser116Pro mutation significantly impaired the binding affinity to heparin resulting in a reduced heparin cofactor activity. In contrast, we found that Ala59Val mutant AT unexpectedly showed a normal affinity to heparin, but severely impaired the heparin cofactor activity. Our findings suggested that FS-3Stop and Met-32Thr mutations are responsible for type I AT deficiency, whereas Ser116Pro and Ala59Val mutations contribute to type II AT deficiency, confirming that there were diverse molecular mechanisms of AT deficiency depend upon discrete AT gene abnormalities as reported previously.

  3. Biochemical activity and gene analysis of inherited protein C and antithrombin deficiency in two Chinese pedigrees

    Institute of Scientific and Technical Information of China (English)

    周荣富; 傅启华; 王文斌; 谢爽; 胡翊群; 王学锋; 王振义; 王鸿利

    2004-01-01

    Background We identified the gene mutations in two Chinese pedigree of type Ⅰ hereditary protein C deficiency and type Ⅰ hereditary antithrombin deficiency.Methods The plasma level of protein C activity (PC∶ A), protein C antigen (PC∶ Ag) , protein S activity, antithrombin activity (AT∶ A) and antithrombin antigen (AT∶ Ag) of propositi and two family members were detected using ELISA and chromogenic assay, respectively. All exons and intron-exon boundaries of protein C gene and antithrombin gene were analyzed by direct sequencing of the corresponding amplified PCR products in DNA from the propositus. Results The plasma PC∶ A and PC∶ Ag of propositus 1 was 26% and 1.43 mg/dl, respectively. The PC∶ Ag and PC∶ A of his father were normal. The decreased PC∶ A level was seen in his mother and 4 of his maternal pedigree. PS∶ A and AT∶ A were all normal in pedigree 1 members. A C5498T heterozygous mutation in exon 3 of protein C gene, resulting in the substitution of Arg for Trp at the 15th amino acid, was identified in propositus 1 and 8 of his relatives. The plasma AT∶ A and AT∶ Ag of propositus 2 was 48.6% and 10.4 mg/dl, respectively. The reduced AT∶ A and AT∶ Ag levels were found in his father and 5 of paternal pedigree. PC∶ A, PC∶ Ag and PS∶ A were all in normal range. A heterozygous 13387-9G deletion in exon 6 of antithrombin gene was identified in propositus 2. This mutation introduced a frameshift and a premature stop at codon 426 and existed in 6 members of pedigree 2.Conclusion The C5498T heterozygous mutation in exon 3 of protein C gene, first reported in China, leads to type I hereditary protein C deficiency. The 13387-9G deletion, a novel mutation, can cause antithrombin deficiency and thrombosis.

  4. Antithrombin Cambridge II(A384S) mutation frequency and antithrombin activity levels in 120 of deep venous thrombosis and 150 of cerebral infarction patients in a single center in Southern China.

    Science.gov (United States)

    Zhang, Guang-sen; Tang, Yang-ming; Tang, Mei-qing; Qing, Zi-Ju; Shu, Chang; Tang, Xiang-qi; Deng, Ming-yang; Tan, Li-ming

    2010-09-01

    Antithrombin Cambridge II(A384S) mutation shows a relatively high frequency in western population. Some studies suggest that the mutation is an independent genetic risk factor both for deep vein thrombosis (DVT) and for arterial thrombosis, but whether the mutation has racial difference or has a general significance for thrombophilia remains unclear. In this study we performed an analysis of the prevalence of the mutation in Chinese southern population; Also, the antithrombin activity levels were evaluated in each investigated individual. The studies included 120 patients with DVT, 150 patients with cerebral infarction, and 110 controls. The mutation was detected using polymerase chain reaction/PvuII restrictive fragment length polymorphism procedures. Antithrombin activity assay was done using chromogenic substrate method. The results showed that no antithrombin Cambridge II mutation was detected in all three groups (DVT, cerebral infarction and controls), the incidence was 0/380. Plasma antithrombin activity was 91.37% +/- 16.15% in the DVT patients and 102.68% +/- 13.10% in the controls; the antithrombin activity was significantly reduced in the DVT group (P Cambridge II mutation has a racial difference, and may not be a valuable risk factor of thrombophilia in Asian population, and antithrombin deficiency remains a major genetic risk factor for DVT patients in China.

  5. Effect of fibronectin on the binding of antithrombin III to immobilized heparin

    NARCIS (Netherlands)

    Byun, Youngro; Jacobs, Harvey A.; Feijen, Jan; Kim, Sung Wan

    1996-01-01

    An objective of this research is to verify the mechanism of anticoagulant activity of surface-immobilized heparin in the presence of plasma proteins. The competition and binding interaction between immobilized heparin and antithrombin III (ATIII)/thrombin have been described in vitro. However, the s

  6. Activation of antithrombin III isoforms by heparan sulphate glycosaminoglycans and other sulphated polysaccharides.

    Science.gov (United States)

    Carlson, T H; Kolman, M R; Piepkorn, M

    1995-07-01

    Antithrombin III occurs naturally as two functionally distinct molecular species that differ in glycosylation at Asn135. Whereas the predominant, glycosylated isoform has high affinity for heparin, a quantitatively minor isoform lacking glycosylation at that site displays relatively higher affinity for both heparins and heparinoids. We characterized the ability of various sulphated polysaccharides to potentiate the rates of thrombin inhibition by the isoforms. High-molecular-weight dextran sulphate was the most effective of those studied, increasing thrombin inhibition by the higher-affinity antithrombin III isoform up to five-fold more efficiently than did heparin fractions with low-affinity for antithrombin III. In addition, dextran sulphate activated the higher-affinity isoform as much as twelve times more effectively than it did the lower-affinity isoform. Pentosan polysulphate was up to three-fold, and some heparan sulphate fractions up to two-fold, more effective with the higher, compared with the lower affinity, isoform. Heparan sulphate preparations less effectively increased the rate of thrombin inhibition than did the other low-affinity polysaccharides. Structure-function studies indicated positive correlations between activity and both polymer length and anionic group density of low-affinity sulphated polysaccharides. The observed effects of the heparan sulphates on this anticoagulant pathway, although of low potency, are consistent with the hypotheses that these substances naturally regulate blood homeostasis in vascular tissues and that much of this function may be mediated by the higher-affinity antithrombin III isoform. PMID:8589216

  7. Anticoagulant and anti-inflammatory effects after peritoneal lavage with antithrombin in experimental polymicrobial peritonitis

    NARCIS (Netherlands)

    S.Q. van Veen; C.W. Cheung; J.C.M. Meijers; T.M. van Gulik; M.A. Boermeester

    2006-01-01

    Background: In sepsis, coagulation inhibition using high-dose systemic antithrombin (AT) tends to improve survival. However, systemic AT use is complicated by increased risk of bleeding (odds ratio 1,7) and clinically important survival increase is seen only in the non-heparinized subgroup. Local (i

  8. Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats

    NARCIS (Netherlands)

    Choi, Goda; Hofstra, Jorrit-Jan H; Roelofs, Joris J T H; Rijneveld, Anita W; Bresser, Paul; van der Zee, Jaring S; Florquin, Sandrine; van der Poll, Tom; Levi, Marcel; Schultz, Marcus J

    2008-01-01

    OBJECTIVE: Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that natural inhibitors of coagulation, including activated protein C, antithrombin, and tissue factor pathway inhibitor, exert lung-protective effects via anticoagulant and possibly anti-inflammatory pathways. We

  9. Identification of antithrombin-modulating genes. Role of LARGE, a gene encoding a bifunctional glycosyltransferase, in the secretion of proteins?

    Directory of Open Access Journals (Sweden)

    María Eugenia de la Morena-Barrio

    Full Text Available The haemostatic relevance of antithrombin together with the low genetic variability of SERPINC1, and the high heritability of plasma levels encourage the search for modulating genes. We used a hypothesis-free approach to identify these genes, evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study (352 individuals from 21 Spanish families. Despite no SNP reaching the genome wide significance threshold, we verified milder positive associations in 307 blood donors from a different cohort. This validation study suggested LARGE, a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin-like linear polysaccharides, as a potential modulator of antithrombin based on the significant association of one SNPs, rs762057, with anti-FXa activity, particularly after adjustment for age, sex and SERPINC1 rs2227589 genotype, all factors influencing antithrombin levels (p = 0.02. Additional results sustained this association. LARGE silencing inHepG2 and HEK-EBNA cells did not affect SERPINC1 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention. Milder effects were observed on α1-antitrypsin, prothrombin and transferrin. Our study suggests LARGE as the first known modifier of plasma antithrombin, and proposes a new role for LARGE in modulating extracellular secretion of certain glycoproteins.

  10. Identification of Antithrombin-Modulating Genes. Role of LARGE, a Gene Encoding a Bifunctional Glycosyltransferase, in the Secretion of Proteins?

    Science.gov (United States)

    de la Morena-Barrio, María Eugenia; Buil, Alfonso; Antón, Ana Isabel; Martínez-Martínez, Irene; Miñano, Antonia; Gutiérrez-Gallego, Ricardo; Navarro-Fernández, José; Aguila, Sonia; Souto, Juan Carlos; Vicente, Vicente; Soria, José Manuel; Corral, Javier

    2013-01-01

    The haemostatic relevance of antithrombin together with the low genetic variability of SERPINC1, and the high heritability of plasma levels encourage the search for modulating genes. We used a hypothesis-free approach to identify these genes, evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study (352 individuals from 21 Spanish families). Despite no SNP reaching the genome wide significance threshold, we verified milder positive associations in 307 blood donors from a different cohort. This validation study suggested LARGE, a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin-like linear polysaccharides, as a potential modulator of antithrombin based on the significant association of one SNPs, rs762057, with anti-FXa activity, particularly after adjustment for age, sex and SERPINC1 rs2227589 genotype, all factors influencing antithrombin levels (p = 0.02). Additional results sustained this association. LARGE silencing inHepG2 and HEK-EBNA cells did not affect SERPINC1 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention. Milder effects were observed on α1-antitrypsin, prothrombin and transferrin. Our study suggests LARGE as the first known modifier of plasma antithrombin, and proposes a new role for LARGE in modulating extracellular secretion of certain glycoproteins. PMID:23705025

  11. Mechanism of poly(acrylic acid) acceleration of antithrombin inhibition of thrombin: implications for the design of novel heparin mimics.

    Science.gov (United States)

    Monien, Bernhard H; Cheang, Kai I; Desai, Umesh R

    2005-08-11

    The bridging mechanism of antithrombin inhibition of thrombin is a dominant mechanism contributing a massive approximately 2500-fold acceleration in the reaction rate and is also a key reason for the clinical usage of heparin. Our recent study of the antithrombin-activating properties of a carboxylic acid-based polymer, poly(acrylic acid) (PAA), demonstrated a surprisingly high acceleration in thrombin inhibition (Monien, B. H.; Desai, U. R. J. Med. Chem. 2005, 48, 1269). To better understand this interesting phenomenon, we have studied the mechanism of PAA-dependent acceleration in antithrombin inhibition of thrombin. Competitive binding studies with low-affinity heparin and a heparin tetrasaccharide suggest that PAA binds antithrombin in both the pentasaccharide- and the extended heparin-binding sites, and these results are corroborated by molecular modeling. The salt-dependence of the K(D) of the PAA-antithrombin interaction shows the formation of five ionic interactions. In contrast, the contribution of nonionic forces is miniscule, resulting in an interaction that is significantly weaker than that observed for heparins. A bell-shaped profile of the observed rate constant for antithrombin inhibition of thrombin as a function of PAA concentration was observed, suggesting that inhibition proceeds through the "bridging" mechanism. The knowledge gained in this mechanistic study highlights important rules for the rational design of orally available heparin mimics. PMID:16078853

  12. An Antithrombin-Heparin Complex Increases the Anticoagulant Activity of Fibrin Clots

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    Lesley J. Smith

    2008-01-01

    Full Text Available Clotting blood contains fibrin-bound thrombin, which is a major source of procoagulant activity leading to clot extension and further activation of coagulation. When bound to fibrin, thrombin is protected from inhibition by antithrombin (AT + heparin but is neutralized when AT and heparin are covalently linked (ATH. Here, we report the surprising observation that, rather than yielding an inert complex, thrombin-ATH formation converts clots into anticoagulant surfaces that effectively catalyze inhibition of thrombin in the surrounding environment.

  13. Rapid high-performance liquid chromatographic quantification of recombinant human antithrombin III during production and purification

    OpenAIRE

    Büntemeyer, Heino; Tebbe, H.; Lütkemeyer, Dirk; Lehmann, Jürgen

    1994-01-01

    For monitoring of recombinant human antithrombin III during cell culture processes and subsequent purification steps a rapid method for quantitative determination was developed. The need for the introduction of this rapid method came from the limited availability of a quantitative enzyme-linked immunosorbent assay (ELISA) and the very time-consuming ELISA procedure. The developed method is based on reversed-phase high-performance liquid chromatography using a C 4 column. The separation by gra...

  14. Increased N-glycosylation efficiency by generation of an aromatic sequon on N135 of antithrombin.

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    Sonia Aguila

    Full Text Available The inefficient glycosylation of consensus sequence on N135 in antithrombin explains the two glycoforms of this key anticoagulant serpin found in plasma: α and β, with four and three N-glycans, respectively. The lack of this N-glycan increases the heparin affinity of the β-glycoform. Recent studies have demonstrated that an aromatic sequon (Phe-Y-Asn-X-Thr in reverse β-turns enhances N-glycosylation efficiency and stability of different proteins. We evaluated the effect of the aromatic sequon in this defective glycosylation site of antithrombin, despite of being located in a loop between the helix D and the strand 2A. We analyzed the biochemical and functional features of variants generated in a recombinant cell system (HEK-EBNA. Cells transfected with wild-type plasmid (K133-Y-N135-X-S137 generated 50% of α and β-antithrombin. The S137T, as previously reported, K133F, and the double mutant (K133F/S137T had improved glycosylation efficiency, leading to the secretion of α-antithrombin, as shown by electrophoretic and mass analysis. The presence of the aromatic sequon did not significantly affect the stability of this conformationally sensitive serpin, as revealed by thermal denaturation assay. Moreover, the aromatic sequon hindered the activation induced by heparin, in which is involved the helix D. Accordingly, K133F and particularly K133F/S137T mutants had a reduced anticoagulant activity. Our data support that aromatic sequons in a different structural context from reverse turns might also improve the efficiency of N-glycosylation.

  15. Comparison of antithrombin activity of the polysulphate chitosan derivatives in in vivo and in vitro system.

    Science.gov (United States)

    Drozd, N N; Sher, A I; Makarov, V A; Galbraikh, L S; Vikhoreva, G A; Gorbachiova, I N

    2001-06-01

    In order to choose the proper method for evaluating the antithrombin activity in samples of chitosan polysulphate (CP) with different polymerization degrees and sulphation degrees, we estimated the ability of direct anticoagulants to depress the coagulability of recalcified sheep blood using the third international heparin standard (A1 - in vitro system) and determined such activity on pharmacodynamic curve (A2 - in vivo system). The curve admits the kinetics of CP elimination to be nonlinear in case of intravenous injection to rabbits, as it is observed in heparin: Ct = C(o)exp(-K(e)lt), where Ct is the CP concentration at the time moment t; C(o) is the CP concentration at the injection moment; Kel is the elimination constant. Besides, it is assumed that there is a linear approximation of the anticoagulant effect on the dose, which finally makes it possible to calculate the specific activity A2: T = KTCt+T(in), where T is the time of clot formation at different time intervals after CP injection; T(in) is the time of clot formation prior to CP injection. T value was assessed in two tests: blood coagulation time (BCT) and activated partial thromboplastin time (APTT). No correlation was observed between A1 and A2. At the same time, the values of Kel and the period of semi-elimination, with the use of the biospecific cetylpyridinium chloride electrophores for the quantitative determination of CP in rabbit's blood taken at different time intervals after injection, showed a close correlation (r = .94, P < .05) between the same parameters, obtained with the help of the rectilinear pharmacodynamic plot in BCT test. Thus, experimentally, it was proven that the assumption of the CP nonlinear elimination and the CP effect-dose dependence was true, which is necessary for A2 calculation. Relatively low molecular weights (MW 61-82 kDa, polymerization degree 188-252 ) and high sulphation patterns (sulphur amounts 15.6-16.9%, sulphation degree 1.58-1.86) were slowly cleared and

  16. Dynamic properties of the native free antithrombin from molecular dynamics simulations: computational evidence for solvent- exposed Arg393 side chain.

    Science.gov (United States)

    Tóth, László; Fekete, Attila; Balogh, Gábor; Bereczky, Zsuzsanna; Komáromi, István

    2015-09-01

    While antithrombin (AT) has small basal inhibitory activity, it reaches its full inhibitory potential against activated blood coagulation factors, FXa, FIXa, and FIIa (thrombin), via an allosteric and/or template (bridging) mechanism by the action of heparin, heparan sulfate, or heparin-mimetic pentasaccharides (PS). From the numerous X-ray structures available for different conformational states of AT, only indirect and incomplete conclusions can be drawn on the inherently dynamic properties of AT. As a typical example, the basal inhibitory activity of AT cannot be interpreted on the basis of "non-activated" free antithrombin X-ray structures since the Arg393 side chain, playing crucial role in antithrombin-proteinase interaction, is not exposed. In order to reveal the intrinsic dynamic properties and the reason of basal inhibitory activity of antithrombin, 2 μs molecular dynamics simulations were carried out on its native free-forms. It was shown from the simulation trajectories that the reactive center loop which is functioning as "bait" for proteases, even without any biasing potential can populate conformational state in which the Arg393 side chain is solvent exposed. It is revealed from the trajectory analysis that the peptide sequences correspond to the helix D extension, and new helix P formation can be featured with especially large root-mean-square fluctuations. Mutual information analyses of the trajectory showed remarkable (generalized) correlation between those regions of antithrombin which changed their conformations as the consequence of AT-PS complex formation. This suggests that allosteric information propagation pathways are present even in the non-activated native form of AT. PMID:25483839

  17. Polyurethane films modified by antithrombin-heparin complex to enhance endothelialization: An original impedimetric analysis

    Energy Technology Data Exchange (ETDEWEB)

    Haddad, S.; Zanina, N. [Biophysic Laboratory, Faculty of Medicine of Monastir, 5019 Monastir (Tunisia) and INSERM U 698 Laboratoire de Bio-Ingenierie de Polymeres Cardiovasculaires, Universite Paris 13, 99, av JB Clement, Institut Galilee, 93430 Villetaneuse (France); Othmane, A. [Biophysic Laboratory, Faculty of Medicine of Monastir, 5019 Monastir (Tunisia); Mora, L., E-mail: Laurence.mora@univ-paris13.fr [INSERM U 698 Laboratoire de Bio-Ingenierie de Polymeres Cardiovasculaires, Universite Paris 13, 99, av JB Clement, Institut Galilee, 93430 Villetaneuse (France)

    2011-08-30

    In this paper, polyurethane (PU) was deposited as a thin layer onto the surface of ITO (indium tin oxide) and was then modified with an antithrombin-heparin complex (ATH). The resulting films were characterized by ATR spectroscopy, contact angle measurements and electrochemical impedance spectroscopy (EIS). Physicochemical characterization confirmed the surface modifications. The obtained films were used as substrates for endothelial cell attachment and growth. These processes were characterized using electrochemical impedance spectroscopy (EIS). We observed that the addition of a small amount of heparin and AT additives onto the polymer surface resulted in a considerable change in the surface characteristics, and we found that PU films that were modified by the ATH complex were able to greatly enhance adhesion and proliferation of endothelial cells (ECs).

  18. Is there evidence that fresh frozen plasma is superior to antithrombin administration to treat heparin resistance in cardiac surgery?

    Science.gov (United States)

    Beattie, Gwyn W; Jeffrey, Robert R

    2014-01-01

    A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was, 'in [patients with heparin resistance] is [treatment with FFP] superior [to antithrombin administration] in [achieving adequate anticoagulation to facilitate safe cardiopulmonary bypass]?' More than 29 papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Antithrombin (AT) binds to heparin and increases the rate at which it binds to thrombin. The levels of antithrombin in the blood are an important aspect of the heparin dose-response curve. When the activated clotting time (ACT) fails to reach a target >480, this is commonly defined as heparin resistance (HR). Heparin resistance is usually treated with a combination of supplementary heparin, fresh frozen plasma (FFP) or antithrombin III concentrate. There is a paucity of evidence on the treatment of heparin resistance with FFP, with only five studies identified, including one retrospective study, one in vitro trial and three case reports. AT has been studied more extensively with multiple studies, including a crossover trial comparing AT to supplemental heparin and a multicentre, randomized, double blind, placebo-controlled trial. Antithrombin (AT) concentrate is a safe and efficient treatment for heparin resistance to elevate the activated clotting time (ACT). It avoids the risk of transfusion-related acute lung injury (TRALI), volume overload, intraoperative time delay and viral or vCJD transmission. Antithrombin concentrates are more expensive than fresh frozen plasma and may put patients at risk of heparin rebound in the early postoperative period. Patients treated with AT have a lower risk of further FFP transfusions during their stay in hospital. We conclude that the treatment of

  19. A capillary zone electrophoresis method to detect conformers and dimers of antithrombin in therapeutic preparations.

    Science.gov (United States)

    Marie, Anne-Lise; Tran, Nguyet Thuy; Saller, François; Abdou, Youmna Mohamed; Zeau, Pascal; Plantier, Jean-Luc; Urbain, Rémi; Borgel, Delphine; Taverna, Myriam

    2016-07-01

    Antithrombin (AT) is a human plasma glycoprotein that possesses anticoagulant and anti-inflammatory properties. However, the native (active) form of AT is unstable and undergoes conformational changes, leading to latent, cleaved, and heterodimeric forms. The presence of these alternative forms mostly inactive can highly impact the quality and therapeutic activity of pharmaceutical AT preparations. We developed a capillary zone electrophoresis method, based on a neutral polyethylene oxide-coated capillary and a buffer close to physiological conditions, enabling the separation of more than eight forms of AT. Several peaks were identified as native, latent, and heterodimeric forms. The CZE method was reproducible with intraday relative standard deviations less than 0.5 and 2% for migration times and peak areas, respectively. The method was applied to the comparison of AT preparations produced by five competitive pharmaceutical companies, and statistical tests were performed. Important differences in the proportion of each form were highlighted. In particular, one AT preparation was shown to contain a high quantity of heterodimer, and two preparations contained high quantities of latent form. In addition, one AT preparation exhibited additional forms, not yet identified. PMID:26989842

  20. Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency.

    Science.gov (United States)

    Rogenhofer, Nina; Bohlmann, Michael K; Beuter-Winkler, Petra; Würfel, Wolfgang; Rank, Andreas; Thaler, Christian J; Toth, Bettina

    2014-03-01

    Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.

  1. Fondaparinux bei Herz-Kreislauf-Erkrankungen: Ein neues Antithrombin mit herausragenden Eigenschaften

    Directory of Open Access Journals (Sweden)

    Huber K

    2008-01-01

    Full Text Available Fondaparinux, ein synthetisches Pentasaccharid, führt zu einer indirekten Hemmung des Gerinnungsfaktors Xa und behindert in der Folge die Bildung von Thrombin. Fondaparinux wurde als Vergleichssubstanz gegenüber unfraktioniertem (Standard- Heparin oder dem niedermolekularen Heparin Enoxaparin in der Prophylaxe oder Therapie von venösen Thrombosen getestet. Zuletzt wurde Fondaparinux auch bei Patienten mit akuten Koronarsyndromen (ACS untersucht: bei Patienten mit ACS ohne ST-Hebung (NSTE-ACS waren sowohl die Blutungsrate als auch die Kurz- und Langzeitmortalität im Fondaparinuxarm (2,5 mg/Tag s. c. signifikant geringer als in den Enoxaparin-behandelten Patienten (1 mg/kg KG 2×/Tag s. c. (OASIS-5-Studie. Bei Patienten mit akutem ST-Strecken-Hebungsinfarkt (STEMI war Fondaparinux in den Subgruppen der konservativ behandelten Patienten (ohne Reperfusion und der Patienten, die eine pharmakologische Reperfusion erhielten (Thrombolyse von Vorteil gegenüber Placebo oder unfraktioniertem Heparin. Hingegen zeigte sich bei Patienten mit STEMI, die einer Akut-PCI unterzogen wurden, eine starke Tendenz zugunsten von unfraktioniertem Heparin gegenüber Fondaparinux (OASIS-6-Studie. Daher wird Fondaparinux in den internationalen Richtlinien als das Antithrombin mit der günstigsten Risiko/Nutzen-Ratio bei NSTEMI aber auch bei STEMI-Patienten mit Ausnahme jener Patienten, die sich einer Akut-PCI unterziehen, empfohlen. Fondaparinux könnte schon in der nahen Zukunft die Heparine in diesen Indikationen weitgehend ersetzen.

  2. Biological Variations of Lupus Anticoagulant, Antithrombin, Protein C, Protein S, and von Willebrand Factor Assays.

    Science.gov (United States)

    Shou, Weiling; Chen, Qian; Wu, Wei; Cui, Wei

    2016-02-01

    The results of lupus anticoagulant (LA), antithrombin (AT), protein C (PC), and protein S (PS) testing, and the values of von Willebrand factor antigen (VWF:Ag) are important in diagnosis and therapeutic monitoring of thrombosis and hemostasis diseases. Till now, no published study has focused on the biological variations in LA testing, and only a few studies have examined the biological variations of AT, PC, PS, and VWF:Ag. With the latest fully automated instruments and improved reagents, the analytical, within-subject, and between-subject biological variations were estimated for these five coagulant parameters in a cohort of 25 apparently healthy subjects. Blood specimens were collected at 8:00 am, 12:00 pm, and 4:00 pm on days 1, 3, and 5. The analytical biological variation (CV(A)) values of all the parameters were less than 3%. The within-subject biological variation (CV(W)) and between-subject biological variation (CV(G)) values of the LA normalized ratio were 4.64 and 6.83%, respectively. No significant differences were observed in the intraday and interday biological variations of LA tests, or in AT, PC, PS, and VWF:Ag values. Additionally, the utility of the conventional population-based reference intervals of the five coagulation parameters was evaluated by the index of individuality, and data on CV(W) and CV(A) were used to calculate the reference change value to identify the significance of changes in serial results from the same individual. PMID:26516946

  3. Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    Masanao Kurata; Kenji Okajima; Toru Kawamoto; Mitsuhiro Uchiba; Nobuhiro Ohkohchi

    2006-01-01

    AIM: To examine whether antithrombin (AT) could prevent hepatic ischemia/reperfusion (I/R)-induced hepatic metastasis by inhibiting tumor necrosis factor (TNF)-α-induced expression of E-selectin in rats.METHODS: Hepatic I/R was induced in rats and mice by clamping the left branches of the portal vein and the hepatic artery. Cancer cells were injected intrasplenically.The number of metastatic nodules was counted on day 7after I/R. TNF-α and E-selectin mRNA in hepatic tissue,serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2,were measured.RESULTS: AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-αand E-selectin in animals subjected to hepatic I/R.Argatroban, a thrombin inhibitor, did not suppress any of these changes. Both AT and argatroban inhibited I/R-induced coagulation abnormalities. I/R-induced increases of hepatic tissue levels of 6-keto-PGF1αwere significantly enhanced by AT. Pretreatment with indomethacin completely reversed the effects of AT.Administration of OP-2507, a stable PGI2 analog, showed effects similar to those of AT in this model. Hepatic metastasis in congenit.al AT-deficient mice subjected to hepatic I/R was significantly increased compared to that observed in wild-type mice. Administration of AT significantly reduced the number of hepatic metastases in congenital AT-deficient mice.CONCLUSION: AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-α-induced expression of E-selectin through an increase in the endothelial production of PGI2. These findings also raise the possibility that AT might prevent hepatic metastasis of tumor cells if administered during the resection of liver tumors.

  4. Antithrombin up-regulates AMP-activated protein kinase signalling during myocardial ischaemia/reperfusion injury.

    Science.gov (United States)

    Ma, Yina; Wang, Jinli; Gao, Junjie; Yang, Hui; Wang, Yanqing; Manithody, Chandrashekhara; Li, Ji; Rezaie, Alireza R

    2015-02-01

    Antithrombin (AT) is a protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to heparan sulfate proteoglycans (HSPGs) on vascular cells. AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischaemia and reperfusion (I/R). To determine whether the cardioprotective signaling function of AT is mediated through the AMPK pathway, we evaluated the cardioprotective activities of wild-type AT and its two derivatives, one having high affinity and the other no affinity for heparin, in an acute I/R injury model in C57BL/6J mice in which the left anterior descending coronary artery was occluded. The serpin derivatives were given 5 minutes before reperfusion. The results showed that AT-WT can activate AMPK in both in vivo and ex vivo conditions. Blocking AMPK activity abolished the cardioprotective function of AT against I/R injury. The AT derivative having high affinity for heparin was more effective in activating AMPK and in limiting infraction, but the derivative lacking affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Activation of AMPK by AT inhibited the inflammatory c-Jun N-terminal protein kinase (JNK) pathway during I/R. Further studies revealed that the AMPK activity induced by AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. These results suggest that AT binds to HSPGs on heart tissues to invoke a cardioprotective function by triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signalling pathways and modulating substrate metabolism during I/R. PMID:25230600

  5. Deficiencies of proteins C, S and Antithrombin and factor V Leiden and the risk of ischemic strokes

    Science.gov (United States)

    Popa, C

    2010-01-01

    Although hypercoagulable states are most often associated with venous thromboses, arterial thromboses are reported in protein C, protein S, antithrombin deficient patients and in those with factor V Leiden, components of hereditary thrombophilia. Because these arterial thromboses (peripheral artery disease, myocardial infarction, and cerebral infarction) mostly affect young persons, aged below 45 years, it is important to test and treat these thrombophilic defects. Because the relation thrombophilia – arterial thromboses is still under debate, due to conflicting data, this article is a review of studies published in literature regarding the implication of the above–mentioned thrombophilic defects in cerebral infarcts. PMID:20945813

  6. On the specificity of heparin/heparan sulfate binding to proteins. Anion-binding sites on antithrombin and thrombin are fundamentally different.

    Directory of Open Access Journals (Sweden)

    Philip D Mosier

    Full Text Available BACKGROUND: The antithrombin-heparin/heparan sulfate (H/HS and thrombin-H/HS interactions are recognized as prototypic specific and non-specific glycosaminoglycan (GAG-protein interactions, respectively. The fundamental structural basis for the origin of specificity, or lack thereof, in these interactions remains unclear. The availability of multiple co-crystal structures facilitates a structural analysis that challenges the long-held belief that the GAG binding sites in antithrombin and thrombin are essentially similar with high solvent exposure and shallow surface characteristics. METHODOLOGY: Analyses of solvent accessibility and exposed surface areas, gyrational mobility, symmetry, cavity shape/size, conserved water molecules and crystallographic parameters were performed for 12 X-ray structures, which include 12 thrombin and 16 antithrombin chains. Novel calculations are described for gyrational mobility and prediction of water loci and conservation. RESULTS: The solvent accessibilities and gyrational mobilities of arginines and lysines in the binding sites of the two proteins reveal sharp contrasts. The distribution of positive charges shows considerable asymmetry in antithrombin, but substantial symmetry for thrombin. Cavity analyses suggest the presence of a reasonably sized bifurcated cavity in antithrombin that facilitates a firm 'hand-shake' with H/HS, but with thrombin, a weaker 'high-five'. Tightly bound water molecules were predicted to be localized in the pentasaccharide binding pocket of antithrombin, but absent in thrombin. Together, these differences in the binding sites explain the major H/HS recognition characteristics of the two prototypic proteins, thus affording an explanation of the specificity of binding. This provides a foundation for understanding specificity of interaction at an atomic level, which will greatly aid the design of natural or synthetic H/HS sequences that target proteins in a specific manner.

  7. The conformational activation of antithrombin. A 2.85-A structure of a fluorescein derivative reveals an electrostatic link between the hinge and heparin binding regions.

    Science.gov (United States)

    Huntington, J A; McCoy, A; Belzar, K J; Pei, X Y; Gettins, P G; Carrell, R W

    2000-05-19

    Antithrombin is unique among the serpins in that it circulates in a native conformation that is kinetically inactive toward its target proteinase, factor Xa. Activation occurs upon binding of a specific pentasaccharide sequence found in heparin that results in a rearrangement of the reactive center loop removing constraints on the active center P1 residue. We determined the crystal structure of an activated antithrombin variant, N135Q S380C-fluorescein (P14-fluorescein), in order to see how full activation is achieved in the absence of heparin and how the structural effects of the substitution in the hinge region are translated to the heparin binding region. The crystal structure resembles native antithrombin except in the hinge and heparin binding regions. The absence of global conformational change allows for identification of specific interactions, centered on Glu(381) (P13), that are responsible for maintenance of the solution equilibrium between the native and activated forms and establishes the existence of an electrostatic link between the hinge region and the heparin binding region. A revised model for the mechanism of the allosteric activation of antithrombin is proposed.

  8. Resolution of preoperative portal vein thrombosis after administration of antithrombin III in living donor liver transplantation: case report.

    Science.gov (United States)

    Imai, H; Egawa, H; Kajiwara, M; Nakajima, A; Ogura, Y; Hatano, E; Ueda, M; Kawaguchi, Y; Kaido, T; Takada, Y; Uemoto, S

    2009-11-01

    A 59-year-old man with hepatitis C virus-associated liver cirrhosis was transferred to our hospital to undergo living donor liver transplantation. Coagulation was impaired (prothrombin time [International Normalized Ratio], 3.27), and antithrombin III (AT-III) activity was 23% (normal, 87%-115%). Contrast-enhanced computed tomography scans revealed portal vein thrombosis (PVT) from the junction between the splenic and superior mesenteric vein to the porta hepatica; the portal vein was completely obstructed (PVT). To prevent further development of PVT, 1500 U of AT-III was administered for 3 days, elevating the AT-III activity to 50%. A contrast-enhanced computed tomography scan obtained 9 days after AT-III administration showed resolution of PVT. Living donor liver transplantation was safely performed without portal vein grafting. Thus, a low AT-III concentration may have an important role in the pathogenesis of PVT in patients with cirrhosis. PMID:19917415

  9. [Preparation and antithrombogenicity of oxidated low molecular weight heparin-antithrombin complex coated-polyvinyl chloride tubing].

    Science.gov (United States)

    Luo, Peng; Liu, Weiyong; Yang, Chun; Zhou, Hua; Cao, Ruijun; Yang, Jian

    2011-02-01

    Based on non-enzymatic protein glycated reaction, the sodium periodate-oxidated low molecular weight heparin-antithrombin covalent complex (SPLMWATH) was produced. By using polyethyleneimine-glutaraldehyde bonding technique, polyvinyl chloride (PVC) tubings were coated with SPLMWATH, heparin and low molecular weight heparin (LMWH). Spectrophotometry and dynamic clotting time experiment were used to determine the synthetic ratio of SPLMWATH, graft density, coating leaching ratio and to evaluate the antithrombogenicity of different coating on the PVC tubings. The results showed that the synthetic ratio of SPLMWATH was approximately 55%, and compared with heparin coating and LMWH coating, the graft density of SPLMWATH coating on the PVC tubing was smaller, but its coating stability and antithrombogenicity were significantly better than that of heparin coating and LMWH coating on the PVC tubings.

  10. Development of Methods for Measuring Protein C Inhibitor and Antithrombin: Use of Monoclonal Antibodies against the Reactive Center Loop-Inserted Forms of the Serpins

    OpenAIRE

    Kjellberg, Margareta

    2007-01-01

    Protein C inhibitor (PCI) and antithrombin (AT) are serine protease inhibitors (serpins) that are involved in the regulation of coagulation. Like other inhibitory serpins, PCI and AT adopt different structural conformations that are related to their functions. The cleaved, inactive form is a result of cleavage by a protease, and the latent form, which is also inactive, can arise due to a mutation in the serpin. Methods that quantify the different forms can be useful as diagnostic tools. The a...

  11. Present and future of anticoagulant therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a perspective from Japan.

    Science.gov (United States)

    Iba, Toshiaki; Thachil, Jecko

    2016-03-01

    In sepsis, the coagulation system is often systemically activated in combination with the simultaneous impairment of fibrinolysis and anticoagulant systems. Since this hypercoagulable state often leads to disseminated intravascular coagulation (DIC), an independent predictor of mortality in critically ill patients, the appropriate management of DIC itself is a crucial part of treatment strategies for severe sepsis. In this context, the Japanese Association of Acute Medicine (JAAM) scoring system for DIC has been proposed as a valid test for diagnosing DIC; this system is also expected to aid in devising specifically tailored management strategies. Anticoagulant therapy is commonly given to septic patients with DIC as part of the standard care in Japan. More recently, antithrombin concentrate and recombinant thrombomodulin have become the two major anticoagulant agents of choice. In relation to the use of antithrombin, recent studies have indicated that the recovery of antithrombin activity to within the normal range (>70%) is necessary if supplementation therapy is to provide a favorable outcome. Recombinant thrombomodulin is slightly more controversial, with favorable results being greater among severe cases of DIC. In the present review, we summarize recent clinical advances in anticoagulant therapy for sepsis-associated DIC. PMID:26588929

  12. Purified radiolabeled antithrombin III metabolism in three families with hereditary AT III deficiency: application of a three-compartment model

    International Nuclear Information System (INIS)

    Purified human radioiodinated antithrombin III (125I-AT III) was used to study its metabolism in six members from three different families with a known hereditary AT III deficiency. Six healthy volunteers served as a control group. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and crossed immunoelectrophoresis (CIE) showed the purified AT III to be homogeneous. Amino acid analysis of the protein revealed a composition identical to a highly purified internal standard. The specific activity was 5.6 U/mg. Analysis of plasma radioactivity data was performed, using a three-compartment model. Neither plasma disappearance half-times nor fractional catabolic rate constants differed significantly between patients and control subjects. The mean absolute catabolic rate in the patient group was significantly lower than that of the control group at 2.57 +/- 0.44 and 4.46 +/- 0.80 mg/kg/day, respectively. In addition, the mean patient alpha 1-phase, flux ratio (k1,2 and k2,1) of the second compartment alpha 2-phase and influx (k3,1) of the third compartment were significantly reduced as compared with control values. It has been tentatively concluded that the observed reduction in the second compartment may be caused by a decrease in endothelial cell surface binding

  13. Circulating microparticles and the risk of thrombosis in inherited deficiencies of antithrombin, protein C and protein S.

    Science.gov (United States)

    Campello, Elena; Spiezia, Luca; Radu, Claudia M; Bulato, Cristiana; Gavasso, Sabrina; Tormene, Daniela; Woodhams, Barry; Dalla Valle, Fabio; Simioni, Paolo

    2016-01-01

    Many subjects carrying inherited thrombophilic defects will never experience venous thromboembolism (VTE) while other individuals developed recurrent VTE with no known additional risk factors. High levels of circulating microparticles (MP) have been associated with increased risk of VTE in patients with factor V Leiden and prothrombin G20210A mutation, suggesting a possible contribution of MP in the hypercoagulability of mild genetic thrombophilia. The role of MP as additional risk factor of VTE in carriers of natural clotting inhibitors defects (severe thrombophilia) has never been assessed. Plasma levels of annexin V-MP, endothelial-derived MP (EMP), platelet-derived MP (PMP), tissue factor-bearing MP (TF+) and the MP procoagulant activity (PPL) were measured in 132 carriers of natural anticoagulant deficiencies (25 antithrombin, 63 protein C and 64 protein S defect) and in 132 age and gender-matched healthy controls. Carriers of natural anticoagulant deficiencies, overall and separately considered, presented with higher median levels of annexin V-MP, EMP, PMP, TF+MP and PPL activity than healthy controls (pEMP and PMP had an adjusted OR for VTE of 3.36 (95% CI, 1.59 to 7.11), 9.26 (95% CI, 3.55 to 24.1) and 2.72 (95%CI, 1.16 to 6.38), respectively. Elevated levels of circulating MP can play a role in carriers of mild and severe inherited thrombophilia. The clinical implications of this association remain to be defined. PMID:26354831

  14. [Study on antiplatelet and antithrombin activitives and effective components variation of Puhuang-Wulingzhi before and after compatibility].

    Science.gov (United States)

    Su, Shu-lan; Xue, Ping; Ouyang, Zhen; Zhou, Wei; Duan, Jin-ao

    2015-08-01

    The changes of bioactive constituents were analyzed for Puhuang-Wulingzhi before and after compatibility and the antiplatelet and antithrombin activitives were evaluated in order to elucidate the scientific and reasonable of Puhuang-Wulingzhi compatibility. UPLC-QTOF-MA-Markerlynx, principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis were used for data analysis and tracking changes of chemical composition during the decocting process. In vitro platelet aggregation induced by ADP, thrombin time(TT) and prothrombin time (PT) were investigated for Puhuang-Wulingzhi before and after compatibility. The results showed that significant differences were found between the mixed decoction and codecoction of Wulingzhi and Puhuang. Five compounds changed obviously were identified as typhaneoside, naringenin, isorhamnetin-3-O-ruinoside, quercetin-3-O-neohesperidoside, kaempferol-3-O-neohesperidoside. The codecoction, comparing with the single decoction, was more significant in antiplatelet aggregation and could prolong thrombin time. In the same crude drug dose, the thrombin time (TT) elongation were greater. These data could provide references for elucidation of bioactive components for this herb pair. PMID:26790290

  15. Comparison of biological activities of human antithrombins with high-mannose or complex-type nonfucosylated N-linked oligosaccharides.

    Science.gov (United States)

    Yamada, Tsuyoshi; Kanda, Yutaka; Takayama, Makoto; Hashimoto, Akitoshi; Sugihara, Tsutomu; Satoh-Kubota, Ai; Suzuki-Takanami, Eri; Yano, Keiichi; Iida, Shigeru; Satoh, Mitsuo

    2016-05-01

    The structure of the N-linked oligosaccharides attached to antithrombin (AT) has been shown to affect its anticoagulant activity and pharmacokinetics. Human AT has biantennary complex-type oligosaccharides with the unique feature of lacking a core fucose, which affects its biological activities by changing its heparin-binding affinity. In human plasma, AT circulates as a mixture of the α-form bearing four oligosaccharides and the β-form lacking an oligosaccharide at Asn135. However, it remains unclear how the immature high-mannose-type oligosaccharides produced by mammalian cells affect biological activities of AT. Here, we succeeded in directly comparing the activities between the high-mannose and complex types. Interestingly, although there were no substantial differences in thrombin inhibitory activity, the high-mannose type showed higher heparin-binding affinity. The anticoagulant activities were increased by heparin and correlated with the heparin-binding affinity, resulting in the strongest anticoagulant activity being displayed in the β-form with the high-mannose type. In pharmacokinetic profiling, the high-mannose type showed a much shorter plasma half-life than the complex type. The β-form was found to have a prolonged plasma half-life compared with the α-form for the high-mannose type; conversely, the α-form showed a longer half-life than the β-form for the complex-type. The present study highlights that AT physiological activities are strictly controlled not only by a core fucose at the reducing end but also by the high-mannose-type structures at the nonreducing end. The β-form with the immature high-mannose type appears to function as a more potent anticoagulant than the AT typically found in human plasma, once it emerges in the blood. PMID:26747427

  16. Engineering D-helix of antithrombin in alpha-1-proteinase inhibitor confers antiinflammatory properties on the chimeric serpin.

    Science.gov (United States)

    Yang, L; Dinarvand, P; Qureshi, S H; Rezaie, A R

    2014-07-01

    Antithrombin (AT) is a heparin-binding serpin in plasma which regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to being an anticoagulant, AT also exhibits antiinflammatory activities when it binds to cell surface heparan sulfate proteoglycans (HSPGs) on the endothelium via its basic residues of D-helix to elicit intracellular signalling responses. By contrast to AT, α1-proteinase inhibitor (α1-PI) is a non-heparin-binding serpin that exhibits very slow reactivity with coagulation proteases and possesses no HSPG-dependent antiinflammatory properties. To determine whether the antiinflammatory signaling specificity of AT can be transferred to α1-PI, we replaced the D-helix of human α1-PI with the corresponding sequence of human AT and expressed the chimeric serpin α1-PI/D-helix) in a bacterial expression system. High molecular weight heparin bound to α1-PI/D-helix and accelerated the inhibition of thrombin by the serpin mutant by a template mechanism reminiscent of the cofactor effect of heparin on inhibition of thrombin by AT. Like AT, α1-PI/D-helix exhibited antiinflammatory properties in both cellular and animal models. Thus, α1-PI/D-helix inhibited the barrier-disruptive effect of proinflammatory cytokines and inhibited the activation of nuclear factor-κB transcription factor in lipopolysaccharide-stimulated endothelial cells by a concentration-dependent manner. Furthermore, the chimeric serpin reduced lipopolysaccharide-mediated lethality, elicited a vascular protective effect and inhibited infiltration of activated leukocytes to the peritoneal cavity of mice in an HMGB1-mediated inflammatory model. These results suggest that grafting the D-helix of AT to α1-PI confers antiinflammatory properties on the serpin and that the chimeric serpin may have therapeutic utility for treating inflammatory disorders. PMID:24522239

  17. Impact of antithrombin Ⅲ on hepatic and intestinal microcirculation in experimental liver cirrhosis and bowel inflammation: An in vivo analysis

    Institute of Scientific and Technical Information of China (English)

    Sasa-Marcel Maksan; Zilfi (U)lger; Martha Maria Gebhard; Jan Schmidt

    2005-01-01

    AIM: To analyze the hepatic and intestinal microcirculation in an animal model of liver cirrhosis and inflammatory bowel disease (IBD) and to characterize the anti-inflammatory action of antithrombin Ⅲ (ATⅢ) on leukocyte kinetics and liver damage.METHODS: Hepatic and intestinal microcirculation was investigated by intravital videomicroscopy. Standardized models of experimental chronic liver cirrhosis and bowel inflammation were employed. Animals were divided into four groups (n = 6/group): controls, animals with cirrhosis,animals with cirrhosis and IBD, animals with cirrhosis and IBD treated with ATⅢ.RESULTS: Cirrhosis facilitated leukocyte rolling and sticking in hepatic sinusoids (1.91±0.28 sticker/μm vs0.5±0.5 sticker/μm in controls, P<0.05). The effect enhanced in animals with cirrhosis and IBD (5.4±1.65sticker/μm), but reversed agter ATⅢ application (3.97±1.04sticker/μm, P<0.05). Mucosal blood flow showed no differences in cirrhotic animals and controls (5.3±0.31nL/min vs5.4±0.25 nL/min) and was attenuated in animals with cirrhosis and IBD significantly (3.49±0.6 nL/min). This effect was normalized in the treatment group (5.13±0.4nL/min, P<0.05). Enzyme values rose during development of cirrhosis and bowel inflammation, and reduced after ATⅢ application (P<0.05).CONCLUSION: Liver cirrhosis in the presence of IBD leads to a significant reduction in mucosal blood flow and an increase in hepatic leukocyte adherence with consecutive liver injury, which can be prevented by administration of ATⅢ.

  18. Analysis of blood coagulation in mice: pre-analytical conditions and evaluation of a home-made assay for thrombin-antithrombin complexes

    Directory of Open Access Journals (Sweden)

    Meijers Joost CM

    2005-08-01

    Full Text Available Abstract Background The use of mouse models for the study of thrombotic disorders has gained increasing importance. Methods for measurement of coagulation activation in mice are, however, scarce. The primary aim of this study was to develop a specific mouse thrombin-antithrombin (TAT ELISA for measurement of coagulation activation and to compare it with two commercially available assays for human TAT complexes. In addition, we aimed to improve methods for mouse plasma anticoagulation and preparation. Methods and results First, for the measurement of TAT-complexes in plasma a mouse specific TAT-ELISA was developed using rabbit polyclonal antibodies raised against mouse thrombin and rat antithrombin, respectively. This ELISA detected an increase in TAT levels in a mouse model of endotoxemia. Two commercial human TAT ELISAs appeared to be less specific for mouse thrombin-rat antithrombin complexes. Second, to prevent clotting of mouse blood sodium citrate was either mixed with blood during collection in a syringe or was injected intravenously immediately prior to blood collection. Intravenous sodium citrate completely inhibited blood coagulation resulting in plasma with consistently low TAT levels. Sodium citrate mixed with blood during collection resulted in increased TAT levels in 4 out of 16 plasma samples. Third, heparinase was added to plasma samples after in vivo injection of different heparin doses to test its neutralizing effect. Heparinase neutralized up to a 20 U of heparin/mouse and resulted in accurate APTT and factor VIII determinations. Conclusion These procedures and reagents for plasma preparation and coagulation testing will improve studies on thrombotic disorders in mice.

  19. 新鲜冰冻血浆与普通冰冻血浆抗凝血酶Ⅲ活性研究%Study on antithrombin III activity between fresh frozen plasma and common frozen plasma

    Institute of Scientific and Technical Information of China (English)

    解学龙; 欧阳龙; 夏耀宗; 张涛

    2015-01-01

    Objective To investigate the antithrombin III activity difference in fresh frozen plasma and common frozen plasma. Methods Determines antithrombin III activity between 30 examples to fresh frozen plasma and 30 examples common frozen plasma by Useing the Shanghai sun antithrombin III reagent box in the German BE Compact-X Full automatic blood coagulation analyzer.Results Antithrombin III activity of 30 cases fresh frozen plasma is 110+8.6 % and antithrombin III activity of 30 cases normal frozen plasma is 90+8.5%.Conclusions Antithrombin III activity of fresh frozen plasma is significantly higher than normal frozen plasma.%目的:探讨抗凝血酶Ⅲ在新鲜冰冻血浆和普通冰冻血浆活性差异。方法:采用上海太阳抗凝血酶Ⅲ试剂盒在德国BE Compact-X全自动血凝仪测定30例新鲜冰冻血浆和30例普通冰冻血浆的凝血酶Ⅲ活性。结果:30例新鲜冰冻血浆和30例普通冰冻血浆的凝血酶Ⅲ活性分别是110+8.6%和90+8.5%。结论:新鲜冰冻血浆抗凝血酶Ⅲ活性明显高于普通冰冻血浆的抗凝血酶Ⅲ活性。

  20. The efficacy of recombinant human activated protein C (rhAPC) vs antithrombin III (at III) vs heparin, in the healing process of partial-thickness burns: a comparative study

    Science.gov (United States)

    Kritikos, O.; Tsagarakis, M.; Tsoutsos, D.; Kittas, C.; Gorgoulis, V.; Papalois, A.; Giannopoulos, A.; Kakiopoulos, G.; Papadopoulos, O.

    2012-01-01

    Summary This is an experimental study regarding the positive effect of recombinant human activated protein C (rhAPC) in the healing process of partial-thickness burns, in comparison to antithrombin III and heparin. On a porcine model we induced superficial partial-thickness and deep partial-thickness burns and performed intravenous administration of the elements of study during the first 48 h. The progress of the condition of the injured tissues was evaluated by histopathological examination at specific time intervals. The results showed an improved healing response of the specimens treated with rhAPC compared to those treated with antithrombin III, heparin, and placebo. PMID:23233823

  1. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin

    NARCIS (Netherlands)

    Mahmoodi, B. K.; Brouwer, J-L P.; Ten Kate, M. K.; Lijfering, W. M.; Veeger, N. J. G. M.; Mulder, A. B.; Kluin-Nelemans, H. C.; van der Meer, J.

    2010-01-01

    Background: Absolute risks of venous thromboembolism (VTE) in protein S-, protein C-, or antithrombin-deficient subjects are mainly based on retrospective data. Screening asymptomatic relatives of these patients is disputed, though studies addressing this issue have yet to be conducted. Methods: We

  2. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin.

    NARCIS (Netherlands)

    Mahmoodi, B.K.; Brouwer, J.L.P.; Kate, M.K. Ten; Lijfering, W.M.; Veeger, N.J.; Mulder, A.B.; Kluin-Nelemans, H.C.; Meer, J. van der

    2010-01-01

    BACKGROUND: Absolute risks of venous thromboembolism (VTE) in protein S-, protein C-, or antithrombin-deficient subjects are mainly based on retrospective data. Screening asymptomatic relatives of these patients is disputed, though studies addressing this issue have yet to be conducted. METHODS: We

  3. Effect of NaC1 on inactivation of bovine thrombin by antithrombin III in the presence of low affinity-heparin or dextran sulfate.

    Science.gov (United States)

    Oshima, G; Nagasawa, K

    1986-02-01

    Heparin with low affinity (LA-heparin) to antithrombin III (AT III) enhanced the rate of inactivation of thrombin by AT III. The enhancement of the rate was saturable with AT III and was proportional to the LA-heparin concentration. Although the rate-enhancement in the presence of LA-heparin decreased with increase in NaC1 concentration, it was comparable with that in the presence of high affinity-heparin (HA-heparin) in the absence of NaC1. Inactivation of thrombin by AT III in the presence of dextran sulfate (DS) was also sensitive to NaC1 concentration. These findings indicate that free AT III is favorable for binding to the complexes of thrombin and highly sulfated polysaccharides having low affinities to AT III in the absence of NaC1.

  4. Concomitant homozygosity for the prothrombin gene variant with mild deficiency of antithrombin III in a patient with multiple hepatic infarctions: a case report

    Directory of Open Access Journals (Sweden)

    Macheta M

    2010-04-01

    Full Text Available Abstract Introduction Hereditary causes of visceral thrombosis or thrombosis should be sought among young patients. We present a case of a young man presenting with multiple hepatic infarctions resulting in portal hypertension due to homozygosity of the prothrombin gene mutation not previously described in literature. Case presentation A 42-year-old Caucasian man with a previous history of idiopathic deep vein thrombosis 11 years earlier presented with vague abdominal pains and mildly abnormal liver function tests. An ultrasound and computed tomography scan showed evidence of hepatic infarction and portal hypertension (splenic varices. A thrombophilia screen confirmed a homozygous mutation for the prothrombin gene mutation, with mildly reduced levels of anti-thrombin III (AT III. Subsequent testing of his father and brother revealed heterozygosity for the same gene mutation. Conclusion Hepatic infarction is unusual due to the rich dual arterial and venous blood supply to the liver. In the absence of an arterial or haemodynamic insult causing hepatic infarction, a thrombophilia should be considered. To our knowledge, this is the first reported case of a hepatic infarction due to homozygosity of the prothrombin gene mutation. It is unclear whether homozygotes have a higher risk of thrombosis than heterozygotes. In someone presenting with a first thrombosis with this mutation, the case for life-long anticoagulation is unclear, but it may be necessary to prevent a second and more severe second thrombotic event, as occurred in this case.

  5. 抗凝血酶-Ⅲ抗炎机制的研究进展%Advancement of anti-inflammatory mechanism of antithrombin-Ⅲ

    Institute of Scientific and Technical Information of China (English)

    孙辉明; 施毅

    2011-01-01

    Antithrombin-Ⅲ (AT-Ⅲ ),a physiological serine protease inhibitor,plays a critical role in the regulation of the coagulation cascade in human being.In addition to regulatory role in the coagulation system,AT-Ⅲ exerts a strong anti-inflammatory activity.This paper reviews the advancement of mechanism of AT-Ⅲ anti-inflammatory property in recent years.%抗凝血酶-Ⅲ是人体内最霞要的天然抗凝物质,其抗凝作用占体内总抗凝作用的50%~70%.近年来研究发现,抗凝血酶Ⅲ除了具有较强的抗凝作用外,还有另一种重要的分子生物学特性,即强大的抗炎作用.本文主要对近年来抗凝血酶Ⅲ抗炎机制的研究进展进行综述.

  6. High prevalence of protein C, protein S, antithrombin deficiency, and Factor V Leiden mutation as a cause of hereditary thrombophilia in patients of venous thromboembolism and cerebrovascular accident

    Science.gov (United States)

    Ali, Nadir; Ayyub, Muhammad; Khan, Saleem Ahmed

    2014-01-01

    Objectives: To determine the frequency of Protein C, Protein S (PC & PS), antithrombin deficiency (AT III) and Factor V Leiden mutation (FVL) as a cause of thrombophilia in the patients with venous thromboembolism (VTE) and cerebrovascular accident (CVA). Methods: It was an observational study conducted at Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, Pakistan. All patients referred for thrombophilia screening from July 2009 to June 2012 were screened. Patients with evidence of VTE or CVA were screened for PC & PS, AT III deficiency, and FVL. Results: Total 404 patients of age between 1-71 years mean 33 ± 14 with male to female ratio of 2.4:1 had evidence of thrombophilia. Two hundred eighteen (54%) patients presented with CVA, 116 (29%) with deep vein thrombosis (DVT), 42 (10.5%) with pulmonary embolism (PE), and 28 (7.5%) with portal or mesenteric vein thrombosis (PV). Protein C & S deficiency was detected in 35/404 (8.7%), ATIII in 9/404 (2%), and FVL in 25/173 patients (14.5%). The findings were suggestive of a significant association of FVL mutation for developing DVT (OR=11.0, 95% C I 4.6-26.3), CVA (OR=5.7, 95% C I 2.1-15.1), and PV (OR=5.4, 95% C I 1.3-21.9). PC & PS deficiency was a significant risk factor for developing PE (OR=3, 95% C I 0.8-11.4). Conclusion: FVL mutation and Protein C & S are the leading causes of thrombophilia with strong association of Factor V Leiden mutation as risk for developing DVT. PMID:25674132

  7. PEGylation of Hirudin and Analysis of Its Antithrombin Activity in vitro%水蛭素聚乙二醇化及其体外抗凝活力分析

    Institute of Scientific and Technical Information of China (English)

    秦海娜; 修志龙; 张代佳; 包永明; 李晓晖; 韩国柱

    2007-01-01

    Hirudin is the most anticoagulant drug found in nature, but its short serum half-life significantly inhibits its clinical application. The PEGylation of hirudin, the most promising anticoagulant drug, was performed in this paper. The optimal reaction conditions for PEGylated hirudin were investigated. When the PEGylation reaction was conducted under 4℃ after 10h, in the borate buffer at pH 8.5, with the molar ratio 250: 1 of PEG to hirudin, a higher modification extent was achieved. Finally, the bioactivity of PEGylated hirudin was measured in vitro.Compared with unmodified hirudin, 26% of anti-thrombin activity was retained.

  8. Antithrombin-Ⅲ without concomitant heparin improves endotoxin-induced acute lung injury rats by inhibiting the activation of mitogen-activated protein kinase

    Institute of Scientific and Technical Information of China (English)

    SUN Hui-ming; HONG Ling-zhi; SHEN Xiao-kun; LIN Xin-qing; SONG Yong; SHI Yi

    2009-01-01

    Background Antithrombin-Ⅲ (AT-Ⅲ), the major inhibitor of thrombin in plasma, also has anti-inflammation property and might have positive effect on sepsis. The present study aimed to investigate the effects of AT-Ⅲ on inflammatory reaction and pulmonary protection in endotoxin-induced acute lung injury (ALI) rat.Methods Sixty male Sprague-Dawley rats were randomly assigned equally to normal control group, ALl group, AT-Ⅲ treatment group, AT-Ⅲ+heparin treatment group, and heparin treatment group. The pulmonary vascular permeability index (PVPI) was measured by single nuclide tracer technique. The activity of AT-Ⅲ in plasma was determined by the method of synthetic chromogenic substrata. Tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) levels in serum were determined by enzyme-linked immunosorbent assay. The expressions of lung tissue mitogen-activated protein kinases (ERK1/2, P38 and JNK MAPK) were determined by Western blotting.Results Rats had significantly improved lung histopathology in the AT-Ⅲ treatment group and heparin treatment group compared with the ALI group. The PVPI of the ALI group was 0.38±0.04, significantly higher than that of the normal control group (0.20±0.02, P <0.01), AT-Ⅲ treatment group (0.30±0.04, P <0.01) and heparin treatment group (0.28±0.04,P <0.01) respectively. There were no significant differences of PVPI in the ALl group and AT-Ⅲ+heparin treatment group.The activity of AT-Ⅲ in plasma in the ALl group was (76±8)%, significantly lower than that of the normal control group ((96±11)%, P <0.05) and AT-Ill treatment group ((105±17)%, P <0.05) respectively. The serum levels of TNF-α and IL-6 of the ALI group were (2.770±0.373) pg/L and (1.615±0.128) ng/ml respectively, significantly higher than those of the normal control group ((0.506±0.093) pg/L and (0.233±0.047) ng/ml respectively, all P <0.01), AT-Ⅲ treatment group ((1.774±0.218) μg/L and (1.140±0145) ng/ml respectively, all P <0.01) and

  9. Ala384Ser polymorphism of antithrombin gene and pulmonary thromboembolism%抗凝血酶基因Ala384Ser多态性与肺血栓栓塞症相关性研究

    Institute of Scientific and Technical Information of China (English)

    白巧红; 刘锦铭; 王鹏; 乐军; 高蓓兰; 褚海青; 李霞; 桂涛

    2009-01-01

    Objective To investigate whether there is an association between the Ala384Ser polymorphsim of antithrombin gene and pulmonary thromboembolism (PTE). Methods Antit.hrombin Ala384Ser was detected by case-control study in 65 patients with PTE and 65 nonthrombosis normal individuals as controls. The antithrombin gene was amplified by polymerase chain reaction (PCR). The Ala384Ser polymorphism was genotyped by PCR-RFLP using Pvu Ⅱ ,and the confirmation of genotypes was performed by sequencing. Results There was significant difference in family history of PTE between China and West countries. There were no significant differences in the family of cardiovascular diseases, personal history of oral contraceptive, trauma,operation,cigarette smoking and alcohol drinking between patients and controls. Frequencies of allele G and T in the controls were 1,0 respectively. The distribution of genotypes met the Hardy-Weinberg equilibrium. There were no significant differences in the frequencies of genotype G/G,G/T and T/T between patients and controls. Conclusions Ala384Ser polymorphism of antithrombin gene is not a risk factor for PTE in Chinese,as the obvious discrepancy in the results with those reported by western country investigators may reflect the plausible pathogenic divergence in PTE among different races.%目的 探讨抗凝血酶基因Ala384Ser多态性与肺血栓栓塞症(pulmonary thromboembolism,PTE)的相关性.方法 采用病例对照研究的方法,运用聚合酶链反应扩增,产物纯化.Pvu Ⅱ限制性内切酶片段长度多态性聚合酶链反应及DNA测序技术对65例PTE患者及65名健康对照者进行抗凝血酶基因Ala384Ser分析.结果 PTE组仅3.3%患者有PTE家族史,这与西方人群报道结果存在显著差别;心血管疾病家族史、口服避孕药、吸烟、饮酒史、外伤及手术史PTE组与对照组比较差异无统计学意义.PTE组、对照组等位基因频率为1、0,符合Hardy-Weinberg平衡定律,G/G、G/T

  10. Correlative Analysis of the Relationships and Differences on D-dimer, Fibrinogen and Antithrombin Ⅲ Between Varied Clinical Periods of Cerebral Infarction%D-D、Fb和AT-Ⅲ在脑梗死不同时期的变化及相关性分析

    Institute of Scientific and Technical Information of China (English)

    徐威香; 武蓉珍; 胡晓蕾

    2012-01-01

    目的:探讨血浆D-二聚体(D-D)、纤维蛋白原(Fb)和抗凝血酶Ⅲ(AT-Ⅲ)在脑梗死(CI)不同时期的变化及其临床意义.方法:根据临床特征,对260例CI患者进行分组,其中CI急性期组80例、进展期组41例、非进展期组65例、康复期组74例;90例体检健康者为正常对照组.采用SYSMEX CA7000血凝仪分别检测其血浆D-D、Fb和AT-Ⅲ水平.结果:CI急性期、进展期、非进展期患者D-D、Fb含量均明显高于正常对照组(P<0.01),AT-Ⅲ低于正常对照组(P<0.01);脑梗死组中,D-D与AT-Ⅲ呈负相关(P<0.01),D-D与Fb呈正相关(P<0.01),AT-Ⅲ与Fb无相关性.结论:CI患者D-D、Fb、AT-Ⅲ变化显著,D-D升高伴随AT-Ⅲ含量降低,提示D-D、Fb、AT-Ⅲ共同参与了梗死发生发展的病理生理过程,可作为CI临床危险分级和病情监测的指标.%Objective To investigate the differences and its clinical significance of D-dimer, fibrinogen and antithrombin Ⅲ between varied clinical periods of cerebral infarction( CI). Methods 328 CI patients were rolled into the study, and they were divided into four groups due to their different clinical periods as follows: group acute period (80) , group progressing(41) , group non-pro-gressing(65) , group convalescence(74). And, 90 healthy volunteers were rolled into the normal control group. Their plasma D-dimer, fibrinogen and antithrombin HI were detected on SYSMEX CA7000 automatic coagulation analyzer. Results D-dimer and fibrinogen of CI patients in the acute, progressing and non-progressing periods were significantly higher (P <0.01) than those of healthy volunteers, while antithrombin Ⅲ of them was significantly lower (P<0.01) than that of healthy volunteers. In CI patients, D-dimer correlated negatively with antithrombin Ⅲ, while positively with fibrinogen. No significant relationship was observed between antithrombin Ⅲ and fibrinogen. ConclUSin D-dimer, fibrinogen and antithrombin Ⅲ of CI patients varied significantly

  11. Interstitial deletion of chromosome 1q [del(1)(q24q25.3)] identified by fluorescence in situ hybridization and gene dosage analysis of apolipoprotein A-II, coagulation factor V, and antithrombin III

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Takako; Yamanouchi, Yasuko; Mori, Yosuke [Teikyo Univ. School of Medicine, Tokyo (Japan)] [and others

    1997-01-20

    We report on a 12-month-old Japanese boy with an interstitial deletion of the long-arm of chromosome 1 and meningomyelocele, hydrocephalus, anal atresia, atrial septal defect, left renal agenesis, bilateral cryptorchidism, talipes equinovarus, low birth weight, growth/developmental retardation, and many minor anomalies. By conventional GTG-banding, his karyotype was first interpreted as 46,XY,de1(1)(q23q24), but it was corrected as 46,XY.ish del(1)(q24q25.3) by fluorescence in situ hybridization using 11 known cosmid clones as probes. His serum levels of apolipoprotein A-II (gene symbol: APOA2, previously assigned to 1q21-q23) and coagulation factor V (F5, 1q21-q25) were normal, while serum concentration and activity of antithrombin III (AT3, 1q23-q25.1) was low. The results indicated that localization of APOA2 and F5 are proximal to the deleted region and AT3 is located within the deletion extent in the patient. 16 refs., 4 figs.

  12. Changes of thrombin-antithrombin complex and other variables in acute respiratory distress syndrome%急性呼吸窘迫综合征中的凝血酶-抗凝血酶等指标的变化

    Institute of Scientific and Technical Information of China (English)

    高志国

    2008-01-01

    目的 探讨D-二聚体、凝血酶-抗凝血酶复合物、纤溶酶-抗纤溶酶复合物、蛋白C在急性呼吸窘迫综合征(ARDS)诊断中临床意义,并为ARDS治疗过程提供血清学依据.方法 实验组选取105例符合ARDS诊断标准患者(对照组选取健康献血员)分别采静脉血,进行凝血酶原时间、凝血酶时间、部分凝血活酶时同、血小板计数、D-D、TAT、PAP、PC八项血清指标的定量测定.结果 ARDS的患者血浆中D-D、TAT、PAP、PC的含量与对照组进行比较,差异有统计学意义(P<0.01).结论 D-D、TAT、PAP、PC浓度在ARDS患者中有明显变化,而PT、TT、APTT、Pt的含量变化不明显.提示在ARDS早期给予抗凝治疗有一定的临床价值.%Objective To measure D-Dimer(DD) ,thrombin-antithrombin complex(TAT), lasmin-antiplasrain complex(PAP) and protein C(PC) in ARDS,to find the clinical significance of them,discuss the objective base in the early diagnosis of ARDS in the lab, and offer the serologic bases in the treatment and prognosis of ARDS.Methods 105 patients of ARDS were selected as the study group, and 105 people were selected as the control group, all of whom were healthy with no thrombus diseases. The venous blood of everyone in both groups was sampied,in order to take a quantitative determination of plasma prothrombin time(PT), prothrombin time(TT), kadin partial thromboplastin time(APTT), the amount of blood platelet, DD, TAT, PAP, PC. Results Serum concentratation of D-D, TAT, PAP was significantly higher in patients in ARDS group than that in control group(P<0.01).Serum concentratation of PC was significantly lower in patients in ARDS group than that in control group (P<0.01). Conclusion Measuring the concentration of DD, TAT, PAP and PC was very important, which not only did good to the early diagnosis of ARDS,but also had a clinic value.

  13. Antithrombin III for critically ill patients

    DEFF Research Database (Denmark)

    Allingstrup, Mikkel; Wetterslev, Jørn; Ravn, Frederikke B;

    2016-01-01

    , bleeding events, the effect on sepsis and disseminated intravascular coagulation (DIC) and the length of stay in the intensive care unit (ICU) and in hospital in general. SEARCH METHODS: We searched the following databases from inception to 27 August 2015: Cochrane Central Register of Controlled Trials...

  14. A study on the relationship between gene polymorphisms of Antithrombin Ⅲ and Factor V and preeclampsia and eclampsia in the Han nationality women of Guangdong, China%广东籍汉族妇女抗凝血酶Ⅲ和Factor V基因多态性与子痫前期和子痫的相关性研究

    Institute of Scientific and Technical Information of China (English)

    苏念军; 李冰; 冯建怀; 于滨

    2011-01-01

    Objective To investigate a potential association of the gene polymorphisms of antithrombin m and Factor V gene with preeclampsia and eclampsia in the Han nationality women of Guangdong,China. Methods The antithrombin Ⅱ gene polymorphisms and Factor V gene Leiden mutation in 54 pregnancy women with preeclampsia and eclampsia (observation group) and 513 normal pregnancy women (control group) were analyzed retrospectively. The polymorphisms were determined by DdeI and Mnll restriction enzyme PCR-RFLP, respectively. Results The frequency of Antithrombin Ⅲ DdeI++, DdeI+-and Ddel-genotypes in observation group was 51.9% ,27.8% and 20.4% ,respectively,while in the control group,the frequency was 66.7 %, 25.5% and 7.8%, respectively. The frequencies of DdeI-genotype in observation group were significantly higher than those in the control group (34.3% ,20.6% ,P<0.01 ). Furthermore, the risk rate of this genotype was 3.025. Factor V gene Leiden mutation was not detected in both observation group and control group patients. Conclusion Antithrombin Ⅲ gene polymorphisms might be a high risk factor of preeclaropsia and eclampsia in Guangdong Hah nationality women.However,Factor V Leiden mutation might not be a high risk factor of preeclampsia and eclampsia in Guangdong Han nationality women.%目的 探讨抗凝血酶III(AT-Ⅲ),凝血因子V (Factor V)基因多态性与广东籍汉族早孕期妇女子痫前期和子痫发生的关系.方法 回顾性分析567例早孕期广东籍汉族妇女AT-Ⅲ及Factor V基因的突变情况,将其中54例妊娠20周后发生子痫前期和子痫的患者作为观察组,513例正常妊娠者作为对照组.基因突变检测分别采用DdeI和MnlI限制性内切酶片段长度多态性分析.结果 观察组AT Ⅲ DdeI++、Ddel+-及DdeI--基因型频率分别为51.9%、27.8%和20.4%,对照组则分别为66.7%,25.5%和7.8%.观察组AT Ⅲ Ddel-基因型频率显著高于对照组(34.3%,20.6%,P<0.01),AT Ⅲ Ddel--

  15. The functional study of antithrombin L99 mutation%抗凝血酶L99氨基酸位点突变对其功能的影响

    Institute of Scientific and Technical Information of China (English)

    郁婷婷; 戴菁; 丁秋兰; 傅启华; 王学锋

    2014-01-01

    Objective To study the molecular mechanisms of inherited antithrombin (AT)defiency caused by AT L99 mutation.Methods Wild type (WT),L99V,L99A,L99I and L99S AT were purified from drosophila expression system.The binding capacity of AT and the low molecular weight heparin sodium was analyzed by the heparin binding assay.Surface plasmon resonance (SPR) was used to detect the binding ability of AT to thrombin (F Ⅱ a) or AT to coagulation factor X a (F X a).The activity of AT (AT∶ A) was detected by chromogenic assay.Results The purified WT and mutant AT were at the same size.No additional band was observed by coomassie blue staining and western blot assay.Compared to the WT AT,the binding abilities of the low molecular weight heparin sodium to the AT L99V,L99A,L99I and L99S were (44.8±3.6)%,(118.9±14.0)%,(15.2±8.8)%,and (23.0±8.2)%,respectively.The binding abilities of F Ⅱ a to AT L99V,L99A,L99I and L99S were 13%,57%,3%,and 29%,while the binding of F X a to AT L99V,L99A,L99I and L99S were 7%,51%,1%,and 25%.The AT∶A of WT,L99V,L99A,L99I and L99S AT were 146.5%,21.4%,120.9%,10.8%,and 39.0%,respectively.Conclusion The binding abilities of AT to heparin,F Ⅱ a and F X a were damaged by the L99 mutation,which resulted in decreased AT∶ A and inherited AT deficiency.%目的 研究抗凝血酶(AT)L99氨基酸位点突变导致遗传性AT缺陷症的分子机制.方法 利用果蝇细胞表达系统表达纯化野生型AT以及L99V、L99A、L99I和L99S等突变型AT蛋白;采用肝素结合实验检测重组AT蛋白与低分子量肝素钠的结合能力;采用表面等离子共振(SPR)技术检测重组AT蛋白与凝血酶(FⅡa)及活化凝血因子X(FXa)的结合能力;将野生型及各突变型AT蛋白的浓度调整至正常AT血浆浓度后,采用发色底物法检测重组AT蛋白活性.结果 考马斯亮蓝染色及免疫印迹法显示各突变蛋白与野生型AT蛋白大小一致,未见明显杂带.

  16. Antithrombin III for critically ill patients

    DEFF Research Database (Denmark)

    Allingstrup, Mikkel; Wetterslev, Jørn; Ravn, Frederikke B;

    2016-01-01

    no statistically significant effect of AT III on mortality (RR 0.95, 95% CI 0.88-1.03, I (2) = 0%, fixed-effect model, 29 trials, 3882 participants). Among those with severe sepsis and disseminated intravascular coagulation (DIC), AT III showed no impact on mortality (RR 0.95, 95% Cl 0.88-1.03, I (2) = 0%, fixed...

  17. The significance of detection of D-dimer, fibrinogen and antithrombin-Ⅲin the patients with typy-2 diabet-ic nephropathy%D-二聚体、纤维蛋白原及抗凝血酶Ⅲ联合检测对早期2型糖尿病肾病的诊断价值

    Institute of Scientific and Technical Information of China (English)

    杨玲

    2015-01-01

    目的:探究D-二聚体、纤维蛋白原( FIB)及抗凝血酶Ⅲ( AT-Ⅲ)联合检测2型糖尿病早期肾损伤的临床诊断价值。方法选取某院2型糖尿病患者206例,根据24 h尿白蛋白排泄率( UAE)分为无蛋白尿组116例( UAE<30 mg/24 h)与微量白蛋白尿组90例(30 mg/24 h≤UAE<300 mg/24 h),并选取同期健康体检者103例作为健康对照组,比较血浆D-二聚体、FIB、AT-Ⅲ3项指标的变化。结果微量白蛋白尿组D-二聚体、FIB含量明显高于无蛋白尿组和健康对照组,差异均有统计学意义(P<0畅05),而三组AT-Ⅲ的活性比较差异无统计学意义(P>0畅05)。3项指标联合检测的微量蛋白尿组患者为93畅3%,比单项检测的阳性率高,差异有统计学意义(P<0畅05)。 D-二聚体、FIB、AT-Ⅲ与尿白蛋白排泄率呈正相关,相关系数(r)依次为0畅812、0畅672、0畅621(P<0畅05)。结论 D-二聚体、FIB检测对于2型糖尿病肾病的早期判断以及疾病的早期预防和病情监测有重要意义。%Objective To explore the D-dimer, fibrinogen (FIB), antithrombin Ⅲ (AT-Ⅲ) joint detection of early renal damage in type 2 diabetes to assess the diagnostic value of clinical application.Methods According to the 24 h urine albumin excre-tion rate ( UAE) , 206 patients selected from type 2 diabetes patients were divided into 116 cases without albuminuria group ( UAE0.05).Three indicators of joint detection of trace albuminuria group of patients was 93.3%, positive rate than single detection are high, the difference was statistically significant (P<0.05).D-dimer, FIB, the AT-Ⅲand UAE are positively related to the level of the correlation coefficient r of 0.812, 0.672, and 0.621 (P<0.05).Conclusion The detection of D-dimer, FIB in type 2 diabetic nephropathy early judgement and early prevention of disease and illness monitoring is im-portant.

  18. Clinical significance on changes of platelet aggregation test, von Willebrand factor,antithrombin and D-dimer assayin acute cerebral infarction patients%急性脑梗死患者血小板聚集功能、血管性血友病因子、抗凝血酶及 D-二聚体测定的临床意义

    Institute of Scientific and Technical Information of China (English)

    叶青跃; 程鹏飞; 周有利; 饶汉武; 黄承芳; 周立

    2015-01-01

    目的:探讨急性脑梗死患者血小板聚集功能( PAgT)、血管性血友病因子( vWF)、抗凝血酶( AT)和D-二聚体( D-dimer)水平变化及临床意义。方法选用相应的方法和仪器测定112例脑梗死及80例健康对照者血(浆) PAgT、vWF、AT和D-dimer水平变化,同时对部分患者进行治疗前、后的对比分析。结果脑梗死患者血中PAgT、vWF、D-dimer等指标均明显高于健康对照组,AT活性较对照组显著降低,差异有统计学意义(P<0.05或P<0.01)。选取经治疗效果明显好转的78例脑梗死患者,出院前取空腹静脉血测定PAgT、vWF、AT、D-dimer等指标,并与治疗前对照,结果治疗后PAgT、vWF、D-dimer降低,AT活性升高,差异有统计学意义(P<0.05或P<0.01)。结论脑梗死患者体内存在明显的凝血及纤溶功能异常,与血管内皮损伤、血小板聚集功能增强、凝血及纤溶功能亢进、抗凝功能降低等多因素有关。 PAgT、vWF、AT、D-dimer可以作为脑梗死患者诊断、治疗监测和预后判断的参考指标。%Objective To evaluate the clinical signification of coagulation ,anti-coagulation and fibrinolysis indexes i.e.platelet aggrega-tion test(PAgT),von Willebrand factor(vWF),antithrombin(AT),D-dimer in acute cerebral infarction patients.Methods vWF was as-sayed using ELISA method,AT was determined by chromogenic substances assay,and Latex enhanced immune turbidimetry for D-dimer. vWF,AT and D-dimer all the parameters were finished by SysmexCA-7000 automated blood coagulation analyzer.PAgT was measured sim-ultaneously using a whole-blood Lumi-Aggregometer by CHRMNO-LOG platelet aggregation apparatus.Results PAgT, vWF, D-dimer were significantly higher in acute cerebral infarction patients group,compared with those in the control group(P<0.05 or P<0.01). while AT was significantly lower(P<0.05).After effective treatment,PAgT,vWF,AT,D-dimer Indicators are all

  19. Correlation of the activities of protein C,antithrombin and coagulation factor Ⅷ with the treatment of lung cancer with pulmonary embolism%蛋白 C、抗凝血酶及凝血因子Ⅷ活性变化与肺癌合并肺栓塞后治疗的关系

    Institute of Scientific and Technical Information of China (English)

    陈环; 张鹏; 刘军锋

    2014-01-01

    Objective To investigate the correlation of the activities of protein C(PC),antithrombin(AT)and coagulation factor Ⅷ(FⅧ)with the treatment of lung cancer with pulmonary embolism(PE).Methods A total of 98 patients with lung cancer and PE were enrolled as lung cancer with PE group.A total of 1 00 patients with lung cancer were enrolled as lung cancer group.Their sex and age were recorded,and lipoprotein(a)[Lp(a)],total cholesterol (TC),triglyceride (TG),C-reactive protein(CRP),thrombin time(TT),platelet (PLT)and fibrinogen(Fbg)in the 2 groups were determined,respectively.PC,AT,FⅧ and D-dimer were determined in lung cancer with PE group after 5-7 d of treatment.Logistic regression analysis was used to analyze the factors influencing coagulation-fibrinolysis after 5-7 d of treatment in lung cancer with PE group.The receiver operating characteristic(ROC)curve was used to analyze the diagnostic efficiency of these factors.Results Lp (a),TC,TG and TT in lung cancer with PE group were significantly higher than those in lung cancer group (P 0.90.Conclusions The influence of PC,AT and FⅧ on coagulation-fibrinolysis should be concerned in midterm treatment of lung cancer with PE,and their activities can be used to assess the therapeutic efficiency and treatment program in a given period.%目的:探讨蛋白C(PC)、抗凝血酶(AT)及凝血因子Ⅷ(FⅧ)活性变化与肺癌合并肺血栓栓塞[简称肺栓塞(PE)]后治疗的关系。方法选择肺癌合并 PE 患者(肺癌+PE 组)98例及肺癌患者(肺癌组)100例。记录两组性别、年龄并检测脂蛋白(a)[Lp(a)]、总胆固醇(TC)、甘油三酯(TG)、C 反应蛋白(CRP)、凝血酶时间(TT)、血小板数量(PLT)、纤维蛋白原(Fbg)等指标。检测肺癌+PE 组治疗5~7 d 及肺癌组入院时的 PC、AT、FⅧ、D-二聚体水平。应用 Logistic 回归分析肺癌合并 PE 后治疗5~7 d 凝血-纤溶状态的影响因素,

  20. Clinical Significance of von Willebrand Factor and Antithrombin in Diabetes Mellitus with Retinopathy%血管性血友病因子与抗凝血酶在糖尿病视网膜病变中的临床意义

    Institute of Scientific and Technical Information of China (English)

    张鹏; 汤荣华

    2012-01-01

    目的 探讨糖尿病微血管视网膜病变患者血管性血友病因子(vWF)、抗凝血酶(AT)的变化及临床意义.方法 将100例2型糖尿病患者分为两组,糖尿病无微血管视网膜病变并发症组53例,糖尿病微血管视网膜病变并发症组47例,设健康人群对照组50例.所有人群入院或体检时即采集静脉血,进行vWF:Ag、AT:A检测.结果 2型糖尿病无微血管视网膜病变并发症组患者血浆vWF:Ag含量较正常对照组增高(P<0.05),2型糖尿病微血管视网膜病变并发症组患者血浆vWF:Ag含量与2型糖尿病无微血管视网膜病变并发症组及正常对照组相比有显著性差异(P<0.05);且2型糖尿病微血管视网膜病变并发症组中背景性病变和增殖性病变患者血浆vWF:Ag含量比较有显著性差异(P<0.05).2型糖尿病无微血管视网膜病变并发症组患者血浆AT活性与正常对照组相比无显著性差异(P>0.05),2型糖尿病微血管视网膜病变并发症组患者血浆AT活性与2型糖尿病无微血管视网膜病变并发症组及正常对照组相比有显著性差异(P<0.05);且2型糖尿病微血管视网膜病变并发症组中背景性病变和增殖性病变患者血浆AT活性比较有显著性差异(P<0.05).结论 血浆vWF:Ag、AT:A的变化与糖尿病微血管视网膜病变的发生、发展有密切关系,监测其水平与活性对糖尿病微血管并发症的治疗和预防有重要的临床意义.%Objective To explore the changes of von Willebrand factor(vWF) and antithrombin(AT) in diabetic patients with retinopathy and its clinical implications. Methods 100 type 2 diabetes mellitus (T2DM) patients were divided into 2 groups,one group included 53 T2DM patients without retinopathy,another group included 47 T2DM patients with retinopathy, 50 healthy peoples were enrolled as control group. Venous blood was collected from all groups and vWF:Ag, AT; A were determined. Results The level of vWF;Ag in T2DM

  1. 二例Ⅰ型抗凝血酶缺陷症患者反复发生静脉血栓的分子机制研究%Molecular mechanisms of recurrent venous thrombosis in two pedigrees with type Ⅰ antithrombin deficiency

    Institute of Scientific and Technical Information of China (English)

    夏燕; 丁秋兰; 许冠群; 张利伟; 戴菁; 陆晔玲; 王学锋; 奚晓东; 王鸿利

    2011-01-01

    Objective To investigate the clinical phenotype,genotype and molecular mechanism of recurrent venous thrombosis in two Chinese pedigrees with type Ⅰ antithrombin (AT) deficiency.Methods The routine coagulation screening tests were detected,thrombin generation tests was performed to evaluate the hypercoagulation.Anticardiolipin antibody (ACA) and lupus anticoagulant (LA) were detected with enzyme-linked immunosorbent assay (ELISA) and diluted viper venom time assay (DVVT),respectively.The activities of protein C,protein S and AT (PC:A,PS:A,AT:A) were tested with chromogenic substrate assay or clotting method.The antigen of AT ( AT:Ag) was performed with immunoturbidimetry methods.Western blot was used to analyze the molecular weight (MW) and the plasma levels of AT:Ag.All 7 exons and the flanking sequences were amplified by PCR.The mutation of AT gene and thrombophilia associated gene polymorphisms were analyzed by direct DNA sequencing.The expression plasmid of Ala404Asp mutant was constructed with site-directed mutagenesis method based on the wild-type (WT) AT cDNA contained in pcDNA 3.1 vector,and transiently expression of AT WT and the Ala404Asp mutant was performed using HEK293T cells.Cultured supernatant and cell lysates were collected and measured for AT:Ag by ELISA and Western blot.Results The results of routine coagulation tests in two probands were normal,thrombin generation tests indicated that proband 1 presented hypercoagulable state with 2.8 and 1.5 times higher of the endogenous thrombin potential (ETP) and peak height compared with that of normal,respectively.The levels of PC:A,PS:A,ACA and LA were normal.AT:A in proband 1 and proband 2 were 45% and 32%,and AT:Ag were almost half of the normal ( 121 mg/L and 158 mg/L),respectively.The results of Western blot showed that both probands' plasma levels of AT:Ag were lower than the normal pooled plasma and MW was normal.Two heterozygous mutations of g.3291 C→T( Thr98 Ile),g.13863 C > A (Ala404

  2. Developmental expression of chicken antithrombin III is regulated by increased RNA abundance and intracellular processing.

    Science.gov (United States)

    Amrani, D L; Rosenberg, J; Samad, F; Bergtrom, G; Banfield, D K

    1993-01-23

    We isolated and sequenced a 432 bp cDNA to cAT-III, that encoded 115 nucleotides of 5' untranslated sequence, a 17 amino acid long signal peptide and residues 1-88 of the mature protein, and used it to prepare a probe for measuring and correlating the developmental changes of steady-state cAT-III mRNA levels with known changes in antigen levels. Densitometric analysis of nuclease protection (n = 2), Northern blot (n = 4), and slot blots (n = 3) of total RNA from chick livers of 16-day-old embryos to 6-day-old chicks showed a 2.6 +/- 0.5-fold increase in steady-state cAT-III mRNA levels. Assay of functional mRNA levels by in vitro translation of poly(A)+ RNA and specific immunoprecipitation of 35S-Met-labelled cAT-III was comparable to RNA analysis (16-day-old embryos vs. 10-day-old hatchlings). We evaluated whether there were developmental differences in post-translational secretion which may also contribute to the regulation of the circulating level of this protein. Pulse-chase studies of freshly-isolated hepatocytes from 16-day-old embryos and 10-day-old hatchlings maintained in suspension demonstrated a approx. 5.0-5.5-fold increase in cAT-III levels at steady-state secretion. The above findings indicate that changes in circulating cAT-III levels during late embryonic development are primarily due to increased abundance of cAT-III mRNA. In addition, we postulate that post-translational intracellular processing may account for further differences in circulating protein levels. PMID:8424948

  3. Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats

    OpenAIRE

    Hofstra, J. J.; Cornet, A.D.; Rooy, de, P.; Vlaar, A.P.; Poll,, A.; Levi, M; Zaat, S. A. J.; Schultz, M.J.

    2009-01-01

    Introduction Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effec...

  4. Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats

    NARCIS (Netherlands)

    J.J. Hofstra; A.D. Cornet; B.F. de Rooy; A.P. Vlaar; T. van der Poll; M. Levi; S.A.J. Zaat; M.J. Schultz

    2009-01-01

    Introduction Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants

  5. Clinical review: Molecular mechanisms underlying the role of antithrombin in sepsis

    OpenAIRE

    Wiedermann, Christian J.

    2006-01-01

    In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review ...

  6. The thrombin E192Q-BPTI complex reveals gross structural rearrangements: implications for the interaction with antithrombin and thrombomodulin.

    OpenAIRE

    van de Locht, A; Bode, W.; Huber, R; Le Bonniec, B F; Stone, S R; Esmon, C T; Stubbs, M T

    1997-01-01

    Previous crystal structures of thrombin indicate that the 60-insertion loop is a rigid moiety that partially occludes the active site, suggesting that this structural feature plays a decisive role in restricting thrombin's specificity. This restricted specificity is typified by the experimental observation that thrombin is not inhibited by micromolar concentrations of basic pancreatic trypsin inhibitor (BPTI). Surprisingly, a single atom mutation in thrombin (E192Q) results in a 10(-8) M affi...

  7. Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model

    OpenAIRE

    Favreau, F.; Thuillier, R.; Cau, J; S. Milin; Manguy, E; Mauco, G; Zhu, X.; Lerman, LO; Hauet, T.

    2009-01-01

    Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran® (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 hours in University of Wisconsin solution. Treatment with M before WI ...

  8. 抗凝血酶治疗弥散性血管内凝血的研究进展%The Treatment of Antithrombin in Disseminated Intravascular Coagulation

    Institute of Scientific and Technical Information of China (English)

    肖慧芳; 朱雄鹏

    2008-01-01

    近年来,随着抗生素治疗及临床监护水平的提高,败血症相关死亡率有所下降,但其并发症的发病率仍在上升,故其总死亡率仍高。弥散性血管内凝血(disseminated intravascular coagulation,DIC)作为其常见的并发症,虽其发病机制、病理过程复杂,但其中天然抗凝途径功能紊乱起着重要作用。抗凝血酶(Antithrombin,AT)是体内一种重要的含量最丰富的天然抗凝蛋白,目前许多动物及临床试验均表明,在败血症相关DIC患者中应用AT可以改善DIC状况,降低死亡率。本文就此作一综述。

  9. Molecular analysis of the genotypes and phenotypes in three pedigrees with inherited antithrombin defidency%三个遗传性抗凝血酶缺陷症家系临床表型和基因型分析

    Institute of Scientific and Technical Information of China (English)

    吴瑛婷; 许冠群; 张利伟; 戴菁; 丁秋兰; 奚晓东; 王学锋; 王鸿利

    2009-01-01

    Objective To investigate the clinical phenotype and genotype in three probands with antithmmbin(AT)deficiency and their families,and to identify the molecular mechanism of AT deficiency.Methods Chromogenic substrate method and immunoturbidimetry assay was used to detect the plasma levels of AT:A and AT:Ag,respectively.Genomic DNA was extracted from the peripheral blood.All 7 exons and the flanking sequences were amplified by PCR.and the abnormal mutant genes were analyzed by direct sequencing.Western blot was used to detect the AT levels and thrombin generation tests were used to detect coagulation status.Results The plasma levels of AT:A and AT:Ag of the three probands declined by 50%.G7386C(Trp225Cys)mutation in exon 4,C2591G(Ser36stop)in exon 2 and C9819T(Arg359stop)in exon 5 were characterized in the three prebands and they could result in W(Trp)225C(Cys)missense mutation,S(Set)36X(stop)nonsense mutation and R(Arg)359X(stop)nonsense mutation respectively,The testing results of phenotype and genotype from some of their family members showed consistent with results from the probands.Western blot results indicated that the Icyels of PC:Ag were lower compared with the normal pooled plasma.The hypercoagulative status was present in the probands using thrombin generation tests.Conclusions Type Ⅰ hereditary AT deficiency was found in these three families.The 3 heterozygous mutations.W225C,S36X and R359X are genetic defects of hereditary AT deficiency.W225C and S36X have not been described before.%目的 探讨遗传性抗凝血酶(AT)缺陷症先证者及其家系成员的AT活性(AT:A)、AT抗原含量(AT:Ag)及基因型在引起遗传性AT缺陷症发病的分子机制.方法 收集3例AT缺陷症先证者及其家系成员血浆标本,采用发色底物法和免疫比浊法分别检测先证者及其家系成员血浆AT:A和AT:Ag,提取外周血基因组DNA.用PCR法扩增AT基冈的全部7个外显子及侧翼序列,通过直接测序分析异常的突变基因.利用蛋白免疫印迹法分析血浆中AT含量的变化,用凝血酶生成试验检测患者体内的凝血状态.结果 3例先证者AT:A和AT:Ag均降低到正常值的50%左右,分别在AT基因外显子4区的第7386位核苷酸发生杂合性G>C突变,导致W(Trp)225 C(Cys)错义突变;2号外显子区第2591位核苷酸发生C>G突变,导致S(Ser)36 X(stop)无义突变;5号外显子区第9819佗核苷酸发生C>T杂合突变,导致R(Arg)359 X(stop)无义突变.部分家系成员表型和基因型榆测结果与先证者一致.蛋白免疫印迹结果显示先证者及其家系成员血浆中的AT含量较正常混合血浆明显减少,凝血酶生成实验显示先证者体内呈现明显的高凝状态.结论 I型遗传性AT缺陷症中,W225C、S36X、R359X引起血浆中AT含量下降,是导致遗传性AT缺陷症的分子致病机制.

  10. 乳香、没药提取物及其配伍对血小板 聚集与抗凝血酶活性的影响%Effect of Extracts from Olibanum and Myrrha and Their Compatibility on Platelet Aggregation and Antithrombin Activity

    Institute of Scientific and Technical Information of China (English)

    蒋海峰; 宿树兰; 欧阳臻; 周卫1; 华永庆1; 段金廒1*; 唐于平1

    2011-01-01

    Objective:Effects of platelet aggregation and thrombin time in vitro in rabbits by water extracts and volatile oil from Olibanum and Myrrha and their compatibility were studied to evaluate their effect and dose-effect relationship. Method; Extracts and oils from Olibanum and Myrrha and their combination in different compatibility on platelet aggregation induced by adenosine diphosphate( ADP)m vitro, thrombosis by using thrombin time (TT) method and their dose-effect relationship were observed. Interaction effects of two drugs used in compatibility were measured by an isobole method. Result; The results showed that all the extracts and their combinations in different compatibility had significant or very significant inhibitory effects on the platelet aggregation induced by ADP. Compatibility of the extracts had synergism effect and its activity was better than both single-use ofextracts. The experimental data of TT indicated that different extracts from Olibanum and Myrrha could all significantly prolong clotting time of blood plasma in rabbits. Except that combination of water extracts of Olibanum: Myrrh (1:1) had antagonism effect, the others had synergism effect. Conclusion: Water extracts and volatile oil from Olibanum and Myrrha and their combinations in different compatibility all showed significant effect in vitro on platelet aggregation and thrombin time in rabbits. Furthermore, except that compatibility of water extracts of Olibanum j Myrrh (1:1) had antagonism effect, the other showed synergistic action. The study provided reference for scientific characters and rationality of herbal compatibility.%目的:通过乳香、没药水提物、挥发油及其配伍组合体外对ADP诱导的家兔血小板聚集及对凝血酶时间影响研究,评价其配伍前后的效应变化与量效关系.方法:采用体外二磷酸腺苷(ADP)诱导的血小板聚集实验观察乳香、没药提取物及不同配伍组合的抗血小板聚集活性及量效关系;采用凝血酶时间(TT)法观察乳香、没药提取物及不同配伍组合对凝血酶的影响及量效关系;采用等效线法评价两药配伍的药效相互作用.结果:血小板聚集实验表明:乳香、没药提取物及其不同配伍组合均能显著或非常显著抑制ADP诱导的家兔血小板聚集,且两药配伍后具有协同增效作用,其活性强于各单用提取物的活性.TT实验研究结果表明:乳香、没药不同提取物均能显著延长家兔血浆凝血时间,配伍后除乳香水提物与没药水提物配伍具有拮抗作用外,其余配伍组合均具有协同增效作用.结论:乳香、没药的水提物、挥发油及其配伍组合对家兔血小板聚集及凝血酶时间的影响均能产生显著效应,除乳香水提物和没药水提物配伍组合对凝血酶时间的影响具有拮抗作用外,其余配伍组合均呈现出协同增效作用.研究结果为揭示中药药对配伍的科学性和合理性提供借鉴与参考.

  11. 凝血酶-抗凝血酶复合物及肠脂肪酸结合蛋白检测在早期诊断肠系膜上动脉栓塞的实验研究%Earlier diagnosis for superior mesenteric artery embolism by detection of thrombin-antithrombin complex and intestinal fatty acid binding protein:an animal experiment

    Institute of Scientific and Technical Information of China (English)

    张义雄; 刘智龄; 宋偲婷; 刘晓亮; 张兴文; 隆艳飞; 肖斌

    2015-01-01

    目的:观察凝血酶-抗凝血酶复合物(TAT)、肠脂肪酸结合蛋白(IFABP)在肠系膜上动脉栓塞(SMAE)模型犬外周血含量的变化,探讨SMAE的早期诊断指标.方法:自体血栓栓塞法建立SMAE动物模型,酶联免疫法检测犬外周血TAT、IFABP及D-二聚体(DD)含量,自动生化分析仪测乳酸脱氢酶(LDH).结果:栓塞后30 min,SMAE组TAT值、IFABP值均明显升高,与正常对照组比较,差异有统计学意义,但与假手术组比较,TAT值栓塞前1h差异无统计学意义,各时间点的IFABP值差异均有统计学意义.SMAE犬外周血DD值、LDH值也明显升高,但升高时间迟于TAT和IFABP.检验效能分析显示:联合TAT和IFABP检测可保持较高的诊断敏感度,并提高诊断特异性.结论:TAT、IFABP可能作为SMAE的早期诊断指标,但需将二者联合检测,以提高诊断特异性.

  12. Relationship between antithrombin-Ⅲ value with acute coronary syndrome and preprocedural TIMI flow grade%抗凝血酶Ⅲ活性与急性冠脉综合征患者及术前TIMI血流的关系

    Institute of Scientific and Technical Information of China (English)

    洪霞; 单培仁; 胡龙; 黄周青; 吴高俊; 肖方毅; 黄伟剑

    2012-01-01

    Objective To explore the differences of antiprothrombin-Ⅲ ( AT-Ⅲ ) value in patients with acute coronary syndrome (ACS) and stable angina pectoris (SAP) and examine the association of AT-Ⅲ value with preprocedural thrombolysis in myocardial infarction (TIMI) flow in ACS patients.Methods This study prospectively included 121 hospitalized ACS patients between January 2011 to June 2011,including ST-segment elevation myocardial infarction (STEMI,n =50 ), non-ST segment elevation myocardial infarction (NSTEMI,n =32) and unstable angina (UAP,n =39).Meanwhile,50 SAP cases during the same period were selected as the control group.The AT-Ⅲ levels were measured by chromogenic substrate method before coronary angiography for all patients. Results (1) The AT-Ⅲ levels were significantly lower in the ACS patients than those in the SAP cases.(2) In the STEMI subgroup,the AT-Ⅲ levels were markedly lower in the patients with preprocedural TIMI flow grade ≤2 versus those with preprocedural TIMI flow grade 3 (86% ± 11% vs 93% ±9%,P <0.05). (3) In the USTEMI/UAP subgroup,the mean levels of AT-Ⅲ were obviously lower in the patients with preprocedural TIMI flow grade ≤ 2 than those with preprocedural TIMI flow grade 3 ( 85% ± 8% vs 95% ± 8%,P < 0.01 ) and were notably lower in the patients with the culprit lesion stenosis ≥70% versus those with stenosis <70% ( 88% ± 9% vs 94% ± 9%,P < 0.01 ).(4) Multivariable analysis identified AT-Ⅲ value as an independent predictor of impaired preprocedural TIMI flow grade of culprit coronary artery in ACS patients.Conclusions The AT-Ⅲ levels were significantly lower in the ACS patients than those in the SAP patients.The activity of AT-Ⅲ is positively correlated with the TIMI flow grade in ACS patients.In contrast,the activity of AT-Ⅲ is negatively correlated with the severity of culprit vessel stenosis in the patients with NSTEMI.Thus AT-Ⅲ level may be used to distinguish high-risk populations in ACS patients at an early stage.%目的 探讨抗凝血酶Ⅲ( AT-Ⅲ)活性在急性冠脉综合征(ACS)与稳定型心绞痛(SAP)患者之间的差别,及其在ACS患者中与术前TIMI血流级别之间的关系.方法 前瞻性纳入2011年1至6月急性冠脉综合征患者121例,包括ST段抬高性心肌梗死(STEMI)50例、非ST段抬高性心肌梗死( NSTEMI)32例、不稳定型心绞痛(UAP) 39例,入选同期50例SAP患者作为对照组,应用发色底物法测量血AT-Ⅲ活性.结果 (1)ACS患者AT-Ⅲ活性明显低于SAP患者(P<0.01).(2)STEMI亚组中,AT-Ⅲ活性水平在犯罪血管术前TIMI血流级别≤2级组明显低于TIMI血流3级组(86%±11%比93%±9%,P<0.05).(3)NSTEMI/UAP亚组中,AT-Ⅲ活性水平在犯罪血管术前TIMI血流级别≤2级组明显低于TIMI血流3级组(85%±8%比95%±8%,P<0.01),且在罪犯血管狭窄程度≥70%组明显低于狭窄程度<70%组(88%±9%比94%±9%,P<0.01).(4)逐步多元回归分析显示,AT-Ⅲ活性水平是预测ACS患者罪犯血管术前TIMI血流受损的独立因素.结论 AT-Ⅲ活性的测定为早期筛选ACS高危人群提供指导意义.

  13. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? A prospective observational study

    DEFF Research Database (Denmark)

    Johansson, Per Ingemar; Sorensen, Anne Marie; Perner, Anders;

    2011-01-01

    ABSTRACT: INTRODUCTION: It is debated whether the early trauma induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated......-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption...

  14. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? A prospective observational study

    DEFF Research Database (Denmark)

    Johansson, Per Ingemar; Sorensen, Anne Marie; Perner, Anders;

    2011-01-01

    -complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption......ABSTRACT: INTRODUCTION: It is debated whether the early trauma induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated...

  15. Effect of estrogen-progestin hormonal replacement therapy on blood coagulation and fibrinolysis in postmenopausal women Efeitos da terapia de reposição hormonal estroprogestativa sobre o sistema de coagulação e de fibrinólise em mulheres na pós-menopausa

    OpenAIRE

    Claudio E Bonduki; Dayse M Lourenço; Eduardo L.A. da Motta; José Maria Soares Jr; Mauro Abi Haidar; Baracat, Edmund C

    2007-01-01

    OBJECTIVE: To evaluate antithrombin III (AT), thrombin (Fragment 1+2 [F1+2] and thrombin-antithrombin [TAT]) generation markers, as well as other coagulation parameters, such as prothrombin time, partial activated thromboplastin time, thrombin time, fibrinogen, euglobulin lysis time, and platelet count, in postmenopausal women after hormonal therapy. STUDY DESIGN: Forty-five patients who received either 0.625 mg/day unopposed oral conjugated equine estrogen (CEE), 0.625 mg/day oral CEE plus m...

  16. 非ST段抬高急性冠脉综合征患者随机应用依诺肝素或普通肝素抗凝治疗的疗效和出血并发症系统综述%Efficacy and Bleeding Complications Among Patients Randomized to Enoxaparin or Unfractionated Heparin for Antithrombin Therapy in Non-ST-Segment Elevation Acute Coronary Syndromes A Systematic Overview

    Institute of Scientific and Technical Information of China (English)

    John L. Petersen; James A. de Lemos; Christopher C. Nessel; Robert A. Harrington; James J. Ferguson; Eugene Braunwald; Robert M. Califf; 徐成斌; Kenneth W. Mahaffey; Vic Hasselblad; Elliott M. Antman; Marc Cohen; Shaun G. Goodman; Anatoly Langer; Michael A. Blazing; Anne Le-Moigne-Amrani

    2005-01-01

    背景:抗凝疗法已成为急性冠脉综合征(acute coronary syndrome,ACS)治疗指南推荐的标准疗法.但是,最近某些试验在ACS患者中对依诺肝素(enoxaparin)与普通肝素(unfractionated heparin)的应用进行了比较,发现这些抗凝疗法的疗效及安全性并不及既往试验结果.目的:有6项随机对照试验对依诺肝素与普通肝素治疗ACS患者进行了比较,对其终点(即全因死亡及非致死性心肌梗死)、输血与大出血进行系统评估.资料来源:从杜克临床研究所(Duke Clinical Research Institute)获取ESSENCE、A to Z及SYNERGY试验的原始数据.由TIMI 11B、ACUTEⅡ及INTERACT研究的主要研究人员提供各自的基线特征和事件发生频率.研究选取:在非ST段抬高ACS患者中比较依诺肝素与普通肝素的6项随机对照试验均入选进行分析.数据提取:从全部试验人群和随机分组前未接受抗凝治疗的亚人群中获取疗效终点和安全性终点.数据综合:应用随机效应经验性贝叶斯模型(random-effects empirical Bayes model),系统评估21 946例患者的结果.依诺肝素与普通肝素30天死亡率无显著差异(3.0%比3.0%,优势比[odds ratio,OR],1.00;95%可信区间[confidence interval,CI],0.85~1.17).在所有试验人群中,依诺肝素与普通肝素相比,30天死亡或非致死性心肌梗死(myocardial infarction,MI)联合终点显著下降,具有统计学差异(10.1%比11.0%;OR,0.91;95%CI,0.83~0.99;所需治疗例数107).随机分组前未接受抗凝治疗的依诺肝素组患者30天死亡或MI联合终点亦显著下降,具有统计学差异(8.0%比9.4%;OR,0.81;95%CI,0.70~0.94;所需治疗例数72).随机分组后第7天,总体安全人群或者随机分组前未接受抗凝治疗的人群输血(OR,1.01;95%CI,0.89~1.14)或大出血的发生率(OR,1.04;95%CI,0.83~1.30)无显著差异.结论:对近22 000例各类ACS患者进行系统回顾发现,在预防死亡或MI联合终点方面依诺肝素较普通肝素更有效.

  17. The fabrication, characterization and application of aptamer-functionalized Si-nanowire FET biosensors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ki Su; Lee, Hyun-Seung; Yang, Jeong-A; Jo, Moon-Ho; Hahn, Sei Kwang [Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784 (Korea, Republic of)], E-mail: skhanb@postech.ac.kr

    2009-06-10

    An aptamer-functionalized silicon-nanowire (Si-NW) field effect transistor (FET) biosensor was successfully fabricated, characterized and applied to real-time electrical detection of binding with the target protein for biomedical applications. Surface modifications were carried out using 3-aminopropyl diethoxysilane and succinic anhydride to introduce amine and carboxyl groups onto Si substrates. Anti-thrombin aptamers with 5{sup '}-end amine groups were chemically grafted onto the surface-modified Si substrates through amide bond formation. Atomic force microscopic (AFM) analyses confirmed the successful immobilization of anti-thrombin aptamers on Si-NWs and their binding with thrombin samples. The anti-thrombin aptamers bound to Si-NWs through the linker appeared to have a mean height of approx. 4 nm and the thrombin/aptamer complex to have a mean height of approx. 8 nm. Fluorescence micrographs visualized the FITC-labeled thrombin after binding to anti-thrombin aptamers immobilized on Si-NWs. Furthermore, the anti-thrombin Si-NW FET biosensor was successfully applied to the real-time detection of electronic signals during and after binding with a thrombin sample at a concentration of approx. 330 pmol l{sup -1} and the thrombin in blood samples.

  18. Combination of a SAW-biosensor with MALDI mass spectrometric analysis.

    Science.gov (United States)

    Treitz, G; Gronewold, T M A; Quandt, E; Zabe-Kühn, M

    2008-05-15

    A S-sens K5 surface acoustic wave biosensor was coupled with mass spectrometry (SAW-MS) for the analysis of a protein complex consisting of human blood clotting cascade factor alpha-thrombin and human antithrombin III, a specific blood plasma inhibitor of thrombin. Specific binding of antithrombin III to thrombin was recorded as a function of time with a S-sens K5 biosensor. Two out of five elements of the sensor chip were used as references. To the remaining three elements coated with RNA anti-thrombin aptamers, thrombin and antithrombin III were bound consecutively. The biosensor measures mass changes on the chip surface showing that 20% of about 400fmol/cm2 thrombin formed a complex with the 1.7-times larger antithrombin III. Mass spectrometry (MS) was applied to identify the bound proteins. Sensor chips with aptamer-captured (1) thrombin and (2) thrombin-antithrombin III complex (TAT-complex) were digested with proteases on the sensor element and subsequently identified by peptide mass fingerprint (PMF) with matrix assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectrometry. A significant identification of thrombin was achieved by measuring the entire digest with MALDI-ToF MS directly from the sensor chip surface. For the significant identification of both proteins in the TAT-complex, the proteolytic peptides had to be separated by nano-capillary-HPLC prior to MALDI-ToF MS. SAW-MS is applicable to protein interaction analysis as in functional proteomics and to miniaturized diagnostics. PMID:18316185

  19. Sulfated glycopolymer thin films - preparation, characterization, and biological activity.

    Science.gov (United States)

    Grombe, Ringo; Gouzy, Marie F; Maitz, Manfred F; Freundenberg, Uwe; Zschoche, Stefan; Simon, Frank; Pompe, Tilo; Sperling, Claudia; Werner, Carsten

    2007-02-12

    The impact of heparinoid characteristics on model surfaces obtained from immobilization of sole sulfate groups as well as sulfated glycosides, sulfated cellulose, and definite heparin has been investigated. The obtained layers were physico-chemically characterized regarding film thickness, chemical composition, wettability, and surface morphology. Antithrombin adsorption, studied by fluorescence labeling, revealed a strong dependence on the presence of glycosidic structures and on the molecular weight of the grafted saccharide. On contact with whole blood, the coatings resulted in a diminished plasmatic and cellular coagulation in vitro, which did not reflect well the antithrombin binding. Therefore, more complex activating pathways are discussed. PMID:17295407

  20. Assessing the relative importance of the biophysical properties of amino acid substitutions associated with human genetic disease

    DEFF Research Database (Denmark)

    Terp, Bent N; Cooper, David N; Christensen, Inge T;

    2002-01-01

    in five human genes encoding arylsulphatase A (ARSA), antithrombin III (SERPINC1), protein C (PROC), phenylalanine hydroxylase (PAH), and transthyretin (TTR). These proteins were chosen on the basis of 1) the availability of a crystallographic structure, and 2) a sufficiently large number of amino acid...

  1. Coagulation and Fibrinolysis Indicators and Placental Malaria Infection in an Area Characterized by Unstable Malaria Transmission in Central Sudan

    Directory of Open Access Journals (Sweden)

    Amged G. Mostafa

    2015-01-01

    Full Text Available This study aimed to investigate coagulation, fibrinolysis indicators, and malaria during pregnancy. Methods. A cross-sectional study was conducted at Medani, Sudan. Sociodemographic characteristics were gathered from each parturient woman (163 and malaria was investigated by blood film and placental histology. Protein C, protein S, antithrombin-III, tissue factor pathway inhibitor (TFPI, and plasminogen activator inhibitor-1 levels (PAI-1 were measured using ELISA. Results. One (0.6%, three (1.8, and 19 (11.7% of the placentae showed active, chronic, and past infection on a histopathological examination, respectively, while 140 (85.9% of them showed no signs of malaria infection. While the mean [SD] of the protein C, antithrombin-III, and TFPI was significantly lower, there was no significant difference in protein S and PAI-1 levels in women with placental malaria infection (n=23 compared to those without placental malaria infection (140. In linear regression, placental malaria infection was associated with antithrombin-III. There was no association between placental malaria infections and protein C, protein S, TFPI, and PAI-1 levels. There was no association between hemoglobin, birth weight, and the investigated coagulation and fibrinolysis indicators. Conclusion. This study showed significantly lower levels of protein C, antithrombin-III, and TFPI in women with placental malaria infections.

  2. Determination of coagulation inhibitor levels and resistance to activated protein C in patients undergoing gastric surgery for benign and malignant disorders

    DEFF Research Database (Denmark)

    Andersen, B S; Rahr, H B; Sørensen, J V

    1997-01-01

    The aim of the present study was to determine plasma levels of protein C antigen (PC:Ag) and activity (PC:Act), tissue factor pathway inhibitor (TFPI), protein S (PS), antithrombin (AT), heparin cofactor II (HCII), and resistance to activated protein C (APCR) before, during and after elective...

  3. The endothelial function in cardiac surgery.

    Science.gov (United States)

    Ranucci, M

    2006-06-01

    Cardiac operations with cardiopulmonary bypass exerts many different actions which modify the natural function of endothelial cells. The main determinant is the activation of the coagulation system both through the intrinsic and extrinsic pathways, leading to an overwhelming thrombin formation. To counteract the coagulant effects of thrombin, heparin is used in large doses. As a result, the endothelium is asked to promote all its anticoagulant properties, basically through the AT release from the surface, the tissue factor pathway inhibitor release, and the activation of the protein C protein S system. At the end of cardiac operations, all these systems are depleted, and low levels of antithrombin, tissue factor pathway inhibitor, protein C are available for further anticoagulant effects. There is the evidence that levels of antithrombin activity below 50% at the end of cardiac operations with cardiopulmonary bypass are associated to bad outcomes in terms of surgical revision rate, thromboembolic events, and neurological events. Exogenous antithrombin administration has a well defined action in limiting thrombin formation during cardiac operations; however, we are still lacking an evidence-based information about the clinical impact of this and others possible preventive strategies based on exogenous administration of antithrombin before or during cardiac operations. PMID:16682923

  4. Drug: D10418 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10418 Drug Delparantag pentahydrochloride (USAN) C56H79N13O12. 5HCl 1305.4805 1308.6111 D10418.gif Restorat...ion of normal coagulation (heparin antagonist) antithrombin III activator [HSA:462

  5. A recombinant wheat serpin with inhibitory activity

    DEFF Research Database (Denmark)

    Rasmussen, Søren K; Dahl, Søren Weis; Nørgård, Anette;

    1996-01-01

    to the subfamily of protein Z-type serpins and the amino acid sequence is 70%, identical with the barley serpins BSZ4 and BSZx and 27-33% identical with human serpins such as alpha(1)-proteinase inhibitor, antithrombin III, and plasminogen activator inhibitor. The cDNA was subcloned in the pET3d expression vector...

  6. Drug: D08795 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available BR:br08301] 6 Agents against pathologic organisms and parasites 63 Biological preparation...s 634 Human blood preparations 6343 Plasma preparations D08795 Human anti-thrombin III, freeze-dried concentrated PubChem: 96025478 ...

  7. Diagnosis and prognosis of overt disseminated intravascular coagulation in a general hospital -- meaning of the ISTH score system, fibrin monomers, and lipoprotein-C-reactive protein complex formation.

    Science.gov (United States)

    Cauchie, Ph; Cauchie, Ch; Boudjeltia, K Zouaoui; Carlier, E; Deschepper, N; Govaerts, D; Migaud-Fressart, M; Woodhams, B; Brohée, D

    2006-06-01

    The meaning, the utility, and the prognostic significance of the International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation (DIC) score and other parameters of coagulation activation including soluble fibrin monomer complexes (SFMC), antithrombin and protein C consumption, and formation of lipoprotein-C-reactive protein (LP-CRP) complexes (MDA slope 1 and flag A2) were evaluated in 165 inpatients from a general hospital for whom DIC testing was required by the attending physicians. Of these 165 patients, 148 had an underlying disease that clearly justified the laboratory request from our systematic post hoc review of the clinical charts. Of these 148 patients, 28 had a positive overt DIC score, 19 had an A2 flag, and 4 had both. The DIC score was strongly related to several major markers of coagulation activation such as D-dimers, thrombin-antithrombin complexes, and soluble fibrin and was inversely related to antithrombin and protein C levels, which began to fall from DIC score 4 or higher. The formation of LP-CRP complexes was only related to Gram-negative sepsis and these patients had a strong inflammatory reaction. Independent risk factors for death were high creatininemia, positive overt DIC score, and/or presence of SFMC. In patients with positive DIC score, SFMC positivity and low levels of antithrombin and/or protein C were additional risk factors. The ISTH overt DIC score proves useful and adequate as a marker for clinically significant DIC. Illness severity is further defined by SFMC, antithrombin, and protein C levels. LP-CRP complexes are related to sepsis but not to actual overt DIC and lethal prognosis.

  8. Deficiency of the natural anticoagulant proteins in women with pregnancy related venous thromboembolism

    Directory of Open Access Journals (Sweden)

    Mitić Gorana

    2009-01-01

    Full Text Available Inherited thrombophilia can be defined as a predisposition to thrombosis caused by heritable defects, such as mutations in genes encoding the natural anticoagulants or clotting factors. Pregnancy related risk of VTE is sixfold increased comparing to non pregnant age matched women. Pregnancy is an independent risk factor for the development of venous thromboembolism and this risk is further increased by the presence of thrombophilia. Aim of the study: The aim of the study was to evaluate the association between deficiency of natural anticoagulants: antithrombin, protein C and protein S and pregnancy related thromboembolism. We have determined the activities of antithrombin, proten C and protein S in 74 women with pregnancy related thrombosis and in 45 healthy women who had at least two uncomplicated pregnancies. Among the women with the history of venous thromboembolism antithrombin deficiency was found in 4 (5.4%, protein C deficiency in 2 (2.7% and protein S deficiency in 5 (6.76%. The total of 11 (14.6% women was found to be deficient. Not a single woman in the control group was found to be deficient in natural anticoagulants. Deficiencies of coagulation inhibitors are associated with an increased risk of venous thrombosis during pregnancy and puerperium (p= 0.006. Antithrombin, protein C and protein S deficient women are at higher risk of developing venous thromboembolism during antepartal period (p= 0.0097. Prophylactic treatment with heparin should be recommended from the very beginning of the following pregnancy in women with antithrombin, protein C or protein S deficiency.

  9. Diagnosis and prognosis of overt disseminated intravascular coagulation in a general hospital -- meaning of the ISTH score system, fibrin monomers, and lipoprotein-C-reactive protein complex formation.

    Science.gov (United States)

    Cauchie, Ph; Cauchie, Ch; Boudjeltia, K Zouaoui; Carlier, E; Deschepper, N; Govaerts, D; Migaud-Fressart, M; Woodhams, B; Brohée, D

    2006-06-01

    The meaning, the utility, and the prognostic significance of the International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation (DIC) score and other parameters of coagulation activation including soluble fibrin monomer complexes (SFMC), antithrombin and protein C consumption, and formation of lipoprotein-C-reactive protein (LP-CRP) complexes (MDA slope 1 and flag A2) were evaluated in 165 inpatients from a general hospital for whom DIC testing was required by the attending physicians. Of these 165 patients, 148 had an underlying disease that clearly justified the laboratory request from our systematic post hoc review of the clinical charts. Of these 148 patients, 28 had a positive overt DIC score, 19 had an A2 flag, and 4 had both. The DIC score was strongly related to several major markers of coagulation activation such as D-dimers, thrombin-antithrombin complexes, and soluble fibrin and was inversely related to antithrombin and protein C levels, which began to fall from DIC score 4 or higher. The formation of LP-CRP complexes was only related to Gram-negative sepsis and these patients had a strong inflammatory reaction. Independent risk factors for death were high creatininemia, positive overt DIC score, and/or presence of SFMC. In patients with positive DIC score, SFMC positivity and low levels of antithrombin and/or protein C were additional risk factors. The ISTH overt DIC score proves useful and adequate as a marker for clinically significant DIC. Illness severity is further defined by SFMC, antithrombin, and protein C levels. LP-CRP complexes are related to sepsis but not to actual overt DIC and lethal prognosis. PMID:16680742

  10. [Danaparoid sodium for dialysis in heparin-associated thrombocytopenia].

    Science.gov (United States)

    Ben Ami, R; Rachmimov, R; Berliner, S

    1999-03-01

    Danaparoid sodium is an antithrombin composed of 3 glycosaminoglycans: heparan sulfate, dermatan sulfate and chondroitin sulfate. Similar to heparin, danaparoid operates by activating antithrombin 3, but does not contain heparin or heparin fragments, and is therefore antigenically distinct. Danaparoid has been advocated as a safe and effective anticoagulant for heparin-associated thrombocytopenia. However, there is little experience in its use as a substitute for heparin in hemodialysis. We report 2 men, aged 82 and 73 years, respectively, who developed thrombocytopenia while undergoing hemodialysis with heparin, and who subsequently underwent successful dialysis with danaparoid. There was a rise in platelet levels in both while receiving danaparoid, and dialysis was completed without hemorrhagic or thrombotic complications. Danaparoid is a safe and effective substitute for heparin, and may be used as an anticoagulant in hemodialysis. PMID:10914239

  11. Acute Escherichia coli mastitis in dairy cattle: diagnostic parameters associated with poor prognosis.

    Science.gov (United States)

    Hagiwara, Seiichi; Mori, Kouichiro; Okada, Hiroyuki; Oikawa, Shin; Nagahata, Hajime

    2014-11-01

    This study aimed to identify the diagnostic characteristics associated with poor prognosis and mortality in dairy cows with acute clinical Escherichia coli mastitis. On 17 dairy farms, 24 dairy cows with acute E. coli mastitis that had received therapeutic treatment were categorized into 2 groups by outcome: 17 cows that recovered (survivors) and 7 cows that died or were euthanized (non-survivors). Two days after onset of acute E. coli mastitis, dysstasia was observed in non-survivors, but not in survivors. Compared with survivors, significantly increased hematocrit (HCT) values and non-esterified fatty acid (NEFA) concentrations, and significantly decreased antithrombin activity and platelet counts were found in non-survivors on days 2 and 3 after therapy. Dysstasia, associated with decreased antithrombin activity and platelet counts, and with increased HCT and NEFA concentrations, was considered to be the major prognostic indicator associated with high mortality after therapeutic treatment in acute E. coli mastitis.

  12. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

    Science.gov (United States)

    Garcia, David A; Baglin, Trevor P; Weitz, Jeffrey I; Samama, Meyer Michel

    2012-02-01

    This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT. PMID:22315264

  13. Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

    OpenAIRE

    Warkentin, Theodore E.; Cook, Richard J.; Marder, Victor J.; Sheppard, Jo-Ann I.; Moore, Jane C.; Eriksson, Bengt I; Greinacher, Andreas; Kelton, John G.

    2005-01-01

    Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti–PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti–PF4/he...

  14. Factor V Leiden and Cardiopulmonary Bypass

    OpenAIRE

    Uppal, Victor; Rosin, Mark; Marcoux, Jo-Anne; Olson, Marnie; Bezaire, Jennifer; Dalshaug, Gregory

    2015-01-01

    We present a case of a patient with factor V Leiden with an antithrombin III activity of 67% who received a successful aortic valve replacement supported by cardiopulmonary bypass (CPB). A safe level of anticoagulation was achieved by monitoring activated clotting time (ACT) and heparin concentration ensuring adequate anticoagulation throughout the procedure. Results from ACT, heparin dose response, heparin protamine titration, and thrombelastography are given. Factor V Leiden patients can be...

  15. Preeclampsia – will Orphan Drug Status facilitate innovative biological therapies?

    OpenAIRE

    Sinuhe eHahn

    2015-01-01

    It is generally accepted that development of novel therapies to treat pregnancy-relates disorders, such as preeclampsia, is hampered to the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder, exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem cells...

  16. Preeclampsia – Will Orphan Drug Status Facilitate Innovative Biological Therapies?

    OpenAIRE

    Hahn, Sinuhe

    2015-01-01

    It is generally accepted that the development of novel therapies to treat pregnancy-related disorders, such as preeclampsia, is hampered by the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder: exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem c...

  17. A Nitric Oxide-Releasing Heparin Conjugate for Delivery of a Combined Antiplatelet/Anticoagulant Agent

    OpenAIRE

    Suchyta, Dakota J.; Handa, Hitesh; Meyerhoff, Mark E.

    2014-01-01

    Heparin is a widely used anticoagulant due to its ability to inhibit key components in the coagulation cascade such as Factor Xa and thrombin (Factor IIa). Its potential to preferentially bind to antithrombin (ATIII) results in a conformational change and activation that leads to the prevention of fibrin formation from fibrinogen and ultimately obstructs a hemostatic plug from forming. Nitric oxide (NO) exhibits potent antiplatelet activity attributed to its capacity to increase the amount of...

  18. Coagulation inhibitors in inflammation.

    Science.gov (United States)

    Esmon, C T

    2005-04-01

    Coagulation is triggered by inflammatory mediators in a number of ways. However, to prevent unwanted clot formation, several natural anticoagulant mechanisms exist, such as the antithrombin-heparin mechanism, the tissue factor pathway inhibitor mechanism and the protein C anticoagulant pathway. This review examines the ways in which these pathways are down-regulated by inflammation, thus limiting clot formation and decreasing the natural anti-inflammatory mechanisms that these pathways possess. PMID:15787615

  19. Structural Determinants of the Capacity of Heparin to Inhibit the Formation of the Human Amplification C3 Convertase

    OpenAIRE

    Kazatchkine, Michel D.; Fearon, Douglas T.; Metcalfe, Dean D.; Rosenberg, Robert D.; Austen, K. Frank

    1981-01-01

    The ability of heparin glycosaminoglycan to prevent formation of the properdin-stabilized amplification C3 convertase is independent of antithrombin binding activity and requires substitution of the amino sugar and a degree of oxygen (O)-sulfation which could be on the uronic acid or the amino sugar. Preparations of heparin glycosaminoglycan isolated by different techniques from different species (rat, human, and porcine) exhibited an equivalent capacity to inhibit generation of the amplifica...

  20. Aptamer Based Microsphere Biosensor for Thrombin Detection

    OpenAIRE

    Xudong Fan; White, Ian M.; Suter, Jonathan D.; Hongying Zhu

    2006-01-01

    We have developed an optical microsphere resonator biosensor using aptamer as receptor for the measurement of the important biomolecule thrombin. The sphere surface is modified with anti-thrombin aptamer, which has excellent binding affinity and selectivity for thrombin. Binding of the thrombin at the sphere surface is monitored by the spectral position of the microsphere's whispering gallery mode resonances. A detection limit on the order of 1 NIH Unit/mL is demonstrated. Control experiments...

  1. The Levels of Tissue Factor Pathway Inhibitor in Sepsis Patients Receiving Prophylactic Enoxaparin

    Directory of Open Access Journals (Sweden)

    Hadil A. Al Otair

    2016-05-01

    Full Text Available Objective: Sepsis syndrome is usually accompanied by activation of blood coagulation mechanisms. Earlier studies found deficiencies of the 3 main natural anticoagulants, antithrombin, protein C, and protein S. However, none of these inhibitors block tissue factor, the prime trigger of coagulation during sepsis that is controlled specifically by the tissue factor pathway inhibitor (TFPI. The aim of this study was to characterize the fluctuations in the levels of natural anticoagulants, particularly TFPI, in the course of sepsis and to find out their association with the anticoagulant action of the lowmolecular-weight heparin enoxaparin. Materials and Methods: We studied 51 consecutive patients with sepsis. Blood samples were collected from patients at baseline (0 h and at 4, 12, and 24 h after enoxaparin administration. The following assays were undertaken using commercial kits: activated partial thromboplastin time, prothrombin time, thrombin time, total and free TFPI, protein C and protein S, antithrombin, fibrinogen, and anti-factor Xa. Results: Before enoxaparin administration, there was significant prolongation of the prothrombin time and activated partial thromboplastin time, and this remained the case in the 3 subsequent samples. There was marked reduction in the levels of antithrombin, protein C, and total and free protein S to below control values throughout the study. In contrast, plasma levels of both total and free TFPI were markedly elevated and increased after enoxaparin therapy. Anti-factor Xa levels were within the therapeutic range throughout. There was no difference in TFPI levels between those patients who died and those who survived. Conclusion: Sepsis triggered marked release of TFPI from endothelial cells. This persisted and was increased further following the administration of enoxaparin. In contrast, there was marked consumption of the natural coagulation inhibitors antithrombin, protein C, and protein S. These results go

  2. In vivo antithrombotic properties of a heparin from the oocyte test cells of the sea squirt Styela plicata(Chordata-Tunicata)

    OpenAIRE

    L. Cardilo-Reis; M.C.M. Cavalcante; C.B.M. Silveira; M.S.G. Pavão

    2006-01-01

    In the ascidian Styela plicata, the oocytes are surrounded by two types of accessory cells named follicle cells and test cells. A heparin-like substance with an anticoagulant activity equivalent to 10% of mammalian heparin and about 5% as potent as the mammalian counterpart for the inhibition of thrombin by antithrombin was isolated from the oocyte test cells. In the present study, we compared the antithrombotic and hemorrhagic effects of sea squirt oocyte test cell heparin with those of porc...

  3. Selected thrombosis and atherosclerosis risk factors in children with idiopathic nephrotic syndrome

    Directory of Open Access Journals (Sweden)

    Beata Bieniaś

    2012-04-01

    Full Text Available The purpose of our study was to evaluate selected thrombosis and atherosclerosis risk factors in children with idiopathic nephrotic syndrome (INS at three  stages of the disease (I – in acute phase before steroid therapy, II – during steroid therapy after resolution of proteinuria, III – in remission after completion of steroid therapy.In all children, serum total homocysteine, lipoprotein (a, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides levels were measured at three stages of the disease. Plasma antithrombin III, fibrinogen and D-dimer levels were also determined.  At all stages of INS, the serum t-HCY levels were similar and significantly higher than in controls.  Serum lipoprotein (a level, plasma antithrombin III, fibrinogen and D-dimer levels were significantly higher at stage I than at stages II, III and controls.In conclusion, children with INS are at high risk of thrombosis and atherosclerosis. Keywords: Idiopathic nephrotic syndrome, Homocysteine, Lipoprotein (a, Antithrombin III, fibrinogen, D-dimer

  4. sEPCR Levels in Chronic Myeloproliferative Diseases and Their Association with Thromboembolic Events: A Case-Control Study

    Directory of Open Access Journals (Sweden)

    Figen Atalay

    2014-06-01

    Full Text Available OBJECTIVE: Venous, arterial, and microcirculatory events are frequently encountered in the clinical course of essential thrombocytosis and polycythemia vera. We aimed to investigate the levels of soluble endothelial protein C receptor (sEPCR in myeloproliferative diseases to see whether there was a difference between the patients with and without history of thromboembolism. METHODS: The study included patients with polycythemia vera (n=12, patients with essential thrombocytosis (n=13, and controls (n=29. In all groups, we measured proteins C and S, antithrombin and sEPCR levels, and plasma concentrations of thrombin-antithrombin complex, prothrombin fragments 1+2, and D-dimer. RESULTS: Comparing the patients with and without history of thromboembolic attack, statistically significant differences were not observed in terms of sEPCR, D-dimer, thrombin-antithrombin complex, prothrombin fragments 1+2, and hematocrit levels (p=0.318, 0.722, 0.743, 0.324, and 0.065, respectively. CONCLUSION: Significant increase in the parameters that reflect activation of coagulation, such as sEPCR, thrombinantithrombin complex, prothrombin fragments 1+2, and D-dimer, reflects the presence of a basal condition that leads to a tendency toward thrombosis development in ET and PV when compared to healthy controls.

  5. Monitoring of Serial Presurgical and Postsurgical Changes in the Serum Proteome in a Series of Patients with Calcific Aortic Stenosis

    Directory of Open Access Journals (Sweden)

    Kazumi Satoh

    2015-01-01

    Full Text Available Background. Comprehensive analysis of proteome differentially expressed in response to surgery or drug treatment is useful to understand biological responses to dispensed interventions. Here we investigated expression changes in sera of patients who suffered from calcific aortic stenosis (CAS, before and after surgery for aortic valve replacement. Materials and Methods. Sera obtained before and after surgery with depletion of highly abundant proteins were analyzed with iTRAQ labeling followed by nanoLC-MALDI-TOF/TOF-MS/MS. Results. Fifty-one proteins shared in five patients were identified with differential levels in postsurgical and presurgical sera. Finally, 16 proteins that show statistically significant levels in patients’ sera compared with those in control sera (P<0.05 were identified. Most of the identified proteins were positive acute-phase proteins. Among three proteins other than acute-phase proteins, we confirmed increased levels of antithrombin-III and zinc-α-2-glycoprotein in postsurgical sera by Western blot analysis using other CAS patients’ sera. Furthermore, antithrombin-III and zinc-α-2-glycoprotein were not found among proteins with differential levels in postsurgical and presurgical sera of patients with aortic aneurysms that we identified in a previous study. Conclusions. The results indicated that antithrombin-III and zinc-α-2-glycoprotein would become unique monitoring proteins for evaluating pathophysiological and biochemical processes occurring before and after surgery for CAS.

  6. [Hypercoagulable workup in ophthalmology. When and what].

    Science.gov (United States)

    Muñoz-Negrete, F J; Casas-Lleras, P; Pérez-López, M; Rebolleda, G

    2009-07-01

    Most ophthalmologic disorders secondary to hypercoagulabe state are due to the confluence of congenital and adquired factors. A systematic workup is mandatory. Most of congenital coagulation disorders cause venous trombosis and are inherited autosomal dominantly. In order of frequency these are factor V Leiden mutation (activated protein C resistance), G20210A mutation of the prothrombin gen and protein C, protein S, and antithrombin III deficiencies. Sickle cell anemia can determine arerial and venous thrombosis. In relation with arterial occlusion, the markers most frequently involved are homcysteine fasting levels and the markers of antiphospholipid antibody syndrome. Both of them can also determine venous thrombosis. Several acquired factors can lead to hypoercoagulable state, especially hyperhomocysteinemia, antiphospholipid antibody syndrome, hepatic disease, alcohol and tobacco intake, oral contraceptives, immobilization, surgeries and malignancies. In central venous occlusion is only necessary to rule out hyperhomocysteinemia and antiphospholipid antibody syndrome in young patients without known risk factors. In central artery occlusion, hypercoagulable workup is only recommended for patients less than 50 years-old with unknown emboli source. In this cases protein C, protein S, and antithrombin III deficiencies, homocystein, sickle cell disease and antiphospholipid antibody syndrome will ruled out. In non arteritic ischemic optic neuropathy hypercoagulable work up is not necessary. In amaurosis fugax without known emboli source, it is recommended to rule out etiologies of arterial occlusion, especially antithrombin III deficiencies, homocystein, sickle cell disease and antiphospholipid antibody syndrome. PMID:19658050

  7. Thrombophilia in complicated pregnancies

    Directory of Open Access Journals (Sweden)

    Ayşe Şahin

    2013-12-01

    Full Text Available Objective: To investigate the incidence and etiology of pregnancy complications associated with thrombophilic factors. Methods: Fifty-four patients with complicated pregnancy and 40 healthy pregnant subjects were included the study. Factor V Leiden (FVL mutation, protein S, protein C, anti-thrombin deficiency levels were investigated. Results: Of the 54 patients with complicated pregnancy, 29 had preeclampsia, 18 had intra uterine growth retardation, and 7 had intrauterine fetal loss. The most common defect was FVL mutation. FVL mutations in patient group and the control group were 27.2% and 10%, respectively, which were statistically significant. The protein S, protein C, and anti-thrombin deficiencies were found higher in the patient group compared to control (p>0.05 for each. Conclusion: FVL mutation was found higher in patient group compared to the control group, Protein C deficiency and anti-thrombin deficiency were related to preeclampsia but not other pregnancy complications. Clinicians should take into account the thrombophilia in complicated pregnancy, especially preeclampsia. J Clin Exp Invest 2013; 4 (4: 497-502

  8. A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding.

    Science.gov (United States)

    Kremers, Romy M W; Bosch, Yvonne P J; Bloemen, Saartje; de Laat, Bas; Weerwind, Patrick W; Mochtar, Bas; Maessen, Jos G; Wagenvoord, Rob J; Al Dieri, Raed; Hemker, H Coenraad

    2016-08-30

    Cardiac surgery with cardiopulmonary bypass (CPB) is associated with blood loss and post-surgery thrombotic complications. The process of thrombin generation is disturbed during surgery with CPB because of haemodilution, coagulation factor consumption and heparin administration. We aimed to investigate the changes in thrombin generation during cardiac surgery and its underlying pro- and anticoagulant processes, and to explore the clinical consequences of these changes using in silico experimentation. Plasma was obtained from 29 patients undergoing surgery with CPB before heparinisation, after heparinisation, after haemodilution, and after protamine administration. Thrombin generation was measured and prothrombin conversion and thrombin inactivation were quantified. In silico experimentation was used to investigate the reaction of patients to the administration of procoagulant factors and/or anticoagulant factors. Surgery with CPB causes significant coagulation factor consumption and a reduction of thrombin generation. The total amount of prothrombin converted and the rate of prothrombin conversion decreased during surgery. As the surgery progressed, the relative contribution of α2-macroglobulin-dependent thrombin inhibition increased, at the expense of antithrombin-dependent inhibition. In silico restoration of post-surgical prothrombin conversion to pre-surgical levels increased thrombin generation excessively, whereas co-administration of antithrombin resulted in the normalisation of post-surgical thrombin generation. Thrombin generation is reduced during surgery with cardiopulmonary bypass because of a balance shift between prothrombin conversion and thrombin inactivation. According to in silico predictions of thrombin generation, this new balance increases the risk of thrombotic complications with prothrombin complex concentrate administration, but not if antithrombin is co-administered.

  9. Cell-based laboratory evaluation of coagulation activation by antineoplastic drugs for the treatment of lymphoid tumors

    Science.gov (United States)

    Tsunaka, Misae; Arai, Reina; Ohashi, Ayaka; Koyama, Takatoshi

    2016-01-01

    Objectives: Combining vorinostat, L-asparaginase, and doxorubicin (Dox) led to improved response rates in the treatment of lymphoid tumors. However, deep-vein thrombosis has been noted as one of the most serious side effects with these drugs, and how these regimens cause deep-vein thrombosis is unclear. Methods: We investigated the procoagulant effects of vorinostat, L-asparaginase, and doxorubicin in lymphoid tumors, focusing on tissue factor, phosphatidylserine, and antithrombin. The human vascular endothelial cell line EAhy926 as well as the lymphoid neoplastic cell lines HUT78 (cutaneous T-cell lymphoma), Molt4 (acute T-lymphoblastic leukemia), and Ramos (Burkitt lymphoma) were employed to investigate these procoagulant effects. Results: Vorinostat, L-asparaginase, and doxorubicin induced exposure of phosphatidylserine and procoagulant activity on the surface of lymphoid tumor cells. Vorinostat and doxorubicin also induced phosphatidylserine exposure and increased procoagulant activity on EAhy926 cells. Expression of tissue factor antigen was induced by doxorubicin on the surface of each type of cells, whereas expression of tissue factor mRNA was unchanged. Secretion of antithrombin from HepG2 cells was reduced only by L-asparaginase. Conclusion: These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells. L-asparaginase may induce a thrombophilic state by reducing the secretion of anticoagulant proteins such as antithrombin. The laboratory methods described here could be useful to evaluate the procoagulant effects of antineoplastic drugs. PMID:27504186

  10. Thrombelastography and biomarker profiles in acute coagulopathy of trauma: a prospective study

    Directory of Open Access Journals (Sweden)

    Larsen Claus F

    2011-10-01

    Full Text Available Abstract Background Severe injury induces an acute coagulopathy associated with increased mortality. This study compared the Thrombelastography (TEG and biomarker profiles upon admission in trauma patients. Methods Prospective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry including standard coagulation tests, hematology, transfusions, Injury Severity Score (ISS and TEG were recorded. Retrospective analysis of thawed plasma/serum for biomarkers reflecting tissue injury (histone-complexed DNA fragments, sympathoadrenal activation (adrenaline, noradrenaline, coagulation activation/inhibition and fibrinolysis (sCD40L, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer, prothrombinfragment 1+2, plasmin/α2-antiplasmin complex, thrombin/antithrombin complex, tissue factor pathway inhibitor, antithrombin, von willebrand factor, factor XIII. Comparison of patients stratified according to ISS/TEG maximum clot strength. Linear regression analysis of variables associated with clot strength. Results Trauma patients had normal (86%, hypercoagulable (11% or hypocoagulable (1% TEG clot strength; one had primary hyperfibrinolysis. Hypercoagulable patients had higher age, fibrinogen and platelet count (all p 10 red blood cells the initial 24 h. Patients with normal or hypercoagulable TEG clot strength had comparable biomarker profiles, but the few patients with hypocoagulable TEG clot strength and/or hyperfibrinolysis had very different biomarker profiles. Increasing ISS was associated with higher levels of catecholamines, histone-complexed DNA fragments, sCD40L, activated protein C and D-dimer and reduced levels of non-activated protein C, antithrombin, fibrinogen and factor XIII (all p 26. In patients with ISS > 26, adrenaline and sCD40L were independently negatively associated with clot strength. Conclusions Trauma patients displayed

  11. Structure function analysis of serpin super-family: "a computational approach".

    Science.gov (United States)

    Singh, Poonam; Jairajpuri, Mohamad Aman

    2014-01-01

    Serine Protease inhibitors (serpins) are a super-family of proteins that controls the proteinases involved in the inflammation, complementation, coagulation and fibrinolytic pathways. Serpins are prone to conformational diseases due to a complex inhibition mechanism that involves large scale conformational change, and their susceptibility to undergo point mutations might lead to functional defects. Serpins are associated with diseases like emphysema/cirrhosis, angioedema, familial dementia, chronic obstructive bronchitis and thrombosis. Serpin polymerization based pathologies are fairly widespread and devising a cure has been difficult due to lack of clarity regarding its mechanism. Serpin can exist in various conformational states and has a variable cofactor binding ability. It has a large genome and proteome database which can be utilized to gain critical insight into their structure, mechanism and defects. Comprehensive computational studies on the serpin family is lacking, most of the work done till date is limited and deals mostly with few individual serpins. We have tried to analyze few aspect of this family using diverse computational biology tools and have shown the following: a) the importance of residue burial linked shift in the conformational stability as a major factor in increasing the polymer propensity in serpins. b) Amino acids involved in the polymerization are in general completely buried in the native conformation. c) An isozyme specific antithrombin study showed the structural basis of improved heparin binding to beta antithrombin as compared to alpha-antithrombin. d) A comprehensive cavity analysis showed its importance in inhibition and polymerizaiton and finally e) an interface analysis of various serpin protease complexes identified critical evolutionary conserved residues in exosite that determines its protease specificity. This work introduces the problem and emphasizes on the need for in-depth computational studies of serpin superfamily

  12. Test of hirudin activity by tracking the binding of hirudin to thrombin in the presence of BS3 cross-linking.

    Science.gov (United States)

    Liu, Yanfang; Yang, Jian; Wang, Jiangmin; Huang, Qingmei; Yang, Xiaohong; Zhang, Jianhua

    2015-10-01

    Hirudin has a great potential in inhibiting thrombin, and its antithrombin activity has direct bearing on its clinical application. Using bovine alpha-thrombin and recombinant hirudin of Poecilobdella javanica purified from Phichia pastoris as materials, this study introduced a novel method to testing antithrombin activity of hirudin visually and dynamically by tracking the binding of hirudin to thrombin. After incubating the mixture of thrombin and hirudin at 37 °C for 5 min, the binding of hirudin to thrombin was cross-linked by bis[sulfosuccinimidyl] suberate for 30 min and visualized by SDS-polyacrylamide gel electrophoresis. With the aid of image analysis on the basis of INRA-Noésis E1D analysis software, antithrombin activity of hirudin was calculated through intensity variations of protein bands of either thrombin-hirudin compound, unbound thrombin, or unbound hirudin. In this regard, activity of the given hirudin was tested to be 5625 ATU/mg based on a single reaction, and 5675.3 ATU/mg based on a series of reactions in a stepwise manner, close to the result of 6000 ATU/mg concluded by titration method. The superiorities of the method include good accuracy (the minimum testable concentration of hirudin is 1.5 μg/ml) and little sample consumption (sample consumption of hirudin is generally 1-11.5 μl using the apparatus of Mini Protean 3 Cell). Easy operation, low input, and equipment requirement also grant it as an effective way. PMID:26332983

  13. Human recombinant interleukin-1 beta- and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells

    International Nuclear Information System (INIS)

    Cytokines are known to tip the balance of the coagulant-anticoagulant molecules on the endothelial cell surface toward intravascular coagulation. Their effects on endothelial cell surface-associated heparin-like compounds have not been examined yet. Incorporation of [35S]sulfate into heparan sulfate on cultured porcine aortic endothelial cells was suppressed by human recombinant interleukin-1 beta (rIL-1 beta) or tumor necrosis factor alpha (rTNF alpha) in a dose- and time-dependent manner with little effect on cell number, protein content, and [3H]leucine incorporation of cells. Maximal inhibition was achieved by incubation of cells with 100 ng/ml of rIL-1 beta or 5 ng/ml of rTNF alpha for 12-24 hours, resulting in a reduction of the synthesis of heparan sulfate on the cell surface by approximately 50%. The dose dependency was consistent with that seen in the stimulation of endothelial cell procoagulant activity by each cytokine. The suppression of heparan sulfate synthesis was sustained for at least 48 hours after pretreatment of cells with cytokines and was unchanged after the addition of indomethacin or polymyxin B. The rate of degradation of prelabeled 35S-heparan sulfate on the cell surface was not altered by cytokine treatments. Neither the size, the net negative charge, nor the proportion of the molecule with high affinity for antithrombin III of endothelial cell heparan sulfate was changed by cytokines. Furthermore, specific binding of 125I-labeled antithrombin III to the endothelial cell surface was reduced to 40-60% of control by cytokines. In parallel with reduction in binding, antithrombin III cofactor activity was partially diminished in cytokine-treated endothelial cells. Thus, cytokine-mediated suppression of heparin-like substance on endothelial cells appears to be another cytokine-inducible endothelial effects affecting coagulation

  14. Influence of dabigatran and rivaroxaban on routine coagulation assays. A nationwide Belgian survey.

    Science.gov (United States)

    Van Blerk, Marjan; Bailleul, Els; Chatelain, Bernard; Demulder, Anne; Devreese, Katrien; Douxfils, Jonathan; Jochmans, Kristin; Mullier, François; Wijns, Walter; Soumali, Mohamed Rida; Coucke, Wim; Vernelen, Kris; Van de Walle, Philippe

    2015-01-01

    The Belgian national External Quality Assessment Scheme performed a nationwide survey using lyophilised plasma samples spiked with dabigatran or rivaroxaban to demonstrate to the Belgian clinical laboratories how these drugs affect their routine coagulation assays prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and antithrombin. Virtually all Belgian laboratories performing routine coagulation testing (189/192) participated in the survey. Both, dabigatran and rivaroxaban significantly prolonged the PT and aPTT in a concentration- and reagent-dependent manner. PT reagents were more influenced by rivaroxaban than by dabigatran and aPTT reagents more influenced by dabigatran than by rivaroxaban. Among PT reagents, Neoplastin R® was the most sensitive to rivaroxaban and Innovin® and Thromborel S® the least sensitive. Converting PT results to INR only increased the variability between reagents. Among aPTT reagents, Actin FSL® was the least sensitive to dabigatran while the other aPTT reagents showed slightly higher sensitivities. The presence of dabigatran led to falsely reduced fibrinogen concentrations when measured with a low thrombin concentration reagent. The presence of dabigatran caused an overestimation of the antithrombin level when measured with a thrombin-based activity assay and the presence of rivaroxaban an overestimation of the antithrombin level when measured with a FXa-based assay. Instrument-related differences were found for all tested parameters. In conclusion, this paper provides detailed information on the effect of dabigatran and rivaroxaban on routine coagulation assays as performed with a large number of reagent/instrument combinations. PMID:25231101

  15. The effects of acclimatization on blood clotting parameters in exertional heat stress

    Directory of Open Access Journals (Sweden)

    Vesić Zoran

    2013-01-01

    Full Text Available Background/Aim. Exertional heat stress is a common problem in military services. Considering the coagulation abnormalities are of major importance in development of severe heat stroke, we wanted to examine changes in hemostatic parameters in soldiers during exertional heat stress test as well as the effects of a 10-day passive or active acclimatization in a climatic chamber. Methods. A total of 40 male soldiers with high aerobic capacity performed exertional heat stress test (EHST either in cool [20ºC, 16ºC wet bulb globe temperature (WBGT], or hot (40ºC, 29ºC, (WBGT environment, unacclimatized (U or after 10 days of passive (P or active (A acclimatization. Physiological strain was measured by tympanic temperatures (Tty and heart rates (HR. Platelet count (PC, antithrombin III (AT, and prothrombin time (PT were assessed in blood samples collected before and immediately after the EHST. Results. EHST in hot conditions induced physiological heat stress (increase in Tty and HR, with a significant increase in prothrombin time in the groups U and A. Platelet counts were significantly higher after the EHST compared to the basic levels in all the investigated groups, regardless environmental conditions and acclimatization state. Antithrombin levels were not affected by EHST whatsoever. Conclusion. In the trained soldiers, physiological heat stress caused mild changes in some serum parameters of blood clotting such as prothrombin time, while others such as antithrombin levels were not affected. Platelet counts were increased after EHST in all groups. A 10-day passive or active acclimatization in climatic chamber showed no effect on parameters investigated.

  16. Protein C activation during the initial phase of experimental acute pancreatitis in the rabbit

    DEFF Research Database (Denmark)

    Ottesen, L H; Bladbjerg, E-M; Osman, M;

    2000-01-01

    activity), anticoagulant proteins (protein C, antithrombin) and fibrinolytic factors (tissue plasminogen activator, plasminogen activator inhibitor-1) were performed for 5 h. RESULTS: ANP was confirmed by elevated serum amylase, development of ascites, and histological changes of the pancreas. A moderate...... of the lungs or kidneys was found in 2 rabbits with ANP. CONCLUSION: An immediate activation of protein C is a specific characteristic of the haemostatic activation in ANP in rabbits. This activation has not been described previously and the possible therapeutic implications ought to be studied....

  17. Rational design of anticoagulant drugs using oligosaccharide chemistry.

    Science.gov (United States)

    El Hadri, Ahmed; Petitou, Maurice

    2011-01-01

    For a long time, heparin and low molecular weight heparins have been the drugs of choice for the management of thrombosis. Discovery of the antithrombin binding domain in heparin, a critical element in the anticoagulant activity of this polysaccharide, allowed a rational approach based on medicinal carbohydrate chemistry in the design of new anticoagulants. The fully synthetic pentasaccharide fondaparinux that selectively targets blood coagulation factor Xa was first to be developed as a drug. Fondaparinux was followed by various heparin mimicking oligosaccharides prepared with a view to replace polydisperse heparin and low molecular weight heparins by structurally-defined anticoagulants with no unwanted side-effects. PMID:21469438

  18. Synthetic oligosaccharides as heparin-mimetics displaying anticoagulant properties.

    Science.gov (United States)

    Avci, Fikri Y; Karst, Nathalie A; Linhardt, Robert J

    2003-01-01

    Heparin and low molecular weight heparins are major clinical anticoagulants and the drugs of choice for the treatment of deep venous thrombosis. The discovery of an antithrombin binding domain in heparin focused interest on understanding the mechanism of heparin's antithrombotic/ anticoagulant activity. Various heparin-mimetic oligosaccharides have been prepared in an effort to replace polydisperse heparin and low molecular weight heparins with a structurally-defined anticoagulant. The goal of attaining a heparin-mimetic with no unwanted side-effects has also provided motivation for these efforts. This article reviews structure-activity relationship (SAR) of structurally-defined heparin-mimetic oligosaccharides. PMID:14529394

  19. Fluorescent reporters of thrombin, heparin cofactor II, and heparin binding in a ternary complex

    OpenAIRE

    Verhamme, Ingrid M.

    2011-01-01

    Thrombin inactivation by heparin cofactor II (HCII) is accelerated by ternary complex formation with heparin. The novel active-site-labeled thrombins, [4′F]FPR-T and [6F]FFR-T, and the exosite I probe, Hir-(54–65)( SO3−), characterized thrombin exosite I and II interactions with HCII and heparin in the complex. HCII binding to exosite I of heparin-bound [4′F]FPR-T caused a saturable fluorescence increase, absent with antithrombin. Heparin binding to exosite II and a second weaker site caus...

  20. Acute platelet changes after large meals of saturated and unsaturated fats.

    Science.gov (United States)

    O'Brien, J R; Etherington, M D; Jamieson, S

    1976-04-24

    Large amounts of saturated fats (S.F.) or unsaturated fats (U.S.F.) were given to healthy volunteers at a single meal. The heparin thrombin clotting-time, which may measure platelet factor 4 released from platelets into the plasma, was shortened after S.F. and prolonged after U.S.F. The antithrombin clotting activity decreased after S.F. and increased after U.S.F. The platelet-count decreased and the platelet volume increased after both S.F. and U.S.F.

  1. Expression of tissue factor in canine mammary tumours and correlation with grade, stage and markers of haemostasis and inflammation

    DEFF Research Database (Denmark)

    Andreasen, Eva Bartholin; Nielsen, Ole Lerberg; Tranholm, M.;

    2016-01-01

    Tissue factor (TF) expression in human cancers has been associated with a procoagulant state and facilitation of metastasis. This study was conducted in order to evaluate if TF was expressed in canine mammary tumours. Forty epithelial mammary tumours from 28 dogs were included. TF expression...... to the cytoplasmic membrane of neoplastic luminal epithelial cells and/or diffusely in the cytoplasm. No association was found between TF expression and stage or grade of disease. A significant association between TF expression and antithrombin and plasminogen was found, and extensive TF expression was seen...

  2. A comparative study of the effect of continuous combined conjugated equine estrogen plus medroxyprogesterone acetate and tibolone on blood coagulability

    DEFF Research Database (Denmark)

    Skouby, SO; Sidelmann, JJ; Nilas, Lisbeth;

    2007-01-01

    in the tibolone group than in the CEE/MPA group. Both doses of tibolone increased APC-R significantly (P pathway inhibitor (TFPI) was lower in the CEE/MPA group than in the tibolone group (67.8 versus 79.9 ng ml(-1); P = 0.03). CEE/MPA reduced the concentration of antithrombin (P = 0.......002), protein S (P coagulability than CEE/MPA and has a potentially favourable effect on APC-R. This may translate...

  3. Range of fractionated plasma products to optimize plasma resources

    Institute of Scientific and Technical Information of China (English)

    Thierry Burnouf

    2010-01-01

    @@ HUMAN PLASMA is a source material that is crucial for the production of unique therapeutic fractionated products. Indeed, plasma contains hundreds of proteins ensuring many physiological functions. The most abun-dant proteins, albumin and immunoglobulin G (IgG) ,are present at about 35 and 10 g/L,respectively,repre-senting about 80% of all plasma proteins. However,other important therapeutic proteins include the coagu-lation factors (factor Ⅷ (F Ⅷ) ; FIX ; Von Willebrand Factor (VWF), fibrinogen) various protease inhibitors (alpha 1-antitrypsin ; antithrombin; C1-esterase) and anticoagulants (protein C) which exhibit potent physi-ological activity.

  4. METHODS OF TREATING OR PREVENTING DEMYELINATION USING THROMBIN INHIBITORS AND METHODS OF DETECTING DEMYELINATION USING NEUROFASCIN 155 | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (“NICHD”), seek CRADA partner or collaboration for development of agents to treat multiple sclerosis or other conditions associated with myelin remodeling by administering an agent that inhibits cleavage of Neurofascin 155 or Caspr1. The agent could be a thrombin inhibitor, an agent that inhibits thrombin expression, an anti-thrombin antibody that specifically inhibits thrombin mediated cleavage of Neurofascin 155, a mutated version or fragment of Neurofascin 155 or Caspr1, or antibodies to Neurofascin 155 or Caspr1.

  5. Quantitative analysis of plasma proteins in whole blood-derived fresh frozen plasma prepared with three pathogen reduction technologies.

    Science.gov (United States)

    Larrea, Luis; Ortiz-de-Salazar, María-Isabel; Martínez, Patricia; Roig, Roberto

    2015-06-01

    Several plasma pathogen reduction technologies (PRT) are currently available. We evaluated three plasma PRT processes: Cerus Amotosalen (AM), Terumo BCT riboflavin (RB) and Macopharma methylene blue (MB). RB treatment resulted in the shortest overall processing time and in the smallest volume loss (1%) and MB treatment in the largest volume loss (8%). MB treatment retained the highest concentrations of factors II, VII, X, IX, Protein C, and Antithrombin and the AM products of factor V and XI. Each PRT process evaluated offered distinct advantages such as procedural simplicity and volume retention (RB) and overall plasma protein retention (MB).

  6. Plasminogen-independent initiation of the pro-urokinase activation cascade in vivo. Activation of pro-urokinase by glandular kallikrein (mGK-6) in plasminogen-deficient mice

    DEFF Research Database (Denmark)

    List, K; Jensen, O N; Bugge, T H;

    2000-01-01

    the cascade by activating pro-uPA. The urine from Plg -/- mice contained active two-chain uPA as well as a proteinase capable of activating exogenously added pro-uPA. The active component was purified and identified by mass spectrometry-based peptide mapping as mouse glandular kallikrein mGK-6 (true tissue...... kallikrein). The pro-uPA converting activity of the mGK-6 enzyme, as well as its ability to cleave a synthetic substrate for glandular kallikrein, was inhibited by the serine proteinase inhibitor leupeptin but not by other serine proteinase inhibitors such as aprotinin, antithrombin III, or alpha(1...

  7. Hormone replacement therapy and hypercoagulability. Results from the Prospective Collaborative Danish Climacteric Study

    DEFF Research Database (Denmark)

    Sidelmann, Johannes Jakobsen; Jespersen, Jørgen; Andersen, Lars F.;

    2003-01-01

    norethindrone acetate, (E). E(2) combined with local delivery of levonorgestrel and (F). E(2)V plus medroxyprogesterone. HRT-induced changes in the concentration of inhibitors of coagulation and markers of fibrin turnover during 12 months of treatment. RESULTS: Significant decreases of antithrombin and protein......-normalised ratio were measured at baseline and after 6 and 12 months of HRT in six groups of healthy postmenopausal women: (A). no HRT (reference group), (B). continuous oestradiol valerate (E(2)V) plus cyproterone acetate, (C). cyclic E(2)V plus cyproterone acetate, (D). continuous combined oestrogen (E(2)) plus...

  8. Purpura fulminans in a patient with mixed connective tissue disease.

    LENUS (Irish Health Repository)

    Murad, Aizuri A

    2013-01-01

    A 43-year-old lady was admitted to the intensive care unit with sepsis. She had a history of mixed connective tissue disease, Raynaud\\'s syndrome and hypothyroidism. 2 days later, she developed a purpuric rash on her face and extremities with a livedoid background. Few days later, her distal fingers and toes became gangrenous which then had to be amputated. Laboratory investigations showed that she was coagulopathic and had multiple organ dysfunctions. Antiphospholipid antibodies were negative; however, protein C and antithrombin III levels were low. A skin biopsy showed fibrinoid necrosis in the vessel wall with microthrombi and red-cell extravasation. A diagnosis of purpura fulminans was made.

  9. Effects of plateletpheresis on blood coagulation parameters in healthy donors at National Blood Centre, Kuala Lumpur, Malaysia.

    Science.gov (United States)

    Siti Nadiah, A K; Nor Asiah, M; Nur Syimah, A T; Normi, M; Anza, E; Aini, A Nor; Mohd Zahari, T H; Shahnaz, M; Faraizah, A K; Faisal, M A

    2013-12-01

    Plateletpheresis is a method used to remove platelet from the body either from random volunteer donors, patient's family members or HLA matched donors. A cross sectional study was carried out on 59 plateletpheresis donors aged between 18 and 55 years at National Blood Center (NBC), Kuala Lumpur. We compared the blood parameters before and after plateletpheresis and we found that the platelet count, FVIII, fibrinogen and thrombophilia markers anti-thrombin (AT), protein C and protein S were significantly reduced (p<0.05) with prolonged PT and APTT. There were significant changes in blood coagulation parameters but it is within acceptable range.

  10. A Case Report of Arterial Thrombosis in Wegener’s Granulomatosis Presenting with Acute Lower Limb Ischemia

    Directory of Open Access Journals (Sweden)

    Z. Basiri

    2012-04-01

    Full Text Available Introduction: Wegener’s Granolomatosis (WG is a systemic, necrotizing, small-vessel vasculitis. Vascular inflammation and occlusion leading to tissue ischemia is a hallmark of WG. WG has a clinical predilection for the upper airways, lungs, and kidneys. Thromboembolic events do not usually occur and arterial thrombosis is extremely rare.Case Report: Here we reported 2 rare cases of arterial thrombosis that caused lower limb ischemia. There were not any risk factors such as deficiency of protein C, protein S or anti-thrombin 3, Factor V Leiden mutation, and anti-phospholipids syndrome. Limb perfusion returned as a result of emergency treatment and ischemia did not occur. High doses of prednisolone and endoxan were administrated for them. Conclusion: The thrombosis seemed to happen due to the inflammation process of the disease itself. Because of possible morbidity of limb gangrene we suggest special notice to limb pain, evaluation by paraclinics such as color doppler sonography or angiography to rule out or rule in thromboembolism, determining whether there are risk factors for thrombosis such as (deficiency of protein C and protein S or anti-thrombin III, Leiden 5 factor mutation and anti-phospholipid antibody syndrome, and treatment or removal of them. If no risk factor is found, high doses of immunosuppressive therapy like steroid and cytotoxic agents like Endoxan will be the choice.(Sci J Hamadan Univ Med Sci 2012;19(1:75-78

  11. Hemostatic system changes predictive value in patients with ischemic brain disorders

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    Raičević Ranko

    2002-01-01

    Full Text Available The aim of this research was to determine the importance of tracking the dynamics of changes of the hemostatic system factors (aggregation of thrombocytes, D-dimer, PAI-1, antithrombin III, protein C and protein S, factor VII and factor VIII, fibrin degradation products, euglobulin test and the activated partial thromboplastin time – aPTPV in relation to the level of the severity of ischemic brain disorders (IBD and the level of neurological and functional deficiency in the beginning of IBD manifestation from 7 to 10 days, 19 to 21 day, and after 3 to 6 months. The research results confirmed significant predictive value of changes of hemostatic system with the predomination of procoagulant factors, together with the insufficiency of fibrinolysis. Concerning the IBD severity and it's outcome, the significant predictive value was shown in the higher levels of PAI-1 and the lower level of antithrombin III, and borderline significant value was shown in the accelerated aggregation of thrombocytes and the increased concentration of D-dimer. It could be concluded that the tracking of the dynamics of changes in parameters of hemostatic system proved to be an easily accessible method with the significant predictive value regarding the development of more severe. IBD cases and the outcome of the disease itself.

  12. Coagulation inhibitors and activated protein C resistance in recurrent pregnancy losses in Indian women

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    P Lalita Jyotsna

    2011-01-01

    Full Text Available Background: Thrombophilias, both acquired and inherited, have been investigated in the etiopathogenesis of unexplained recurrent pregnancy loss. Aim: To study coagulation inhibitors and activated protein C resistance (APCR in recurrent pregnancy losses (RPL occurring in second and third trimesters. Materials and Methods: A total of 30 pregnant women (group A with two or more recurrent unexplained fetal loses were evaluated for APCR, protein C deficiency, protein S deficiency, antithrombin deficiency, and antiphospholipid antibodies (APLA. Thirty age-matched controls were taken (group B comprising of pregnant women with at least one live issue. Statistical Analysis: Comparisons between two group frequencies and group means were made using Chi square test and Student′s t test, respectively. Results: Protein C and protein S levels were reduced in group A compared with group B and the difference was statistically significant (P=0.005 and P=0.032, respectively. The mean value of antithrombin was slightly reduced in group A compared with group B. APCR was observed in 16.6% cases and 3.3% controls. However, the difference was not statistically significant. APLA was observed in 20% cases and none of the controls. Of these, lupus anticoagulant was positive in 16.6% cases and anticardiolipin antibodies in 10% cases. Combined defects were seen in seven patients. Conclusion: There is a significant risk of RPL in pregnant women with thrombophilias. Therefore, screening for thrombophilias may be justified in pregnant women with unexplained recurrent fetal wastage, especially in second and third trimester.

  13. Effect of Age on the Hemostatic Function in Patients with Degenerative Diseases of the Large Joints

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    Igor L. Shlykov, PhD¹, ScD¹

    2013-06-01

    Full Text Available Background: Aging is associated with an increased hypercoagulable state. Degenerative diseases of the large joints are also accompanied by increased coagulation activity. We investigated the effect of age on the hemostatic function in patients with osteoarthritis. Material and Methods: The study included 192 patients with osteoarthritis admitted to the clinic for primary hip or knee arthroplasty. The patients were categorized into 5 age groups: the age group under 40 years, the 41–to-50 -year age group, the 51–to-60-year age group, the 61-to-70- year age group, and the age group over 70 years. The general blood clotting tests, platelet number, fibrinogen, antithrombin, protein C, TAT, D-dimer, vonWillebrand factor (vWF, PAI-1, ß-thromboglobulin were determined. Results: Among patients with osteoarthritis, the antithrombin III level significantly decreased by the age of 50; however, above the age of 60 there was a distinct decrease in platelet count, and over the age of 70 the activity of the extrinsic coagulation pathway and the plasminogen level dropped significantly. TAT and D-dimer levels were elevated in most of the patients. Conclusion: The decrease in platelet count coupled with the activity of the extrinsic coagulation pathway in elderly osteoarthritic patients may increase blood loss during total arthroplasty; also, the drop in the anticoagulant and fibrinolytic potential may play a negative role in strengthening the prothrombotic state during the postoperative period.

  14. Cerebral Vein Thrombosis:Screening of Acquired and Hereditary Thrombophilic Risk Factors

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    Sarraf Payam

    2009-10-01

    Full Text Available Cerebral vein thrombosis (CVT is an infrequent condition with a large variety of causes that can lead to serious disabilities. However, in 20% to 35% of cases, no cause is found. In this study we evaluated the hereditary (P & C Proteins, antithrombin, mutation of prothrombin G20210A and factor V Leiden, other risk factors (hyperhomocycteinemia, factor VIII, ACL-ab, APL-ab, and OCP and clinical manifestations among a population of Iranian patients with CVT. 18 women and 10 men aged 16 to 50 years with CVT were screened for inherited and acquired coagulation risk factors. No one had an abnormal ACL-ab, APL-ab or antithrombin III deficiency. One had prothrombin G20210A mutation (heterozygot (3.6%. Hyperhomocycteinemia was observed in 5 patients (17.9%. APC-R was decreased in 3 (10.7%. 2 had positive factor V Leiden mutation (heterozygot (7.1%. 17 had an increased of factor VIII (60.7. PS and PC deficiencies were each detected in two cases (7.1%. Conclusion: Our study suggests that screening for inherited thrombophilia may be an integral part in the diagnostic workup and duration of treatment in patients with CVT.

  15. Bivalirudin in combination with heparin to control mesenchymal cell procoagulant activity.

    Directory of Open Access Journals (Sweden)

    Xavier Stephenne

    Full Text Available Islet and hepatocyte transplantation are associated with tissue factor-dependent activation of coagulation which elicits instant blood mediated inflammatory reaction, thereby contributing to a low rate of engraftment. The aim of this study was i to evaluate the procoagulant activity of human adult liver-derived mesenchymal progenitor cells (hALPCs, ii to compare it to other mesenchymal cells of extra-hepatic (bone marrow mesenchymal stem cells and skin fibroblasts or liver origin (liver myofibroblasts, and iii to determine the ways this activity could be modulated. Using a whole blood coagulation test (thromboelastometry, we demonstrated that all analyzed cell types exhibit procoagulant activity. The hALPCs pronounced procoagulant activity was associated with an increased tissue factor and a decreased tissue factor pathway inhibitor expression as compared with hepatocytes. At therapeutic doses, the procoagulant effect of hALPCs was inhibited by neither antithrombin activators nor direct factor Xa inhibitor or direct thrombin inhibitors individually. However, concomitant administration of an antithrombin activator or direct factor Xa inhibitor and direct thrombin inhibitor proved to be a particularly effective combination for controlling the procoagulant effects of hALPCs both in vitro and in vivo. The results suggest that this dual antithrombotic therapy should also improve the efficacy of cell transplantation in humans.

  16. Effects of fused hirudin on activity of thrombin and function of platelets

    Institute of Scientific and Technical Information of China (English)

    SHEN Li; CHEN Shao-ping; CAI Zai-long; YANG Sheng-sheng; QIN Yong-wen

    2005-01-01

    Objective: To investigate whether fused hirudin peptide has both antithrombin and antiplatelet functions. Methods: The core region of fused hirudin was the C-terminal tail of hirudin(hirudin53-64),which could bind to the anion binding exosite (ABE) of thrombin.Arg-Pro-Pro-Gly-Phe(RPPGF) amino acid sequence,a metabolite of bradykinin,was added to the N-terminus of hirudin53-64.It bound to the active site of thrombin.Additionally,Arg-Gly-Asp(RGD)amino acid sequence,an inibitor of glycoprotein Ⅱb/Ⅲa( GP Ⅱb/Ⅲa) receptor,was linked to C-terminus of hirudin53-64.This 26-animo acid-fused hirudin peptide was artificially synthesized,purified and analysed. Results: Fused hirudin peptide significantly lengthened the activated partial thromboplastin time(APTT),thrombin time(TT)and prothrombin time(PT) and inhibited the amidolytic activity of thrombin.The ADP-induced platelet aggregation was markedly inhibited by fused hirudin peptide. Conclusion: Fused hirudin peptide has activity of antithrombin as well as antiplatelet.Therefore bifunctional anticoagulation peptide has capacity to target various components of haemostatic process and may become more powerful antithrombosis agent.

  17. New anticoagulants for the prevention of venous thromboembolism

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    Cecilia Becattini

    2010-04-01

    Full Text Available Cecilia Becattini, Alessandra Lignani, Giancarlo AgnelliInternal and Cardiovascular Medicine and Stroke Unit, University of Perugia, ItalyAbstract: Anticoagulant drugs have an essential role in the prevention and treatment of thromboembolic diseases. Currently available anticoagulants substantially reduce the incidence of thromboembolic events in a number of clinical conditions. However, these agents have limitations that strengthen the case for the development of new anticoagulants. An ideal anticoagulant should be at least as effective as those currently in use, as well as safe, simple to use, and widely applicable. The majority of new anticoagulants currently under investigation are small molecules with a selective and direct anti-Xa or antithrombin action, allowing oral administration in fixed doses. These new agents are in different phases of clinical development. The anti-Xa agent rivaroxaban and the antithrombin agent dabigatran are already available for the prophylaxis of venous thromboembolism in some countries. Apixaban is in an advanced phase of clinical development and several anti-Xa agents are currently approaching phase III clinical trials. Promising results in terms of efficacy and safety profiles have been obtained with these agents in different clinical conditions. Differences in pharmacokinetics and pharmacodynamics could offer the potential for individualized anticoagulant therapies in the near future.Keywords: anticoagulant therapy, antithrombotic therapy, anticoagulants, direct thrombin inhibitors, factor Xa inhibitors

  18. New anticoagulants for the prevention of venous thromboembolism

    Science.gov (United States)

    Becattini, Cecilia; Lignani, Alessandra; Agnelli, Giancarlo

    2010-01-01

    Anticoagulant drugs have an essential role in the prevention and treatment of thromboembolic diseases. Currently available anticoagulants substantially reduce the incidence of thromboembolic events in a number of clinical conditions. However, these agents have limitations that strengthen the case for the development of new anticoagulants. An ideal anticoagulant should be at least as effective as those currently in use, as well as safe, simple to use, and widely applicable. The majority of new anticoagulants currently under investigation are small molecules with a selective and direct anti-Xa or antithrombin action, allowing oral administration in fixed doses. These new agents are in different phases of clinical development. The anti-Xa agent rivaroxaban and the antithrombin agent dabigatran are already available for the prophylaxis of venous thromboembolism in some countries. Apixaban is in an advanced phase of clinical development and several anti-Xa agents are currently approaching phase III clinical trials. Promising results in terms of efficacy and safety profiles have been obtained with these agents in different clinical conditions. Differences in pharmacokinetics and pharmacodynamics could offer the potential for individualized anticoagulant therapies in the near future. PMID:20531960

  19. Clinical evaluation of the centrifugal pump in open heart surgery: a comparative study of different pumps.

    Science.gov (United States)

    Takarabe, K; Yoshikai, M; Murayama, J; Hamada, M; Ito, T

    1997-07-01

    The centrifugal pump is now widely used in open heart surgery for its clinical benefits related to the blood elements and the coagulation system. The purpose of this study was to compare the clinical performances of and the outcomes offered by 4 types of centrifugal pumps. For each pump, we investigated the effects on the blood elements, coagulation system, complements, and immunoglobulins during open heart surgery. Four types of centrifugal pumps were used: the HPM-15 (Nikkiso Co.), the Capiox (Terumo Co.), the Lifestream (St. Jude Medical Co.), and the BP-80 (Medtronic, BioMedicus Co.). The platelet count, lactate dehydrogenase (LDH), antithrombin III (AT III), thrombin-antithrombin complex (TAT), complements (C3, C4, and CH50), and immunoglobulins (IgG, IgA, and IgM) were measured before and after cardiopulmonary bypass (CPB). The platelet count was decreased more significantly by the HPM-15 than by any of the other pumps. The other parameters showed no difference among the 4 pumps. In clinical use, each of the 4 types of centrifugal pumps was safe.

  20. Clinical use of centrifugal pumps and the roller pump in open heart surgery: a comparative evaluation.

    Science.gov (United States)

    Yoshikai, M; Hamada, M; Takarabe, K; Okazaki, Y; Ito, T

    1996-06-01

    Centrifugal pumps have been used widely as the main pump in open heart surgery to reduce damage to blood elements and to reduce the activation of the coagulation system. The purpose of this study was the evaluation and comparison of the effects of two types of centrifugal pumps and of one type of roller pump on blood elements, the coagulation system, complements, and immunoglobulins. Two types of centrifugal pumps (Lifestream; St. Jude Medical, Chelmsford, Massachusetts; and BP-80: Medtronic, BioMedicus, Inc., Eden Prairie, Minnesota, U.S.A.) and one roller pump (Mera Co.) were used separately as the main pump for cardiopulmonary bypass (CPB) in 29 patients. Platelet counts, lactate dehydrogenase, antithrombin III, thrombin-antithrombin complex (TAT), complements (C3, C4, and CH50) and immunoglobulins G, A, and M values were measured before and after CPB and compared. Values, except those for TAT, showed no significant difference among the three groups. The TAT values increased less in each of the centrifugal pump groups than in the roller pump group. This finding suggests that thrombin synthesis might be suppressed by the use of a centrifugal pump.

  1. Arteriovenous thrombosis in chronic renal failure patients receving renal replacement therapy

    International Nuclear Information System (INIS)

    To determine the frequency of thrombotic complications and to identify factors associated with arteriovenous thrombosis in patients of chronic renal failure receiving renal replacement therapy. Of the 3000 patients evaluated, 61 End Stage Renal Disease (ESRD) patients on regular dialysis, having recent renal transplant, were selected for the study after informed consent. These patients had arteriovenous thrombosis with temporary central lines thrombosis and vascular access problems. Cases of congenital or acquired thrombotic disorders, e.g. with malignancy, DIC, liver disease, systemic lupus erythematosus or other immunologic diseases, pregnancy or women using oral contraceptives, were excluded. Similarly, patients taking any type of anticoagulant therapy during the preceding one week were not included in the study. Findings were recorded in a structured questionnaire. Laboratory analysis was done after clinical and radiological evaluation. Thrombophilia screening included antithrombin, protein C, protein S deficiencies and lupus anticoagulant. Forty-seven out of 61 patients selected were positive for thrombophilia screening with protein C deficiency in 26.2%, protein S deficiency in 16.3%, antithrombin in 5%, lupus anticoagulant in 13.1% and combined deficiency was observed in 16.3%. Of the 3000 patients, 61 with frequency of 2% were found to be deficient in one or had combined deficiency of these. Thus, the study of ESRD patients presenting with arteriovenous thromboembolism emphasizes the need to reconsider the perception that this clinical entity is rare and requires further studies. (author)

  2. Hyperprolactinemia during antipsychotics treatment increases the level of coagulation markers

    Directory of Open Access Journals (Sweden)

    Ishioka M

    2015-02-01

    Full Text Available Masamichi Ishioka, Norio Yasui-Furukori, Norio Sugawara, Hanako Furukori, Shuhei Kudo, Kazuhiko Nakamura Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan Objective: The strong association between psychiatric patients who receive antipsychotics and the incidence of venous thromboembolism (VTE is known. Although previous reports suggest that hyperprolactinemia often increases markers of activated coagulation, few studies have examined the direct relationship between the prolactin level elevated by antipsychotics and activated markers of activated coagulation.Method: The participants included 182 patients with schizophrenia (male =89, female =93 who received antipsychotic treatments for at least 3 months. Markers of VTE (D-dimer, fibrin/fibrinogen degradation products, and thrombin–antithrombin complex and serum prolactin concentrations were measured.Results: Prolactin levels were significantly correlated with the logarithmic transformation of the D-dimer (r=0.320, P=0.002 and fibrin/fibrinogen degradation product levels (r=0.236, P=0.026 but not of the thrombin–antithrombin complex level (r=0.117, ns among men. However, no correlations were found between the VTE markers and prolactin levels among women. These results were confirmed using multiple regression analyses that included demographic factors and antipsychotic dosages. Conclusion: The current study indicates that hyperprolactinemia is associated with an increase in markers of activated coagulation among men receiving antipsychotics. This finding clinically implies that monitoring and modulating prolactin levels among men are important to decrease the risk of VTE. Keywords: prolactin, antipsychotics, venous thromboembolism

  3. Heparin based polyurethanes: A state-of-the-art review.

    Science.gov (United States)

    Zia, Fatima; Zia, Khalid Mahmood; Zuber, Mohammad; Tabasum, Shazia; Rehman, Saima

    2016-03-01

    Polyurethanes (PUs) are considered currently as one of the established bio compatible and blood compatible biomaterials offering tremendous structure-property relationship. But few limitations such as low resistance to micro-emboli and thrombi are still associated with these biomaterials that restricted their applications and hence need to be modified. Heparin, a highly sulfonated and negatively charged member of glycosaminoglycan family is well established for their anti-thrombin, anticoagulant and many biological activities that make it a highly attractive candidate capable of modifying or tailoring polymer properties. Incorporation of heparin for the improvement of biocompatibility of PUs is an interesting approach and enabling emerging technology. This review focuses on the methods used for modification of PUs via heparin with their pros and cons. The major PU-heparin systems with the recent developments and their possible biomedical applications are discussed.

  4. [The correction of functional disorders of the hemostatic system and of the rheological properties of the blood in dogs in the late period of hemorrhagic shock by the intravenous transfusion of lactoprotein].

    Science.gov (United States)

    Oborin, A N; Uspenskiĭ, B A; Kondratskiĭ, B A; Mindiuk, M V

    1992-01-01

    In 9 dogs with severe hemorrhagic shock, the effect of hemocorrector "Lactoprotein" on the indices of coagulative hemostasis and rheologic blood properties was studied. It was established that in intravenous transfusion of lactoprotein at a dose of 10 ml/kg permitting to lead the animals out from the state of shock, the syndromes of disseminated intravascular coagulation and high viscosity of the blood were cupped off. However, by the end of 48 hours of observation, fibrinogen level in the blood of the animals increased sharply, while antithrombin-III concentration and hematocrit decreased. Together with recommendation to use lactoprotein in the complex of shock therapy at all the stages of medical evacuation, the conclusion about necessity to perform at the early postshock period the differential component hemo- and anticoagulative therapy has been made. PMID:1291772

  5. 一例接受阿那曲唑和预防性那屈肝素治疗的乳腺癌妇女发生肺动脉栓塞%Pulmonary thromboembolism in a breast cancer woman receiving anastrozole and prophylactic nadroparin

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Hormonal treatment is widely accepted for the adjuvant treatment of breast carcinoma, in order to get a reduction in the synthesis of estrogen or to block estrogen receptors in tumors that are hormone dependent. There are multiple risk factors that contribute to hypercoagulability in cancer patients. Hormonal therapy and chemotherapy are the main one. Type and stage of malignancy are other risk factors; so age, immobility and surgery are. The main antineoplastic therapy with definitive hypercoagulable effect is tamoxifen, because it can cause reduction in the concentrations of antithrombin Ⅲ and protein C. Here, we explain the case of a 75-year-old postmenopausal woman presenting with breast carcinoma who suffered from pulmonary thromboembolism during the treatment with anastrozole although she was taking nadroparin.

  6. Advances in farm animal transgenesis.

    Science.gov (United States)

    Kues, Wilfried A; Niemann, Heiner

    2011-11-01

    The first transgenic livestock were produced in 1985 by microinjection of foreign DNA into zygotic pronuclei. This was the method of choice for more than 20 years, but more efficient protocols are now available, including somatic cell nuclear transfer and lentiviral transgenesis. Typical applications include carcass composition, lactational performance and wool production, as well as enhanced disease resistance and reduced environmental impact. Transgenic farm animal production for biomedical applications has found broad acceptance. In 2006 the European Medicines Agency (EMA) approved commercialization of the first recombinant pharmaceutical protein, antithrombin, produced in the mammary gland of transgenic goats. As the genome sequencing projects for various farm animal species are completed, it has become feasible to perform precise genetic modifications employing the emerging tools of lentiviral vectors, small interfering ribonucleic acids, meganucleases, zinc finger nucleases and transposons. We anticipate that genetic modification of farm animals will be instrumental in meeting global challenges in agricultural production and will open new horizons in biomedicine.

  7. Coagulation and fibrinolysis during lung surgery:an experimental study

    DEFF Research Database (Denmark)

    Trabjerg, Theis B; Sander, Klaus D; Nybo, Mads;

    2014-01-01

    OBJECTIVES: Postoperative thromboembolism is a serious complication, but the incidence following surgery for lung cancer appears to be much lower compared with other surgical specialties. The reason is unknown and one may speculate that the lungs are reservoirs of anticoagulants or fibrinolytic...... substances, which are released by manipulation of the lung parenchyma during surgery. METHODS: Standardized lung manipulation, single-lung ventilation and pneumonectomy were performed in 10 anaesthetized pigs. Baseline and serial postmanipulation intravenous and intra-arterial blood samples were analysed...... but significant decrease in antithrombin and a significant increase in aPTT. All other measured substances were virtually constant. CONCLUSIONS: A wide range of fibrinolytic and anticoagulant substances remained unchanged during experimental lung manipulation. Minor changes were transient and not considered...

  8. Effect of laser infrared therapy on several rheological indices of blood and on the homeostasis of patients with post-infarction cardiosclerosis

    Science.gov (United States)

    Volov, N. A.; Kudinova, M. A.; Fedulaeva, A. I.; Fedulaev, Yu. N.; Gordeev, I. G.

    2001-04-01

    An investigation was made on 38 patients affected by exertion angina pectoris of the I-III functional classes. The patients survived a Q-associated myocardial infarction not earlier than 1 year ago. The patients were treated according to a 10-session course of laser infrared therapy. The dynamics of several hemorheological indices (such as blood viscosity, the hematocrit of venous blood, fibrinogen, fibronectine, thrombocyte aggregation, antithrombin III, and the activated partial thrombplastin time) was estimated prior to the treatment, 5 - 7 days after the beginning of laser therapy, and 30 days after the beginning of laser therapy treatment. It was found that laser therapy was capable of producing a significant decrease in the blood viscosity, fibrinogen level, and in the aggregation of thrombocytes. Moreover, laser infrared therapy carried out on patients affected by post-infarction cardiosclerosis and by stable exertion stenocardia of the I-III functional classes produced a reliable normalization of hemorheological indices of the blood.

  9. Heparin kinetics

    International Nuclear Information System (INIS)

    The author has studied the kinetics of heparin and heparin fractions after intravenous administration in humans and in this thesis the results of this study are reported. Basic knowledge about the physico-chemical properties of heparin and its interactions with proteins resulting in anticoagulant and lipolytic effects are discussed in a review (chapter II), which also comprises some clinical aspects of heparin therapy. In chapter III the kinetics of the anticoagulant effect are described after intravenous administration of five commercial heparin preparations. A mathematical model is presented that fits best to these kinetics. The kinetics of the anticoagulant and lipolytic effects after intravenous injection of various 35S-radiolabelled heparin fractions and their relationship with the disappearance of the radiolabel are described in chapter IV. Chapter V gives a description of the kinetics of two radiolabels after injection of in vitro formed complexes consisting of purified, 125I-radiolabelled antithrombin III and various 35S-radiolabelled heparin fractions. (Auth.)

  10. Chorioamnionitis caused by Serratia marcescens in a non-immunocompromised host.

    Science.gov (United States)

    Shimizu, S; Kojima, H; Yoshida, C; Suzukawa, K; Mukai, H Y; Hasegawa, Y; Hitomi, S; Nagasawa, T

    2003-11-01

    A 26 year old pregnant woman with antithrombin III deficiency developed recurrent septicaemia with Serratia marcescens. In spite of the administration of antibiotics, high grade fever persisted. She subsequently manifested lower abdominal pain, and spontaneous abortion occurred. After the abortion, she became completely afebrile. The amnion was turbid, and microscopic examination of the placenta showed haemorrhage and massive infiltration of neutrophils, suggestive of infectious chorioamnionitis. Pulsed field gel electrophoresis showed that isolates from the blood, urine, and vaginal discharge were genetically identical. Intravenous pyelography revealed that she had a bilateral completed double ureter. It was thought that a urinary tract anomaly caused infection with S marcescens, and the pathogen spread to the chorioamnion via the bloodstream. This is the first report of chorioamnionitis caused by S marcescens in a non-immunocompromised host. In addition, these findings indicate that the chorioamnion can serve as a site for persistent infection in normal pregnancies. PMID:14600137

  11. A STUDY ON EARLY ONSET CORONARY ARTERY DISEASE IN RELATION TO HYPER HOMOCYSTEINEMIA IN PATIENTS YOUNGER THAN 40 YEARS OF AGE

    Directory of Open Access Journals (Sweden)

    Sugunakar

    2013-12-01

    Full Text Available ABSTRACT: There has been a rising incidence of myocardial infarction as a whole in recent times much because of changing pattern of life style , urbanization , changing food habits , and increase in cigarette smoking , psycho social stress and increase in the incidence of diabete s mellitus. Adding to this there is drastic increase in the incidence of MI in young people much to the influence of novel risk factors which are of current debate especially homocysteine , lipoprotein little (a , fibrinogen , anticardiolipin antibody , prote in C , protein S and antithrombin deficiency. The first ever positive prospective study on plasma homocystein and CAD was reported in 1992 by Selhubetal who showed an association of plasma homocysteine with extracranial carotid stenosis in the elderly. We r eport our study to analyze the special risk factors of MI in patients younger than 40years of age in special reference to serum homocysteine levels.

  12. Cerebral venous sinus thrombosis as presenting feature of ulcerative colitis.

    Science.gov (United States)

    Ennaifer, R; Moussa, A; Mouelhi, L; Salem, M; Bouzaidi, S; Debbeche, R; Trabelsi, S; Najjar, T

    2009-01-01

    Thrombosis is a well recognized complication of inflammatory bowel disease that occurs in 1.3 to 6.4% of patients, however, cerebral vascular involvement is unusual. We present the case of a 16-year-old female in whom cerebral venous thrombosis was the presenting symptom of an active ulcerative pancolitis. Thrombophilia screen (plasma levels of proteins C and S, antithrombin, antibeta2-glycoprotein, lupus anticoagulant and anticardiolipin antibodies, activated protein C resistance, homocystein level antinuclear antibodies) was negative. The patient was successfully treated with anticoagulant therapy, phenobarbital and sulfasalazine. Cerebral venous thrombosis is an exceptional presenting feature of ulcerative colitis. Disease activity may play a major role in the occurrence of thrombosis. PMID:19902870

  13. Etiological analysis of presumed perinatal stroke.

    Science.gov (United States)

    Kocaman, Canan; Yilmaz, Yuksel

    2012-02-01

    This study aimed to investigate the maternal, pre- and perinatal, and prothrombotic factors with congenital hemiparesis due to presumed perinatal stroke (PPS). Prothrombotic risk factors including protein C and S, antithrombin III, lipoprotein (a), homocystein, factor VIII levels; anticardiolipin antibodies and lupus anticoagulant; methylenetetrahydrofolate reductase mutations, factor V Leiden, prothrombin G20210A mutations were investigated. Arterial ischemic stroke was detected in 60% and periventricular venous infarction in 40%. At least one prothrombotic risk factor was present in 69%, two in 17%, and three or more in 8.5% of cases. The most common combination was methylenetetrahydrofolate reductase C677T and factor V Leiden heterozygosity. The etiology and pathogenesis of PPS is still unclear. According to this study, most of the patients with PPS might have one or more prothrombotic risk factors and certain prenatal risk factors including intrauterine growth retardation, twin gestation and preeclampsia might be related to PPS. PMID:21561729

  14. Agents for the treatment of heparin-induced thrombocytopenia.

    Science.gov (United States)

    Warkentin, Theodore E

    2010-08-01

    Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect characterized by platelet activation, hypercoagulability, and increased risk of thrombosis, both venous and arterial. A diagnosis of HIT usually signifies that heparin products, including unfractionated and low-molecular-weight heparin, are contraindicated. Although it is uncertain whether heparin continuation really worsens clinical outcomes, it is clear that vitamin K antagonists such as warfarin do worsen outcomes, as they promote microvascular thrombosis, with the potential for limb amputation (venous limb gangrene). Thus, alternative nonheparin anticoagulants are at the forefront of HIT therapy. This review proposes that alternative anticoagulants (danaparoid, fondaparinux) that share certain properties of heparin-namely its irreversible antithrombin-mediated inhibition of factor Xa-and that have relatively long half-lives, have several advantages in the therapy for HIT over short-acting agents that inhibit thrombin directly (recombinant hirudin, argatroban, and bivalirudin). PMID:20659659

  15. Paralytic Ileus due to Superior Mesenteric Venous Thrombosis after Transarterial Injection for Hepatocellular Carcinoma.

    Science.gov (United States)

    Nakajima, Yuki; Takahashi, Atsushi; Kanno, Yukiko; Gunji, Naohiko; Imaizumi, Hiromichi; Hayashi, Manabu; Okai, Ken; Abe, Kazumichi; Watanabe, Hiroshi; Ohira, Hiromasa

    2016-01-01

    A 69-year-old man was admitted to hospital with abdominal pain. In the four years prior to his presentation, he had undergone repeated transarterial chemoembolizations and injections for hepatocellular carcinoma. He underwent his 8th transcatheter arterial therapy one month prior to admission. Abdominal X-rays and contrast-enhanced computed tomography showed large amounts of small intestinal gas and venous thrombosis from the portal vein to the superior mesenteric vein, respectively. The thrombosis was reduced after anticoagulation therapy (heparin, antithrombin III, danaparoid sodium and warfarin). This is the first case report of paralytic ileus due to superior mesenteric venous thrombosis after transcatheter arterial therapy for hepatocellular carcinoma with an arterioportal shunt. PMID:26726083

  16. Bugs as drugs, part two: worms, leeches, scorpions, snails, ticks, centipedes, and spiders.

    Science.gov (United States)

    Cherniack, E Paul

    2011-03-01

    In this second of a two-part series analyzing the evidence for the use of organisms as medicine, the use of a number of different "bugs" (worms, leeches, snails, ticks, centipedes, and spiders) is detailed. Several live organisms are used as treatments: leeches for plastic surgery and osteoarthritis and the helminths Trichuris suis and Necator americanus for inflammatory bowel disease. Leech saliva is the source of a number of anticoagulants, including the antithrombin agent hirudin and its synthetic analogues, which have been approved for human use. Predatory arthropods, such as certain species of snails, spiders, scorpions, centipedes, and ticks provide a trove of potential analgesic peptides in their venom. A synthetic analogue of a snail venom peptide, ziconotide, has been approved for human use and is used as an alternative to opioids in severe pain cases. Arthropods, such as ticks, have venom that contains anticoagulants and centipede venom has a protein that corrects abnormalities in lipid metabolism. PMID:21438646

  17. [Basic values of blood coagulation parameters in pigs (Sus scrofa domesticus)].

    Science.gov (United States)

    Hahn, N; Popov-Cenic, S; Dorer, A

    1996-01-01

    On 23 clinical healthy pigs (2-4 months of age, body weight 13-42 kg) under ketamin-pentobarbital anaesthesia blood plasma coagulation parameters have been investigated. To obtain basic values 26 parameters were measured: number of thrombocytes, parameters of thrombelastogram and resonance-thrombogram, prothrombin time, activated partial thromboplastin time, thrombin time, reptilase time, factors I, II, V, VII, VIII, X, antithrombin III, plasminogen, alpha 1-antitrypsin, alpha 2-antiplasmin, alpha 2-macroglobulin, fibrin degradation products D and E and euglobulin lysis-time. Parameters calculated in percent should be measured against a pig plasma pool. Measurement against a human plasma pool are hardly valid in values higher than 100%. In comparison to man the results indicate modifications of fibrinogenesis and fibrinolysis in pigs.

  18. The coagulopathy in sepsis: significance and implications for treatment

    Directory of Open Access Journals (Sweden)

    Berardino Pollio

    2011-09-01

    Full Text Available Sepsis related coagulopathy ranges from mild laboratory alterations up to severe disseminated intravascular coagulation (DIC. There is evidence that DIC is involved in the pathogenesis of microvascular dysfunction contributing to organ failure. Additionally, the systemic activation of coagulation, by consuming platelets and coagulation factors, may cause bleeding. Thrombin generation via the tissue factor/factor VIIa route, contemporary depression of antithrombin and protein C anticoagulant system, as well as impaired fibrin degradation, due to high circulating levels of PAI-1, contribute to enhanced intravascular fibrin deposition. This deranged coagulopathy is an independent predictor of clinical outcome in patients with severe sepsis. Innovative supportive strategies aiming at the inhibition of coagulation activation comprise inhibition of tissue factor-mediated activation or restoration of physiological anticoagulant pathways, as the administration of recombinant human activated protein C or concentrate. In spite of some promising initial studies, additional trials are needed to define their clinical effectiveness in adults and children with severe sepsis.

  19. Three Novel Rhusouyangins A~C from the Roots of Rhus semialata

    Institute of Scientific and Technical Information of China (English)

    OUYANG,Ming-An; SU,Ren-Kuan; WEIN,Yung-Shung; KUO,Yueh-Hsiung

    2004-01-01

    @@ The root of Rhus semialata (Anacardiaceae) was a folk herb for treating diarrhea, spermatorrhea and malaria.[1,2]Recently, it was found to have other activity of inhibitors of Iκ Bα kinase.[3] inhibited human cell proliferation activated by IL-1β and IL-6, antifungal activity and antithrombin activity. The roots of it, collected from the island of Taiwan, was extracted with MeOH. The n-BuOH-soluble materials of the extract were subjected to Sephadex LH-20 (H2O/MeOH)column chromatography and then separated by RP-18 and Silica gel to yield rhusouyangins A (1), B (2), and C (3) as colorless amorphous solids, together with 2,3-cis-3,4-trans-4',7-dihydroxyflavan-3,4-diol, 2,3-trans-3,4-cis-4',7-dihydroxyflavan-3,4-diol, 3',5,5',7-tetrahydroxyflavanone.

  20. Factor V Leiden and Cardiopulmonary Bypass

    Science.gov (United States)

    Uppal, Victor; Rosin, Mark; Marcoux, Jo-Anne; Olson, Marnie; Bezaire, Jennifer; Dalshaug, Gregory

    2015-01-01

    Abstract: We present a case of a patient with factor V Leiden with an antithrombin III activity of 67% who received a successful aortic valve replacement supported by cardiopulmonary bypass (CPB). A safe level of anticoagulation was achieved by monitoring activated clotting time (ACT) and heparin concentration ensuring adequate anticoagulation throughout the procedure. Results from ACT, heparin dose response, heparin protamine titration, and thrombelastography are given. Factor V Leiden patients can be safely anti-coagulated using heparin for CPB procedures when monitored with ACT, heparin protamine titration, and thrombelastography. Postoperative chest tube losses were 360 mL, less than half our institutional average. Anticoagulation for the pre-and post-operative phase is also discussed. PMID:26834284

  1. Bleeding risk stratification in an era of aggressive management of acute coronary syndromes

    Institute of Scientific and Technical Information of China (English)

    Emad; Abu-Assi; Sergio; Raposeiras-Roubín; José; María; García-Acu?a; José; Ramón; González-Juanatey

    2014-01-01

    Major bleeding is currently one of the most common non-cardiac complications observed in the treatment of patients with acute coronary syndrome(ACS). Hemorrhagic complications occur with a frequency of 1% to 10% during treatment for ACS. In fact, bleeding events are the most common extrinsic complication associated with ACS therapy. The identification of clinical characteristics and particularities of the antithrombin therapy associated with an increased risk of hemorrhagic complications would make it possible to adopt prevention strategies, especially among those exposed to greater risk. The international societies of cardiology renewed emphasis on bleeding risk stratification in order to decide strategy and therapy for patients with ACS. With this review, we performed an update about the ACS bleeding risk scores most frequently used in daily clinical practice.

  2. [Variations in hemostasis and fibrinolysis during the treatment of acute myocardial infarct (AMI) with tissue-type plasminogen activator (TTPA). A study of 17 cases].

    Science.gov (United States)

    Izaguirre Avila, R; Ruiz de Chávez Cervantes, A; Villavicencio, R; Gómez Trigos, A; Mar Chavira, R; Spíndola, M del C; Casanova, J M

    1993-01-01

    The aim of this trial was to estimate changes in the coagulation and fibrinolysis systems during the thrombolytic treatment with recombinant human tissue-type plasminogen activator (rt-PA) in patients with acute myocardial infarction and correlate with hemorrhagic complications. We studied 17 patients with a 3 hours-continuous systemic infusion of 100 mg of rt-PA. Prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen splits products, plasminogen, alfa-2-antiplasmin (a-2AP) and antithrombin III (AT-III) were performed before, during and after infusion. Most patients showed lengthening coagulation times. Fibrinogen and plasminogen were decreased and PDF was increased. No variations in alpha-2AP or AT-III were observed. The recuperation of fibrinogen levels occurred in 3 hours and there was hyperfibrinogenemia after day 3. No hemorrhagic complication was observed in patients with abnormalities in these coagulation or fibrinolytic tests. PMID:8347053

  3. Molecular evolution of serpins: homologous structure of the human α1-antichymotrypsin and α1-antitrypsin genes

    International Nuclear Information System (INIS)

    α1-Antichymotrypsin belongs to a supergene family that includes α1-antitrypsin, antithrombin III, ovalbumin, and angiotensinogen. The human chromosomal α1-antichymotrypsin gene has been cloned and its molecular structure established. The gene is approximately 12 kb in length and contains five exons and four introns. The locations of the introns within the α1-antichymotrypsin gene are identical with those of the human α1-antitrypsin and angiotensinogen genes. Other members of this supergene family contain introns located at nonhomologous positions of the genes. The homologous organization of the α1-antichymotrypsin and α1-antitrypsin genes corresponds with the high degree of homology between their protein sequences and suggest that these loci arose by recent gene duplication. A model is presented for the evolution of both the genomic structure and the protein sequences of the serine protease inhibitor superfamily

  4. [The pathogenesis of subclinical laminitis in dairy cattle: studies of the hoof status, rumen status and blood coagulation factors].

    Science.gov (United States)

    Brandejsky, F; Stanek, C; Schuh, M

    1994-02-01

    In 50 dairy cows of the breed "Braunvieh" (36 heifers, 14 cows) of one herd the claw score was recorded over a period of 2 months before parturition until 6 months after parturition. The claw scores were correlated with the clinical findings, the ruminal function and the blood coagulation factors calcium-thromboplastin (TPZ), partial thromboplastin time (PTT), thrombin time (TZ) and antithrombin III (AT III) evaluated one day and one week after calving. The claw score increased from the first to the second examination, remaining on the same level in the postpartal period. No correlation between the claw scores and the ruminal function was evident. In comparison with a control group, TPZ and PTT were found higher one day and one week after parturition in the experimental group. Blood coagulation factors and claw scores were found uncorrelated.

  5. Integrated laboratory coagulation tests in hypercoagulation diagnosis and thrombosis risk assessment. Part I. The pathophysiology of thrombosis and hypercoagulation

    Directory of Open Access Journals (Sweden)

    E. N. Lipets

    2015-01-01

    Full Text Available Thrombosis is a fatal hemostatic disorders occurring in various conditions ranging from pregnancy and surgery to cancer, sepsis and heart attack. Despite the availability of different anticoagulants and accumulated clinical experience, proving their effectiveness, thrombosis remains a major cause of morbidity and mortality. This is largely due to the fact that conventional laboratory coagulation tests are not sufficiently sensitive to the hypercoagulable state, and they are difficult to use for assessing the risk of thrombosis. Specific molecular markers (D-dimers, fibrinopeptide, thrombin-antithrombin complex are more effective, but also have a large number of disadvantages. A possible solution is the use of integrated test, which simulate in vitro the majority of the physiological coagulation processes. In the first part of this paper the biochemical processes that cause the risk of thrombosis were discussed.

  6. Structural characterization of pharmaceutical heparins prepared from different animal tissues.

    Science.gov (United States)

    Fu, Li; Li, Guoyun; Yang, Bo; Onishi, Akihiro; Li, Lingyun; Sun, Peilong; Zhang, Fuming; Linhardt, Robert J

    2013-05-01

    Although most pharmaceutical heparin used today is obtained from porcine intestine, heparin has historically been prepared from bovine lung and ovine intestine. There is some regulatory concern about establishing the species origin of heparin. This concern began with the outbreak of mad cow disease in the 1990s and was exacerbated during the heparin shortage in the 2000s and the heparin contamination crisis of 2007-2008. Three heparins from porcine, ovine, and bovine were characterized through state-of-the-art carbohydrate analysis methods with a view profiling their physicochemical properties. Differences in molecular weight, monosaccharide and disaccharide composition, oligosaccharide sequence, and antithrombin III-binding affinity were observed. These data provide some insight into the variability of heparins obtained from these three species and suggest some analytical approaches that may be useful in confirming the species origin of a heparin active pharmaceutical ingredient. PMID:23526651

  7. Production of recombinant proteins in milk of transgenic and non-transgenic goats

    Directory of Open Access Journals (Sweden)

    Raylene Ramos Moura

    2011-10-01

    Full Text Available Among all the transgenic mammalians produced so far, goats have represented an excellent model of transgenesis when considering the factors such as the market demand for protein, volume of milk produced per lactation and reproductive rate. Various recombinant proteins have been obtained from the transgenic and non-transgenic goats, and among these, human antithrombin, produced by the transgenic goats, was the first recombinant protein of animal origin to be released as a drug for the clinical use in humans. This review reports the aspects inherent to the production of recombinant proteins in the goats, from the production of the animal bioreactors up to the expression of these proteins in their milk.

  8. 双作用靶点水蛭素Ⅲ突变体库(R33G34D35X36-rHV3)的构建及最适突变体筛选%Construction of R33G34D35X36-rHV3 Mutant Library and Screening for Optimal Dual-Site Targeting Hirudin Ⅲ

    Institute of Scientific and Technical Information of China (English)

    许静; 王航; 谭树华

    2011-01-01

    构建水蛭素Ⅲ(HVⅢ)突变体库R33G34D35X36-rHVⅢ,从中筛选出具有与重组水蛭素Ⅲ(rHV3)抗凝血酶活性比活力相当,同时又具有很强的抗ADP诱导的血小板聚集抑制率的双作用靶点水蛭素Ⅲ突变体.通过基因定点突变技术构建水蛭素Ⅲ突变库R33G34D355X36-rHVⅢ,表达纯化后通过凝血酶滴定方法测定其抗凝血酶比活性,同时测定其抗ADP诱导的血小板聚集比活性.结果显示所有突变体的抗凝血酶比活性未发生变化,但各突变体抗ADP诱导的血小板聚集的比活性各异,当第36位为Met和Ser时所表现的抗ADP诱导的血小板聚集的比活性最强.由此可知水蛭素Ⅲ(HVⅢ)突变体库R33G34D355X36-rHVⅢ中第36位氨基酸种类对其抗凝血酶活性影响不大,但对其抗ADP诱导的血小板聚集的比活性影响较大,当该位点为Met和Ser时突变体具有很好的抗凝血酶和抗ADP诱导的血小板聚集的双重药理活性.%To construct recombinant hirudin II (Rhv III ) mutant library R33 G34 D35 X36 - Rhv M and to screen out the mutant which was well-matched in the anti-thrombin specific activity against recombinant hirudin HI (Rhv3), and also had bifunctional target with a strong activity of ADP induced platelet aggregation inhibition. Site-directed mutagenesis was used to build up hirudin III mutant library R33G34D35X36 - Rhv III. After expression and purification, the anti-thrombin specific activity was determined by titration of thrombin and the anti-platelet aggregation induced by ADP inhibition was also measured. The results showed that there was no difference in the anti-thrombin specific activity between all mutants, but there was difference in the ADP-induced platelet aggregation inhibition activity, which was the strongest when the site 36 was Met or Ser. These results indicated that the site 36 amino acid has little effect on the anti-thrombin specific activity in the recombinant hirudin III (Rhv III) mutant R33G34D

  9. Sulfated levan from Halomonas smyrnensis as a bioactive, heparin-mimetic glycan for cardiac tissue engineering applications.

    Science.gov (United States)

    Erginer, Merve; Akcay, Ayca; Coskunkan, Binnaz; Morova, Tunc; Rende, Deniz; Bucak, Seyda; Baysal, Nihat; Ozisik, Rahmi; Eroglu, Mehmet S; Agirbasli, Mehmet; Toksoy Oner, Ebru

    2016-09-20

    Chemical derivatives of levan from Halomonas smyrnensis AAD6(T) with low, medium and high levels of sulfation were synthesized and characterized by FTIR and 2D-NMR. Sulfated levan samples were found to exhibit anticoagulation activity via the intrinsic pathway like heparin in a dose-dependent manner. Exceptionally high heparin equivalent activity of levan sulfate was shown to proceed via thrombin inhibition where decreased Factor Xa activity with increasing concentration was observed in antithrombin tests and above a certain concentration, levan sulfate showed a better inhibitor activity than heparin. In vitro experimental results were then verified in silico by docking studies using equilibrium structures obtained by molecular dynamic simulations and results suggested a sulfation dependent binding mechanism. With its high biocompatibility and heparin mimetic activity, levan sulfate can be considered as a suitable functional biomaterial to design biologically active, functionalized, thin films and engineered smart scaffolds for cardiac tissue engineering applications. PMID:27261753

  10. Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome.

    Science.gov (United States)

    Glas, G J; Van Der Sluijs, K F; Schultz, M J; Hofstra, J-J H; Van Der Poll, T; Levi, M

    2013-01-01

    Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho-alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator-induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ARDS and pneumonia. PMID:23114008

  11. COAGULATION ACTIVITY IN LIVER DISEASE

    Directory of Open Access Journals (Sweden)

    Dr. Sheikh Sajjadieh Mohammad Reza

    2009-07-01

    Full Text Available Patients with advanced hepatic failure may present with the entire spectrum of coagulation factor deficiencies. This study was designed to determine laboratory abnormalities in coagulation in chronic liver disease and the association of these abnormalities with the extent of chronic hepatitis and cirrhosis. Coagulation markers were assayed in 60 participants: 20 patients with chronic hepatitis, 20 patients with cirrhosis, and 20 healthy individuals (control. Plasma levels of anti-thrombin III were determined by a chromogenic substrate method, and plasma concentrations of fibrinogen were analyzed by the Rutberg method. Commercially available assays were used for laboratory coagulation tests. The levels of coagualation activity markers in patients with chronic liver disease were significantly different in comparison to those in healthy participants. These results indicate the utility of measuring markers for coagulation activity in determining which cirrhosis patients are more susceptible to disseminated intravascular coagulation.

  12. Disturbance of hepatic and intestinal microcirculation in experimental liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Sasa-Marcel Maksan; Eduard Ryschich; Zilfi (U)lger; Martha Maria Gebhard; Jan Schmidt

    2005-01-01

    AIM: To analyze hepatic, mesenteric and mucosal microcirculation and leukocyte-endothelium interaction (LEI) in a rat model with liver cirrhosis.METHODS: Hepatic cirrhosis was induced in Wistar rats by gavage with carbon tetrachloride, and intravital videomicroscopy was performed in liver, mesentery and small intestine mucosa. Special emphasis is given on microcirculatory and morphometric changes during cirrhotic portal hypertension.RESULTS: LEI was influenced significantly in the cirrhotic liver but not in the gut. Blood flow measurement showed significant differences among liver, main mesenteric vessels and the mucosa. The results of our study indicate that liver cirrhosis leads to alterations in hepatic and mesenteric blood flow but not in mucosal blood flow.CONCLUSION: The enhanced inflammatory response in hepatic microvessels may be caused by a decrease of antithrombin Ⅲ levels and could be responsible for disturbances of organ pathology.

  13. Livedoid vasculopathy: A review of pathogenesis and principles of management.

    Science.gov (United States)

    Vasudevan, Biju; Neema, Shekhar; Verma, Rajesh

    2016-01-01

    Livedoid vasculopathy is a rare cutaneous disease manifesting as recurrent ulcers on the lower extremities. The ulceration results in atrophic, porcelain white scars termed as atrophie blanche. The pathogenesis is yet to be understood with the main mechanism being hypercoagulability and inflammation playing a secondary role. The important procoagulant factors include protein C and S deficiency, factor V Leiden mutation, antithrombin III deficiency, prothrombin gene mutation and hyperhomocysteinemia. Histopathology of livedoid vasculopathy is characterized by intraluminal thrombosis, proliferation of the endothelium and segmental hyalinization of dermal vessels. The treatment is multipronged with anti-thrombotic measures such as anti-platelet drugs, systemic anticoagulants and fibrinolytic therapy taking precedence over anti-inflammatory agents. Colchicine, hydroxychloroquine, vasodilators, intravenous immunoglobulin, folic acid, immunosuppressive therapy and supportive measures are also of some benefit. A multidisciplinary approach would go a long way in the management of these patients resulting in relief from pain and physical as well as psychological scarring.

  14. [Thrombosis and disorders of hemostasis in nephrotic syndrome].

    Science.gov (United States)

    Kanfer, A

    1992-01-01

    Thromboses and disorders of hemostasis in nephrotic syndrome. Thromboembolic complications are common in nephrotic syndrome (NS). This article reviews the factors of thrombogenesis in NS, including: 1) a hypercoagulable state with platelet hyperaggregability, hyperfibrinogenemia and elevated factor VIII, decrease in plasma levels of coagulation inhibitors antithrombin III and free protein S, reduced fibrinolytic activity; 2) excessive intravascular thrombin formation marked by increased plasma levels of fibrinopeptide A. The intensity of hemostasis disorders coincides with that of NS. Most disorders are related to hypoalbuminemia and proteinuria. In agreement with experimental data, the role of intraglomerular activation of coagulation during active phases of glomerulopathies has to be considered. This could explain the predominance of renal vein thrombosis in several glomerulopathies with NS. Several coagulation disorders in SN have implications for therapy.

  15. The Anticoagulation Effects of Glycosaminoglycan from Mactra veneriformis

    Directory of Open Access Journals (Sweden)

    Yue Wang

    2015-07-01

    Full Text Available In this study, the anticoagulation effect of glycosaminoglycan from Mactra veneriformis was studied. The results showed that glycosaminoglycan mainly exerted anticoagulation via antithrombin III. Glycosaminoglycan could passivate the function of heparin cofactor II inhibiting thrombin activity. Glycosaminoglycan significantly reduced the activities of coagulation factor II, V, VII, X, VIII, IX, XI, XII as well as fibrinogen content in the plasma (p<0.05, p<0.01. Besides, glycosaminoglycan could extend blood recalcification time in rats by shielding Ca2+ in plasma and significantly reduced Ca2+ concentration in rats and mice serum (p<0.05, p<0.01. Glycosaminoglycan reduced the Ca2+ concentration in serum in a more intensive way than that of heparin sodium (p<0.05, p<0.01.

  16. Predictors of fatal outcomes resulting from acute Escherichia coli mastitis in dairy cows.

    Science.gov (United States)

    Hagiwara, Seiichi; Mori, Kouichiro; Nagahata, Hajime

    2016-06-01

    To evaluate the prognostic criteria for identifying cows at an increased risk of a fatal outcome from acute Escherichia coli mastitis, the potential cut-off values for five diagnostic parameters associated with a high mortality were determined by receiver operator characteristic curve analysis. These criteria were hematocrit value >32%, blood non-esterified fatty acid concentration >0.4 mEq/l, antithrombin activity <120%, platelet count <15 × 10(4)/ml and presence of dysstasia. Exceeding the cut-off values for at least three parameters on day 2 after onset predicted fatality (predictive value 87.5). When these prognostic criteria were applied to 34 clinical cases, cows that met three criteria were seven times more likely to die than cows that met fewer than three criteria. PMID:26875836

  17. Modeling the microscopic electrical properties of thrombin binding aptamer (TBA) for label-free biosensors

    CERN Document Server

    Alfinito, Eleonora; Cataldo, Rosella; De Nunzio, Giorgio; Giotta, Livia; Guascito, Maria Rachele

    2016-01-01

    Aptamers are chemically produced oligonucleotides, able to bind a variety of targets such as drugs, proteins and pathogens with high sensitivity and selectivity. Therefore, aptamers are largely employed for producing label-free biosensors, with significant applications in diagnostics and drug delivery. In particular, the anti-thrombin aptamers are biomolecules of high interest for clinical use, because of their ability to recognize and bind the thrombin enzyme. Among them, the DNA 15-mer thrombin-binding aptamer (TBA), has been widely explored concerning both its structure, which was resolved with different techniques, and its function, especially about the possibility of using it as the active part of biosensors. This paper proposes a microscopic model of the electrical properties of TBA and the aptamer-thrombin complex, combining information from both structure and function. The novelty consists in describing both the aptamer alone and the complex as an impedance network, thus going deeper inside the issues...

  18. Acquired and Heritable Thrombophilia in Indian Patients With Pediatric Deep Venous Thrombosis (DVT).

    Science.gov (United States)

    Pai, Navin; Ghosh, Kanjaksha; Shetty, Shrimati

    2014-09-01

    Deep venous thrombosis (DVT) in children is more often associated with underlying pathological conditions than with hereditary thrombophilia. The present study is a retrospective analysis of thrombophilia in 285 pediatric patients with venous thrombosis at different sites. Four common thrombophilia markers, that is protein C, protein S, antithrombin III, and factor V Leiden (FVL) mutation, were analyzed. Thrombosis in hepatic and portal veins was more common in pediatric patients (73%) when compared to other sites (27%). Overall, hereditary thrombophilia accounted for 15.5% of the patients with venous thrombosis. The FVL mutation, which was the major causative factor in Budd-Chiari syndrome and portal vein thrombosis cases in the adult group, was not a major contributing factor in pediatric group, that is, 1.8% of the patients. In conclusion, the risk factors for venous thrombosis vary in different age groups.

  19. Non-essential genes in the vaccinia virus HindIII K fragment: a gene related to serine protease inhibitors and a gene related to the 37K vaccinia virus major envelope antigen.

    Science.gov (United States)

    Boursnell, M E; Foulds, I J; Campbell, J I; Binns, M M

    1988-12-01

    The complete nucleotide sequence of a cloned copy of the HindIII K fragment of the WR strain of vaccinia virus has been determined. Eight open reading frames (ORFs) have been identified, on the basis of size and codon usage. The predicted amino acid sequences of the putative genes have been compared to the Protein Identification Resource and to published vaccinia virus sequences. One gene, predicted to encode a 42.2K protein, is highly related to the family of serine protease inhibitors. It shows approximately 25% identity to human antithrombin III and 19% identity to the cowpox virus 38K protein gene which is also related to serine protease inhibitors. The product of another gene shows a similar high level of identity to the 37K vaccinia virus major envelope antigen. The existence of viable deletion mutants and recombinants containing foreign DNA inserted into both these genes indicates that they are non-essential.

  20. [The feasibility of Erwinia asparaginase for pediatric patients who developed an allergic reaction to E.coli asparaginase during treatment of acute lymphoblastic leukemia].

    Science.gov (United States)

    Takahashi, Hiroyoshi; Koh, Katsuyoshi; Kato, Motohiro; Isobe, Kiyotaka; Yasui, Naoko; Mori, Makiko; Akiyama, Kosuke; Kikuchi, Akira; Hanada, Ryoji

    2013-04-01

    Asparaginase (ASNase) is one of the most important key drugs in the treatment of acute lymphoblastic leukemia (ALL). However, clinical hypersensitivity reactions often occur and lead to the discontinuation of ASNase treatment. Here, we report a retrospective study of 68 Erwinia ASNase (Erw-ASNase) administrations in 11 patients with childhood ALL who developed allergic reactions to E.coli-ASNase in our hospital between 2006 and 2012. The median age of the patients was 6 (range, 0 to 14). Erw-ASNase purchased overseas by the patients' guardians had already been administered when we obtained informed consent from the guardians. In all patients, fibrinogen and/or anti-thrombin III levels were decreased, but thrombosis did not develop. There was only one mild adverse event (grade 2 urticaria) in one patient, in whom Erw-ASNase could be continued after increasing the doses of premedication with antihistamine and prednisolone. Erw-ASNase could be safely administered to all patients.

  1. Anti-thrombotic effects of selective estrogen receptor modulator tamoxifen.

    Science.gov (United States)

    Nayak, Manasa K; Singh, Sunil K; Roy, Arnab; Prakash, Vivek; Kumar, Anand; Dash, Debabrata

    2011-10-01

    Tamoxifen is a known anti-cancer drug and established estrogen receptor modulator. Few clinical studies have earlier implicated the drug in thrombotic complications attributable to lower anti-thrombin and protein S levels in plasma. However, action of tamoxifen on platelet signalling machinery has not been elucidated in detail. In the present report we show that tamoxifen is endowed with significant inhibitory property against human platelet aggregation. From a series of in vivo and in vitro studies tamoxifen was found to inhibit almost all platelet functions, prolong tail bleeding time in mouse and profoundly prevent thrombus formation at injured arterial wall in mice, as well as on collagen matrix perfused with platelet-rich plasma under arterial shear against the vehicle dimethylsulfoxide (DMSO). These findings strongly suggest that tamoxifen significantly downregulates platelet responses and holds potential as a promising anti-platelet/anti-thrombotic agent.

  2. Hemostatic response to surgical neutering via ovariectomy and ovariohysterectomy in dogs

    DEFF Research Database (Denmark)

    Moldal, Elena R.; Kristensen, Annemarie Thuri; Peeters, Marijke E.;

    2012-01-01

    Objective-To investigate the hemostatic response to surgery and compare the response for ovariohysterectomy with that for ovariectomy and to evaluate the usefulness of thromboelastography on plasma samples. Animals-42 female dogs. Procedures-Dogs were assigned to undergo ovariohysterectomy or...... antigen, fibrinogen, antithrombin, and protein C; activity of factor VIII; activated partial thromboplastin time; prothrombin time; and thrombin time. The fibrinolytic response was assessed via concentrations of D-dimer, plasminogen, and α-2-antiplasmin (plasmin inhibitor). Results-Substantial hemostatic...... prothrombin and thrombin times. The dogs also typically had activation of the fibrinolytic system, as evidenced by increased postoperative concentrations of D-dimer, plasminogen, and plasmin inhibitor. Differences between the 2 groups could not be detected for any variables. Conclusions and Clinical Relevance...

  3. Changes in blood levels of proteinase inhibitors, pregnancy zone protein, steroid carriers and complement factors induced by oral contraceptives

    DEFF Research Database (Denmark)

    Nielsen, C H; Poulsen, H K; Teisner, B;

    1993-01-01

    levels of antithrombin III (AT III), alpha 2-macroglobulin (alpha 2M) alpha 1-antitrypsin (alpha 1at), complement factors (factor B, C3, C4), pregnancy zone protein (PZP), corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) and albumin were measured before treatment and during...... the first and third treatment cycles. AT III levels decreased and alpha 1at levels increased in all three groups during treatment. alpha 2M increased during cycle 3 in the Trinordiol and Gynatrol groups. CBG, PZP and SHBG levels increased in all 3 groups, the CBG and PZP increase being higher...... in the Marvelon group than in the Gynatrol group. Increases in SHBG levels were found in the order Marvelon > Trinordiol > Gynatrol. Plasma levels of complement factors B, C3 and C4 remained unchanged. It is concluded that the increase in alpha 1at partly compensates for the fall in AT III, that the rise in PZP...

  4. 肿瘤性DIC实验室指标诊断阳性率分析%Analysis of Laboratory Index Positive Diagnostic Rate of Malignancy Tumor with Disseminated Intravascular Coagulation

    Institute of Scientific and Technical Information of China (English)

    尹茜

    2015-01-01

    目的探讨恶性肿瘤合并弥散性血管内凝血(Dis eminated Intravascular Coagulation,DIC)时,实验室检测指标DIC三项咱D-二聚体(D-dimer,DD)、纤维蛋白原降解产物(Fibrinogen Degradation Product,FDP)、抗凝血酶原II(AntithrombinII,ATII)暂和凝血常规咱凝血酶原时间(Prothrombin Time,PT)、活化部分凝血酶原时间(Activated Partial Prothrombin Time,APTT)、纤维蛋白原(Fibrinogen,FIB)检测阳性率的情况,并比较各组之间的有效性。方法回顾性分析78例恶性肿瘤患者的临床及实验室资料。结果 DD是恶性肿瘤合并DIC时诊断阳性率最高的指标。结论在肿瘤合并DIC时,DD的诊断价值最有意义。%Objective To explore malignancy tumor with disseminated intravascular coagulation,which laboratory index of D-dimer、fibrinogen degradation product、AntithrombinI I、prothrombin time、activated partial prothrombin time、fibrinogen are the positive indicator.Methods Clinical and laboratory data for 78 cases of DIC with malignancy tumor were retrospectively analysed.Result:D-dimer is the most ef ective indicator of DIC with malignancy tumor.Results The diagnosis index of:DD is the highest positive rate of malignant tumor complicated with DIC. Conclusion In the tumor with DIC, the diagnostic value of DD was the most significant.

  5. Circulating Thrombotic Risk Factors in Young Patients with Coronary Artery Disease Who Are on Statins and Anti-platelet Drugs.

    Science.gov (United States)

    George, Reema; Sivadasanpillai, Harikrishnan; Jayakumari, Narayani; Bhatt, Anugya; Thulaseedharan, Jissa V; Tharakan, Jaganmohan A

    2016-07-01

    Thrombotic risk factors may contribute to premature coronary artery disease (CAD), in addition to the conventional risk factors. There is paucity of data on studies evaluating the role of thrombotic factors in premature CAD in Indian patients. Thus a case-control study was performed to evaluate the role of thrombotic and atherogenic factors in young patients with angiographically proven CAD who are on treatment with statins and anti-platelet drugs. 152 patients (≤55 years) with angiographically proven CAD and 102 asymptomatic controls were recruited. Clinical and biochemical data were obtained in both groups. Blood levels of thrombotic factors-fibrinogen, antithrombin-III, tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von-Willebrand factor (v-WF), lipoprotein(a) [Lp(a)] and homocysteine were analyzed. Patients had high levels of conventional CAD risk factors (diabetes mellitus, smoking, hypertension, dyslipidemia and positive family history) compared to controls. Logistic regression analysis revealed that low antithrombin-III (odds ratio/OR 11.2; 95 % confidence interval/CI 2.29-54.01), high fibrinogen (OR 6.04; 95 % CI 1.09-33.21) and high Lp(a) (OR 4.54; 95 % CI 0.92-22.56), as important, independent risk factors in patients. PAI-1(OR 0.15; 95 % CI 0.03-0.69) levels were significantly lower in patients. But other thrombotic risk factors studied (t-PA, v-WF and homocysteine) were comparable among patients and controls. The treatment using statins and anti-platelet drugs might be contributing to the control of some of the thrombotic risk factors. The strategies aiming at lowering the levels of thrombotic risk factors along with conventional risk factors may be useful in primary and secondary prevention of CAD. PMID:27382201

  6. Deciphering the main venom components of the ectoparasitic ant-like bethylid wasp, Scleroderma guani.

    Science.gov (United States)

    Zhu, Jia-Ying

    2016-04-01

    Similar to venom found in most venomous animals, parasitoid venoms contain a complex cocktail of proteins with potential agrichemical and pharmaceutical use. Even though parasitoids are one of the largest group of venomous animals, little is known about their venom composition. Recent few studies revealed high variated venom composition existing not only in different species but also between closely related strains, impling that increasing information on the venom proteins from more greater diversity of species of different taxa is key to comprehensively uncover the complete picture of parasitoid venom. Here, we explored the major protein components of the venom of ectoparasitic ant-like bethylid wasp, Scleroderma guani by an integrative transcriptomic-proteomic approach. Illumina deep sequencing of venom apparatus cDNA produced 49,873 transcripts. By mapping the peptide spectral data derived from venom reservoir against these transcripts, mass spectrometry analysis revealed ten main venom proteins, including serine proteinase, metalloprotease, dipeptidyl peptidase IV, esterase, antithrombin-III, acid phosphatase, neural/ectodermal development factor IMP-L2 like protein, venom allergen 3, and unknown protein. Interestingly, one serine proteinase was firstly identified with rarely high molecular weight about 200 kDa in parasitoid venom. The occurrence of abundant acid phosphatase, antithrombin-III and venom allergen 3 demonstrated that S. guani venom composition is similar to that of social wasp venoms. All identified venom genes showed abundantly biased expression in venom apparatus, indicating their virulent functions involved in parasitization. This study shed light on the more better understanding of parasitoid venom evolution across species and will facilitate the further elucidation of function and toxicity of these venom proteins. PMID:26853496

  7. Evaluation of selected thrombotic factors among pregnant women with preeclampsia and normal pregnant women

    Science.gov (United States)

    Saghafi, Nafiseh; Mohammadzadeh Vatanchi, Atieh; Tara, Fatemeh; Pourali, Leila; Dadgar, Salmeh

    2014-01-01

    Background: Preeclampsia is one of the common complications during pregnancy with considerable maternal and fetal mortality and morbidity. Hypercoagulability due to thrombophilic factors is discussed as the etiology involved in this disease. Objective: The aim of this study was to evaluate selected thrombotic factors among pregnant women with preeclampsia and normal pregnant women. Materials and Methods: This case-control study was performed on 200 pregnant women at third trimester of pregnancy between 2012 and 2013. 100 pregnant women admitted to Qaem and Imam Reza hospitals of Mashhad, due to preeclampsia, were selected as case group and 100 pregnant women without preeclampsia referred to OB/GYN clinic of these hospitals as control group. Blood samples were taken from two groups for evaluation of the coagulation factors including factor V Leiden, protein C, protein S, antithrombin III, anti-cardiolipin antibodies, and lupus anticoagulant antibodies. Results: Two groups were not significantly different in terms of maternal age and parity (p>0.05). Levels of factor V Leiden, protein C, protein S, antithrombin III, anti-cardiolipin antibodies and lupus anticoagulant antibodies were compared between two groups. The number of patients with abnormal factor V Leiden and protein C was significantly higher in case group than in the control group (p<0.01 respectively), but other factors were not significant different between two groups. Thrombophilia disorders were significantly more in case group compared to control (p<0.001). Conclusion: The risk of thrombophilia disorders is higher in preeclamptic patients than normal pregnant women. PMID:25709635

  8. Systemic coagulation parameters in mice after treatment with vascular targeting agents

    Directory of Open Access Journals (Sweden)

    Gottstein Claudia

    2005-12-01

    Full Text Available Abstract Background Vascular targeting of malignant tumors has become a clinically validated new treatment approach with clear patient benefit. However clinical studies have also revealed that some types of vascular targeting agents (VTAs are prone to coagulation system side effects. It is therefore essential to predetermine coagulation parameters in preclinical studies. As of to date, this has rarely been done, predominantly due to technical issues. The goal of this study was to establish and apply a standardized process, whereby systemic coagulation activation can be routinely measured in mice. Results We have evaluated a number of sampling techniques and coagulation tests regarding their suitability for this purpose. We were able to adapt two assays measuring soluble fibrin, a marker for a prethrombotic status. Thus, soluble fibrin could be measured for the first time in mice. All assays were validated in a positive control model for systemic coagulation activation, i.e. lipopolysaccharide-induced endotoxemia. Based on our results, we selected a panel of coagulation tests, which are both feasable and informative for preclinical testing of VTAs: soluble fibrin, thrombin-antithrombin complexes, free antithrombin III, white blood cell counts and platelet counts. The effect of tumor transplants on coagulation parameters was evaluated using this panel. We then applied this set of assays in treatment studies with a VTA developed in our laboratory to investigate a potential systemic coagulation activation. Conclusion We have established a standardized panel of assays that can be used to test murine blood samples for coagulation activation in preclinical studies. All tests are feasible to perform in any research laboratory without specialized equipment. In addition, this is the first report to measure soluble fibrin, an early marker of systemic coagulation activation, in mice. The panel was applied on tumor bearing mice and mice treated with a VTA

  9. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels.

    Science.gov (United States)

    Uitte de Willige, Shirley; de Visser, Marieke C H; Houwing-Duistermaat, Jeanine J; Rosendaal, Frits R; Vos, Hans L; Bertina, Rogier M

    2005-12-15

    We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen gamma' (gammaA/gamma' plus gamma'/gamma') levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen gamma' levels and reduced ratios of fibrinogen gamma' to total fibrinogen. Multivariate analysis showed that reduced fibrinogen gamma' levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen gamma' to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5). We propose that FGG-H2 influences thrombosis risk through htSNP 10034C/T [rs2066865] by strengthening the consensus of a CstF site and thus favoring the formation of gammaA chain above that of gamma' chain. Fibrinogen gamma' contains a unique high-affinity, nonsubstrate binding site for thrombin, which seems critical for the expression of the antithrombin activity that develops during fibrin formation (antithrombin 1).

  10. Enhanced P-selectin expression on platelet-a marker of platelet activation, in young patients with angiographically proven coronary artery disease.

    Science.gov (United States)

    George, Reema; Bhatt, Anugya; Narayani, Jayakumari; Thulaseedharan, Jissa Vinoda; Sivadasanpillai, Harikrishnan; Tharakan, Jaganmohan A

    2016-08-01

    P-selectin (CD62p) exposure is an established marker for platelet activation. P-selectin exposure can trigger variety of thrombotic and inflammatory reactions. In patients with coronary artery disease (CAD), platelets are activated, and hence, there is increased P-selectin exposure. The role of P-selectin exposure in patients on treatment with statins and anti-platelets is conflicting. A case-control study was performed to determine P-selectin exposure in consecutively recruited 142 patients (age ≤ 55 years) with angiographically proven CAD on treatment and 92 asymptomatic controls. P-selectin exposure was determined by flow cytometry. Data on conventional risk factors were obtained along with estimation of levels of thrombotic [fibrinogen, lipoprotein (a), tissue plasminogen activator, plasminogen activator inhibitor-1, homocysteine and von Willebrand factor] and anti-thrombotic factors (antithrombin III). The P-selectin exposure was compared among patient groups who had different modes of presentation of CAD and categories of CAD disease severity. The patients were followed up for a period of 26 months. The results indicate that P-selectin exposure was significantly elevated in patients (mean ± SD 9.24 ± 11.81) compared to controls (mean ± SD 1.48 ± 2.85) with p P-selectin exposure showed significant negative correlation with antithrombin III levels. P-selectin exposure was higher in patients who presented with acute coronary syndromes than those who presented with effort angina. Cardiovascular event rate was 6 % on follow-up. The study establishes that thrombotic-inflammatory pathways enhancing P-selectin exposure unrelated to treatment might be activated in patients, while the event rate remained lowered, and hence, treatment strategies should be inclusive to control these factors.

  11. Expression and Characterization of Gly-317 Variants of Factor IX Causing Variable Bleeding in Hemophilia B Patients.

    Science.gov (United States)

    Lu, Qiuya; Yang, Likui; Manithody, Chandrashekhara; Wang, Xuefeng; Rezaie, Alireza R

    2015-06-23

    We recently identified two hemophilia B patients who carried Gly-317 to Arg (FIX-G317R) or Gly-317 to Glu (FIX-G317E) substitutions in their FIX gene. The former mutation caused severe and the latter moderate bleeding in afflicted patients. To understand the molecular basis for the variable clinical manifestation of Gly-317 mutations, we prepared recombinant G317R and G317E derivatives of FIX and compared their kinetic properties to those of recombinant wild-type FIX in appropriate assay systems. Both physiological activators, factor XIa and extrinsic Tenase (factor VIIa-tissue factor), activated both zymogen variants with an ∼1.5-fold elevated K(m); however, extrinsic Tenase activated FIX-G317E with an ∼2-fold improved k(cat). By contrast to zymogen activation, the catalytic activities of both FIXa-G317R and FIXa-G317E enzymes toward the natural substrate, factor X, were dramatically (>4 orders of magnitude) impaired, but their apparent affinity for interaction with factor VIIIa was only slightly (<2-fold) decreased. Further studies revealed that the reactivity of FIXa-G317R and FIXa-G317E with antithrombin has been impaired 10- and 13-fold, respectively, in the absence and 166- and 500-fold, respectively, in the presence of pentasaccharide. As expected, the clotting activities of FIX variants could not be measured by the aPTT assay. These results implicate a critical role for Gly-317 in maintaining normal catalytic function for FIX/FIXa in the clotting cascade. The results further suggest that improved k(cat) of FIX-G317E activation in the extrinsic pathway together with dramatically impaired reactivity of FIXa-G317E with antithrombin may account for the less severe bleeding phenotype of a hemophilia B patient carrying the FIX-G317E mutation. PMID:26023895

  12. Contraception and Thrombophilia - A statement from the German Society of Gynecological Endocrinology and Reproductive Medicine (DGGEF e. V. and the Professional Association of the German Gynaecologists (BVF e. V.

    Directory of Open Access Journals (Sweden)

    Rabe T

    2011-01-01

    Full Text Available Venous thromboembolism (VTE is responsible for more than half a million deaths annually in the European Union, most in older people following surgery, but some in women of reproductive age using various hormonal contraceptives. In some parts of the population inherited defects of the blood coagulation system (factor V Leiden, prothrombin G20210A, protein C, protein S and antithrombin deficiency are responsible for an increased risk of VTE, which is also influenced by concomitant factors: e.g. long-distance travel, immobilisation, advanced age, cigarette smoking, high BMI, surgery, malignancy, fluid loss, pregnancy, oral contraceptive use and hormone replacement therapy (HRT. Laboratory testing: General screening for thrombophilia prior to the prescription of oral contraceptives (OC is not recommended. Laboratory testing for thrombophilia should be limited to women with a positive family and/or personal history of VTE or vascular occlusion. – Factor V Leiden is by far the most common congenital thrombophilia. Heterozygous factor V Leiden (5-fold increased VTE risk is present in 3–13%, homozygous factor V Leiden (10-fold increased VTE risk in up to 0.2–1% of people of European origin. – Prothrombin mutation G20210A: Autosomal dominant mutation inheritance (2% of people of European origin leads to a 3-fold increase in VTE risk is substantially increased if one or more additional risk factors are present such as factor V Leiden or protein C, S, or antithrombin deficiency. – Protein C and protein S: VTE risk increases with protein C or S deficiency (odds-ratio 3–15 and 5–11, respectively. – Antithrombin deficiency leads to a 4 to 50-fold increase in VTE risk depending on the type of deficiency. Female hormonal contraceptives containing progestogens with or without combination with a synthetic estrogens (mainly ethinylestradiol [EE] or a natural estrogen (e.g. estradiol or its derivative estradiol valerate affect the incidence of VTE in

  13. 体积排阻色谱法测定低分子量肝素抗凝血因子Xa的活性%An assay for anti-factor Xa activity of low molecular weight heparins by high performance liquid size exclusion chromatography

    Institute of Scientific and Technical Information of China (English)

    张倩倩; 康经武

    2013-01-01

    发展了一种基于体积排阻色谱测定低分子量肝素(LMWH)抗凝血活性的方法.利用肝素与抗凝血酶Ⅲ(ATⅢ)结合后可增强ATⅢ对凝血因子Xa (FXa)抑制作用的原理,通过测定加入LMWH后FXa水解其生色底物产生对硝基苯胺(pNA)这一反应的抑制程度确定LMWH的活性.首先将含有一定浓度LMWH的缓冲溶液与ATⅢ溶液混合,然后依次加入FXa和生色底物,分别孵育一段时间.底物被FXa水解,产生游离的pNA.体积排阻色谱可将小分子产物pNA与其他大分子分离开,因而可以在pNA的最大吸收波长下得到高灵敏度的测定,并且不再受其他成分的干扰.该方法重复性好,灵敏度高,极大地减少了样品的消耗量,降低了成本,并且还可进行各种复杂样品(如血浆)中LMWH抗FXa活性的监测.%The "gold standard" assay for monitoring low molecular weight heparins (LMWHs) activity is the chromogenic-based anti-factor Xa assay.The methodology of an anti-factor Xa assay is that LMWH is added to a known amount of excess factor Xa and excess antithrombin.It will bind to antithrombin and form a triplet complex with factor Xa,inhibiting the activity of factor Xa.However,the residual factor Xa can still hydrolyze chromogenic peptide substrate,releasing the chromophore for photometric detection.The absorbance is inversely proportional to the amount of heparin/LMWH.The results are given in anticoagulant concentration in units/ mL of anti-factor Xa,such that high values indicate high levels of anticoagulation and low values indicate low levels of anticoagulation.Herein,a novel assay method for anti-FXa activity of LMWHs using high performance liquid size exclusion chromatography (SEC) is reported,in which antithrombin m (AT m) was diluted by the buffer solution contained LMWHs.Subsequently,exogenous FXa and p-nitroaniline coupled peptide substrate were added and incubated for a period,separately.The resulting mixture was separated based on size by SEC

  14. Survival of heparins, oral anticoagulants, and aspirin after the year 2010.

    Science.gov (United States)

    Fareed, Jawed; Hoppensteadt, Debra A; Fareed, Daniel; Demir, Muzaffer; Wahi, Rakesh; Clarke, Melaine; Adiguzel, Cafer; Bick, Rodger

    2008-02-01

    The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants, and aspirin. Despite remarkable progress in life sciences, these drugs still remain a challenge and a mystery to us, and their use is far from optimized. The development of low-molecular-weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. Additional drugs from this knowledge will continue to develop; however, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, glycoprotein IIb/IIIa inhibitors, and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains as the approach of choice to manage thrombotic disorders. The new anticoagulant targets, including specific sites in the hemostatic network such as tissue factor, individual clotting factors (IIa, VIIa, IXa, Xa, XIIa, and XIIIa), recombinant forms of serpins (antithrombin, heparin cofactor II, and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin, and site-specific serine protease inhibitor complexes have also been developed. There is a major thrust on the development of orally bioavailable anticoagulant drugs (anti-Xa and anti-IIa agents), which are slated to replace oral anticoagulants. Both the anti-factor Xa and antithrombin agents have been developed for oral use and have provided impressive clinical outcomes in sponsor trials for the postsurgical prophylaxis of venous thrombosis; however, safety concerns related to liver enzyme elevations and

  15. Comparison of fondaparinux sodium and low molecular weight heparin in the treatment of hypercoagulability secondary to traumatic infection

    Institute of Scientific and Technical Information of China (English)

    Baiqiang Li; Kang Wang; Xin Zhao; Chao Lin; Haichen Sun

    2015-01-01

    Purpose:To compare the effects and side-effects of fondaparinux sodium and low molecular weight heparin in patients with hypercoagulability accompanied with traumatic infection.Methods:Thirty-six patients with post-traumatic infections in our hospital intensive care center were diagnosed with hypercoagulability from February 2012 to February 2013.These patients were randomly divided into 2 groups.In group F (18 patients),the patients were treated with fondaparinux sodium,2.5 mg,1/d for 11 d.In group L (18 patients),the patients were treated with low molecular weight heparin,4100 U,1/12 h for 11 d.The incidence of deep vein thrombosis,bleeding events and multiple organ dysfunction syndrome (MODS) and mortality of two groups after anticoagulation therapy were analyzed.Fibrinogen,D-dimer level and activity of antithrombin Ⅲ were measured by the coagulation analyzer.Results:The incidence of deep vein thrombosis,MODS incidence and mortality were not significantly different between the two groups.The rate of bleeding evens in group F was lower than group L (p < 0.05).Antithrombin Ⅲ got an upward trend after anticoagulant therapy,in which it was higher in group F than in group L on the 5th d and 11th d (p < 0.05).Fibrinogen levels were gradually increased,and there was no significant difference between two groups (p > 0.05).D-dimer was significantly decreased after anticoagulant therapy for 5 d (p < 0.01),and there were significant differences between two groups on the 5th d and 7th d (p < 0.05).It showed no significant difference on the 11th d (p > 0.05).Conclusion:Fondaparinux sodium and low molecular weight heparin can effectively improve coagulopathy in patients with traumatic infection.Compared with low molecular weight heparin,fondaparinux sodium may reduce the risk of bleeding events in patients with hypercoagulability accompanied by traumatic infection.

  16. IMPACT OF OBESITY ON ENDOTOXIN-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION.

    Science.gov (United States)

    Duburcq, Thibault; Tournoys, Antoine; Gnemmi, Viviane; Hubert, Thomas; Gmyr, Valery; Pattou, François; Jourdain, Mercé

    2015-10-01

    An early activation of coagulation and fibrinolysis occurs during sepsis, leading to the syndrome of disseminated intravascular coagulation (DIC). Obesity has been demonstrated to be a hypercoagulable and hypofibrinolytic state, but its impact on DIC has never been studied. In this study, we aimed to determine if obesity impairs DIC in an acute endotoxic shock model using minipigs. This was a prospective, comparative, and experimental ancillary study approved by the Animal Ethics Committee. Pigs were chosen as a clinically relevant species, resembling humans in coagulation reactions. Four groups of five "Yucatan" minipigs were studied: lean and obese control groups, a lean lipopolysaccharide (LPS) group receiving Escherichia coli endotoxin (LPS), and an obese LPS group receiving the same endotoxin dose. We measured standard coagulation parameters (prothrombin time [PT], platelet count, and fibrinogen levels), thrombin-antithrombin complexes, tissue-type plasminogen activator, and plasminogen activator inhibitor-1. All measurements were performed at baseline and 30, 60, 90, 150, and 300 min. Results were given as median with interquartile ranges. At baseline, platelet count (477 [428 - 532] G/L vs. 381 [307 - 442] G/L; P = 0.005) and fibrinogen levels (4.6 [3.8 - 5.2] g/L vs. 2 [1.8 - 2.9] g/L; P coagulation parameters (PT, platelet count, and fibrinogen levels) and the increase in thrombin-antithrombin complexes (581 [382 - 1,057] μg/mL vs. 247 [125 - 369] μg/mL at 150 min; P = 0.03) were significantly more important in the obese LPS group compared with those in the lean LPS group. Concerning the fibrinolytic reaction, we found a slightly more elevated increase of plasminogen activator inhibitor-1 in the obese LPS group at 300 min (481 [365 - 617] ng/mL vs. 355 [209 - 660] ng/mL; P = 0.66). In our model of endotoxic shock, obese pigs developed a more severe DIC with a more severe procoagulant response.

  17. Quality of therapeutic plasma-requirements for marketing authorization.

    Science.gov (United States)

    Heiden, Margarethe; Seitz, Rainer

    2002-10-31

    Fresh frozen plasma (FFP) contains higher levels of intact coagulation factors and coagulation and fibrinolysis inhibitors than solvent/detergent-treated plasma (SD plasma), and also greater residual cell contamination. SD plasma is a particle-free plasma of uniform quality. SD treatment, however, has the specific result of reducing the activities of some inhibitors. Both plasma types carry a minimal residual risk of transmitting human immunodeficiency virus (HIV)-1/2, hepatitis virus B (HBV), and hepatitis virus C (HCV), but SDP is, in addition, also safe with respect to other lipid-enveloped viruses and perhaps with respect to hepatitis virus A (HAV), also due to its antibody (Ab) content. Future revisions of therapeutic plasma safety and quality standards should consider the following points:For FFP:reduce residual cell count in all FFP units to values below 5 x 10(6) leukocytes/l;screen donors for Parvovirus B19 genome and antibodies in order to establish a sufficiently large collection of genome-negative and antibody-positive donors whose FFP can be used for selected patients;For SDP:introduce pool testing for Parvovirus B19 genome; fix an upper limit for genome and a lower limit for antibody content;in addition to the standard quality control methods for therapeutic plasma, focus on assays to test for functionally intact proteinase inhibitors such as alpha(2)antiplasmin (alpha(2)AP) and alpha(1)proteinase inhibitor (alpha(1)PI) that are important for plasma indications. Commercially available kits may not be sufficient to show changes in inhibition kinetics. For both types:introduce an activation marker such as thrombin-antithrombin complex (TAT) as a random test to monitor activation processes during withdrawal, separation, manufacturing, and storage;abolish inappropriate parameters like Antithrombin III (AT III) and coagulation factor XI that are not relevant for changes in plasma quality;finally, support every effort towards establishing an efficient

  18. Efficacy L-Arginine In Patients With Nonalcoholic Steatohepatitis Associated With Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Oleksandr Fediv

    2015-01-01

    Full Text Available Abstract Background and Purpose Recent research in the field of hematology indicate that among the many pathogenic mechanisms of development and progression of nonalcoholic steatohepatitis NASH which occurs on the background of the metabolic syndrome an important role is played by endothelial dysfunction and violations of haemocoagulation. The aim of this research was to study the effectiveness of L-arginine as it corrects endothelial dysfunction and disorders of homeostasis haemocoagulation link in patients with NASH associated with the metabolic syndrome. Subjects and Methods 128 patients with nonalcoholic steatohepatitis associated with metabolic syndrome were examined. Some patients 63 persons received standard treatment according to national guidelines. To another group 65 patients on the background of basic therapy L-arginine hydrochloride followed by transition to oral form of L-arginine aspartate was administered. Blood levels of stable nitrogen monoxide metabolites nitrites nitrates endothelin-1 and plasma recalcification time prothrombin time thrombin time activated partial thromboplastin time fibrinogen plasma level activity of antithrombin III and coagulation factor XIII potential activity of plasminogen plasma fibrinolytic blood activity were studied. Results Originally significantly increased levels of endothelin-1 decreased after the therapy in all studied groups but more noticeable changes in the group with L-arginine appointment were observed p0.05. In the studied groups normalization of stable nitrogen monoxide metabolites after treatment was also noticed. Significant p0.05 increase in all haemocoagulation time characteristics and activities of antithrombin-III and factor XIII was found. The positive effect of L-arginine on blood fibrinolytic activity was noted. Discussion and Conclusion Combined therapy of nonalcoholic steatohepatitis associated with metabolic syndrome with a differentiated degreeal L-arginine assignment by

  19. 肺癌患者凝血功能与肺癌分期的关系%The Relationship Between Blood Coagulation Function and Lung Cancer Staging

    Institute of Scientific and Technical Information of China (English)

    何丽钦; 钟可芳

    2012-01-01

    Objective To explore the relationship between the function of blood coagulation in patients with lung cancer and lung cancer staging. Methods EIISA assay for detection of 140 cases of advanced malignant tumor patients and 30 cases of normal human blood coagulation and anticoagulation activity related to laboratory indexes, including plasma fibrinogen ( Fb) , antithrombin III( AT-III) , von Willebrand factor ( Vwf ) , D-D ( D-dimer ). Results The patients with advanced malignant plasma D- dimer, fibrinogen, thrombin antithrombin III and von Willebrand factor antigen levels were significantly elevated and indexes in patients with lung cancer clinical staging with increased. Conclusion The patients with lung cancer usually presence of coagulation, anticoagulation and activation of fibrinolytic system, exists high coagulation state, thus, high coagulation state and clinical staging of lung cancer was positively related to.%目的 探讨肺癌患者凝血功能与肺癌分期的关系.方法 采用ELISA、免疫比浊法检测140例晚期恶性肿瘤患者和30例正常人的凝血、抗凝活性相关的实验室指标,包括血浆纤维蛋白原( Fb),抗凝血酶Ⅲ (AT-Ⅲ),血管性血友病因子 ( vWF),D-二聚体( D-D).结果 晚期恶性肿瘤患者的血浆D-D、Fb、AT-Ⅲ、vWF抗原的水平较正常人显著升高;在肺癌Ⅲ期、Ⅳ期与Ⅰ期相比明显增高(P<0.05),差异有统计学意义;Ⅱ期与Ⅰ期相比增高不明显(P>0.05),差异没有统计学意义.结论 肺癌患者存在凝血、抗凝、纤溶系统的激活,机体呈现高凝状态,并且高凝状态与肺癌临床分期呈正相关.

  20. Changing trends in anti-coagulant therapies. Are heparins and oral anti-coagulants challenged?

    Science.gov (United States)

    Fareed, J; Iqbal, O; Cunanan, J; Demir, M; Wahi, R; Clarke, M; Adiguzel, C; Bick, R

    2008-06-01

    The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants and aspirin. Despite progress in the sciences, these drugs still remain a challenge and mystery. The development of low molecular weight heparins (LMWHS) and the synthesis of heparinomimetics represent a refined use of heparin. Additional drugs will continue to develop. However, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant targets, such as tissue factor, individual clotting factors, recombinant forms of serpins (antithrombin, heparin co-factor II and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin and site specific serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anti-Xa and IIa agents, which are slated to replace oral anticoagulants. Both the anti-factor Xa and anti-IIa agents have been developed for oral use and have provided impressive clinical results. However, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the US Food and Drug Administration did not approve the orally active antithrombin agent Ximelagatran for several indications. The synthetic pentasaccharide (Fondaparinux) has undergone clinical development. Unexpectedly, Fondaparinux also produced major

  1. Logic gates and antisense DNA devices operating on a translator nucleic Acid scaffold.

    Science.gov (United States)

    Shlyahovsky, Bella; Li, Yang; Lioubashevski, Oleg; Elbaz, Johann; Willner, Itamar

    2009-07-28

    A series of logic gates, "AND", "OR", and "XOR", are designed using a DNA scaffold that includes four "footholds" on which the logic operations are activated. Two of the footholds represent input-recognition strands, and these are blocked by complementary nucleic acids, whereas the other two footholds are blocked by nucleic acids that include the horseradish peroxidase (HRP)-mimicking DNAzyme sequence. The logic gates are activated by either nucleic acid inputs that hybridize to the respective "footholds", or by low-molecular-weight inputs (adenosine monophosphate or cocaine) that yield the respective aptamer-substrate complexes. This results in the respective translocation of the blocking nucleic acids to the footholds carrying the HRP-mimicking DNAzyme sequence, and the concomitant release of the respective DNAzyme. The released product-strands then self-assemble into the hemin/G-quadruplex-HRP-mimicking DNAzyme that biocatalyzes the formation of a colored product and provides an output signal for the different logic gates. The principle of the logic operation is, then, implemented as a possible paradigm for future nanomedicine. The nucleic acid inputs that bind to the blocked footholds result in the translocation of the blocking nucleic acids to the respective footholds carrying the antithrombin aptamer. The released aptamer inhibits, then, the hydrolytic activity of thrombin. The system demonstrates the regulation of a biocatalytic reaction by a translator system activated on a DNA scaffold. PMID:19507821

  2. Chemiluminescence and chemiluminescence resonance energy transfer (CRET) aptamer sensors using catalytic hemin/G-quadruplexes.

    Science.gov (United States)

    Liu, Xiaoqing; Freeman, Ronit; Golub, Eyal; Willner, Itamar

    2011-09-27

    The incorporation of hemin into the thrombin/G-quadruplex aptamer assembly or into the ATP/G-quadruplex nanostructure yields active DNAzymes that catalyze the generation of chemiluminescence. These catalytic processes enable the detection of thrombin and ATP with detection limits corresponding to 200 pM and 10 μM, respectively. The conjugation of the antithrombin or anti-ATP aptamers to CdSe/ZnS semiconductor quantum dots (QDs) allowed the detection of thrombin or ATP through the luminescence of the QDs that is powered by a chemiluminescence resonance energy-transfer (CRET) process stimulated by the hemin/G-quadruplex/thrombin complex or the hemin/G-quadruplex/ATP nanostructure, in the presence of luminol/H(2)O(2). The advantages of applying the CRET process for the detection of thrombin or ATP, by the resulting hemin/G-quadruplex DNAzyme structures, are reflected by low background signals and the possibility to develop multiplexed aptasensor assays using different sized QDs. PMID:21866963

  3. Prothrombotic SERPINC1 gene polymorphism may affect heparin sensitivity among different ethnicities of Chinese patients receiving heart surgery.

    Science.gov (United States)

    Wang, Jiang; Ma, Hai-Ping; Ti, Ai Lai Ti Ta Lai; Zhang, Yong-Qiang; Zheng, Hong

    2015-11-01

    The purpose of this study was to investigate a possible correlation between single-nucleotide polymorphisms (SNPs) of the antithrombin (gene, SERPINC1, and perioperative sensitivity to heparin in patients receiving heart surgery. The SERPINC1 genotype and allele frequency, coagulation parameters 24 hours before and after surgery, and clinical findings were compared among 3 ethnic groups, Han, Uighur, and Kazakh, patientswho received heart surgery. In Han patients, longer coagulation time as well as higher heparin and protamine dosage was observed. SERPINC1 gene sequencing identified 2 mutations in exon 5, g.981A>G (rs5877) and g.1011A>G (rs5878). The minor allele frequency of allele (A>G) for rs5877 and rs5878 was higher in the Han patients and was significantly different among the ethnic groups (P = .004 and P = .006, respectively). The increased SERPINC1 SNP frequency among Han patients receiving heart surgery might contribute to the differences in their perioperative sensitivity to heparin.

  4. Heparin-based nanocapsules as potential drug delivery systems.

    Science.gov (United States)

    Baier, Grit; Winzen, Svenja; Messerschmidt, Claudia; Frank, Daniela; Fichter, Michael; Gehring, Stephan; Mailänder, Volker; Landfester, Katharina

    2015-06-01

    Herein, the synthesis and characterization of heparin-based nanocapsules (NCs) as potential drug delivery systems is described. For the synthesis of the heparin-based NCs, the versatile method of miniemulsion polymerization at the droplets interface was achieved resulting in narrowly distributed NCs with 180 nm in diameter. Scanning and transmission electron microscopy images showed clearly NC morphology. A highly negative charge density for the heparin-based NCs was determined by measuring the electro-kinetic potential. Measuring the activated clotting time demonstrated the biological intactness of the polymeric shell. The ability of heparin-based NCs to bind to antithrombin (AT III) was investigated using isothermal titration calorimetry and dynamic light scattering experiments. The chemical stability of the NCs was studied in physiological protein-containing solutions and also in medically interesting fluids such as sodium chloride 0.9%, Ringer's solution, and phosphate buffer saline using dynamic light scattering and measuring the fluorescence intensity. The impressive uptake of NCs in different cells was confirmed by fluorescence-activated cell sorting, confocal laser scanning microscopy, and transmission electron microscopy. The low toxicity of all types of NCs was demonstrated.

  5. Interactions between nattokinase and heparin/GAGs.

    Science.gov (United States)

    Zhang, Fuming; Zhang, Jianhua; Linhardt, Robert J

    2015-12-01

    Nattokinase (NK) is a serine protease extracted from a traditional Japanese food called natto. Due to its strong fibrinolytic and thrombolytic activity, NK is regarded as a valuable dietary supplement or nutraceutical for the oral thrombolytic therapy. In addition, NK has been investigated for some other medical applications including treatment of hypertension, Alzheimer's disease, and vitreoretinal disorders. The most widely used clinical anticoagulants are heparin and low molecular weight heparins. The interactions between heparin and proteins modulate diverse patho-physiological processes and heparin modifies the activity of serine proteases. Indeed, heparin plays important roles in almost all of NK's potential therapeutically applications. The current report relies on surface plasmon resonance spectroscopy to examine NK interacting with heparin as well as other glycosaminoglycans (GAGs). These studies showed that NK is a heparin binding protein with an affinity of ~250 nM. Examination with differently sized heparin oligosaccharides indicated that the interaction between NK and heparin is chain-length dependent and the minimum size for heparin binding is a hexasaccharide. Studies using chemically modified heparin showed the 6-O-sulfo as well as the N-sulfo groups but not the 2-O-sulfo groups within heparin, are essential for heparin's interaction with NK. Other GAGs (including HS, DS, and CSE) displayed modest binding affinity to NK. NK also interfered with other heparin-protein interactions, including heparin's interaction with antithrombin and fibroblast growth factors.

  6. Pharmacology of Heparin and Related Drugs.

    Science.gov (United States)

    Mulloy, Barbara; Hogwood, John; Gray, Elaine; Lever, Rebecca; Page, Clive P

    2016-01-01

    Heparin has been recognized as a valuable anticoagulant and antithrombotic for several decades and is still widely used in clinical practice for a variety of indications. The anticoagulant activity of heparin is mainly attributable to the action of a specific pentasaccharide sequence that acts in concert with antithrombin, a plasma coagulation factor inhibitor. This observation has led to the development of synthetic heparin mimetics for clinical use. However, it is increasingly recognized that heparin has many other pharmacological properties, including but not limited to antiviral, anti-inflammatory, and antimetastatic actions. Many of these activities are independent of its anticoagulant activity, although the mechanisms of these other activities are currently less well defined. Nonetheless, heparin is being exploited for clinical uses beyond anticoagulation and developed for a wide range of clinical disorders. This article provides a "state of the art" review of our current understanding of the pharmacology of heparin and related drugs and an overview of the status of development of such drugs.

  7. [Adult-onset rare diseases].

    Science.gov (United States)

    Pfliegler, György; Kovács, Erzsébet; Kovács, György; Urbán, Krisztián; Nagy, Valéria; Brúgós, Boglárka

    2014-03-01

    The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.).

  8. Warfarin-induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome.

    Science.gov (United States)

    Warkentin, Theodore E; Cook, Richard J; Sarode, Ravi; Sloane, Debi A; Crowther, Mark A

    2015-07-23

    Venous limb gangrene (VLG) can occur in cancer patients, but the clinical picture and pathogenesis remain uncertain. We identified 10 patients with metastatic cancer (7 pathologically proven) who developed severe venous limb ischemia (phlegmasia/VLG) after initiating treatment of deep-vein thrombosis (DVT); in 8 patients, cancer was not known or suspected at presentation. The patients exhibited a novel, clinically distinct syndrome: warfarin-associated supratherapeutic international normalized ratio (INR; median, 6.5) at onset of limb ischemia, rising platelet count during heparin anticoagulation, and platelet fall after stopping heparin. Despite supratherapeutic INRs, patient plasma contained markedly elevated thrombin-antithrombin (TAT) complex levels (indicating uncontrolled thrombin generation) and protein C (PC) depletion; this profile resembles the greatly elevated TAT/PC activity ratios reported in patients with warfarin-associated VLG complicating heparin-induced thrombocytopenia. Analyses of vitamin K-dependent factors in 6 cancer patients with available serial plasma samples showed that variations in the INR corresponded most closely with changes in factor VII, with a highly collinear relationship between VII and PC. We conclude that venous limb ischemia/gangrene is explained in some cancer patients by profoundly disturbed procoagulant-anticoagulant balance, whereby warfarin fails to block cancer-associated hypercoagulability while nonetheless contributing to severe PC depletion, manifest as a characteristic supratherapeutic INR caused by parallel severe factor VII depletion. PMID:25979950

  9. Structure and biological activity of a fucosylated chondroitin sulfate from the sea cucumber Cucumaria japonica.

    Science.gov (United States)

    Ustyuzhanina, Nadezhda E; Bilan, Maria I; Dmitrenok, Andrey S; Shashkov, Alexander S; Kusaykin, Mikhail I; Stonik, Valentin A; Nifantiev, Nikolay E; Usov, Anatolii I

    2016-05-01

    A fucosylated chondroitin sulfate (FCS) was isolated from the body wall of Pacific sea cucumber Cucumaria japonicaby extraction in the presence of papain followed by Cetavlon precipitation and anion-exchange chromatography. FCS was shown to contain D-GalNAc, D-GlcA, L-Fuc and sulfate in molar proportions of about 1:1:1:4.5. Structure of FCS was elucidated using NMR spectroscopy and methylation analysis of the native polysaccharide and products of its desulfation and carboxyl reduction. The polysaccharide was shown to contain a typical chondroitin core → 3)-β-D-GalNAc-(1 → 4)-β-D-GlcA-(1 →. Sulfate groups in this core occupy O-4 and the majority of O-6 of GalNAc. Fucosyl branches are represented by 3,4- and 2,4-disulfated units in a ratio of 4:1 and are linked to O-3 of GlcA. In addition, ∼ 33% of GlcA are 3-O-sulfated, and hence, the presence of short fucooligosaccharide chains side by side with monofucosyl branches cannot be excluded. FCS was shown to inhibit platelets aggregation in vitro mediated by collagen and ristocetin, but not adenosine diphosphate, and demonstrated significant anticoagulant activity, which is connected with its ability to enhance inhibition of thrombin and factor Xa by antithrombin III, as well as to influence von Willebrand factor activity. The latest property significantly distinguished FCS from low-molecular-weight heparin. PMID:26681734

  10. Evaluation of current and new biomarkers in severe preeclampsia: a microarray approach reveals the VSIG4 gene as a potential blood biomarker.

    Directory of Open Access Journals (Sweden)

    Julien Textoris

    Full Text Available Preeclampsia is a placental disease characterized by hypertension and proteinuria in pregnant women, and it is associated with a high maternal and neonatal morbidity. However, circulating biomarkers that are able to predict the prognosis of preeclampsia are lacking. Thirty-eight women were included in the current study. They consisted of 19 patients with preeclampsia (13 with severe preeclampsia and 6 with non-severe preeclampsia and 19 gestational age-matched women with normal pregnancies as controls. We measured circulating factors that are associated with the coagulation pathway (including fibrinogen, fibronectin, factor VIII, antithrombin, protein S and protein C, endothelial activation (such as soluble endoglin and CD146, and the release of total and platelet-derived microparticles. These markers enabled us to discriminate the preeclampsia condition from a normal pregnancy but were not sufficient to distinguish severe from non-severe preeclampsia. We then used a microarray to study the transcriptional signature of blood samples. Preeclampsia patients exhibited a specific transcriptional program distinct from that of the control group of women. Interestingly, we also identified a severity-related transcriptional signature. Functional annotation of the upmodulated signature in severe preeclampsia highlighted two main functions related to "ribosome" and "complement". Finally, we identified 8 genes that were specifically upmodulated in severe preeclampsia compared with non-severe preeclampsia and the normotensive controls. Among these genes, we identified VSIG4 as a potential diagnostic marker of severe preeclampsia. The determination of this gene may improve the prognostic assessment of severe preeclampsia.

  11. Effects of carboxymethyl chitosan on the blood system of rats

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Dawei [College of Marine Life Sciences, Ocean University of China, Qingdao 266003 (China); Han, Baoqin, E-mail: baoqinh@ouc.edu.cn [College of Marine Life Sciences, Ocean University of China, Qingdao 266003 (China); Dong, Wen; Yang, Zhao; Lv, You; Liu, Wanshun [College of Marine Life Sciences, Ocean University of China, Qingdao 266003 (China)

    2011-04-29

    Highlights: {yields} We report, for the first time, the safety of carboxymethyl chitosan in blood system. {yields} CM-Chitosan has no significant effects on coagulation function of rats. {yields} CM-Chitosan has no significant effects on anticoagulation performance of rats. {yields} CM-Chitosan has no significant effects on fibrinolytic function of rats. {yields} CM-Chitosan has no significant effects on hemorheology of rats. -- Abstract: Carboxymethyl chitosan (CM-chitosan), a derivative of chitosan, was extensively studied in the biomedical materials field for its beneficial biological properties of hemostasis and stimulation of healing. However, studies examining the safety of CM-chitosan in the blood system are lacking. In this study CM-chitosan was implanted into the abdominal cavity of rats to determine blood indexes at different times and to evaluate the effects of CM-chitosan on the blood system of rats. Coagulation function was reflected by thrombin time (TT), prothrombin time (PT), activated partial thromboplatin time (APTT), fibrinogen (FIB) and platelet factor 4 (PF4) indexes; anti-coagulation performance was assessed by the index of antithrombinIII (ATIII); fibrinolytic function was reflected by plasminogen (PLG) and fibrin degradation product (FDP) indexes; and blood viscosity (BV) and plasma viscosity (PV) indexes reflected hemorheology. Results showed that CM-chitosan has no significant effects on the blood system of rats, and provides experimental basis for CM-chitosan to be applied in the field of biomedical materials.

  12. Anticoagulant, antiplatelet and antianemic effects of Punica granatum (pomegranate) juice in rabbits.

    Science.gov (United States)

    Riaz, Azra; Khan, Rafeeq A

    2016-04-01

    Pomegranate (Punica granatum L., Punicaceae) is a good source of minerals and phytochemicals with diverse pharmacological activities such as anxiolytic, antidepressant, hypoglycemic, hypolipidemic, and anti-inflammatory activities. Effects of P. granatum on blood parameters and coagulation have, however, been little studied. The aim of the study was to assess the outcome of P. granatum on coagulation and anticoagulation factors at different doses on blood samples of healthy white rabbits. Blood samples of the animals were collected twice during the study and biochemical assays were performed to assess the effect on hematological, coagulation, anticoagulation, and platelet aggregation. Significant changes were observed in erythrocytes, hemoglobin, and mean corpuscular hemoglobin concentration, while bleeding and thrombin time were also prolonged significantly. There was significant increase in protein C, thrombin antithrombin complex levels, and decrease in platelet aggregation and fibrinogen concentration, in a dose-dependent manner. The results of hematological and coagulation assays lead to the speculation about a possible antianemic and cardioprotective effect of P. granatum. PMID:26881853

  13. Biopolymer-modified graphite oxide nanocomposite films based on benzalkonium chloride-heparin intercalated in graphite oxide

    Energy Technology Data Exchange (ETDEWEB)

    Meng Na; Zhou Ninglin; Shen Jian [Jiangsu Engineering Research Center for Biomedical Function Materials, Nanjing Normal University, Nanjing 210046 (China); Zhang Shuangquan, E-mail: zhouninglin@njnu.edu.cn, E-mail: jshen@njnu.edu.cn, E-mail: shuangquanz@yahoo.com [Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Life Sciences College, Nanjing Normal University, Nanjing 210046 (China)

    2010-05-07

    Heparin is a potent anticoagulant agent that interacts strongly with antithrombin III to prevent the formation of fibrin clots. In the present work, poly(dimethylsiloxane)(PDMS)/graphite oxide-benzalkonium chloride-heparin (PDMS/modified graphite oxide) nanocomposite films were obtained by the solution intercalation technique as a possible drug delivery system. The heparin-benzalkonium chloride (BAC-HEP) was intercalated into graphite oxide (GO) layers to form GO-BAC-HEP (modified graphite oxide). Nanocomposite films were characterized by XRD, SEM, TEM, ATR-FTIR and TGA. The modified graphite oxide was observed to be homogeneously dispersed throughout the PDMS matrix. The effect of modified graphite oxide on the mechanical properties of the nanocomposite film was investigated. When the modified graphite oxide content was lower than 0.2 wt%, the nanocomposites showed excellent mechanical properties. Furthermore, nanocomposite films become delivery systems that release heparin slowly to make the nanocomposite films blood compatible. The in vitro studies included hemocompatibility testing for effects on platelet adhesion, platelet activation, plasma recalcification profiles, and hemolysis. Results from these studies showed that the anticoagulation properties of PDMS/GO-BCA-HEP nanocomposite films were greatly superior to those for no treated PDMS. Cell culture assay indicated that PDMS/GO-BCA-HEP nanocomposite films showed enhanced cell adhesion.

  14. Semisynthesis and analysis of lipophilically modified unfractionated and low molecular mass heparins.

    Science.gov (United States)

    Malsch, R; Harenberg, J; Guerrini, M; Torri, G; Casu, B; Heene, D L

    1994-01-01

    Unfractionated heparin and LMMH were substituted with different lipophilic organic compounds. Specifically endpoint attached (LMMH-tyramine and LMMH-tyramine-FITC) and nonspecifically substituted heparins (acylated heparins, and LMMH-biotin and LMMH-cholesterol hemisuccinate) were obtained. The lipophilically substituted heparins were analysed by HPSEC and showed different retention times, high peak purity, different UV/VIS absorbances, and areas under the absorbance time curve. The determination of the average molecular mass Mn, Mm, and Mz and the polydispersity P was performed by PAGE. The substituted heparins showed an increase in their molecular mass Mm, ranging from 2.9 to 129.7% unfractionated heparin and 3.9 to 224.0% (LMMH) compared with the parent compounds (unfractionated heparin and LMMH). The anticoagulant activity was measured by anti-Factor Xa. Lipophilically modified heparin had an aXa activity ranging from 52 to 168 U/mg (unfractionated) and 60 to 108 U/mg (LMMH) and antithrombin activity ranging from 31 to 270 U/mg (unfractionated) and 5 to 15 U/mg (LMMH). The thrombin generation inhibition assay demonstrated an effective anticoagulant potency of the modified compounds. They were neutralized by different amounts (1.1 to 4.1, w/w) of protamin. 1H NMR spectroscopy revealed the specific endpoint attachment of tyramine to LMMH and FITC to LMMH-tyramine. The lipophilically modified heparins showed intact anticoagulant properties and are now used for pharmacokinetic investigations. PMID:7997890

  15. [Heparin-induced thrombocytopenia: recent data].

    Science.gov (United States)

    Gruel, Y; Rollin, J; Leroux, D; Pouplard, C

    2014-03-01

    Despite less frequent, heparin-induced thrombocytopenia (HIT) remains a severe complication of treatment with heparin, and is important to diagnose and manage appropriately. HIT results from an atypical immune response to heparin, with the synthesis of IgG antibodies specific to heparin-modified platelet factor 4 (PF4) which activate platelets, leukocytes and the endothelium. This activation explains that low platelet count is associated with thrombotic events in 50% of patients. The diagnosis of HIT is sometimes evoked because of atypical manifestations (i.e. cutaneous necrosis, amnesia, hypotension or dyspnea following intravenous injection of heparin). Biological assays are always necessary to confirm HIT in case of clinical suspicion, and specific rapid tests are now available for detecting anti-PF4 antibodies. However, their specificity is poor and functional assays such as serotonin release assay or platelet aggregation test are often necessary. Argatroban that is a direct antithrombin drug can be used in patients with severe renal failure and will be preferred to danaparoid sodium in this situation. Fondaparinux is not licensed for treating confirmed HIT and can only be used in case of suspicion. The early detection of HIT is based on the monitoring of platelet count recommended in surgical patients receiving a low molecular weight heparin and in all patients treated with unfractionated heparin. PMID:24074968

  16. 3,4,9,10-Perylenetetracarboxylic dianhydride functionalized graphene sheet as labels for ultrasensitive electrochemiluminescent detection of thrombin.

    Science.gov (United States)

    Gan, Xianxue; Yuan, Ruo; Chai, Yaqin; Yuan, Yali; Cao, Yaling; Liao, Yuhong; Liu, Huijing

    2012-05-13

    A novel tracer, 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA) functionalized graphene sheet (GS) composite (GS-TCDA), is employed to label the secondary anti-thrombin aptamer (TBA) to construct an ultrasensitive electrochemiluminescent sandwich-type aptasensor. The GS provided large surface area for loading abundant PTCDA and TBA with good stability and biocompatibility. Because of the excellent electroconductivity of GS and the desirable optical properties of PTCDA, the as-formed Apt II bioconjugate considerably amplified the electrochmiluminescence (ECL) signal of peroxydisulfate (S(2)O(8)(2-)) and worked as the desirable label for Apt II. On the basis of the considerably amplified ECL signal and sandwich format, an extremely wide range from 1 fM to 1 nM with an ultralow detection limit of 0.33 fM for thrombin was obtained. Additionally, the selectivity and stability of the proposed aptasensor were also excellent. Thus, this procedure has great promise for detection of thrombin present at ultra-trace levels during early stage of diseases. PMID:22541015

  17. Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin

    Science.gov (United States)

    Foley, Jonathan H.; Walton, Bethany L.; Aleman, Maria M.; O'Byrne, Alice M.; Lei, Victor; Harrasser, Micaela; Foley, Kimberley A.; Wolberg, Alisa S.; Conway, Edward M.

    2016-01-01

    Thrombus formation leading to vaso-occlusive events is a major cause of death, and involves complex interactions between coagulation, fibrinolytic and innate immune systems. Leukocyte recruitment is a key step, mediated partly by chemotactic complement activation factors C3a and C5a. However, mechanisms mediating C3a/C5a generation during thrombosis have not been studied. In a murine venous thrombosis model, levels of thrombin–antithrombin complexes poorly correlated with C3a and C5a, excluding a central role for thrombin in C3a/C5a production. However, clot weight strongly correlated with C5a, suggesting processes triggered during thrombosis promote C5a generation. Since thrombosis elicits fibrinolysis, we hypothesized that plasmin activates C5 during thrombosis. In vitro, the catalytic efficiency of plasmin-mediated C5a generation greatly exceeded that of thrombin or factor Xa, but was similar to the recognized complement C5 convertases. Plasmin-activated C5 yielded a functional membrane attack complex (MAC). In an arterial thrombosis model, plasminogen activator administration increased C5a levels. Overall, these findings suggest plasmin bridges thrombosis and the immune response by liberating C5a and inducing MAC assembly. These new insights may lead to the development of strategies to limit thrombus formation and/or enhance resolution. PMID:27077125

  18. Heparin coating of tantalum coronary stents reduces surface thrombin generation but not factor IXa generation.

    Science.gov (United States)

    Blezer, R; Cahalan, L; Cahalan, P T; Lindhout, T

    1998-07-01

    In the present study we used an in-vitro technique to examine initiation and propagation of blood coagulation at the surface of tantalum coronary stents exposed to flowing platelet-rich and platelet-free plasma. The time course of factor IXa production at the surface of the stent was not influenced by platelets. In spite of a significant factor IXa production, no thrombin activity was detected when the tantalum stent was exposed to platelet-free plasma; only when the stent was exposed to platelet-rich plasma was extensive thrombin production observed. These findings indicate that tantalum triggers blood coagulation, but that (adherent) platelets are essential for thrombin generation. Heparin-coated tantalum stents exposed to flowing platelet-rich plasma showed that factor IXa generation was slightly reduced compared with the bare stent. However, the heparin coating drastically delayed the onset of thrombin generation and largely reduced the steady-state production of thrombin. We found a clear relationship between the antithrombin binding capacity and the antithrombogenic potential of the heparin-coated stents. The mode of action of immobilized heparin is thought to abrogate thrombin generation by inhibiting thrombin-dependent positive feedback reactions at the surface of the coronary stent. PMID:9712292

  19. [A sudden rise in INR due to combination of Tribulus terrestris, Avena sativa, and Panax ginseng (Clavis Panax)].

    Science.gov (United States)

    Turfan, Murat; Tasal, Abdurrahman; Ergun, Fatih; Ergelen, Mehmet

    2012-04-01

    Warfarin sodium is an antithrombin agent used in patients with prosthetic valve and atrial fibrillation. However, there are many factors that can change the effectiveness of the drug. Today, herbal mixtures promoted through targeted print and visual media can lead to sudden activity changes in patients using warfarin. In this case report we will present two cases with a sudden rise in INR due to using combination of Tribulus terrestris, Avena sativa and Panax ginseng (Panax Clavis). Two patients who used warfarin due to a history of aortic valve replacement (case 1) and atrial fibrillation (case 2) were admitted to the hospital due very high levels of INR detected during routine follow-up. Both patients had used an herbal medicine called ''Panax'' during the last month. The patients gave no indication regarding a change in diet or the use of another agent that might interact with warfarin. In cases where active bleeding could not be determinated, we terminated the use of the drug and re-evaluated dosage of warfarin before finally discharging the patient. PMID:22864323

  20. Poor prognosis of hypocoagulability assessed by thrombin generation assay in disseminated intravascular coagulation.

    Science.gov (United States)

    Lee, Kyunghoon; Kim, Ji-Eun; Kwon, Jihyun; Kim, Inho; Yoon, Sung-Soo; Park, Seonyang; Han, Kyou-Sup; Kim, Hyun Kyung

    2014-04-01

    Overall assessment of the hemostatic system including procoagulant and anticoagulant changes may help assess the clinical status and prognosis of disseminated intravascular coagulation (DIC). The thrombin generation assay provides useful information about the global hemostatic status. Therefore, we measured several parameters of global hemostatic potential by the thrombin generation assay in patients suspected of having DIC. A total of 114 patients with suspected DIC were included. The thrombin generation assay was performed on the calibrated automated thrombogram using tissue factor with or without the addition of thrombomodulin, showing three parameters: lag time, endogenous thrombin potential (ETP), and peak thrombin. Both 1 and 5 pmol/l tissue factor-stimulated ETP and peak thrombin were well correlated with DIC severity. Interestingly, antithrombin level greatly affected ETP, whereas protein C influenced lag time. Prognostic analysis revealed that the area under the curve of peak thrombin stimulated by 1 pmol/l tissue factor was superior to that of D-dimer. Moreover, multivariate Cox analysis showed that the lag time and time to peak with both 1 and 5 pmol/l tissue factor were independent prognostic markers. ETP and peak thrombin well reflect DIC severity. Hypocoagulability manifesting as prolonged lag time and time to peak is expected to be an independent prognostic marker in DIC.

  1. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan.

    Science.gov (United States)

    Iba, T; Gando, S; Thachil, J

    2014-07-01

    The current management of disseminated intravascular coagulation (DIC) is based on aggressive treatment of the underlying condition and resuscitation with appropriate blood products. Anticoagulant therapy has appeared and disappeared in the different guidelines and important documents detailing the treatment of DIC. For example, Surviving Sepsis Campaign (SSC) guidelines, the 'global standard' for the management of severe sepsis, had recombinant activated protein C highly recommended in the original version, but this was withdrawn in the latest version due to the lack of evidence. In contrast, recent international guidance released from the International Society on Thrombosis and Haemostasis has introduced the potential efficacy of other agents. In sepsis-related DIC, the basis for anticoagulant therapy comes from the mounting evidence for the anti-inflammatory effects which these agents possess and can prove beneficial in septic situations. Several studies have clearly shown the important cross-talk between coagulation and inflammation in patients with sepsis. More recently, neutrophil extracellular traps and damage-associated molecular patterns (DAMPs), especially histones, have been demonstrated to play a crucial role in the coagulopathy of sepsis. Once again, the natural anticoagulants have an important function in neutralizing the effects of DAMPs and histones. In this review, in addition to examining the important role of anticoagulants in the septic milieu, the clinical studies examining antithrombin, recombinant thrombomodulin and plasma-derived activated protein C are detailed. However, large-scale randomized controlled trials are yet to be performed, with important consideration of the timing, dosage and duration of treatment.

  2. [Progress in diagnosis and treatment for disseminated intravascular coagulation].

    Science.gov (United States)

    Wada, Hideo; Matsumoto, Takeshi; Aota, Takumi; Yamashita, Yoshiki

    2015-02-01

    As the development of a hypercoagulable state in the setting of disseminated intravascular coagulation (DIC) induces localized infection, therapy for DIC should be evaluated according to the findings of examinations for both severe sepsis and DIC. DIC is classified into the following types: "bleeding type," "organ failure type," "asymptomatic type," and "complication type." The "bleeding type" and "organ failure type" are considered to reflect the "plasmin inhibitor (PI) deficiency type" and "antithrombin (AT) deficiency type," respectively. In order to improve the diagnosis of DIC, in particular limitations in global coagulation tests, the Japanese Society of Thrombosis and Hemostasis recently proposed tentative diagnostic criteria for DIC using hemostatic molecular markers and AT. The recommendations for treatment of DIC, especially the use of AT concentrates, recombinant activated protein C and thrombomodulin, vary among several guidelines for the management of DIC. These agents inhibit the effects of key proteases in activating coagulation and consequently exert an anti-inflammatory effect on DIC. Hence, it is necessary to extensively evaluate these agents in well-conducted clinical trials.

  3. Global fibrinolytic capacity in pediatric patients with sepsis and disseminated intravascular coagulation.

    Science.gov (United States)

    Bay, Ali; Oner, Ahmet Faik; Kose, Dogan; Dogan, Murat

    2006-10-01

    There are many complex pathophysiologic changes of the coagulation system in sepsis. The fibrinolytic system was evaluated in septic children using the global fibrinolytic capacity (GFC), a new technique reflecting the overall fibrinolytic activity. The study consisted of 24 children with sepsis, 36 children with sepsis plus disseminated intravascular coagulation (DIC), and 20 healthy age-matched control individuals. Compared with controls, 86% of sepsis patients and 87% of sepsis plus DIC patients had decreased GFC levels. Between the sepsis plus DIC and sepsis groups there was no significant difference in terms of GFC levels. While 19 patients (52.7%) died in the sepsis plus DIC group, only three patients (12.5%) died in the sepsis group. When survivors and nonsurvivors were compared in terms of coagulation tests, there were significant differences for protein C, antithrombin, platelet, fibrinogen, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and white blood cell values. In conclusion, the level of GFC reduced in most of the pediatric sepsis patients but no difference was observed between patients with sepsis and patients with sepsis plus DIC. While inhibition of fibrinolysis is an important finding in sepsis, the mortality is mainly associated with the presence of end-organ damage and the status of coagulation parameters.

  4. Disseminated intravascular coagulation: testing and diagnosis.

    Science.gov (United States)

    Wada, Hideo; Matsumoto, Takeshi; Yamashita, Yoshiki; Hatada, Tsuyoshi

    2014-09-25

    Abnormalities of the hemostatic system in patients with DIC result from the sum of vectors for hypercoagulation and hyperfibrinolysis. DIC is classified into hyperfibrinolysis, hypercoagulation, massive bleeding or nonsymptomatic types according to the balance of the two vectors. Both the antithrombin (AT) and protein C (PC) levels are significantly low in patients with septic DIC, and reduced amounts of AT and PC result in the lack of inhibition of thrombin and activated FVIII, respectively. Thrombin activates FVIII, while activated FVIII accelerates the coagulation pathway to generate thrombin; thus activation of the coagulation system persists. Three sets of diagnostic criteria have been established by the Japanese Ministry of Health, Labour and Welfare, International Society of Thrombosis and Haemostasis and Japanese Association for Acute Medicine, respectively. Although these three diagnostic criteria score hemostatic abnormalities using similar global coagulation tests, the sensitivity and/or specificity for death differ. Treatment with AT or activated PC may not improve the outcomes of patients with sepsis at the early stage, although they may improve the outcomes in those with DIC. Therefore, new diagnostic criteria for determining the appropriate time to initiate anticoagulant treatment are required.

  5. Laboratory testing in disseminated intravascular coagulation.

    Science.gov (United States)

    Favaloro, Emmanuel J

    2010-06-01

    The diagnosis of disseminated intravascular coagulation (DIC) relies on clinical signs and symptoms, identification of the underlying disease, the results of laboratory testing, and differentiation from other pathologies. The clinical features mainly depend on the underlying cause of the DIC. The laboratory diagnosis of DIC uses a combination of tests because no single test result alone can firmly establish or rule out the diagnosis. Global tests of hemostasis may initially provide evidence of coagulation activation and later in the process provide evidence of consumption of coagulation factors, but their individual diagnostic efficiency is limited. Fibrinolytic markers, in particular D-dimer, are reflective of activation of both coagulation and fibrinolysis, so that a normal finding can be useful for ruling-out DIC. Decreased levels of the natural anticoagulants (in particular, antithrombin and protein C) are frequently observed in patients with DIC, but their measurement is not normally incorporated into standard diagnostic algorithms. New tests are being explored for utility in DIC, and some additional tests may be useful on a case-by-case basis, depending on the proposed cause of the DIC or their local availability. For example, clot waveform analysis is useful but currently limited to a single instrument. Also, procalcitonin is an inflammatory biomarker that may be useful within the context of septic DIC, and activated factor X clotting time is an emerging test of procoagulant phospholipids that also seems to hold promise in DIC.

  6. Concentration of D-dimers in healthy cats and sick cats with and without disseminated intravascular coagulation (DIC).

    Science.gov (United States)

    Tholen, Inger; Weingart, Christiane; Kohn, Barbara

    2009-10-01

    The objective of this prospective study was to measure concentrations of D-dimers in 48 cats with various diseases and in 20 healthy cats to evaluate the sensitivity and specificity for D-dimers to diagnose disseminated intravascular coagulation (DIC). The cats were classified as having DIC if an underlying disease and at least three of the following criteria were present: thrombocytopenia, prolonged activated partial thromboplastin time, prothrombin time or thrombin time, schistocytes and/or a reduced antithrombin activity. D-dimer concentrations were measured using a semi-quantitative latex agglutination (LA) test (Accuclot D-Dimer, Sigma Diagnostics). The D-dimer test was positive for 8/12 cats with DIC and for 16/36 sick cats without DIC. D-dimers were negative for all healthy control cats. The comparison of the sick cats with DIC and those without DIC revealed a specificity and sensitivity of the D-dimer test of 56% and 67%; a comparison of the results for healthy cats and cats with DIC revealed a specificity and sensitivity of 100% and 67%, respectively. The D-dimer LA test is only of limited value for the diagnosis of DIC in cats.

  7. Coagulation disorders in the patients with deep vein thrombosis of lower extremity

    Directory of Open Access Journals (Sweden)

    Milić Dragan J.

    2003-01-01

    Full Text Available PURPOSE Venous thromboembolism is a relevant social and health care problem for its high incidence, pulmonary embolism-related mortality and long-term sequelae which may be disabling (post-thrombotic syndrome and ulceration. PROCEDURES The aim of our work was to establish the presence of coagulation disorders (hypercoagulable states in the patients with deep vein thrombosis (DVT of the leg. Prospectively we have analyzed a group of 30 patients with echosono-graphicaly verified DVT of the leg who were admitted to the department of vascular surgery from August 1st 2000 to July 31st 2001.The following parameters were monitored: prothrombin time (PT partial thromboplastin time (PTT, fibrinogen (Fib, alpha 2 antiplasmin (A-2 AP, D-dimer (DD, antithrombin III (AT III and factor VII. FINDINGS Activation of the coagulation process was registered. The values of monitored coagulation parameters are shown in table 1. Plasma levels of monitored parameters in the patients with DVT of the leg were significantly higher than in the control subjects. CONCLUSION In patients with a DVT a hypercoagulable state is common finding. Some parameters of coagulation activity such as D-dimer might be of great interest in the diagnostic strategy of DVT.

  8. Low paediatric thrombin generation is caused by an attenuation of prothrombin conversion.

    Science.gov (United States)

    Kremers, Romy M W; Wagenvoord, Rob J; de Laat, H Bas; Monagle, Paul; Hemker, H Coenraad; Ignjatovic, Vera

    2016-06-01

    Thrombin generation (TG) is decreased in children. TG is determined by two underlying processes: the conversion of prothrombin to thrombin and the inactivation of thrombin. Therefore, lower TG capacity in children can either be caused by a reduction of prothrombin conversion, an increase of thrombin inactivation, or both. In 36 children and 8 adults, TG and the factors that determine thrombin inactivation (antithrombin, α2Macroglobulin (α2M) and fibrinogen) were measured. Prothrombin conversion, thrombin inhibitor complex formation, and the overall thrombin decay capacity were determined. In silico modelling was performed to determine the contribution prothrombin conversion and thrombin inactivation to deviant paediatric TG. Both the amount of prothrombin converted and the maximal prothrombin conversion rate are significantly reduced in children as compared to adults. This is partly due to the prothrombin levels being lower and partly to a lower prothrombin conversion rate. The overall thrombin decay capacity is not significantly different in children, but α2Macroglobulin plays a more important role than it does in adults. In silico experiments demonstrate that reduced prothrombin conversion and to a lesser extent elevated α2M levels provide an explanation for low TG in children. Young age has a dual effect on prothrombin conversion. Lower plasma prothrombin levels result in decreased prothrombin conversion but the rate of prothrombin conversion is also decreased, i. e. the development of prothrombinase is lower than in adults.

  9. Impact of the factor V Leiden mutation on the outcome of pneumococcal pneumonia: a controlled laboratory study

    Science.gov (United States)

    2010-01-01

    Introduction Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The factor V Leiden (FVL) mutation results in resistance of activated FV to inactivation by activated protein C and thereby in a prothrombotic phenotype. Human heterozygous FVL carriers have been reported to be relatively protected against sepsis-related mortality. We here determined the effect of the FVL mutation on coagulation, inflammation, bacterial outgrowth and outcome in murine pneumococcal pneumonia. Methods Wild-type mice and mice heterozygous or homozygous for the FVL mutation were infected intranasally with 2*106 colony forming units of viable S. pneumoniae. Mice were euthanized after 24 or 48 hours or observed in a survival study. In separate experiments mice were treated with ceftriaxone intraperitoneally 24 hours after infection and euthanized after 48 hours or observed in a survival study. Results The FVL mutation had no consistent effect on activation of coagulation in either the presence or absence of ceftriaxone therapy, as reflected by comparable lung and plasma levels of thrombin-antithrombin complexes and fibrin degradation products. Moreover, the FVL mutation had no effect on lung histopathology, neutrophil influx, cytokine and chemokine levels or bacterial outgrowth. Remarkably, homozygous FVL mice were strongly protected against death due to pneumococcal pneumonia when treated with ceftriaxone, which was associated with more pronounced FXIII depletion; this protective effect was not observed in the absence of antibiotic therapy. Conclusions Homozygosity for the FVL mutation protects against lethality due to pneumococcal pneumonia in mice treated with antibiotics. PMID:20682036

  10. Cerebral venous thrombosis associated with homozygous factor V Leiden mutation in a 15-year-old girl of Tunisian origin

    Science.gov (United States)

    Salem-Berrabah, Olfa Ben; Fekih-Mrissa, Nejiba; Laayouni, Samy; Gritli, Nasreddine; Mrissa, Ridha

    2011-01-01

    Cerebral venous thrombosis (CVT) is a rare disease. It has numerous and complex etiologies. Inherited or acquired prothrombotic states play a key role in the development of this disease, such as factor V G1691A mutation (FV Leiden). A 15-year-old girl presented to the Department of Neurology with a complaint of severe headache with visual blurring. The diagnosis of CVT was not initially suspected because of the patient's condition on presentation. An MRI showed thrombosis in the superior sagittal sinus, confirming venous stroke. Anticardiolipin and antiphospholipid antibodies were assessed. In addition, inherited prothrombotic defects, such as protein C, protein S, and antithrombin deficiencies, and genetic mutations for FV Leiden, prothrombin gene G20210A (FII G20210A), and methyltetrahydrofolate reductase C677T (MTHFR C677T) were studied. All results were unremarkable except for the unique homozygous FV Leiden mutation, which likely contributed to this prothrombotic situation. This study highlights the fact that FV Leiden may play a significant role in the onset of CVT in young patients. PMID:22048515

  11. Characterisation of serpin polymers in vitro and in vivo.

    Science.gov (United States)

    Belorgey, Didier; Irving, James A; Ekeowa, Ugo I; Freeke, Joanna; Roussel, Benoit D; Miranda, Elena; Pérez, Juan; Robinson, Carol V; Marciniak, Stefan J; Crowther, Damian C; Michel, Claire H; Lomas, David A

    2011-03-01

    Neuroserpin is a member of the serine protease inhibitor or serpin superfamily of proteins. It is secreted by neurones and plays an important role in the regulation of tissue plasminogen activator at the synapse. Point mutations in the neuroserpin gene cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. This is one of a group of disorders caused by mutations in the serpins that are collectively known as the serpinopathies. Others include α(1)-antitrypsin deficiency and deficiency of C1 inhibitor, antithrombin and α(1)-antichymotrypsin. The serpinopathies are characterised by delays in protein folding and the retention of ordered polymers of the mutant serpin within the cell of synthesis. The clinical phenotype results from either a toxic gain of function from the inclusions or a loss of function, as there is insufficient protease inhibitor to regulate important proteolytic cascades. We describe here the methods required to characterise the polymerisation of neuroserpin and draw parallels with the polymerisation of α(1)-antitrypsin. It is important to recognise that the conditions in which experiments are performed will have a major effect on the findings. For example, incubation of monomeric serpins with guanidine or urea will produce polymers that are not found in vivo. The characterisation of the pathological polymers requires heating of the folded protein or alternatively the assessment of ordered polymers from cell and animal models of disease or from the tissues of humans who carry the mutation.

  12. Inhibition of coagulation proteases and thrombosis and sub-chronic toxicological study of a sulfated polysaccharidic fraction from the red alga Gelidiella acerosa

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    Ismael Nilo Lino de Queiroz

    2014-10-01

    Full Text Available Metabolites isolated from Gelidiella species (Rhodophyta have been few studied. We evaluated a sulfated polysaccharidic fraction from G. acerosa collected from two Brazilian beaches on the northwestern coast of Brazil (Flecheiras-F and Pedra Rachada-PR on coagulation proteases and thrombosis. Their toxicity in vivo was also assessed. Enzymatic extractions yielded 1.40%, and similar chromatographic profiles (DEAE-cellulose were obtained, with fractions (Ga-I→V containing differences among the relative proportions of sulfate (5-42%, and revealing charge density patterns by electrophoresis. Ga-IV-PR had a discrete effect (3.01 IU mg-1 on normal human coagulation compared with heparin (193 IU mg-1 and was tested on coagulation proteases (thrombin and factor Xa in the presence of antithrombin and in a model of venous thrombosis in rats using thromboplastin as the thrombogenic stimulus. The systems were inhibited; but at higher doses (>1.0 mg kg-1, this fraction reverted the antithrombotic effect. Regarding the toxicological study, consecutive Ga-IV (9 mg kg-1 for 14 days did not cause mortality in mice, but some biochemical and hematological parameters were discretely altered. Histopathological analysis revealed that increased liver and spleen sizes had no toxicological significance. Therefore, G. acerosa does not biochemically change its matrix polysaccharide composition and proved to be safe antithrombotic agent.

  13. Improved blood compatibility of polyethersulfone membrane with a hydrophilic and anionic surface.

    Science.gov (United States)

    Nie, Shengqiang; Xue, Jimin; Lu, Yi; Liu, Yeqiu; Wang, Dongsheng; Sun, Shudong; Ran, Fen; Zhao, Changsheng

    2012-12-01

    In this study, a novel triblock copolymer of poly (styrene-co-acrylic acid)-b-poly (vinyl pyrrolidone)-b-poly(styrene-co-acrylic acid) (P(St-co-AA)-b-PVP-b-P(St-co-AA)) is synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and used for the modification of blood contacting surface of polyethersulfone (PES) membrane to improve blood compatibility. The synthesized block copolymer can be directly blended with PES to prepare PES membranes by a liquid-liquid phase separation technique. The compositions and structure of the PES membranes are characterized by thermogravimetric analysis (TGA), ATR-FTIR, X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM); the surface charge density of the modified PES membrane was measured by Zeta-potential; the blood compatibility of the PES membranes was assessed by detecting bovine serum albumin (BSA) and bovine serum fibrinogen (BFG) adsorption, platelet adhesion, activated partial thromboplastin time (APTT), platelet activation, and thrombin-antithrombin III (TAT) generation. The results indicated that the blood compatibility of the modified PES membrane was improved due to the membrane surface modification by blending the amphiphilic block copolymer and the surface segregation of the block copolymer.

  14. Structural features and inactivation of coagulation proteases of a sulfated polysaccharidic fraction from Caulerpa cupressoides var. lycopodium (Caulerpaceae, Chlorophyta - doi: 10.4025/actascitechnol.v35i4.16709

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    José Ariévilo Gurgel Rodrigues

    2013-10-01

    Full Text Available Studies on biopolymers from macroalgae suggested sulfated polysaccharides (SPs as research agents to investigate events related to haemostasis. Caulerpa cupressoides var. lycopodium is a marine green alga containing three SPs fractions (SP1, SP2 and SP3. SP2 had anticoagulant (in vitro and anti- and prothrombotic (in vivo actions; however, its effect on the coagulation system is not fully understood. This study aimed to determine the infrared (IR spectroscopy, chemical composition (CC, elemental microanalysis (EM, molecular weight (MW and the effect on coagulation proteases of SP2. The presence of sulfate ester, galactose-6-sulfate, uronic acid and glycoside linkages for IR spectrum; contents of sulfate (28%, total sugars (40% and uronic acids (7.18% for CC; and content of carbon (21.98%, sulfate (4.27%, nitrogen (1.3% and hydrogen (4.86% for EM were obtained. The average molecular weights of four different SPs (SP-1, SP-2, SP-3 and SP-4 subfractions from the SP2 ranged from ~ 8 to >100 kDa. SP2 was tested on coagulation proteases (thrombin and factor Xa in the presence of antithrombin (AT and heparin cofactor II (HCII using human plasma, being both thrombin and factor Xa target proteases inhibited, but requiring a concentration of about 2.5-fold higher of HCII than the thrombin inactivation by AT.   

  15. What neurosurgeons need to know about dabigatran etexilate (pradax®/pradaxa®/prazaxa®)

    Science.gov (United States)

    Dwyer, Christopher Michael; Damodaran, Omprakash; Heckelmann, Michael; Sheridan, Mark Michael

    2015-01-01

    Dabigatran etexaliate is a novel oral anticoagulant that directly inhibits thrombin. It offers a number of substantial medical benefits over other oral and parenteral anticoagulants but its advent raises important neurosurgical considerations. Dabigatran has important potential benefits. Unlike warfarin, it does not require routine blood tests to monitor its anticoagulative effect and there is no need for dose titration. Drug interactions are greatly simplified when compared to warfarin as dabigatran is not metabolized by cytochrome p450 isoenzymes. As a result, dabigatran has been approved in many jurisdictions for DVT prophylaxis after orthopaedic surgery and also for the prevention of embolic events associated with non-valvular atrial fibrillation. There are, however, important neurosurgical challenges associated with regular dabigatran use. Unlike current anti-coagulants, there is no specific reversal agent for dabigatran. Known reversal options include activated charcoal (within one to two hours of intake) and renal dialysis. Protamine sulfate and vitamin K are unlikely to affect the activity of dabigatran. Platelet concentrates will not inactivate dabigatran's anti-thrombin properties. Assessing the degree of anticoagulation is difficult as conventional markers of serum coagulability are typically normal in patients taking dabigatran. The potential neurosurgical challenges of dabigatran were cast in sharp relief by a recent case report from the United States that is considered in this note. In the absence of a clear reversal pathway, we propose a treatment algorithm for chronic dabigatran use based on the replacement of any deficient factors and rapid access to renal dialysis. PMID:25972932

  16. What neurosurgeons need to know about dabigatran etexilate (pradax(®)/pradaxa(®)/prazaxa(®)).

    Science.gov (United States)

    Dwyer, Christopher Michael; Damodaran, Omprakash; Heckelmann, Michael; Sheridan, Mark Michael

    2015-01-01

    Dabigatran etexaliate is a novel oral anticoagulant that directly inhibits thrombin. It offers a number of substantial medical benefits over other oral and parenteral anticoagulants but its advent raises important neurosurgical considerations. Dabigatran has important potential benefits. Unlike warfarin, it does not require routine blood tests to monitor its anticoagulative effect and there is no need for dose titration. Drug interactions are greatly simplified when compared to warfarin as dabigatran is not metabolized by cytochrome p450 isoenzymes. As a result, dabigatran has been approved in many jurisdictions for DVT prophylaxis after orthopaedic surgery and also for the prevention of embolic events associated with non-valvular atrial fibrillation. There are, however, important neurosurgical challenges associated with regular dabigatran use. Unlike current anti-coagulants, there is no specific reversal agent for dabigatran. Known reversal options include activated charcoal (within one to two hours of intake) and renal dialysis. Protamine sulfate and vitamin K are unlikely to affect the activity of dabigatran. Platelet concentrates will not inactivate dabigatran's anti-thrombin properties. Assessing the degree of anticoagulation is difficult as conventional markers of serum coagulability are typically normal in patients taking dabigatran. The potential neurosurgical challenges of dabigatran were cast in sharp relief by a recent case report from the United States that is considered in this note. In the absence of a clear reversal pathway, we propose a treatment algorithm for chronic dabigatran use based on the replacement of any deficient factors and rapid access to renal dialysis. PMID:25972932

  17. Sulodexide: implicazioni cliniche ed economiche

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    Orietta Zaniolo

    2005-06-01

    Full Text Available Sulodexide is a highly purified glycosaminoglycan approved for leg ulcers treatment. It contains two principal components: heparan sulfate, a fast-moving heparin fraction, (80% and dermatan sulfate (20%. Sulodexide is available as an oral agent and as an injectable preparation. Its pharmacological action is obtained by dose-dependent coagulation factors inhibition: dermatan sulfate upgrades the physiological action of a selective thrombin inhibitor, heparin cofactor II, and heparan sulfate depresses activated factor X, via an increase of antithrombin III action. The antithrombotic action is enhanced by platelet aggregation inhibition and by the activation of the fibrinolytic system. This paper summarizes the results of some of the main trials that evaluated sulodexide in the treatment of peripheral occlusive arterial disease and venous leg ulcers; a trial on prevention of recurrent deep venous thrombosis with sulodexide is also reviewed. We analyzed data about the clinical and economical impact of chronic venous insufficiency with a particular attention to the cost of medication, hospitalization and management of leg ulcers. The hypothetical savings correlated to the reduction of leg ulcers incidence and healing time attainable with sulodexide have been estimated. A comparison between the different acquisition costs of the drugs frequently used to treat leg ulcers is also provided. Finally we reviewed some quality of life trials in which the psychological and sociological influence of the disease and its treatments on the patient are assessed.

  18. Relative Tissue Factor Deficiency Attenuates Ventilator-Induced Coagulopathy but Does Not Protect against Ventilator-Induced Lung Injury in Mice

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    Esther K. Wolthuis

    2012-01-01

    Full Text Available Preventing tissue-factor-(TF- mediated systemic coagulopathy improves outcome in models of sepsis. Preventing TF-mediated pulmonary coagulopathy could attenuate ventilator-induced lung injury (VILI. We investigated the effect of relative TF deficiency on pulmonary coagulopathy and inflammation in a murine model of VILI. Heterozygous TF knockout (TF+/− mice and their wild-type (TF+/+ littermates were sedated (controls or sedated, tracheotomized, and mechanically ventilated with either low or high tidal volumes for 5 hours. Mechanical ventilation resulted in pulmonary coagulopathy and inflammation, with more injury after mechanical ventilation with higher tidal volumes. Compared with TF+/+ mice, TF+/− mice demonstrated significantly lower pulmonary thrombin-antithrombin complex levels in both ventilation groups. There were, however, no differences in lung wet-to-dry ratio, BALF total protein levels, neutrophil influx, and lung histopathology scores between TF+/− and TF+/+ mice. Notably, pulmonary levels of cytokines were significantly higher in TF+/− as compared to TF+/+ mice. Systemic levels of cytokines were not altered by the relative absence of TF. TF deficiency is associated with decreased pulmonary coagulation independent of the ventilation strategy. However, relative TF deficiency does not reduce VILI and actually results in higher pulmonary levels of inflammatory mediators.

  19. The relationship between thrombophilic mutations and preeclampsia: a prospective case-control study

    International Nuclear Information System (INIS)

    Preeclampsia and its association with thrombophillia remain controversial, due to inconsistent results in different studies, which different ethnic groups, selection criteria, and patient numbers. The aim of this study was to determine the relationship between thrombophillia and preeclamptic patients in our region. In a prospective case-control study, we compared 100 consecutive women with preeclampsia and eclampsia (group 1) with 100 normal pregnant women (group 2). All women were tested two months after delivery for mutations of factor V Leiden, methylenetetrahydrofolate reductase (MTHFR), and prothrombin gene mutation mutataion as well as for deficiencies of protein C, protein S, and antithrmbin III. A thrombophilic mutation was found in 42 (42%) and 28(28%) women in group I and group II, respectively (P+0.27, OR 1.5, 95% CI 1.0-2.2). The incidence of Factor V Leiden mutation (heterozygous), prothrombin mutation (heterozygous), prothrombin mutation (homozygous), MTHFR mutation (homozygous) was not statistically significant in group 1 compared with group 2 (P>0.05). Also, deficiencies of protein S, protein c and antithrombin III were not statistically significant in group I com pared with group II (P>0.05). There was no difference in thrombophilic mutations between preeclamptic patients and normal pregnant women in our region. Therefore, we suggest that preeclamptic patients should not be tested for thrombophilia. (author)

  20. Antiplatelet treatment and prothrombotic diathesis following endovascular abdominal aortic aneurysm repair.

    Science.gov (United States)

    Trellopoulos, G; Georgiadis, G S; Nikolopoulos, E S; Kapoulas, K C; Georgakarakos, E I; Lazarides, M K

    2014-10-01

    Prothrombotic diathesis expressed by elevated levels of coagulation-specific biomarkers has been reported in patients with abdominal aortic aneurysm (AAA) and after AAA endovascular repair (EVAR). This study investigates the effect of antiplatelet agents (APLs) on the prothrombotic diathesis in the post-EVAR period. Forty elective EVAR patients had thrombin-antithrombin complex, d-dimer, fibrinopeptide A, and high-sensitivity C-reactive protein measured before, at 24 hours, 1 month, and 6 months after EVAR. Patients receiving APLs postoperatively were compared with those not receiving APLs. All biomarkers were above the normal limits preoperatively and increased significantly 24 hours postoperatively followed by a drop at 1 and 6 months. No statistically significant changes were noted among patients receiving APLs in comparison with those not receiving APLs. The preoperative and postoperative prothrombotic diathesis of AAA following EVAR was confirmed in line with other reports. There was however no significant alteration of the examined biomarkers in patients receiving APLs. PMID:24101707

  1. Molecular design, synthesis and anticoagulant activity evaluation of fluorinated dabigatran analogues.

    Science.gov (United States)

    Wang, Fei; Ren, Yu-Jie; Dong, Ming-Hui

    2016-06-15

    In the present study, a series of unreported fluorinated dabigatran analogues, which were based on the structural scaffold of dabigatran, were designed by computer-aided simulation. Fifteen fluorinated dabigatran analogues were screened and synthesized. All target compounds were characterized by (1)H NMR, (13)C NMR, (19)F NMR and HRMS. According to the preliminary screening results of inhibition ratio, eleven analogues (inhibition ratio >90%) were evaluated for antithrombin activity in vitro (IC50). The test results expressed that all the analogues showed effective inhibitory activities against thrombin. Especially, compounds 8f, 8k and 8o, with IC50 values of 1.81, 3.21 and 2.16nM, respectively, showed remarkable anticoagulant activities which were in the range of reference drug dabigatran (IC50=1.23nM). Moreover, compounds 8k and 8o were developed to investigate their anticoagulant activities in vivo. In those part, compound 8o exhibited a fairly strong inhibitory action for arteriovenous thrombosis with inhibition ratio of 84.66%, which was comparable with that of dabigatran (85.07%). Docking simulations demonstrated that these compounds could act as candidates for further development of novel anticoagulant drugs.

  2. The effects of danaparoid, dalteparin and heparin on tissue factor-induced experimental disseminated intravascular coagulation and bleeding time in the rat.

    Science.gov (United States)

    Miyake, Y; Yokota, K; Fujishima, Y; Sukamoto, T

    2001-07-01

    Danaparoid and heparin, on the basis of anti-activated factor X (anti-FXa) activity, were equipotent in accelerating the rate of interaction of FXa and antithrombin III. In rat tissue factor-induced disseminated intravascular coagulation (DIC) models, an intravenous administration of danaparoid inhibited the decrease in plasma fibrinogen and platelet counts and the increase in serum fibrinogen degradation products. Expressed on the basis of anti-FXa activity, these effects were comparable with those of dalteparin and heparin. In rat mesenteric small artery and vein, less bleeding was observed after intravenous administration of danaparoid than after dalteparin or heparin. Danaparoid did not affect adenosine diphosphate- or collagen-induced platelet aggregation, and showed weaker inhibitory effects on aggregation induced by thrombin, or collagen + thrombin, than did dalteparin or heparin. These findings suggest that danaparoid may be useful for the prevention of DIC and has less tendency to cause bleeding than dalteparin or heparin, probably as a result of its weaker ability to inhibit platelet aggregation. PMID:11505077

  3. Thrombophilia

    Directory of Open Access Journals (Sweden)

    Maurizio Zangari

    2008-01-01

    Full Text Available Thrombophilia or hypercoagulable state is a clinical condition characterized by a tendency to develop venous (less frequently arterial thrombosis. The development of a venous thromboembolic episode (VTE is the result of environmental risk factors such as age, male sex, obesity, the exposure to “risk periods” of immobilization, trauma, cancer, pregnancy or the use of exogenous hormones or antineoplastic medications often on a background of a congenital procoagulant state. Table 1 summarizes the most frequently inherited and acquired thrombophilic conditions in a population of patients with a first episode of VTE.In patients with venous thrombosis before the early nineties a biologic cause of thrombophilia was detectable in only 5% to 15% of cases and was confined to deficiencies of antithrombin, protein C, and protein S. The discovery of two prothrombotic mutations prevalent in white populations, the factor V-Arg506Gln mutation (factor V Leiden and the prothrombin G20210A mutation has significantly increased the number of patients with recognizable hereditary risk factor. The antiphospholipid antibody syndrome and elevated plasma homocysteine levels are also frequently identifiable risk factors in patients presenting with venous as well as arterial thrombosis.

  4. Structure and anticoagulant properties of sulfated glycosaminoglycans from primitive Chordates

    Directory of Open Access Journals (Sweden)

    PAVÃO MAURO S. G.

    2002-01-01

    Full Text Available Dermatan sulfates and heparin, similar to the mammalian glycosaminoglycans, but with differences in the degree and position of sulfation were previously isolated from the body of the ascidian Styela plicata and Ascidia nigra. These differences produce profound effects on their anticoagulant properties. S. plicata dermatan sulfate composed by 2-O-sulfatedalpha-L-iduronic acid and 4-O-sulfated N-acetyl-beta-D-galactosamine residues is a potent anticoagulant due to a high heparin cofactor II activity. Surprisingly, it has a lower potency to prevent thrombus formation on an experimental model and a lower bleeding effect in rats than the mammalian dermatan sulfate. In contrast, A. nigra dermatan sulfate, also enriched in 2-O-sulfated alpha-L-iduronic acid, but in this case sulfated at O-6 of the N-acetyl-beta-D-galactosamine units, has no in vitro or in vivo anticoagulant activity, does not prevent thrombus formation but shows a bleeding effect similar to the mammalian glycosaminoglycan. Ascidian heparin, composed by 2-O-sulfated alpha-L-iduronic acid, N- and 6-O-sulfated glucosamine (75% and alpha-L-iduronic acid, N- and 6-O-sulfated glucosamine (25% disaccharide units has an anticoagulant activity 10 times lower than the mammalian heparin, is about 20 times less potent in the inhibition of thrombin by antithrombin, but has the same heparin cofactor II activity as mammalian heparin.

  5. Hemocompatibility of Axial Versus Centrifugal Pump Technology in Mechanical Circulatory Support Devices.

    Science.gov (United States)

    Schibilsky, David; Lenglinger, Matthias; Avci-Adali, Meltem; Haller, Christoph; Walker, Tobias; Wendel, Hans Peter; Schlensak, Christian

    2015-08-01

    The hemocompatible properties of rotary blood pumps commonly used in mechanical circulatory support (MCS) are widely unknown regarding specific biocompatibility profiles of different pump technologies. Therefore, we analyzed the hemocompatibility indicating markers of an axial flow and a magnetically levitated centrifugal device within an in vitro mock loop. The HeartMate II (HM II; n = 3) device and a CentriMag (CM; n = 3) adult pump were investigated in a human whole blood mock loop for 360 min using the MCS devices as a driving component. Blood samples were analyzed by enzyme-linked immunosorbent assay for markers of coagulation, complement system, and inflammatory response. There was a time-dependent activation of the coagulation (thrombin-antithrombin complexes [TAT]), complement (SC5b-9), and inflammation system (polymorphonuclear [PMN] elastase) in both groups. The mean value of TAT (CM: 4.0 μg/L vs. 29.4 μg/L, P centrifugal CM device showed significantly lower activation of coagulation and inflammation than that of the HM II axial flow pump. Both HM II and CM have demonstrated an acceptable hemocompatibility profile in patients. However, there is a great opportunity to gain a clinical benefit by developing techniques to lower the blood surface interaction within both pump technologies and a magnetically levitated centrifugal pump design might be superior.

  6. [Novel oral anticoagulants (NOAC)].

    Science.gov (United States)

    Ieko, Masahiro

    2015-10-01

    Novel oral anticoagulants (NOACs), a direct thrombin inhibitor (TDI), and direct factor Xa inhibitors (Xa-INHs) have mainly been used for prevention of stroke associated with atrial fibrillation in place of warfarin. DTI obstructs tenase by inhibiting thrombin generated in the initial phase and feedback to the amplification phase of cell-based coagulation reactions. Xa-INHs inhibit factor Xa activity in the prothrombinase complex of the propagation phase. Since the half-life of NOACs is in the approximate range of 8-14 hours, there are peak and trough periods in the blood concentrations of these agents. During the trough period, a small amount of thrombin is generated and plays a physiological role. The antithrombotic effect of NOACs is exerted during the peak period in combination with the effects of physiological coagulation inhibitors (PCIs) such as antithrombin in the trough period. Endothelial cells are the site for action of PCIs, such that it is important that they remain in a good state for effective anticoagulation by NOACs within the lesions. In a meta-analysis of NOACs vs. warfarin treatment, the former significantly reduced stroke or systemic embolic events by 19% as compared with warfarin, due mainly to a reduction in hemorrhagic stroke, while NOAC administration also significantly reduced intracranial hemorrhage by 52%. PMID:26458452

  7. Preeclampsia - will orphan drug status facilitate innovative biological therapies?

    Science.gov (United States)

    Hahn, Sinuhe

    2015-01-01

    It is generally accepted that the development of novel therapies to treat pregnancy-related disorders, such as preeclampsia, is hampered by the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder: exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem cells. As these projects are being carried out by small biotech enterprises, the question arises of how they are able to fund such undertakings. A novel strategy adopted by two of these companies is that they successfully petitioned US and EU agencies in order that preeclampsia is accepted in the register of rare or orphan diseases. This provides a number of benefits including market exclusivity, assistance with clinical trials, and dedicated funding schemes. Other strategies to supplement meager research funds, especially to test novel approaches, could be crowdfunding, a venture that relies on intimate interaction with advocacy groups. In other words, preeclampsia meets Facebook. Perhaps similar strategies can be adopted to examine novel therapies targeting either the imbalance in pro- or anti-angiogenic growth factors, complement activation, reduced levels of placenta protein 13, or excessive neutrophil activation evident in preeclampsia.

  8. Preeclampsia – will Orphan Drug Status facilitate innovative biological therapies?

    Directory of Open Access Journals (Sweden)

    Sinuhe eHahn

    2015-02-01

    Full Text Available It is generally accepted that development of novel therapies to treat pregnancy-relates disorders, such as preeclampsia, is hampered to the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder, exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem cells. As these projects are being carried out by small biotech enterprises, the question arises of how they are able to fund such undertakings. A novel strategy adopted by two of these companies is that they successfully petitioned US and EU agencies in order that preeclampsia be accepted in the register of rare or orphan diseases. This provides a number of benefits including market exclusivity, assistance with clinical trials and dedicated funding schemes. Other strategies to supplement meager research funds, especially to test novel approaches, could be crowdfunding, a venture which relies on intimate interaction with advocacy groups. In other words, preeclampsia meets Facebook. Perhaps similar strategies can be adopted to examine novel therapies targeting either the imbalance in angiogenic growth factors, complement activation, reduced levels of placenta protein 13 or excessive neutrophil activation evident in preeclampsia.

  9. Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice.

    Science.gov (United States)

    de Boer, Johannes D; Berkhout, Lea C; de Stoppelaar, Sacha F; Yang, Jack; Ottenhoff, Roelof; Meijers, Joost C M; Roelofs, Joris J T H; van't Veer, Cornelis; van der Poll, Tom

    2015-10-15

    Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.

  10. Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation.

    Directory of Open Access Journals (Sweden)

    Rolf Burghaus

    Full Text Available Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist, enoxaparin (an indirect thrombin/Factor Xa inhibitor and dabigatran (a direct thrombin inhibitor. A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data. Unlike previous models, the current model takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, and possesses some unique features, including a blood flow component and a portfolio of drug action mechanisms. This study aimed to use the model to compare the mechanism of action of rivaroxaban with that of warfarin, and to evaluate the efficacy and safety of different rivaroxaban doses with other anticoagulants included in the model. Rather than reproducing known standard clinical measurements, such as the prothrombin time and activated partial thromboplastin time clotting tests, the anticoagulant benchmarking was based on a simulation of physiologically plausible clotting scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity for tissue factor concentration inducing clotting, and a steep concentration-effect relationship, rapidly flattening towards higher inhibitor concentrations, both suggesting a broad therapeutic window. The predicted dosing window is highly accordant with the final dose recommendation based upon extensive clinical studies.

  11. Use of prostaglandin I2 analog in treatment of massive hepatic necrosis associated with endothelial cell injury and diffuse sinusoidal fibrin deposition.

    Science.gov (United States)

    Fujiwara, K; Mochida, S; Ohno, A; Arai, M; Matsui, A; Masaki, N; Hirata, K; Tomiya, T; Yamaoka, M; Nagoshi, S

    1995-01-01

    Endothelial cell damage causes massive hepatic necrosis as a result of fibrin deposition in the hepatic sinusoids. When a stable analog of prostaglandin I2, beraprost sodium, was administered to rats given either dimethylnitrosamine, carbon tetrachloride, or endotoxin following Corynebacterium parvum administration, the hepatic necrosis produced in each was attenuated, but to a greater extent in the dimethylnitrosamine and endotoxin/Corynebacterium parvum models, where fibrin deposition in the hepatic sinusoids occurs, as compared to the carbon tetrachloride model, where such fibrin deposition does not occur. Beraprost sodium reduced the expected increase of portal venous pressure in the endotoxin/Corynebacterium parvum model without affecting plasma thrombin-antithrombin III complex levels. Beraprost sodium also significantly reduced cell killing of both isolated rat hepatocytes and hepatic sinusoidal endothelial cells exposed to tert-butyl hydroperoxide when compared to controls. Beraprost sodium could prove to be a therapeutic candidate for the treatment of hepatic necrosis, particularly in cases associated with fibrin deposition in the hepatic sinusoids because of its fibrin clot-clearing action. PMID:7821117

  12. Risk Factors for Portal Vein Thrombosis in Patients With Cirrhosis Awaiting Liver Transplantation in Shiraz, Iran

    Directory of Open Access Journals (Sweden)

    Bagheri Lankarani

    2015-12-01

    Full Text Available Background Portal vein thrombosis is a fairly common and potentially life-threatening complication in patients with liver cirrhosis. The risk factors for portal vein thrombosis in these patients are still not fully understood. Objectives This study aimed to investigate the associations between various risk factors in cirrhotic patients and the development of portal vein thrombosis. Patients and Methods In this case-control study performed at the Shiraz organ transplantation center, Iran, we studied 219 patients (> 18 years old with liver cirrhosis, who were awaiting liver transplants in our unit, from November 2010 to May 2011. The patients were evaluated by history, physical examination, and laboratory tests, including factor V Leiden, prothrombin gene mutation, Janus Kinase 2 (JAK2 mutation, and serum levels of protein C, protein S, antithrombin III, homocysteine, factor VIII, and anticardiolipin antibodies. Results There was no statistically significant difference in the assessed hypercoagulable states between patients with or without portal vein thrombosis. A history of previous variceal bleeding with subsequent endoscopic treatment in patients with portal vein thrombosis was significantly higher than in those without it (P = 0.013, OR: 2.526, 95% CI: 1.200 - 5.317. Conclusions In our population of cirrhotic patients, treatment of variceal bleeding predisposed the patients to portal vein thrombosis, but hypercoagulable disorders by themselves were not associated with portal vein thrombosis.

  13. Emerging antithrombotic drugs: A review

    Directory of Open Access Journals (Sweden)

    P Sikka

    2011-01-01

    Full Text Available Thromboembolic disorders are one of the disorders for which the researchers are still in search for a safe and efficient drug. Despite the widespread use of antithrombotic drugs for the prevention and treatment of arterial and venous thrombosis, thromboembolic diseases continue to be a major cause of death and disability worldwide. This shows the researchers′ inefficiency in searching efficacious and safe antithrombotic drugs. The researchers have reached to the basic mechanism of thrombus formation and by interrupting various steps of this mechanism, they can prevent as well as treat thromboembolic disorders. In continuation of Aspirin, now, the researchers are using clopedogrel, Ticlopidine and GpIIb/IIIa inhibitors (Abciximab, Tirofiban and Eptifibatide. Warfarin is an old antithrombotic drug, which is still being used but due to various side effects and drug interactions, they are bound to use newer drugs. Newer antiplatelet drugs include prasugrel, ticagrelor, cangrelor and elinogrel whereas newer thrombin inhibitors are Ximelgatran and Dabigatran. Apixaban and edoxaban are also newer entry in this category as Factor Xa inhibitors. Idrabiotaparinux is an indirect inhibitor of Xa as it accelerates the activity of antithrombin. Moreover, researches and trials for better and safe drugs are going on.

  14. Newer antithrombotic drugs

    Science.gov (United States)

    Sikka, Pranav; Bindra, V. K.

    2010-01-01

    Thromboembolic disorders are one of the disorders for which we are still on the look out for a safe and efficient drug. Despite the widespread use of antithrombotic drugs for the prevention and treatment of arterial and venous thrombosis, thromboembolic diseases continue to be a major cause of death and disability worldwide. This shows our inefficiency in searching efficacious and safe antithrombotic drugs. We have reached the basic mechanism of thrombus formation and by interrupting various steps of this mechanism, we can prevent as well as treat thromboembolic disorders. In continuation of Aspirin, now, we are using Clopidogrel, Ticlopidine and GpIIb/IIIa inhibitors (Abciximab, Tirofiban and Eptifibatide). Warfarin is an old antithrombotic drug which is still being used; but due to various side effects and drug interactions, we are bound to use newer drugs. Newer antiplatelet drugs include Prasugrel, Ticagrelor and Cangrelor, whereas newer thrombin inhibitors are Ximelgatran and Dabigatran. Apixaban is also a newer entry in this category as factor Xa inhibitor. Idrabiotaparinux is an indirect inhibitor of Xa as it accelerates the activity of antithrombin. Moreover, researches and trials for better and safe drugs are ongoing. PMID:21572750

  15. Complications of bariatric surgery: Presentation and emergency management.

    Science.gov (United States)

    Kassir, Radwan; Debs, Tarek; Blanc, Pierre; Gugenheim, Jean; Ben Amor, Imed; Boutet, Claire; Tiffet, Olivier

    2016-03-01

    The epidemic in obesity has led to an increase in number of so called bariatric procedures. Doctors are less comfortable managing an obese patient after bariatric surgery. Peri-operative mortality is less than 1%. The specific feature in the obese patient is that the classical signs of peritoneal irritation are never present as there is no abdominal wall and therefore no guarding or rigidity. Simple post-operative tachycardia in obese patients should be taken seriously as it is a WARNING SIGNAL. The most common complication after surgery is peritonitis due to anastomotic fistula formation. This occurs typically as an early complication within the first 10 days post-operatively and has an incidence of 1-6% after gastric bypass and 3-7% after sleeve gastrectomy. Post-operative malnutrition is extremely rare after restrictive surgery (ring, sleeve gastrectomy) although may occur after malabsorbative surgery (bypass, biliary pancreatic shunt) and is due to the restriction and change in absorption. Prophylactic cholecystectomy is not routinely carried out during the same procedure as the bypass. Superior mesenteric vein thrombosis after bariatric surgery is a diagnosis which should be considered in the presence of any postoperative abdominal pain. Initially a first etiological assessment is performed (measurement of antithrombin III and of protein C and protein S, testing for activated protein C resistance). If the least doubt is present, a medical or surgical consultation should be requested with a specialist practitioner in the management of obese patients as death rates increase with delayed diagnosis. PMID:26808323

  16. Lack of Association between Recurrent Pregnancy Loss and Inherited Thrombophilia in a Group of Colombian Patients

    Science.gov (United States)

    Cardona, Henry; Castañeda, Serguei A.; Cardona Maya, Wálter; Alvarez, Leonor; Gómez, Joaquín; Gómez, Jorge; Torres, José; Tobón, Luis; Bedoya, Gabriel; Cadavid, Ángela P.

    2012-01-01

    Studies have shown an association between recurrent pregnancy loss and inherited thrombophilia in Caucasian populations, but there is insufficient knowledge concerning triethnic populations such as the Colombian. The aim of this study was to evaluate whether inherited thrombophilia is associated with recurrent pregnancy loss. Methods. We conducted a case-control study of 93 patients with recurrent pregnancy loss (cases) and 206 healthy multiparous women (controls) in a Colombian subpopulation. Three single nucleotide polymorphisms (SNPs) markers of the inherited thrombophilias factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T were genotyped by PCR-RFLP. Activated protein C resistance and plasma levels of antithrombin, protein C, and protein S were also measured. Results. The frequency of thrombophilia-associated SNPs, activated protein C resistance, and anticoagulant protein deficiencies, was low overall, except for the methylenetetrahydrofolate reductase C677T SNP. The differences between patients and controls had no statistical significance. Conclusion. Our study confirms the low prevalence of inherited thrombophilias in non-Caucasian populations and it is unlikely that the tested thrombophilias play a role in the pathogenesis of recurrent pregnancy loss in this Colombian population. PMID:22577540

  17. [Adult-onset rare diseases].

    Science.gov (United States)

    Pfliegler, György; Kovács, Erzsébet; Kovács, György; Urbán, Krisztián; Nagy, Valéria; Brúgós, Boglárka

    2014-03-01

    The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.). PMID:24566697

  18. [Nephrotic syndrome revealed by pulmonary embolism: about four cases].

    Science.gov (United States)

    Chaudesaygues, E; Grasse, M; Marchand, L; Villar, E; Aupetit, J-F

    2014-11-01

    Nephrotic syndrom is an association of proteinuria>3g/d or 50mg/kg/d, an hypoalbuminemiadiabetes, high blood pressure and amyloidosis. We present four cases about nephrotic syndrome after thromboembolic disease. In every case, patients show a pulmonary embolism symptomatic of a nephrotic syndrom, whose diagnostic could be delayed up to six months after first pulmonary symptoms. This raised the problem of renal biopsy in these patients who need anticoagulation. In minimal change nephrosis, without hematuria, high blood pressure or renal dysfonction, a corticosteroid therapy test could be done assuming that is corticosensitive minimal glomerular injury. In every case, anticoagulation course must be completed and maintained in case of patent nephrotic syndrom with an albuminemia under 20g/L. In case of pulmonary embolism or deep vein thrombosis, idiopathic-looking, a nephrotic syndrome must be sought-after. The two diagnosis ways are the proteinuria on the urine dipstick and the hypoproteinemia on usual biology. The main mechanism is the coagulation factor leak, side effect of the nephrotic syndrom, notably because of the antithrombin III. PMID:25281996

  19. Lack of Association between Recurrent Pregnancy Loss and Inherited Thrombophilia in a Group of Colombian Patients

    Directory of Open Access Journals (Sweden)

    Henry Cardona

    2012-01-01

    Full Text Available Studies have shown an association between recurrent pregnancy loss and inherited thrombophilia in Caucasian populations, but there is insufficient knowledge concerning triethnic populations such as the Colombian. The aim of this study was to evaluate whether inherited thrombophilia is associated with recurrent pregnancy loss. Methods. We conducted a case-control study of 93 patients with recurrent pregnancy loss (cases and 206 healthy multiparous women (controls in a Colombian subpopulation. Three single nucleotide polymorphisms (SNPs markers of the inherited thrombophilias factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T were genotyped by PCR-RFLP. Activated protein C resistance and plasma levels of antithrombin, protein C, and protein S were also measured. Results. The frequency of thrombophilia-associated SNPs, activated protein C resistance, and anticoagulant protein deficiencies, was low overall, except for the methylenetetrahydrofolate reductase C677T SNP. The differences between patients and controls had no statistical significance. Conclusion. Our study confirms the low prevalence of inherited thrombophilias in non-Caucasian populations and it is unlikely that the tested thrombophilias play a role in the pathogenesis of recurrent pregnancy loss in this Colombian population.

  20. Intraperitoneal administration of activated protein C prevents postsurgical adhesion band formation.

    Science.gov (United States)

    Dinarvand, Peyman; Hassanian, Seyed Mahdi; Weiler, Hartmut; Rezaie, Alireza R

    2015-02-19

    Postsurgical peritoneal adhesion bands are the most important causes of intestinal obstruction, pelvic pain, and female infertility. In this study, we used a mouse model of adhesion and compared the protective effect of activated protein C (APC) to that of the Food and Drug Administration-approved antiadhesion agent, sodium hyaluronate/carboxymethylcellulose (Seprafilm) by intraperitoneal administration of either APC or Seprafilm to experimental animals. Pathological adhesion bands were graded on day 7, and peritoneal fluid concentrations of tissue plasminogen activator (tPA), d-dimer, thrombin-antithrombin complex, and cytokines (IL-1β, IL-6, interferon-γ, tumor necrosis factor-α, transforming growth factor-β1) were evaluated. Inflammation scores were also measured based on histologic data obtained from peritoneal tissues. Relative to Seprafilm, intraperitoneal administration of human APC led to significantly higher reduction of postsurgical adhesion bands. Moreover, a markedly lower inflammation score was obtained in the adhesive tissues of the APC-treated group, which correlated with significantly reduced peritoneal concentrations of proinflammatory cytokines and an elevated tPA level. Further studies using variants of human APC with or without protease-activated receptor 1 (PAR1) signaling function and mutant mice deficient for either endothelial protein C receptor (EPCR) or PAR1 revealed that the EPCR-dependent signaling activity of APC is primarily responsible for its protective activity in this model. These results suggest APC has therapeutic potential for preventing postsurgical adhesion bands. PMID:25575539

  1. Preeclampsia – Will Orphan Drug Status Facilitate Innovative Biological Therapies?

    Science.gov (United States)

    Hahn, Sinuhe

    2015-01-01

    It is generally accepted that the development of novel therapies to treat pregnancy-related disorders, such as preeclampsia, is hampered by the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder: exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem cells. As these projects are being carried out by small biotech enterprises, the question arises of how they are able to fund such undertakings. A novel strategy adopted by two of these companies is that they successfully petitioned US and EU agencies in order that preeclampsia is accepted in the register of rare or orphan diseases. This provides a number of benefits including market exclusivity, assistance with clinical trials, and dedicated funding schemes. Other strategies to supplement meager research funds, especially to test novel approaches, could be crowdfunding, a venture that relies on intimate interaction with advocacy groups. In other words, preeclampsia meets Facebook. Perhaps similar strategies can be adopted to examine novel therapies targeting either the imbalance in pro- or anti-angiogenic growth factors, complement activation, reduced levels of placenta protein 13, or excessive neutrophil activation evident in preeclampsia. PMID:25767802

  2. CLINICAL SIGNIFICANCE OF HEMOSTATIC MOLECULAR MARKERS IN ACUTE LEUKEMIA

    Institute of Scientific and Technical Information of China (English)

    吴方; 王学锋; 璩斌; 王鸿利; 沈志祥; 王振义

    2002-01-01

    Objective To elucidate the clinical significance of hemostatic molecular markers changes in acute leukemia (AL). Methods A series of hemostatic molecular markers including tissue factor ( TF) , tissue factor pathway inhibitor (TFPI), thrombin-antithrombin complex (TAT), plasmin anti-plasmin complex (PAP), urokinase-type plasminogen activator (u-PA), and urokinase-type plasminogen activator receptor ( uPAR) were measured in AL. Results The plasma level of TF, TAT, u-PA and u-PAR was significantly elevated before treatment, while in acute myeloid leukemia ( AML ) , only the level of TFPl and PAP increased.After treatment, TF and TAT remained at high level in AML, u-PA and u-PAR were still abnormal except in patients who obtained complete remission ( CR ). PAP and u-PA elevated remarkably in patient with severe hemorrhage. Conclusion The results indicated that there was hemostatic abnormal as well as hyperfibrinolysis in AL, which varied with different type of AL and can be ameliorated with clinical improvement. The measurement of TF, TAT, PAP may provide useful information for the diagnosis of DIC ; u-PA, u-PAR may be considered as useful markers for prognosis. Patient with sever hemorrhage should be treated with antifibrinolysis drugs, and great attention should be paid to prevent hypercoagulability in patients with AML after chemotherapeutic treatment.

  3. Elucidating novel serum biomarkers associated with pulmonary tuberculosis treatment.

    Directory of Open Access Journals (Sweden)

    Mary A De Groote

    Full Text Available In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention's Tuberculosis Trials Consortium (TBTC Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB. We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy.

  4. Nebulized anticoagulants limit coagulopathy but not inflammation in pseudomonas aeruginosa-induced pneumonia in rats.

    Science.gov (United States)

    Cornet, Alexander D; Hofstra, Jorrit J; Vlaar, Alexander P; van den Boogaard, Floor E; Roelofs, Joris J; van der Poll, Tom; Levi, Marcel; Groeneveld, A B Johan; Schultz, Marcus J

    2011-10-01

    Disturbed alveolar fibrin turnover is a characteristic feature of pneumonia. Inhibitors of coagulation could exert lung-protective effects via anticoagulant (inhibiting fibrin deposition) and possibly anti-inflammatory pathways, but could also affect host defense. In this randomized controlled in vivo laboratory study, rats were challenged intratracheally with Pseudomonas aeruginosa, inducing pneumonia, and randomized to local treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin, or danaparoid. Induction of P. aeruginosa pneumonia resulted in activation of pulmonary coagulation and inhibition of pulmonary fibrinolysis, as reflected by increased pulmonary levels of thrombin-AT complexes and fibrin degradation products and decreased pulmonary levels plasminogen activator activity. Pseudomonas aeruginosa pneumonia was accompanied by systemic coagulopathy, since systemic levels of thrombin-AT complexes increased, and systemic levels of plasminogen activator activity decreased. Although rh-APC and plasma-derived AT potently limited pulmonary coagulopathy, neither heparin nor danaparoid affected net pulmonary fibrin turnover. Recombinant human APC also displayed systemic anticoagulant effects. Neither bacterial clearance nor pulmonary inflammation was affected by anticoagulant therapy. Nebulization of rh-APC or plasma-derived AT attenuated pulmonary coagulopathy, but not bacterial clearance or inflammation, in a rat model of P. aeruginosa pneumonia. PMID:21897338

  5. Surgical revascularisation in patients with severe limb ischaemia induces a pro-thrombotic state.

    Science.gov (United States)

    Collins, P; Ford, I; Greaves, M; Macaulay, E; Brittenden, J

    2006-08-01

    Platelet and coagulation activation are implicated in the increased incidence of ischaemic events seen in patients with peripheral arterial disease. This study aimed to assess the effect of surgical revascularisation on platelet aggregation and coagulation in patients with severe limb ischaemia (SLI). Twenty-two patients had blood samples taken: prior to surgery, on reperfusion, 2, 24 and 48 h post-surgery. Platelet aggregation through COX-mediated and thrombin receptor activator peptide (TRAP)-stimulated GPIIb/IIIa pathways was measured by the Ultegra point of care system. Thrombin-antithrombin III Complex (TAT) and D-dimer were measured by ELISA. COX-mediated aggregation increased significantly at reperfusion and remained elevated at 24 h [median increase from baseline of 9% (range -16 to 33%) P = 0.011]. TRAP-stimulated aggregation increased significantly at reperfusion and remained elevated at 2 h post-surgery [median increase 18% (range -71 to 45%); P = 0.007]. TAT levels were significantly elevated from reperfusion and remained so at 48 h (P coagulation and fibrinolytic pathways despite the use of aspirin and heparin. Thus in the early post-operative these patients exhibit a pro-thrombotic state. PMID:16928603

  6. Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome.

    Science.gov (United States)

    Sebag, Sara C; Bastarache, Julie A; Ware, Lorraine B

    2011-09-01

    Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by excessive intraalveolar fibrin deposition, driven, at least in part by inflammation. The imbalance between activation of coagulation and inhibition of fibrinolysis in patients with ALI/ARDS favors fibrin formation and appears to occur both systemically and in the lung and airspace. Tissue factor (TF), a key mediator of the activation of coagulation in the lung, has been implicated in the pathogenesis of ALI/ARDS. As such, there have been numerous investigations modulating TF activity in a variety of experimental systems in order to develop new therapeutic strategies for ALI/ARDS. This review will summarize current understanding of the role of TF and other proteins of the coagulation cascade as well the fibrinolysis pathway in the development of ALI/ARDS with an emphasis on the pathways that are potential therapeutic targets. These include the TF inhibitor pathway, the protein C pathway, antithrombin, heparin, and modulation of fibrinolysis through plasminogen activator- 1 (PAI-1) or plasminogen activators (PA). Although experimental studies show promising results, clinical trials to date have proven unsuccessful in improving patient outcomes. Modulation of coagulation and fibrinolysis has complex effects on both hemostasis and inflammatory pathways and further studies are needed to develop new treatment strategies for patients with ALI/ARDS. PMID:21401517

  7. New anticoagulants.

    Science.gov (United States)

    Weitz, J I; Bates, S M

    2005-08-01

    The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing. PMID:16102051

  8. Serpins in thrombosis, hemostasis and fibrinolysis.

    Science.gov (United States)

    Rau, J C; Beaulieu, L M; Huntington, J A; Church, F C

    2007-07-01

    Hemostasis and fibrinolysis, the biological processes that maintain proper blood flow, are the consequence of a complex series of cascading enzymatic reactions. Serine proteases involved in these processes are regulated by feedback loops, local cofactor molecules, and serine protease inhibitors (serpins). The delicate balance between proteolytic and inhibitory reactions in hemostasis and fibrinolysis, described by the coagulation, protein C and fibrinolytic pathways, can be disrupted, resulting in the pathological conditions of thrombosis or abnormal bleeding. Medicine capitalizes on the importance of serpins, using therapeutics to manipulate the serpin-protease reactions for the treatment and prevention of thrombosis and hemorrhage. Therefore, investigation of serpins, their cofactors, and their structure-function relationships is imperative for the development of state-of-the-art pharmaceuticals for the selective fine-tuning of hemostasis and fibrinolysis. This review describes key serpins important in the regulation of these pathways: antithrombin, heparin cofactor II, protein Z-dependent protease inhibitor, alpha(1)-protease inhibitor, protein C inhibitor, alpha(2)-antiplasmin and plasminogen activator inhibitor-1. We focus on the biological function, the important structural elements, their known non-hemostatic roles, the pathologies related to deficiencies or dysfunction, and the therapeutic roles of specific serpins. PMID:17635716

  9. Robustness of nanofiltration for increasing the viral safety margin of biological products.

    Science.gov (United States)

    Caballero, Santiago; Diez, José M; Belda, Francisco J; Otegui, Magdalena; Herring, Steven; Roth, Nathan J; Lee, Douglas; Gajardo, Rodrigo; Jorquera, Juan I

    2014-03-01

    In this study, the virus-removal capacity of nanofiltration was assessed using validated laboratory scale models on a wide range of viruses (pseudorabies virus; human immunodeficiency virus; bovine viral diarrhea virus; West Nile virus; hepatitis A virus; murine encephalomyocarditis virus; and porcine parvovirus) with sizes from 18 nm to 200 nm and applying the different process conditions existing in a number of Grifols' plasma-derived manufacturing processes (thrombin, α1-proteinase inhibitor, Factor IX, antithrombin, plasmin, intravenous immunoglobulin, and fibrinogen). Spiking experiments (n = 133) were performed in process intermediate products, and removal was subsequently determined by infectivity titration. Reduction Factor (RF) was calculated by comparing the virus load before and after nanofiltration under each product purification condition. In all experiments, the RFs were close to or greater than 4 log10 (>99.99% of virus elimination). RF values were not significantly affected by the process conditions within the limits assayed (pH, ionic strength, temperature, filtration ratio, and protein concentration). The virus-removal capacity of nanofiltration correlated only with the size of the removed agent. In conclusion, nanofiltration, as used in the manufacturing of several Grifols' products, is consistent, robust, and not significantly affected by process conditions.

  10. Anti-Diabetic Effects of Madecassic Acid and Rotundic Acid

    Directory of Open Access Journals (Sweden)

    Yuan-Man Hsu

    2015-12-01

    Full Text Available Anti-diabetic effects of madecassic acid (MEA and rotundic acid (RA were examined. MEA or RA at 0.05% or 0.1% was supplied to diabetic mice for six weeks. The intake of MEA, not RA, dose-dependently lowered plasma glucose level and increased plasma insulin level. MEA, not RA, intake dose-dependently reduced plasminogen activator inhibitor-1 activity and fibrinogen level; as well as restored antithrombin-III and protein C activities in plasma of diabetic mice. MEA or RA intake decreased triglyceride and cholesterol levels in plasma and liver. Histological data agreed that MEA or RA intake lowered hepatic lipid droplets, determined by ORO stain. MEA intake dose-dependently declined reactive oxygen species (ROS and oxidized glutathione levels, increased glutathione content and maintained the activity of glutathione reductase and catalase in the heart and kidneys of diabetic mice. MEA intake dose-dependently reduced interleukin (IL-1β, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels in the heart and kidneys of diabetic mice. RA intake at 0.1% declined cardiac and renal levels of these inflammatory factors. These data indicated that MEA improved glycemic control and hemostatic imbalance, lowered lipid accumulation, and attenuated oxidative and inflammatory stress in diabetic mice. Thus, madecassic acid could be considered as an anti-diabetic agent.

  11. Des-gamma-carboxyprothrombin (PIVKA-II) levels in maternal serum throughout gestation.

    Science.gov (United States)

    Nishiguchi, Tomizo; Matsuyama, Kaoru; Kobayashi, Takao; Kanayama, Naohiro

    2005-06-01

    The status of vitamin K in pregnant women was investigated using the highly sensitive method for des-gamma-carboxyprothrombin (protein induced by vitamin K absence [PIVKA-II]), electrochemiluminescence immunoassay. A gradual elevation of PIVKA-II related to gestational weeks was observed in healthy pregnant women, suggesting that a modest vitamin K deficiency takes place in gestation. Furthermore, throughout gestation the majority of pregnant women exceeded the healthy adult levels in PIVKA-II. Among complicated gestations of preeclampsia, a remarkable elevation of PIVKA-II was observed in severe preeclampsia, in which a high correlation between PIVKA-II level and coagulation parameters, including thrombin-antithrombin (TAT) complexes, was revealed. These data were suggestive that the vitamin K status readily decreased into a deficient status in hypercoagulative conditions. Among other complicated gestations, a moderate elevation of PIVKA-II was demonstrated in hyperemetic conditions, and, if at all, only a slight elevation of PIVKA-II was observed in other maternal diseases. The present study is the first report regarding the changes of PIVKA-II in pregnant women.

  12. Plasma functionalization of polycarbonaturethane to improve endothelialization--Effect of shear stress as a critical factor for biocompatibility control.

    Science.gov (United States)

    Lukas, Karin; Thomas, Ulrich; Gessner, André; Wehner, Daniel; Schmid, Thomas; Schmid, Christof; Lehle, Karla

    2016-04-01

    Medical devices made of polycarbonaturethane (PCU) combine excellent mechanical properties and little biological degradation, but restricted hemocompatibility. Modifications of PCU might reduce platelet adhesion and promote stable endothelialization. PCU was modified using gas plasma treatment, binding of hydrogels, and coupling of cell-active molecules (modified heparin, anti-thrombin III (ATIII), argatroban, fibronectin, laminin-nonapeptide, peptides with integrin-binding arginine-glycine-aspartic acid (RGD) motif). Biocompatibility was verified with static and dynamic cell culture techniques. Blinded analysis focused on improvement in endothelial cell (EC) adhesion/proliferation, anti-thrombogenicity, reproducible manufacturing process, and shear stress tolerance of ECs. EC adhesion and antithrombogenicity were achieved with 9/35 modifications. Additionally, 6/9 stimulated EC proliferation and 3/6 modification processes were highly reproducible for endothelialization. The latter modifications comprised immobilization of ATIII (A), polyethyleneglycole-diamine-hydrogel (E) and polyethylenimine-hydrogel connected with modified heparin (IH). Under sheer stress, only the IH modification improved EC adhesion within the graft. However, ECs did not arrange in flow direction and cell anchorage was restricted. Despite large variation in surface modification chemistry and improved EC adhesion under static culture conditions, additional introduction of shear stress foiled promising preliminary data. Therefore, biocompatibility testing required not only static tests but also usage of physiological conditions such as shear stress in the case of vascular grafts. PMID:26762398

  13. Thrombin Activatable Fibrinolysis Inhibitor in Preeclmapsia and Gestational Hypertension throughout the Gestation

    Institute of Scientific and Technical Information of China (English)

    Yinghong ZHANG; Yu HU; Tao GUO; Wenning WEI; Xiaoping ZHANG

    2008-01-01

    To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia (PE) and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithrombin (TAT) complex. Thirty normal pregnant women served as controls. ELISA was employed for the detection. The results showed that the TAFI antigen levels in normal pregnancy group, gestational hypertension group and PE group were (85.35±24.69)%, (99.65±18.27)%, (110.12±23.36)%; (97.06±21.40)%, (114.08±27.76)%, (125.49±24.70)%; (106.6±19.21)%, (129.2±25.07)%, (139.1±30.12)%, in the 1st, 2nd and 3rd trimester respectively. No significant differences were found between the normal pregnancy group and gestational hypertension group but significant difference existed between normal pregnancy group and PE group in each tri- mester (P<0.05). TAT complexes were significantly higher in patients with PE than that in controls (P<0.05), but no correlation was found between TAT and TAFI. It is concluded that TAFI may con- tributed to the impairment of fibrinolysis in the patients with PE and may serves as a sensitive indi- cator for PE, but it may not help in the diagnosis of the gestational hypertension.

  14. [Comparison between the centrifugation on MPA C10 (Roche Diagnostics) and the centrifugation according recommendations of GEHT (Groupe d'étude de l'hémostase et de la thrombose) for the daily hemostasis assays].

    Science.gov (United States)

    Flamant, Fabrice; Borg, Jeanne-Yvonne; Lenormand, Bernard; Le Cam-Duchez, Véronique

    2014-01-01

    Actually, many laboratories tend to acquire pre analytic automates to prepare specimens for analysis. For haemostasis, these pre analytical modules are not always in agreement with the recommendations from the Groupe d'étude de l'hémostase et de la thrombose (GEHT). For example in the MPA C10 module (Roche Diagnostics) the speed of centrifugation was not rather fast compared with the GEHT recommandations. Then, to be able to use this automate for routine coagulation assays, we compared results of Quick time, activated partial prothombin time, fibrinogen, factor II, factor V, factor VII, factor X and antithrombin levels and unfractioned heparin anti-Xa activity measurement after MPA (1,885 g - 999 sec) or GEHT (2,500 g - 900 sec) protocol of centrifugation. First, we verified platelet counts: in 82% of specimens, the platelet counts were under 10.10(9)/L after centrifugation on MPA module. Moreover, a good correlation was observed in all comparisons. Then we concluded the MPA C10 module was usable for routine coagulation tests.

  15. Clinical Presentation, Management, and Outcomes of Deep Vein Thrombosis Based on Doppler Ultrasonography Examination.

    Science.gov (United States)

    Al-Thani, Hassan; El-Menyar, Ayman; Asim, Mohammad; Kiliyanni, Abdul Salim

    2016-07-01

    We studied the frequency, clinical presentation, and outcomes of deep vein thrombosis (DVT). Serial Doppler ultrasonography was performed between 2008 and 2013 for 6420 patients with suspected DVT. Diagnosis was confirmed in 662 (10.3%) participants (mean age: 50 ± 17 years; 51% females). Obesity, diabetes mellitus, and malignancy were reported in 47%, 28%, and 16%, respectively. Abnormal protein C, protein S, factor V Leiden, or antithrombin III were found in 9%, 7%, 3.8%, and 4%, respectively. Left, right, and both legs were involved in 55%, 37%, and 8%, respectively. Common femoral, popliteal, and posterior tibial veins were affected in 48.5%, 72%, and 71%, respectively. Postthrombotic syndrome, pulmonary embolism, and death were reported in 50%, 12.2%, and 15% of cases, respectively. Kaplan-Meier survival curves and Cox regression analysis showed that gender had no impact on mortality during follow-up; however, age (>50 years) was associated with greater risk of death (hazard ratio: 6.54; 95% confidence interval: 3.2-13.3). These findings will improve our understanding of the various risk factors and help develop institutional guidelines for the management of patients with DVT. PMID:26345414

  16. Haemostatic reference intervals in pregnancy

    DEFF Research Database (Denmark)

    Szecsi, Pal Bela; Jørgensen, Maja; Klajnbard, Anna;

    2010-01-01

    Haemostatic reference intervals are generally based on samples from non-pregnant women. Thus, they may not be relevant to pregnant women, a problem that may hinder accurate diagnosis and treatment of haemostatic disorders during pregnancy. In this study, we establish gestational age-specific refe......Haemostatic reference intervals are generally based on samples from non-pregnant women. Thus, they may not be relevant to pregnant women, a problem that may hinder accurate diagnosis and treatment of haemostatic disorders during pregnancy. In this study, we establish gestational age......-specific reference intervals for coagulation tests during normal pregnancy. Eight hundred one women with expected normal pregnancies were included in the study. Of these women, 391 had no complications during pregnancy, vaginal delivery, or postpartum period. Plasma samples were obtained at gestational weeks 13......-20, 21-28, 29-34, 35-42, at active labor, and on postpartum days 1 and 2. Reference intervals for each gestational period using only the uncomplicated pregnancies were calculated in all 391 women for activated partial thromboplastin time (aPTT), fibrinogen, fibrin D-dimer, antithrombin, free protein S...

  17. NCO-sP(EO-stat-PO Coatings on Gold Sensors—a QCM Study of Hemocompatibility

    Directory of Open Access Journals (Sweden)

    Frank K. Gehring

    2011-05-01

    Full Text Available The reliability of implantable blood sensors is often hampered by unspecific adsorption of plasma proteins and blood cells. This not only leads to a loss of sensor signal over time, but can also result in undesired host vs. graft reactions. Within this study we evaluated the hemocompatibility of isocyanate conjugated star shaped polytheylene oxide—polypropylene oxide co-polymers NCO-sP(EO-stat-PO when applied to gold surfaces as an auspicious coating material for gold sputtered blood contacting sensors. Quartz crystal microbalance (QCM sensors were coated with ultrathin NCO-sP(EO-stat-PO films and compared with uncoated gold sensors. Protein resistance was assessed by QCM measurements with fibrinogen solution and platelet poor plasma (PPP, followed by quantification of fibrinogen adsorption. Hemocompatibility was tested by incubation with human platelet rich plasma (PRP. Thrombin antithrombin-III complex (TAT, β-thromboglobulin (β-TG and platelet factor 4 (PF4 were used as coagulation activation markers. Furthermore, scanning electron microscopy (SEM was used to visualize platelet adhesion to the sensor surfaces. Compared to uncoated gold sensors, NCO-sP(EO-stat-PO coated sensors revealed significant better resistance against protein adsorption, lower TAT generation and a lower amount of adherent platelets. Moreover, coating with ultrathin NCO-sP(EO-stat-PO films creates a cell resistant hemocompatible surface on gold that increases the chance of prolonged sensor functionality and can easily be modified with specific receptor molecules.

  18. Blood peptidome-degradome profile of breast cancer.

    Directory of Open Access Journals (Sweden)

    Yufeng Shen

    Full Text Available BACKGROUND: Cancer invasion and metastasis are closely associated with activities within the degradome; however, little is known about whether these activities can be detected in the blood of cancer patients. METHODOLOGY AND PRINCIPAL FINDINGS: The peptidome-degradome profiles of pooled blood plasma sampled from 15 breast cancer patients (BCP and age, race, and menopausal status matched control healthy persons (HP were globally characterized using advanced comprehensive separations combined with tandem Fourier transform mass spectrometry and new data analysis approaches that facilitated top-down peptidomic analysis. The BCP pool displayed 71 degradome protein substrates that encompassed 839 distinct peptidome peptides. In contrast, the HP 50 degradome substrates found encompassed 425 peptides. We find that the ratios of the peptidome peptide relative abundances can vary as much as >4000 fold between BCP and HP. The experimental results also show differential degradation of substrates in the BCP sample in their functional domains, including the proteolytic and inhibitory sites of the plasmin-antiplasmin and thrombin-antithrombin systems, the main chains of the extracellular matrix protection proteins, the excessive degradation of innate immune system key convertases and membrane attack complex components, as well as several other cancer suppressor proteins. CONCLUSIONS: Degradomics-peptidomics profiling of blood plasma is highly sensitive to changes not evidenced by conventional bottom-up proteomics and potentially provides unique signatures of possible diagnostic utility.

  19. Alveolar rhabdomyosarcoma with massive disseminated intravascular coagulopathy treated with systemic chemotherapy.

    Science.gov (United States)

    Yoon, Byung Gyu; Baek, Hee Jo; Oh, Burm Seok; Han, Dong Kyun; Choi, Yoo Duk; Kook, Hoon

    2015-12-01

    It is uncommon for pediatric patients with rhabdomyosarcoma to present with clinical and/or laboratory features of disseminated intravascular coagulation (DIC). We report a case of metastatic alveolar rhabdomyosarcoma with severe bleeding because of DIC in a 13-year-old boy. He experienced persistent oozing at the site of a previous operation, gross hematuria, and massive epistaxis. Two weeks after initiating combination chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide, the patients' laboratory indications of DIC began to resolve. During this period, the patient received massive blood transfusion of a total of 311 units (26 units of red blood cells, 26 units of fresh frozen plasma, 74 units of platelet concentrates, 17 units of single donor platelets, and 168 units of cryoprecipitate), antithrombin-III and a synthetic protease inhibitor. Despite chemotherapy and radiation therapy, he died 1 year later because of disease progression. In children with metastatic rhabdomyosarcoma and massive DIC, prompt chemotherapy and aggressive supportive care is important to decrease malignancy-triggered procoagulant activities.

  20. A study of some aspects of auto immunity in children with thalassemia major

    International Nuclear Information System (INIS)

    This study is subjected to estimate the study of the most common autoimmune complications in thalassaemic and the prevalence of different auto anti-bodies so as to evaluate its correlation with personal data including age, sex, growth parameters, Hepatitis C virus infection ferritin level and type of iron chelation therapy methodology : Different Abs including anti-cardiolipin, anti-tistone, ANA, Anti-erythropoietin by ELISA technique Hepatitis C virus by ELISA. Ferritin by IRMA (Immune radiometric assay), Protein C, S. Anti-thrombin III by ELISA result of the study were analyzed by appropriate statistical methods .The results showed that age of Hepatitis C virus negative cases was significantly lower than Hepatitis C virus Positive cases, ferritin levels were significantly higher in patients on defripone than those as desferrioxamine, anti-erythropoietin was detected in 93.3% of cases regarding the antithrombotic factors deficiency. Protein C was deficient in 26.67% of cases. Protein S was deficient in 13.33% only and no cases showed anti thrombin III deficiency. No special relation was found between these abnormalities and type of chelation , Conclusions: Auto-immunity may be a cofactor in the development of life threatening complication

  1. Factor V Leiden mutation does not affect coagulopathy or outcome in lethal H1N1 influenza.

    Science.gov (United States)

    Schouten, M; van der Sluijs, K F; Roelofs, J J T H; Levi, M; Van't Veer, C; van der Poll, T

    2010-12-01

    Influenza A is a major cause of mortality. Knowledge on coagulation activation in influenza infection is limited. The factor V Leiden (FVL) mutation is possibly subject to positive selection pressure. It is unknown whether this mutation impacts on the outcome of severe influenza. In the present study, the effect of lethal influenza on pulmonary and systemic coagulation activation and whether or not FVL mutation alters coagulation activation in and the course of lethal influenza, was determined. Wild-type mice, and mice heterozygous or homozygous for FVL were infected intranasally with a lethal dose of H1N1 (haemagglutinin 1 and neuraminidase 1) influenza A. Mice were sacrificed after 48 or 96 h for determination of coagulation activation, histopathology, pulmonary inflammatory parameters and viral load, or were observed in a survival study. Extensive local and systemic coagulation activation during lethal influenza was demonstrated by increased lung and plasma levels of thrombin-antithrombin complexes and fibrin degradation products, and by pulmonary fibrin deposition. FVL mutation did not influence the procoagulant response, lung histopathology or survival. FVL mice demonstrated elevated viral loads 48 h after infection. In conclusion, coagulation is activated locally and systemically during lethal murine influenza A infection. The FVL mutation does not influence coagulation activation, lung inflammation or survival in lethal influenza A. PMID:20413539

  2. [Thrombotic complications in the nephrotic syndrome].

    Science.gov (United States)

    Keusch, G

    1989-08-01

    Thromboembolic episodes are one of the most serious complications in patients with nephrotic syndrome, with an overall incidence of 25%. The most frequent site of thrombosis is the renal vein, with a reported incidence varying from 2-42%. Arterial thromboses are much less common than venous thromboses, with an overall incidence of 3%. Clinical course of renal vein thrombosis may be acute or chronic. Renal venography is the method of choice in its diagnosis. Duplex scanning, computed tomography and magnetic resonance imaging may be as accurate as venography. Once the diagnosis of renal vein thrombosis is established, anticoagulation therapy should be started. Thrombectomy or thrombolytic therapy seem to have little to offer over oral anticoagulation. The increased incidence of thrombotic complications in nephrotic syndrome may be due to a hypercoagulable state distinguished by an increase in coagulation factors (V, VIII, X and fibrinogen); a decrease in the levels of coagulation inhibitors (antithrombin III, protein S); an increase in alpha 2-antiplasmin activity; and exaggerated platelet adhesiveness and aggregation. This pre-thrombotic state may be aggravated by additional rheological factors (immobilization, diuretic therapy etc.). Serum albumin has been found to be an appropriate parameter to assess the risk of thrombosis development in these patients. A serum albumin level below 20 g/l carries a high risk of thromboembolic complications. Prophylactic anticoagulation therapy is therefore indicated in patients with serum albumin below 20 g/l.

  3. Venous thromboembolism: The intricacies

    Directory of Open Access Journals (Sweden)

    Dutta T

    2009-01-01

    Full Text Available Venous thromboembolism (VTE has been a subject of great interest of late. Since Rudolph Virchow described the famous Virchow′s triad in 1856, there have been rapid strides in the understanding of the pathogenesis and factors responsible for it. Discovery of various thrombophilic factors, both primary and acquired, in the last 40 years has revolutionized prognostication and management of this potentially life-threatening condition due to its associated complication of pulmonary thromboembolism. Detailed genetic mapping and linkage analyses have been underlining the fact that VTE is a multifactorial disorder and a complex one. There are many gene-gene and gene-environment interactions that alter and magnify the clinical picture in this disorder. Point in case is pregnancy, where the risk of VTE is 100-150 times increased in the presence of Factor V Leiden, prothrombin mutation (Prothrombin 20210A and antithrombin deficiency. Risk of VTE associated with long-haul air flight has now been well recognized. Thrombotic events associated with antiphospholipid syndrome (APS are 70% venous and 30% arterial. Deep venous thrombosis and pulmonary embolism are the most common venous events, though unusual cases of catastrophes due to central vein thrombosis like renal vein thrombosis and Budd-Chiari syndrome (catastrophic APS may occur.

  4. Multiple coagulation defects and the Cohen syndrome.

    Science.gov (United States)

    Schlichtemeier, T L; Tomlinson, G E; Kamen, B A; Waber, L J; Wilson, G N

    1994-04-01

    A 13-year-old male presented with new onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs. Laboratory investigation demonstrated combined deficiency of protein C, protein S, and antithrombin III. He and his 17-year-old sister had a mental retardation-multiple anomaly syndrome associated with microcephaly, unusual facies, and lax connective tissue. Their dysmorphology included elongated faces with narrow forehead, arched eyebrows, large mouth with down-turned corners, malformed teeth, and furrowed tongue. Both had Marfanoid habitus with lax joints, pectus excavatum, kyphoscoliosis, and flat narrow feet. The most likely diagnosis for these siblings is the autosomal recessive Cohen syndrome of mental retardation, congenital hypotonia with Marfanoid habitus, microcephaly, pleasant affect, micrognathia, and open mouth with prominent incisors. The sagittal sinus thrombosis, left frontal intracranial hemorrhage, carotid aneurysm, tortuous descending aorta, and deep venous thrombosis suffered by the male sibling adds the Cohen syndrome to genetic vasculopathies that may be associated with stroke.

  5. Glycoprotein fucosylation is increased in seminal plasma of subfertile men

    Directory of Open Access Journals (Sweden)

    Beata Olejnik

    2015-04-01

    Full Text Available Fucose, the monosaccharide frequent in N- and O-glycans, is a part of Lewis-type antigens that are known to mediate direct sperm binding to the zona pellucida. Such interaction was found to be inhibited in vitroby fucose-containing oligo- and polysaccharides, as well as neoglycoproteins. The objective of this study was to screen seminal plasma proteins of infertile/subfertile men for the content and density of fucosylated glycoepitopes, and compare them to samples of fertile normozoospermic subjects. Seminal proteins were separated in polyacrylamide gel electrophoresis and blotted onto nitrocellulose membrane and probed with fucose-specific Aleuria aurantia lectin (AAL. Twelve electrophoretic bands were selected for quantitative densitometric analysis. It was found that the content, and especially the density of fucosylated glycans, were higher in glycoproteins present in seminal plasma of subfertile men. No profound differences in fucosylation density were found among the groups of normozoospermic, oligozoospermic, asthenozoospermic, and oligoasthenozoospermic subfertile men. According to the antibody probing, AAL-reactive bands can be attributed to male reproductive tract glycoproteins, including prostate-specific antigen, prostatic acid phosphatase, glycodelin and chorionic gonadotropin. Fibronectin, α1 -acid glycoprotein, α1 -antitrypsin, immunoglobulin G and antithrombin III may also contribute to this high fucosylation. It is suggested that the abundant fucosylated glycans in the sperm environment could interfere with the sperm surface and disturb the normal course of the fertilization cascade.

  6. A comparison of haemocoagulation tests in the experimental endotoxin model DIC and in rats whole-body irradiated by 250 Gy

    International Nuclear Information System (INIS)

    A comparison of results of tests performed with the endotoxin model of disseminated intravascular coagulation (DIC) and with irradiated groups of rats led to the conclusion that after whole-body irradiation with the high dose of 250 Gy, DIC occurs, in spite of the fact that the first stage, the hypercoagulation condition, can hardly be observed. In the experimental endotoxin model, an increase of activated partial thromboplastin test (APTT) values and prolongation of the thrombin time was observed up to 24 hours for two endotoxin doses. After both endotoxin doses, the fibrinogen level was transiently decreased with a subsequent increase. The fibrin monomers correspond to a decrease in the fibrinogen level. After the first dose, they were positive between the 3rd and 12th hours, and after the second dose, positivity was observed 6 hours after the application. The antithrombin III level was decreased after 12 hours for both endotoxin doses. The thrombocyte count was considerably reduced already from the 6th hour after administering endotoxin to the end of the experiment. Considerable changes in thrombocyte aggregation were observed only 3 hours after administering the second dose. When comparing the resulting values of these tests with values observed in irradiated animals, a certain agreement was found in the nature of the changes after exposure to 250 Gy. The fibrinogen level was transiently decreased 3 hours after irradiation, when considerable changes in the thrombocyte aggregation also occurred. (author) 5 figs., 17 refs

  7. Diagnostic uses of snake venom.

    Science.gov (United States)

    Marsh, N A

    2001-01-01

    Snake venom toxins are invaluable for the assay of coagulation factors and for the study of haemostasis generally. Thrombin-like enzymes (SVTLE) are used for fibrinogen and fibrinogen breakdown product assays as well as detecting dysfibrinogenaemias. Since SVTLE are not inhibited by heparin, they can be used for assaying antithrombin III in samples containing heparin. Snake venom prothrombin activators are utilised in prothrombin assays, whilst Russell's viper venom (RVV) can be used to assay clotting factors V, VII, X and lupus anticoagulants (LA). Activators from the taipan, Australian brown snake and saw-scaled viper have also been used to assay LA. Protein C (PC) and activated PC (APC) resistance can be measured by means of RVV, Protac (from Southern copperhead snake venom) and STA-Staclot (from Crotalus viridis helleri) whilst von Willebrand factor can be studied with Botrocetin (Bothrops jararaca). Finally, snake venom C-type lectins and metalloproteinase disintegrins are being used to study platelet glycoprotein receptors and show great potential for use in the routine coagulation laboratory. PMID:11910187

  8. Review of fondaparinux sodium injection for the prevention of venous thromboembolism in patients undergoing surgery

    Directory of Open Access Journals (Sweden)

    David Bergqvist

    2006-12-01

    Full Text Available David BergqvistDepartment of Surgery, University Hospital, Uppsala, SwedenAbstract: The antithrombin binding sequence of heparin, a pentasaccharide, has been synthesized as fondaparinux, an indirect, selective, and reversible factor Xa inhibitor. It can be administered subcutaneously, is well absorbed, and has a half-life of c. 17 hours permitting once-daily injection. It has been evaluated in an extensive study program in major orthopedic surgery, including hip fracture, and in major abdominal surgery with a large proportion of surgery for cancer. The effect is at least as effective as for low-molecular-weight heparins and it has also been shown effective for extended prophylaxis in hip fracture patients. Several thousands of patients have been studied and the substance is safe, although a slightly higher frequency of bleedings is found than in patients on low-molecular-weight heparins. There is no specific antidote but if necessary, recombinant activated factor VII can be used. Other side-effects are rare. Fondaparinux is cost saving and sometimes cost neutral when compared with enoxaparin. Keywords: fondaparinux, venous thrombosis, venous thromboembolism, surgery, orthopedic surgery, major abdominal surgery, bleeding complications

  9. Hemocompatibility of Axial Versus Centrifugal Pump Technology in Mechanical Circulatory Support Devices.

    Science.gov (United States)

    Schibilsky, David; Lenglinger, Matthias; Avci-Adali, Meltem; Haller, Christoph; Walker, Tobias; Wendel, Hans Peter; Schlensak, Christian

    2015-08-01

    The hemocompatible properties of rotary blood pumps commonly used in mechanical circulatory support (MCS) are widely unknown regarding specific biocompatibility profiles of different pump technologies. Therefore, we analyzed the hemocompatibility indicating markers of an axial flow and a magnetically levitated centrifugal device within an in vitro mock loop. The HeartMate II (HM II; n = 3) device and a CentriMag (CM; n = 3) adult pump were investigated in a human whole blood mock loop for 360 min using the MCS devices as a driving component. Blood samples were analyzed by enzyme-linked immunosorbent assay for markers of coagulation, complement system, and inflammatory response. There was a time-dependent activation of the coagulation (thrombin-antithrombin complexes [TAT]), complement (SC5b-9), and inflammation system (polymorphonuclear [PMN] elastase) in both groups. The mean value of TAT (CM: 4.0 μg/L vs. 29.4 μg/L, P centrifugal CM device showed significantly lower activation of coagulation and inflammation than that of the HM II axial flow pump. Both HM II and CM have demonstrated an acceptable hemocompatibility profile in patients. However, there is a great opportunity to gain a clinical benefit by developing techniques to lower the blood surface interaction within both pump technologies and a magnetically levitated centrifugal pump design might be superior. PMID:26234452

  10. Analysis on the risk factors of lower extremity deep venous thrombosis after cesarean section%剖宫产术后下肢深静脉血栓形成的危险因素分析

    Institute of Scientific and Technical Information of China (English)

    高丹丽; 杨小杰; 林黎明

    2012-01-01

    Objective: To explore the risk factors of lower extremity deep venous thrombosis ( LEDVT) after cesarean section. Methods: A total of 20 998 patients who underwent cesarean section in Tangshan maternal and child health hospital, Tangshan workers hospital, and Xiehe hospital from January 2008 to January 2012 were selected, related tests were carried out before cesarean section, then color ultrasonography of bilateral lower extremities was performed at 2 - 7 days after cesarean section; except the patients with LEDVT, two times of peoples were selected from the whole population as control group; the influencing factors of LEDVT were analyzed by univariate and multivariate logistic regression analysis. Results; A total of 716 postoperative patients met the diagnostic criteria of LEDVT, the incidence of LEDVT was 3. 41%. Among the measurement data, the body mass index (BMI) , activated partial thromboplastin time ( APTT) , fibrinogen, D - dimer, antithrombin Ⅲ , and C — reactive protein ( CRP) in case group were statistically significantly higher than those in control group. Among the enumeration data, the incidences of LEDVT in the patients with the histories of hypertension, diabetic mellitus, smoking, thrombus, and oral administration of contraceptive were significantly higher than those in control group. Univariate logistic regression analysis showed that age, BMI, APTT, D - dimer, antithrombin Ⅲ , CRP, the medical histories of hypertension, diabetic mellitus, smoking, thrombus, and oral administration of contraceptive, and lacking sports were the independent risk factors of LEDVT; multivariate logistic regression analysis showed that age, BMI, D - dimer, antithrombin Ⅲ , and CRP were the independent risk factors of LEDVT. Conclusion: The incidence of LEDVT after cesarean section was high; the occurrence of LEDVT was correlated with age, BMI, D - dimer, antithrombin Ⅲ , and CRP. It is suggested to screen LEDVT routinely at 2 -7 days after cesarean section

  11. Hemothorax under thrombolytic therapy with recombinant tissue: plasminogen activator (rt-PA) in a 16-year-old girl.

    Science.gov (United States)

    Varnholt, V; Ringe, H; Nietsch, L; Gaedicke, G

    1999-12-01

    We present the case of a 16-year-old girl with an extended thrombosis of the femoral and iliac vein and the inferior vena cava during pleuropneumonia; predisposing risk factors for thrombophilia were: use of contraceptives, nicotine abuse and congenital deficiency of antithrombin III (not previously diagnosed). Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA; initial dose: 0.08 mg/kg/h) was started. 2 days later--after diagnosis of an extended hemothorax: 1500 ml blood were obtained after thoracocentesis, transfusion of packed red blood cells was necessary--rt-PA was stopped, with only heparin (400 U/kg/d) being administered. 36 h later--the thrombosis had not yet changed--the thrombolytic therapy with rt-PA was continued in a markedly reduced dose (0.015 mg/kg/d) with no further bleeding complications. 8 days later--after successful thrombolysis--t-PA was stopped, heparin was given for another 10 days, then cumarin was administered orally. PMID:10650854

  12. Oral and parenteral anticoagulants: New kids on the block

    Directory of Open Access Journals (Sweden)

    S Aditya

    2012-01-01

    Full Text Available Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin, ultra low molecular weight heparins (semuloparin, RO-14, inhibitors of activated factor II (dabigatran, AZD0837, X (rivaroxaban, apixaban, edoxaban, betrixaban, IX (REG1,2, XI (antisense oligonucleotides, BMS 262084, clavatadine A, VII/tissue factor (tifacogin, PCI 274836, and BMS 593214, V (recomodulin, solulin, VIII (TB402, dual thrombin/factor X inhibitors (EP21709, tanogitran, and newer vitamin K antagonists (tecarfarin. Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms "anticoagulants", "blood coagulation inhibitors", "anticoagulants and venous thromboembolism", "anticoagulants and atrial fibrillation", and "′antithrombins." Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.

  13. Characterization of IXINITY® (Trenonacog Alfa, a Recombinant Factor IX with Primary Sequence Corresponding to the Threonine-148 Polymorph

    Directory of Open Access Journals (Sweden)

    Dougald M. Monroe

    2016-01-01

    Full Text Available The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148 polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant]. Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslational modifications. Activity was assessed as the ability to activate factor X (FX both with and without factor VIIIa (FVIIIa and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band on Coomassie-stained gels; activity assays were normal and showed 97%  γ-carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa; once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX.

  14. Hemostatic Markers in Congestive Heart Failure Dogs with Mitral Valve Disease

    Directory of Open Access Journals (Sweden)

    Kreangsak Prihirunkit

    2014-01-01

    Full Text Available Prothrombin time (PT, activated partial thromboplastin time (APTT, fibrinogen, D-dimer, antithrombin III (AT III, protein C (PC, factor VII (F.VII, and factor VIII (F.VIII, as well as hematocrit (HCT, platelets number (PLT, total plasma protein (TP, and albumin (ALB, were studied on fifty-eight congestive heart failure (CHF dogs with mitral valve disease (MVD and fifty control dogs. All of variables of MVD group, except APTT, were significantly different (P<0.5 from control group. The variables were also compared among functional classes of CHF dogs and control dogs. It was determined that the higher the functional class of CHF dogs was, the greater the levels of fibrinogen and D-dimer were, whereas the lesser the activities of AT III and PC were presented. Additionally, TP had linear correlation with fibrinogen, D-dimer, HCT, and PLT (r=0.31, 0.30, 0.43, and 0.38, resp., P<0.5. These findings suggested that fibrinogen and D-dimer were the factors predisposing hypercoagulability through an increase in blood viscosity. The hemorheological abnormalities would shift an overall hemostatic balance toward a more thrombotic state in CHF dogs with MVD.

  15. Preeclampsia - will orphan drug status facilitate innovative biological therapies?

    Science.gov (United States)

    Hahn, Sinuhe

    2015-01-01

    It is generally accepted that the development of novel therapies to treat pregnancy-related disorders, such as preeclampsia, is hampered by the paucity of research funding. Hence, it is with great interest to become aware of at least three novel therapeutic approaches for the treatment of this disorder: exploiting either the anticoagulant activity of antithrombin, the free radical scavenging activity of alpha-1-microglobulin, or the regenerative capacity of placenta-derived mesenchymal stem cells. As these projects are being carried out by small biotech enterprises, the question arises of how they are able to fund such undertakings. A novel strategy adopted by two of these companies is that they successfully petitioned US and EU agencies in order that preeclampsia is accepted in the register of rare or orphan diseases. This provides a number of benefits including market exclusivity, assistance with clinical trials, and dedicated funding schemes. Other strategies to supplement meager research funds, especially to test novel approaches, could be crowdfunding, a venture that relies on intimate interaction with advocacy groups. In other words, preeclampsia meets Facebook. Perhaps similar strategies can be adopted to examine novel therapies targeting either the imbalance in pro- or anti-angiogenic growth factors, complement activation, reduced levels of placenta protein 13, or excessive neutrophil activation evident in preeclampsia. PMID:25767802

  16. [A sudden rise in INR due to combination of Tribulus terrestris, Avena sativa, and Panax ginseng (Clavis Panax)].

    Science.gov (United States)

    Turfan, Murat; Tasal, Abdurrahman; Ergun, Fatih; Ergelen, Mehmet

    2012-04-01

    Warfarin sodium is an antithrombin agent used in patients with prosthetic valve and atrial fibrillation. However, there are many factors that can change the effectiveness of the drug. Today, herbal mixtures promoted through targeted print and visual media can lead to sudden activity changes in patients using warfarin. In this case report we will present two cases with a sudden rise in INR due to using combination of Tribulus terrestris, Avena sativa and Panax ginseng (Panax Clavis). Two patients who used warfarin due to a history of aortic valve replacement (case 1) and atrial fibrillation (case 2) were admitted to the hospital due very high levels of INR detected during routine follow-up. Both patients had used an herbal medicine called ''Panax'' during the last month. The patients gave no indication regarding a change in diet or the use of another agent that might interact with warfarin. In cases where active bleeding could not be determinated, we terminated the use of the drug and re-evaluated dosage of warfarin before finally discharging the patient.

  17. Searching for preventive measures of cardiovascular events in aged Japanese taxi drivers--the daily rhythm of cardiovascular risk factors during a night duty day.

    Science.gov (United States)

    Hattori, M; Azami, Y

    2001-12-01

    Previous studies have shown that Japanese taxi drivers are exposed to more risk factors and have a higher mortality rate due to cardiovascular disease than other occupational groups. We investigated the effect of night taxi driving with a view to preventing acute events of cardiovascular disease among aged taxi drivers. Twenty-nine taxi drivers (41-67 years old) were examined for urine normetanephrine/creatinine, von Willebrand factor, anti-thrombin III, t-plasminogen activator-plasminogen activator inhibitor 1-complex, hematocrit, blood glucose and blood pressure in the morning and at midnight during a duty day and in the following morning. At the same time, the blood pressure and blood glucose of 46 taxi drivers (43-67 years old) in the morning after a night duty with little sleep and in the morning after daytime work and subsequent night sleep were compared. The results obtained indicate that the aggravation of sympathetic nervous system functions with disturbed circadian rhythms, increased blood coagulation and blood concentration, endothelial injury and the elevation of blood glucose at midnight or the next morning were induced by their night work. These conditions are supposed to favour acute vascular events in aged taxi drivers. Preventive measures considered include social support for anticoagulant food and water intake, short exercise and walking as well as taking a rest and a nap during night work.

  18. Regulation of protein C inhibitor (PCI) activity by specific oxidized and negatively charged phospholipids.

    Science.gov (United States)

    Malleier, Julia M; Oskolkova, Olga; Bochkov, Valery; Jerabek, Ingrid; Sokolikova, Barbora; Perkmann, Thomas; Breuss, Johannes; Binder, Bernd R; Geiger, Margarethe

    2007-06-01

    Protein C inhibitor (PCI) is a serpin with affinity for heparin and phosphatidylethanolamine (PE). We analyzed the interaction of PCI with different phospholipids and their oxidized forms. PCI bound to oxidized PE (OxPE), and oxidized and unoxidized phosphatidylserine (PS) immobilized on microtiter plates and in aqueous suspension. Binding to OxPE and PS was competed by heparin, but not by the aminophospholipid-binding protein annexin V or the PCI-binding lipid retinoic acid. PS and OxPE stimulated the inhibition of activated protein C (aPC) by PCI in a Ca(++)-dependent manner, indicating that binding of both, aPC (Ca(++) dependent) and PCI (Ca(++) independent), to phospholipids is necessary. A peptide corresponding to the heparin-binding site of PCI abolished the stimulatory effect of PS on aPC inhibition. No stimulatory effect of phospholipids on aPC inhibition was seen with a PCI mutant lacking the heparin-binding site. A heparin-like effect of phospholipids (OxPE) was not seen with antithrombin III, another heparin-binding serpin, suggesting that it is specific for PCI. PCI and annexin V were found to be endogenously colocalized in atherosclerotic plaques, supporting the hypothesis that exposure of oxidized PE and/or PS may be important for the local regulation of PCI activity in vivo.

  19. Characterization of IXINITY® (Trenonacog Alfa), a Recombinant Factor IX with Primary Sequence Corresponding to the Threonine-148 Polymorph.

    Science.gov (United States)

    Monroe, Dougald M; Jenny, Richard J; Van Cott, Kevin E; Buhay, Shelly; Saward, Laura L

    2016-01-01

    The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148) polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant)]). Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslational modifications. Activity was assessed as the ability to activate factor X (FX) both with and without factor VIIIa (FVIIIa) and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band on Coomassie-stained gels; activity assays were normal and showed factor IX (FIXa) per IU of FIX. The molecule has >97%  γ-carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa); once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX. PMID:26997955

  20. Complications of bariatric surgery: Presentation and emergency management.

    Science.gov (United States)

    Kassir, Radwan; Debs, Tarek; Blanc, Pierre; Gugenheim, Jean; Ben Amor, Imed; Boutet, Claire; Tiffet, Olivier

    2016-03-01

    The epidemic in obesity has led to an increase in number of so called bariatric procedures. Doctors are less comfortable managing an obese patient after bariatric surgery. Peri-operative mortality is less than 1%. The specific feature in the obese patient is that the classical signs of peritoneal irritation are never present as there is no abdominal wall and therefore no guarding or rigidity. Simple post-operative tachycardia in obese patients should be taken seriously as it is a WARNING SIGNAL. The most common complication after surgery is peritonitis due to anastomotic fistula formation. This occurs typically as an early complication within the first 10 days post-operatively and has an incidence of 1-6% after gastric bypass and 3-7% after sleeve gastrectomy. Post-operative malnutrition is extremely rare after restrictive surgery (ring, sleeve gastrectomy) although may occur after malabsorbative surgery (bypass, biliary pancreatic shunt) and is due to the restriction and change in absorption. Prophylactic cholecystectomy is not routinely carried out during the same procedure as the bypass. Superior mesenteric vein thrombosis after bariatric surgery is a diagnosis which should be considered in the presence of any postoperative abdominal pain. Initially a first etiological assessment is performed (measurement of antithrombin III and of protein C and protein S, testing for activated protein C resistance). If the least doubt is present, a medical or surgical consultation should be requested with a specialist practitioner in the management of obese patients as death rates increase with delayed diagnosis.

  1. Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin

    Science.gov (United States)

    Verespy III, Stephen; Mehta, Akul Y.; Afosah, Daniel; Al-Horani, Rami A.; Desai, Umesh R.

    2016-01-01

    Allosteric partial inhibition of soluble, monomeric proteases can offer major regulatory advantages, but remains a concept on paper to date; although it has been routinely documented for receptors and oligomeric proteins. Thrombin, a key protease of the coagulation cascade, displays significant conformational plasticity, which presents an attractive opportunity to discover small molecule probes that induce sub-maximal allosteric inhibition. We synthesized a focused library of some 36 sulfated coumarins to discover two agents that display sub-maximal efficacy (~50%), high potency (150-fold). Michaelis-Menten, competitive inhibition, and site-directed mutagenesis studies identified exosite 2 as the site of binding for the most potent sulfated coumarin. Stern-Volmer quenching of active site-labeled fluorophore suggested that the allosteric regulators induce intermediate structural changes in the active site as compared to those that display ~80–100% efficacy. Antithrombin inactivation of thrombin was impaired in the presence of the sulfated coumarins suggesting that allosteric partial inhibition arises from catalytic dysfunction of the active site. Overall, sulfated coumarins represent first-in-class, sub-maximal inhibitors of thrombin. The probes establish the concept of allosteric partial inhibition of soluble, monomeric proteins. This concept may lead to a new class of anticoagulants that are completely devoid of bleeding. PMID:27053426

  2. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis.

    Science.gov (United States)

    Xu, Xinsen; Zhou, Yanyan; Miao, Runchen; Chen, Wei; Qu, Kai; Pang, Qing; Liu, Chang

    2016-06-01

    We performed weighted gene coexpression network analysis (WGCNA) to gain insights into the molecular aspects of hepatocellular carcinoma (HCC). Raw microarray datasets (including 488 samples) were downloaded from the Gene Expression Omnibus (GEO) website. Data were normalized using the RMA algorithm. We utilized the WGCNA to identify the coexpressed genes (modules) after non-specific filtering. Correlation and survival analyses were conducted using the modules, and gene ontology (GO) enrichment was applied to explore the possible mechanisms. Eight distinct modules were identified by the WGCNA. Pink and red modules were associated with liver function, whereas turquoise and black modules were inversely correlated with tumor staging. Poor outcomes were found in the low expression group in the turquoise module and in the high expression group in the red module. In addition, GO enrichment analysis suggested that inflammation, immune, virus-related, and interferon-mediated pathways were enriched in the turquoise module. Several potential biomarkers, such as cyclin-dependent kinase 1 (CDK1), topoisomerase 2α (TOP2A), and serpin peptidase inhibitor clade C (antithrombin) member 1 (SERPINC1), were also identified. In conclusion, gene signatures identified from the genome-based assays could contribute to HCC stratification. WGCNA was able to identify significant groups of genes associated with cancer prognosis. PMID:27052251

  3. The role of biochemical risk factors in the etiology of AIS in children and adults.

    Science.gov (United States)

    Kopyta, Ilona; Zimny, Mikołaj; Sarecka-Hujar, Beata

    2015-01-01

    Stroke is an abrupt onset of both focal and global neurological deficits secondary to a vascular event lasting more than 24 h and with a vascular background as its only cause. It can be triggered by a rupture of a blood vessel, aneurysm (hemorrhagic stroke, HS), thrombosis or embolisms (ischemic stroke, IS). In developed countries, it is the third most common cause of death in the adult population. Stroke in children is a rare disorder with a reported frequency of about 3 cases per 100,000 children per year. The history of acute brain ischemia is burdened with neurological complications such as motor impairment, speech impairment and intellectual delay. Moreover, in children after AIS seizures and epilepsy are also quite common. Stroke is a heterogeneous disorder; its risk factors in adults are well known, however, in pediatrics, in more than 20% cases, the cause of stroke is impossible to determine. Due to the fact that stroke usually arises as a consequence of the cerebral thrombosis, many of the mechanisms responsible for its occurrence can be considered as risk factors. We have reviewed the recent case-control studies conducted on pediatric patients regarding biochemical risk factors such as elevated levels of homocysteine, fibrinogen, protein C, protein S, antithrombin III, lipoprotein(a), cholesterol and its fractions, and compared them with the results obtained from adult patients. PMID:25428197

  4. Venous thrombosis in athletes.

    Science.gov (United States)

    Grabowski, Gregory; Whiteside, William K; Kanwisher, Michael

    2013-02-01

    Because deep vein thrombosis (DVT) can occur following orthopaedic procedures, knowledge of hereditary and acquired risk factors for DVT is essential. Hereditary forms of thrombophilia include factor V Leiden and prothrombin G20210A mutations, and deficiencies of antithrombin III, protein C, and protein S. Acquired risk factors include but are not limited to trauma, immobilization, and surgical procedures. In general, athletes have a low risk of venous thrombosis; however, this population is exposed to many acquired thrombogenic risk factors, including hemoconcentration, trauma, immobilization, long-distance travel, and the use of oral contraceptives. Thus, orthopaedic surgeons should consider screening athletes for thrombogenic risk factors, including history of venous thrombosis, hypercoagulable disorders, or high altitude exercise, during preparticipation physicals and preoperative examinations. If a patient is determined to be at high risk of DVT, preventive measures such as physical antithrombotic measures and/or low-molecular-weight heparin should be instituted. If an athlete develops a DVT, a risk factor assessment should be conducted along with anticoagulation treatment in accordance with the American College of Chest Physicians guidelines. PMID:23378374

  5. The Hemostatic System and Angiogenesis in Malignancy

    Directory of Open Access Journals (Sweden)

    Marek Z. Wojtukiewicz

    2001-01-01

    Full Text Available Coagulopathy and angiogenesis are among the most consistent host responses associated with cancer. These two respective processes, hitherto viewed as distinct, may in fact be functionally inseparable as blood coagulation and fibrinolysis, in their own right, influence tumor angiogenesis and thereby contribute to malignant growth. In addition, tumor angiogenesis appears to be controlled through both standard and non-standard functions of such elements of the hemostatic system as tissue factor, thrombin, fibrin, plasminogen activators, plasminogen, and platelets. “Cryptic” domains can be released from hemostatic proteins through proteolytic cleavage, and act systemically as angiogenesis inhibitors (e.g., angiostatin, antiangiogenic antithrombin III aaATIII. Various components of the hemostatic system either promote or inhibit angiogenesis and likely act by changing the net angiogenic balance. However, their complex influences are far from being fully understood. Targeted pharmacological and/ or genetic inhibition of pro-angiogenic activities of the hemostatic system and exploitation of endogenous angiogenesis inhibitors of the angiostatin and aaATIII variety are under study as prospective anti-cancer treatments.

  6. Spectroscopic and Electrochemical Detection of Thrombin/5'-SH or 3'-SH Aptamer Immobilized on (porous) Gold Substrates

    Energy Technology Data Exchange (ETDEWEB)

    Park, Buem Jin; Sa, Young Seung; Kim, Yong Hwan; Kim, Young Hun [Kwangwoon University, Seoul (Korea, Republic of)

    2012-01-15

    Thrombin is a serine protease that catalyzes the conversion of soluble fibrinogen to insoluble fibrin, and thus induces physiological and pathological blood coagulation. Therefore, it is important to detect thrombin in blood serum for purposes of diagnosis. To achieve this goal, it has been suggested that a 15-mer aptamer strongly binds with thrombin to form a G-quartet structure of the aptamer. Generally, 5'-end thiol-functionalized aptamer has been used as an anti-thrombin binder. Herein, we evaluate the possibility of utilizing a 3'-SH aptasensor for thrombin detection using SPR spectroscopy, and compare the enhancement of the electrochemical signal of the thrombin-aptamer bound on a porous gold substrate. Although the two aptamers have similar configurations, in SPR analysis, the 3'-SH aptamer was a effective aptasensor as well as 5'-SH aptamer. Results from electrochemical analysis showed that the porous gold substrate acted as a good substrate for an aptasensor and demonstrated 5-fold enhancement of current change, as compared to gold thin film.

  7. Syntenic assignment of human chromosome 1 homologous loci in the bovine.

    Science.gov (United States)

    Threadgill, D S; Threadgill, D W; Moll, Y D; Weiss, J A; Zhang, N; Davey, H W; Wildeman, A G; Womack, J E

    1994-08-01

    Three mouse chromosomes (MMU 1, 3, and 4) carry homologs of human chromosome 1 (HSA 1) genes. A similar situation is found in the bovine, where five bovine chromosomes (BTA 2, 3, 5, 16, and unassigned syntenic group U25) contain homologs of HSA 1 loci. To evaluate further the syntenic relationship of HSA 1 homologs in cattle, 10 loci have been physically mapped through segregation analysis in bovine-rodent hybrid somatic cells. These loci, chosen for their location on HSA 1, are antithrombin 3 (AT3), renin (REN), complement component receptor 2 (CR2), phosphofructokinase muscle type (PFKM), Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog (FGR), alpha fucosidase (FUCA1), G-protein beta 1 subunit (GNB1), alpha 1A amylase, (AMY1), the neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and alpha skeletal actin (ACTA1). AT3, REN, CR2, and GNB1 mapped to BTA 16, PFKM to BTA 5, AMY1A and NRAS to BTA 3, FGR and FUCA1 to BTA 2, and ACTA1 to BTA 28. PMID:8001974

  8. Anticoagulant response to Agkistrodon contortrix venom (ACV test): a new global test to screen for defects in the anticoagulant protein C pathway.

    Science.gov (United States)

    Robert, A; Eschwège, V; Hameg, H; Drouet, L; Aillaud, M F

    1996-04-01

    As specific assays used to identify defects in the protein C (PC) anticoagulant pathway are laborious and expensive, we describe here a global test to screen for these defects. This assay is expressed as the ratio of two activated partial thromboplastin times, one in the absence and one in the presence of 0,125 U/ml of the PC activator of Agkistrodon contortrix venom (ACV). Eight of the 168 healthy volunteers of the control group exhibited an ACV ratio below the lower normal limit of 3.37 [6 subjects with the mutation Arg 506 to Gln in their factor V gene (FV R506Q) and one with PS deficiency]. 128 patients who have had at least one episode of deep-vein thrombosis were retrospectively studied. All patients carrying FV Q506R (n = 48), PC deficiency (n = 14) or combined defects, i.e. FV Q506R and PC deficiency (n = 4) or FV Q506R and PS deficiency (n = 3), had ACV ratios ACV ratios which overlapped normal range. ACV ratios of one out of seven patients with antithrombin deficiency, and 10% of patients without identified defect in the PC anticoagulant pathway (n = 30) were ACV ratio raised to 3.70 could lead to a test identifying all patients with a defect in the PC anticoagulant pathway.

  9. Treatment of Venous Thromboembolism With New Anticoagulant Agents.

    Science.gov (United States)

    Becattini, Cecilia; Agnelli, Giancarlo

    2016-04-26

    Venous thromboembolism (VTE) is a common disease associated with high risk for recurrences, death, and late sequelae, accounting for substantial health care costs. Anticoagulant agents are the mainstay of treatment for deep vein thrombosis and pulmonary embolism. The recent availability of oral anticoagulant agents that can be administered in fixed doses, without laboratory monitoring and dose adjustment, is a landmark change in the treatment of VTE. In Phase III trials, rivaroxaban, apixaban, edoxaban (antifactor Xa agents), and dabigatran (an antithrombin agent) were noninferior and probably safer than conventional anticoagulation therapy (low-molecular-weight heparin followed by vitamin K antagonists). These favorable results were confirmed in specific patient subgroups, such as the elderly and fragile. However, some patients, such as those with cancer or with intermediate- to high-risk pulmonary embolism, were underrepresented in the Phase III trials. Further clinical research is required before new oral anticoagulant agents can be considered standard of care for the full spectrum of patients with VTE. PMID:27102510

  10. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine.

    Science.gov (United States)

    Mezzano, D; Muñoz, X; Martínez, C; Cuevas, A; Panes, O; Aranda, E; Guasch, V; Strobel, P; Muñoz, B; Rodríguez, S; Pereira, J; Leighton, F

    1999-06-01

    We studied hemostatic and inflammatory cardiovascular risk factors (CVRF), and total plasma homocysteine (tHcy) in 26 vegetarians (23 lacto- or ovolactovegetarians and 3 vegans), matched by age, sex and socioeconomic status with omnivorous controls. Vegetarians had significantly lower proportion of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in plasma lipids, significantly shortened bleeding time, and increased blood platelet count and in vitro platelet function (aggregation and secretion). Plasma levels of all coagulation or fibrinolytic factors and natural inhibitors synthesized in the liver were lower in vegetarians than in controls. Whereas for some factors this decrease was statistically significant (fibrinogen, factor VIIc, antithrombin III, protein S, plasminogen) for the remaining (factors VIIIc, Vc, prothrombin, protein C) a trend in the same direction was found. For hemostatic proteins of predominantly extrahepatic origin (von Willebrand factor. tPA, PAI-1) this tendency was not present. No significant differences in inflammatory proteins (C-reactive protein and alpha1-protease inhibitor) were detected in both groups. tHcy was significantly increased in vegetarians, and correlated only with cobalamin levels. The increased platelet function and tHcy found in vegetarians may counteract the known cardiovascular health benefits of vegetarian diet (VD). PMID:10404767

  11. Effects of carboxymethyl chitosan on the blood system of rats

    International Nuclear Information System (INIS)

    Highlights: → We report, for the first time, the safety of carboxymethyl chitosan in blood system. → CM-Chitosan has no significant effects on coagulation function of rats. → CM-Chitosan has no significant effects on anticoagulation performance of rats. → CM-Chitosan has no significant effects on fibrinolytic function of rats. → CM-Chitosan has no significant effects on hemorheology of rats. -- Abstract: Carboxymethyl chitosan (CM-chitosan), a derivative of chitosan, was extensively studied in the biomedical materials field for its beneficial biological properties of hemostasis and stimulation of healing. However, studies examining the safety of CM-chitosan in the blood system are lacking. In this study CM-chitosan was implanted into the abdominal cavity of rats to determine blood indexes at different times and to evaluate the effects of CM-chitosan on the blood system of rats. Coagulation function was reflected by thrombin time (TT), prothrombin time (PT), activated partial thromboplatin time (APTT), fibrinogen (FIB) and platelet factor 4 (PF4) indexes; anti-coagulation performance was assessed by the index of antithrombinIII (ATIII); fibrinolytic function was reflected by plasminogen (PLG) and fibrin degradation product (FDP) indexes; and blood viscosity (BV) and plasma viscosity (PV) indexes reflected hemorheology. Results showed that CM-chitosan has no significant effects on the blood system of rats, and provides experimental basis for CM-chitosan to be applied in the field of biomedical materials.

  12. Coagulant and anticoagulant activities of Bothrops lanceolatus (Fer de lance) venom.

    Science.gov (United States)

    Lôbo de Araújo, A; Kamiguti, A; Bon, C

    2001-01-01

    Bothrops lanceolatus venom contains caseinolytic, phospholipase, esterase and haemorrhagic activities. We have investigated the coagulant and anticoagulant actions of B. lanceolatus venom on human citrated plasma and on purified plasma components. Although B. lanceolatus venom up to 50 microg/ml was unable to clot citrated plasma, at concentrations > or = 5 microg/ml the venom dose-dependently clotted purified human fibrinogen, indicating the presence of a thrombin-like enzyme. Human plasma (final concentration > or = 12.5%) dose-dependently inhibited the venom-induced fibrinogen clotting. This finding suggested that endogenous plasma protease inhibitors can affect the venom's action on fibrinogen. To investigate this possibility, B. lanceolatus venom was incubated with different plasma protease inhibitors and the activity on fibrinogen tested. alpha(2)-Macroglobulin and alpha(1)-antitrypsin did not interfere with the coagulant activity of the venom whereas the antithrombin-III/heparin complex partially inhibited this activity. A non-toxic, acidic phospholipase A(2) purified from B. lanceolatus venom prolonged the activated partial thromboplastin time in human plasma from 39.7+/-0.5 s (control with saline) to 60.2+/-0.9 s with 50 microg of PLA(2) (p<0.001), suggesting an anticoagulant activity associated with this enzyme. This anticoagulant activity may account for some of the effects of the venom on blood coagulation. PMID:10978756

  13. Preparation and characterization of deuterium-labeled glycosaminoglycans.

    Science.gov (United States)

    Naggi, A; Casu, B; Crippa, B; Magnaghi, S; Silvestro, L; Torri, G

    1994-01-01

    Heparin, NAcHep, DS, and CS were labeled with deuterium by N-reacetylating, with the deuterated acetic anhydride (CD3CO)2O, GAGs previously N-deacetylated (by hydrazinolysis) to the desired extent. Degrees of deuteration of the present preparations, as determined by 2H- and 1H-NMR were 15%, 51%, 49%, and 79% for heparin, NAcHep, DS, and CS, respectively. The NMR analysis (including the 13C spectra) of the labeled products indicated that deuterium labeling did not involve any substantial modification of the GAG structures. Also NMR signals associated with specific sequences of heparin for antithrombin and of DS for heparin cofactor II were essentially the same in the unlabeled and in the deuterated GAGs. The substantial retention of the original structure was confirmed by data on the degree of sulfation (by conductimetry) and on the electrophoretic mobility in acid buffer. On the other hand, HPLC/SEC data indicated some depolymerization of heparin and DS in the N-deacetylation step of the labeling reactions. HPLC/MS spectrometry permitted a clear identification of disaccharide and tetrasaccharide fragments obtained from deuterated GAGs by enzymic (heparinase, chondroitinase ABC) or chemical depolymerization (deaminative cleavage, Smith degradation), opening new prospects for studies of human pharmacokinetics, with differentiation of exogenous from endogenous GAGs.

  14. EFFECTS OF ANTICOAGULATION PROTEIN DEFECT IN MATERNAL PLASMA ON SPONTANEOUS ABORTION

    Institute of Scientific and Technical Information of China (English)

    Chun-mei Bai; Shui-qing Ma; Ming-ying Gai; Lian-kai Fan; Feng-yan Ren; Guang-sheng Fan

    2004-01-01

    Objective To investigate the mechanism of anticoagulation protein defect in the pathogenesis of unexplained recurrent miscarriage.Methods Fifty-seven patients with a history of unexplained abortion were enrolled as the investigation group for tests of protein C, protein S, antithrombin Ⅲ (AT-Ⅲ), as well as activated protein C resistance (APC-R). The control group consisted of fifty healthy women with a history of hormal pregnancy and delivery. Blood samples were obtained for measuring serum activity of protein C, protein S, AT- Ⅲ, and APC-R. Patients with positive APC-R were tested for factor Ⅴ (FV) Leiden gene mutation by PCR-RFLP method.Results Of the 57 patients, 12 (21.1%), 1 (1.8%), and 5 (8.8%) cases were found with protein S, protein C, and AT-Ⅲdeficiency respectively, and 13 (22.8%) cases with positive results of APC-R. Of the control group, no protein C or AT-Ⅲdeficiency was ever found, whereas 2 (4.0%) volunteers were presented with protein S deficiency and 3 (6.0%) with positive results of APC-R. No FV Leiden gene mutation was identified in all the patients with positive APC-R results. Late spontaneous abortion cases had higher incidence of anticoagulation protein defect than the early cases.Conclusion Anticoagulation protein defect may play a role in the pathogenesis of fetal loss, especially for those occurring in late stage of pregnancy.

  15. Effect of estrogen-progestin hormonal replacement therapy on blood coagulation and fibrinolysis in postmenopausal women Efeitos da terapia de reposição hormonal estroprogestativa sobre o sistema de coagulação e de fibrinólise em mulheres na pós-menopausa

    Directory of Open Access Journals (Sweden)

    Claudio E Bonduki

    2007-01-01

    Full Text Available OBJECTIVE: To evaluate antithrombin III (AT, thrombin (Fragment 1+2 [F1+2] and thrombin-antithrombin [TAT] generation markers, as well as other coagulation parameters, such as prothrombin time, partial activated thromboplastin time, thrombin time, fibrinogen, euglobulin lysis time, and platelet count, in postmenopausal women after hormonal therapy. STUDY DESIGN: Forty-five patients who received either 0.625 mg/day unopposed oral conjugated equine estrogen (CEE, 0.625 mg/day oral CEE plus medroxyprogesterone acetate (MP, or 50 µg/day transdermal 17beta-estradiol plus MP, were included. Tests were performed before (T0 and after 3 (T3, 6 (T6 and 12 (T12 months of treatment. AT was determined by an amidolytic method, whereas F1+2 and TAT complex were measured by ELISA. RESULTS: There was a significant reduction in the AT level of patients who received oral CEE plus MP at T3. There was no AT reduction in patients taking either oral CEE alone or transdermal 17beta-estradiol plus MP. F1+2 increased in all patients, but it reached statistical significance only in patients receiving transdermal 17beta-estradiol MP at T3. CONCLUSIONS: The CEE associated with MP treatment may reduce AT levels, whereas unopposed CEE or transdermal 17beta-estradiol plus MP does not change AT. These changes might not be clinically relevant in the general population; however, hormonal replacement therapy may increase the risk of thrombosis in women with congenital or acquired thrombophilia.OBJETIVO: Avaliar os marcadores antitrombina III (AT, fragmento 1 + 2 da trombina (F1+2 e complexo trombina-antitrombina (TAT, bem como outros parâmetros da coagulação, como tempo de pró-trombina, tempo parcial de tromboplastina ativado, tempo de trombina, fibrinogênio e tempo de lise da euglobulina em mulheres na pós-menopausa após terapia hormonal. DESENHO DO ESTUDO: Foram incluídas 45 voluntárias que receberam estrogênios conjugados eqüinos (ECE 0,625 mg/dia, isoladamente ou

  16. Inhaled unfractionated heparin improves abnormalities of alveolar coagulation, fibrinolysis and inflammation in endotoxemia-induced lung injury rats

    Institute of Scientific and Technical Information of China (English)

    WANG Zong-yu; WU Sheng-nan; ZHU Zhao-zhong; YANG Ba-xian; ZHU Xi

    2013-01-01

    Background Acute lung injury/acute respiratory distress syndrome presents with not only local inflammation,but also pulmonary coagulopathy which is characterized by an alveolar procoagulant response,anticoagulant inhibition,fibrinolytic supression and fibrin deposition.We thus had hypothesized that if aerosolized unfractionated heparin was inhaled into alveolar spaces,it could block the procoagulant tendency,lessen depletion of coagulation factors,and even influence the inflammatory response.We also assessed the effects of different administration regimens of heparin.Methods Male Wistar rats were given inhaled heparin starting 30 minutes before (prophylactic heparin) or 2 hours after (therapeutic heparin) intravenous lipopolysaccharide (LPS) was administered at 6-hour intervals; control groups received inhaled normal saline with or without being exposed to LPS.Thrombin-antithrombin complexes,activated protein C,tissue type and urokinase type plasminogen activators (t-PNu-PA),plasminogen activator inhibitor-1 (PAl-1),tumor necrosis factor-α,interleukin-6 in bronchoalveolar lavage,and lung tissue myeloperoxidase activity,and histology score were measured at three time-points.PAI-1/(t-PA + u-PA) was calculated based on the before-mentioned parameters.Statistical analysis was made using one-way analysis of variance (ANOVA) with post hoc test or Student's t test in the case of heterogeneity of variance.Results An alveolar procoagulant reaction,depressed fibrinolysis,and inflammatory response occurred in endotoxemia-induced lung injury.Local prophylactic application of heparin attenuated coagulation and early inflammation,promoted fibrinolysis,and reduced the histology score.Therapeutic application of heparin had similar,but weaker effects.Conclusions Intrapulmonary application of unfractionated heparin by inhalation might inhibit alveolar procoagulant reaction and the early inflammatory response,promote flbrinolysis,and alleviate pulmonary pathology in endotoxemia

  17. Interactions of Intact Unfractionated Heparin with Its Client Proteins Can Be Probed Directly Using Native Electrospray Ionization Mass Spectrometry.

    Science.gov (United States)

    Zhao, Yunlong; Abzalimov, Rinat R; Kaltashov, Igor A

    2016-02-01

    Heparin and related members of the glycosaminoglycan (GAG) family are highly polyanionic linear saccharides that play important roles in a variety of physiological processes ranging from blood coagulation to embryo- and oncogenesis, tissue regeneration, and immune response regulation. These diverse functions are executed via a variety of mechanisms, including protein sequestration, activation, and facilitation of their interactions with cell-surface receptors, but deciphering the specific molecular mechanisms is frequently impossible due to the extremely high degree of GAG heterogeneity. As a result, the vast majority of studies of heparin (or related GAGs) interactions with its client proteins use synthetically produced heparin mimetics with defined structure or short heparin fragments. In this work we use native electrospray ionization mass spectrometry (ESI MS) in combination with limited charge reduction in the gas phase to obtain meaningful information on noncovalent complexes formed by intact unfractionated heparin and antithrombin-III, interaction which is central to preventing blood clotting. Complexes of different stoichiometries are observed ranging from 1:1 to 1:3 (heparin/protein ratio). In addition to binding stoichiometry, the measurements allow the range of heparin chain lengths to be obtained for each complex and the contribution of each complex to the total ionic signal to be calculated. Incorporation of ion mobility measurements in the experimental workflow allows the total analysis time to be shortened very significantly and the charge state assignment for the charge-reduced species to be verified. The possibility to study interactions of intact unfractionated heparin with a client protein carried out directly by native ESI MS without the need to use relatively homogeneous surrogates demonstrated in this work opens up a host of new exciting opportunities and goes a long way toward ameliorating the persistent but outdated view of the

  18. Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia.

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    Ted Wun

    Full Text Available BACKGROUND: Sickle cell anemia is an inherited disorder of hemoglobin that leads to a variety of acute and chronic complications. Abnormal cellular adhesion, mediated in part by selectins, has been implicated in the pathophysiology of the vaso-occlusion seen in sickle cell anemia, and selectin inhibition was able to restore blood flow in a mouse model of sickle cell disease. METHODS: We performed a Phase 1 study of the selectin inhibitor GMI 1070 in patients with sickle cell anemia. Fifteen patients who were clinically stable received GMI 1070 in two infusions. RESULTS: The drug was well tolerated without significant adverse events. There was a modest increase in total peripheral white blood cell count without clinical symptoms. Plasma concentrations were well-described by a two-compartment model with an elimination T1/2 of 7.7 hours and CLr of 19.6 mL/hour/kg. Computer-assisted intravital microscopy showed transient increases in red blood cell velocity in 3 of the 4 patients studied. CONCLUSIONS: GMI 1070 was safe in stable patients with sickle cell anemia, and there was suggestion of increased blood flow in a subset of patients. At some time points between 4 and 48 hours after treatment with GMI 1070, there were significant decreases in biomarkers of endothelial activation (sE-selectin, sP-selectin, sICAM, leukocyte activation (MAC-1, LFA-1, PM aggregates and the coagulation cascade (tissue factor, thrombin-antithrombin complexes. Development of GMI 1070 for the treatment of acute vaso-occlusive crisis is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT00911495.

  19. The role of autolysis loop in determining the specificity of coagulation proteases

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    L. Yang

    2007-08-01

    Full Text Available We recently demonstrated that the substitution of the autolysis loop (residues 143 to 154 in the chymotrypsin numbering system of activated protein C (APC with the corresponding loop of factor Xa (fXa renders the APC mutant (APC/fX143-154 susceptible to inhibition by antithrombin (AT in the presence of pentasaccharide. Our recent results further indicated, that in addition to an improvement in the reactivity of APC/fX143-154 with AT, both the amidolytic and anti-factor Va activities of the mutant APC have also been significantly increased. Since the autolysis loop of APC is five residues longer than the autolysis loop of fXa, it could not be ascertained whether this loop in the mutant APC specifically interacts with the activated conformation of AT or if a shorter autolysis loop is responsible for a global improvement in the catalytic activity of the mutant protease. To answer this question, we prepared another APC mutant in which the autolysis loop of the protease was replaced with the corresponding loop of trypsin (APC/Tryp143-154. Unlike an ~500-fold improvement in the reactivity of APC/fX143-154 with AT in the presence of pentasaccharide, the reactivity of APC/Tryp143-154 with the serpin was improved ~10-fold. These results suggest that both the length and structure of residues of the autolysis loop are critical for the specificity of the coagulation protease interaction with AT. Further factor Va inactivation studies with the APC mutants revealed a similar role for the autolysis loop of APC in the interaction with its natural substrate.

  20. Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

    International Nuclear Information System (INIS)

    Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin–antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. - Highlights: • TFPI administration to rats after mustard inhalation reduces airway cast formation. • Inhibition of thrombin activation is the likely mechanism for limiting casts. • Rats given TFPI had

  1. A Simple Method for Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation of Key Principles from Heparin/Heparan Sulfate-Binding Proteins.

    Science.gov (United States)

    Sarkar, Aurijit; Desai, Umesh R

    2015-01-01

    Glycosaminoglycans (GAGs) affect human physiology and pathology by modulating more than 500 proteins. GAG-protein interactions are generally assumed to be ionic and nonspecific, but specific interactions do exist. Here, we present a simple method to identify the GAG-binding site (GBS) on proteins that in turn helps predict high specific GAG-protein systems. Contrary to contemporary thinking, we found that the electrostatic potential at basic arginine and lysine residues neither identifies the GBS consistently, nor its specificity. GBSs are better identified by considering the potential at neutral hydrogen bond donors such as asparagine or glutamine sidechains. Our studies also reveal that an unusual constellation of ionic and non-ionic residues in the binding site leads to specificity. Nature engineers the local environment of Asn45 of antithrombin, Gln255 of 3-O-sulfotransferase 3, Gln163 and Asn167 of 3-O-sulfotransferase 1 and Asn27 of basic fibroblast growth factor in the respective GBSs to induce specificity. Such residues are distinct from other uncharged residues on the same protein structure in possessing a significantly higher electrostatic potential, resultant from the local topology. In contrast, uncharged residues on nonspecific GBSs such as thrombin and serum albumin possess a diffuse spread of electrostatic potential. Our findings also contradict the paradigm that GAG-binding sites are simply a collection of contiguous Arg/Lys residues. Our work demonstrates the basis for discovering specifically interacting and druggable GAG-protein systems based on the structure of protein alone, without requiring access to any structure-function relationship data.

  2. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception.

    Science.gov (United States)

    van Vlijmen, Elizabeth F W; Veeger, Nic J G M; Middeldorp, Saskia; Hamulyák, Karly; Prins, Martin H; Büller, Harry R; Meijer, Karina

    2011-08-25

    Current guidelines discourage combined oral contraceptive (COC) use in women with hereditary thrombophilic defects. However, qualifying all hereditary thrombophilic defects as similarly strong risk factors might be questioned. Recent studies indicate the risk of venous thromboembolism (VTE) of a factor V Leiden mutation as considerably lower than a deficiency of protein C, protein S, or antithrombin. In a retrospective family cohort, the VTE risk during COC use and pregnancy (including postpartum) was assessed in 798 female relatives with or without a heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin G20210A mutation. Overall, absolute VTE risk in women with no, single, or combined defects was 0.13 (95% confidence interval 0.08-0.21), 0.35 (0.22-0.53), and 0.94 (0.47-1.67) per 100 person-years, while these were 0.19 (0.07-0.41), 0.49 (0.18-1.07), and 0.86 (0.10-3.11) during COC use, and 0.73 (0.30-1.51), 1.97 (0.94-3.63), and 7.65 (3.08-15.76) during pregnancy. COC use and pregnancy were independent risk factors for VTE, with highest risk during pregnancy postpartum, as demonstrated by adjusted hazard ratios of 16.0 (8.0-32.2) versus 2.2 (1.1-4.0) during COC use. Rather than strictly contraindicating COC use, we advocate that detailed counseling on all contraceptive options, including COCs, addressing the associated risks of both VTE and unintended pregnancy, enabling these women to make an informed choice. PMID:21659542

  3. A Simple Method for Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation of Key Principles from Heparin/Heparan Sulfate-Binding Proteins.

    Directory of Open Access Journals (Sweden)

    Aurijit Sarkar

    Full Text Available Glycosaminoglycans (GAGs affect human physiology and pathology by modulating more than 500 proteins. GAG-protein interactions are generally assumed to be ionic and nonspecific, but specific interactions do exist. Here, we present a simple method to identify the GAG-binding site (GBS on proteins that in turn helps predict high specific GAG-protein systems. Contrary to contemporary thinking, we found that the electrostatic potential at basic arginine and lysine residues neither identifies the GBS consistently, nor its specificity. GBSs are better identified by considering the potential at neutral hydrogen bond donors such as asparagine or glutamine sidechains. Our studies also reveal that an unusual constellation of ionic and non-ionic residues in the binding site leads to specificity. Nature engineers the local environment of Asn45 of antithrombin, Gln255 of 3-O-sulfotransferase 3, Gln163 and Asn167 of 3-O-sulfotransferase 1 and Asn27 of basic fibroblast growth factor in the respective GBSs to induce specificity. Such residues are distinct from other uncharged residues on the same protein structure in possessing a significantly higher electrostatic potential, resultant from the local topology. In contrast, uncharged residues on nonspecific GBSs such as thrombin and serum albumin possess a diffuse spread of electrostatic potential. Our findings also contradict the paradigm that GAG-binding sites are simply a collection of contiguous Arg/Lys residues. Our work demonstrates the basis for discovering specifically interacting and druggable GAG-protein systems based on the structure of protein alone, without requiring access to any structure-function relationship data.

  4. Evaluation of serum asymmetric dimethylarginine levels in patients with psoriasis vulgaris

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    Recep Bilgiç

    2015-12-01

    Full Text Available Background and Design: In this study, we aimed to evaluate the serum asymmetric dimethylarginine (ADMA levels and investigate the relationship between the severity of the disease and other cardiovascular risk factors in patients with psoriasis. Materials and Methods: This is a prospective, single-center, and controlled clinical study. Forty male patients with psoriasis and forty healthy male volunteers were included in the study. The psoriasis area severity index (PASI was used for evaluating the disease severity. Results: Forty consecutive male patients with psoriasis aged between 20 and 41 years (mean: 26.03±6.55 as study group and forty healthy male volunteers aged between 20 and 32 years (mean: 23.40±3.57 as control group were included in the study. There was no statistically significant difference in ADMA, homocysteine, vitamin B12, high density lipoprotein (HDL, and antithrombin III levels between the study and control groups. In psoriatic group, a mean 1.19-fold increase was observed in the serum ADMA levels in association with increased severity of PASI scores but it was not statistically significant. In the patient group, waist circumference (p=0.03, total cholesterol (p=0.007, low density lipoprotein (LDL cholesterol (p=0.014 and fibrinogen (p=0.049 levels were higher and folic acid (p=0.04 levels were lower than in the control group. In terms of laboratory parameters, a significant negative relationship between ADMA and HDL (p=0.045, and LDL (p=0.04 and total cholesterol (p=0.01 was found only in the control group. Conclusion: It seems that psoriasis with concomitant atherogenic dyslipidemia, enflammation and tendency to obesity is an independent risk factor for cardiovascular diseases and this risk seems to be present since earlier ages in correlation with disease severity. Extensive studies are needed to clearly demonstrate the relationship between this situation and serum ADMA levels in patients with psoriasis

  5. Structural and functional characterization of cleavage and inactivation of human serine protease inhibitors by the bacterial SPATE protease EspPα from enterohemorrhagic E. coli.

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    André Weiss

    Full Text Available EspPα and EspI are serine protease autotransporters found in enterohemorrhagic Escherichia coli. They both belong to the SPATE autotransporter family and are believed to contribute to pathogenicity via proteolytic cleavage and inactivation of different key host proteins during infection. Here, we describe the specific cleavage and functional inactivation of serine protease inhibitors (serpins by EspPα and compare this activity with the related SPATE EspI. Serpins are structurally related proteins that regulate vital protease cascades, such as blood coagulation and inflammatory host response. For the rapid determination of serpin cleavage sites, we applied direct MALDI-TOF-MS or ESI-FTMS analysis of coincubations of serpins and SPATE proteases and confirmed observed cleavage positions using in-gel-digest of SDS-PAGE-separated degradation products. Activities of both serpin and SPATE protease were assessed in a newly developed photometrical assay using chromogenic peptide substrates. EspPα cleaved the serpins α1-protease inhibitor (α1-PI, α1-antichymotrypsin, angiotensinogen, and α2-antiplasmin. Serpin cleavage led to loss of inhibitory function as demonstrated for α1-PI while EspPα activity was not affected. Notably, EspPα showed pronounced specificity and cleaved procoagulatory serpins such as α2-antiplasmin while the anticoagulatory antithrombin III was not affected. Together with recently published research, this underlines the interference of EspPα with hemostasis or inflammatory responses during infection, while the observed interaction of EspI with serpins is likely to be not physiologically relevant. EspPα-mediated serpin cleavage occurred always in flexible loops, indicating that this structural motif might be required for substrate recognition.

  6. New developments in the management of moderate-to-severe hemophilia B.

    Science.gov (United States)

    Nazeef, Moniba; Sheehan, John P

    2016-01-01

    Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX) activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV) access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP) represent fusion proteins with the immunoglobulin G1 (IgG1) Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the

  7. Potential Risk Factors Associated With Vascular Diseases in Patients Receiving Treatment for Hypertension

    Science.gov (United States)

    Kim, Hyunjung; Park, Joonhong; Chae, Hyojin; Lee, Gun Dong; Lee, Sang Yoon; Lee, Jong Min; Oh, Yong-Seog

    2016-01-01

    Background Currently, the hypertension (HTN) patients undergo appropriate medical treatment, and traditional risk factors are highly controlled. Therefore, potential risk factors of atherosclerotic vascular diseases (AVD) and venous thromboembolisms (VTE) in HTN should be reconsidered. We investigated thrombophilic genetic mutations and existing biomarkers for AVD or VTE in HTN patients receiving treatment. Methods A total of 183 patients were enrolled: AVD with HTN (group A, n=45), VTE with HTN (group B, n=62), and HTN patients without any vascular diseases (group C, n=76). The lipid profile, homocysteine (Hcy) levels, D-dimers, fibrinogen, antithrombin, lupus anticoagulant, and anti-cardiolipin antibody (aCL) were evaluated. Prothrombin G20210A, Factor V G1691A, and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were analyzed. Results All patients revealed wild type prothrombin G20210A and Factor V G1691A polymorphisms. The frequency of MTHFR polymorphisms was 677CT (n=84, 45.9%); 677TT (n=46, 25.1%); 1298AC (n=46, 25.1%); and 1298CC (n=2, 1.1%). The MTHFR 677TT genotype tended to increase the odds ratio (OR) to AVD events in HTN patients (OR 2.648, confidence interval 0.982-7.143, P=0.05). The group A demonstrated significantly higher Hcy levels (P=0.009), fibrinogen (P=0.004), and platelet counts (P=0.04) than group C. Group B had significantly higher levels of D-dimers (P=0.0001), platelet count (P=0.0002), and aCL (P=0.02) frequency than group C. Conclusions The MTHFR 677TT genotype and Hcy level could be potential risk factors associated with development of AVD in HTN patients receiving treatment. D-dimer and aCL might be useful to estimate the occurrence of VTE in them. PMID:26915609

  8. How I diagnose and manage HIT.

    Science.gov (United States)

    Warkentin, Theodore E

    2011-01-01

    Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4)/polyanion complexes. Platelet activation assays, such as the serotonin-release assay, are superior to PF4-dependent immunoassays in discerning which heparin-induced antibodies are clinically relevant. When HIT is strongly suspected, standard practice includes substituting heparin with an alternative anticoagulant; the 2 US-approved agents are the direct thrombin inhibitors (DTIs) lepirudin and argatroban, which are "niche" agents used only to manage HIT. However, only ~ 10% of patients who undergo serological investigation for HIT actually have this diagnosis. Indeed, depending on the clinical setting, only 10%-50% of patients with positive PF4-dependent immunoassays have platelet-activating antibodies. Therefore, overdiagnosis of HIT can be minimized by insisting that a positive platelet activation assay be required for definitive diagnosis of HIT. For these reasons, a management strategy that considers the real possibility of non-HIT thrombocytopenia is warranted. One approach that I suggest is to administer an indirect, antithrombin (AT)-dependent factor Xa inhibitor (danaparoid or fondaparinux) based upon the following rationale: (1) effectiveness in treating and preventing HIT-associated thrombosis; (2) effectiveness in treating and preventing thrombosis in diverse non-HIT situations; (3) both prophylactic- and therapeutic-dose protocols exist, permitting dosing appropriate for the clinical situation; (4) body weight-adjusted dosing protocols and availability of specific anti-factor Xa monitoring reduce risk of under- or overdosing (as can occur with partial thromboplastin time [PTT]-adjusted DTI therapy); (5) their long half-lives reduce risk of rebound hypercoagulability; (6) easy coumarin overlap; and (7) relatively low cost. PMID:22160026

  9. Coupled plasma filtration adsorption in experimental peritonitis-induced septic shock.

    Science.gov (United States)

    Sykora, Roman; Chvojka, Jiri; Krouzecky, Ales; Radej, Jaroslav; Kuncova, Jitka; Varnerova, Veronika; Karvunidis, Thomas; Novak, Ivan; Matejovic, Martin

    2009-05-01

    The coupled plasma filtration adsorption (CPFA) was developed as an adsorptive hemopurification method aimed at nonselective removal of circulating soluble mediators potentially involved in the pathogenesis of sepsis. We hypothesized that this nonselective hemopurification could protect from detrimental consequences of long-term, volume-resuscitated porcine septic shock. In 16 anesthetized, mechanically ventilated, and instrumented pigs, the hyperdynamic septic shock secondary to peritonitis was induced by intraperitoneally inoculating feces and maintained for 22 h with fluid resuscitation and norepinephrine infusion as needed to maintain MAP above 65 mmHg. After 12 h of peritonitis, animals were randomized to receive either supportive treatment (control, n = 8) or CPFA treatment (CPFA, n = 8). Systemic, hepatosplanchnic, and renal hemodynamics; oxygen exchange; energy metabolism (lactate/pyruvate and ketone body ratios); ileal mucosal and renal cortex microcirculation; systemic inflammation (TNF-alpha, IL-6); nitrosative/oxidative stress (thiobarbituric acid reactive species, nitrates + nitrites); and endothelial/coagulation dysfunction (asymmetric dimethylarginine, von Willebrand factor, thrombin-antithrombin complexes, platelet count) were assessed before and 12, 18, and 22 h of peritonitis. Coupled plasma filtration adsorption neither delayed the development of hypotension nor reduced the dose of norepinephrine. The treatment failed to attenuate sepsis-induced alterations in microcirculation, surrogate markers of cellular energetics, endothelial injury, and systemic inflammation. Similarly, CPFA did not protect from lung and liver dysfunction and even aggravated sepsis-induced disturbances in coagulation and oxidative/nitrosative stress. In this porcine model of septic shock, the early treatment with CPFA was not capable of reversing the sepsis-induced disturbances in various biological pathways and organ systems. Both the efficacy and safety of this method

  10. Tanshinone ⅡA protects rabbits against LPS-induced disseminated intravascular coagulation (DIC)

    Institute of Scientific and Technical Information of China (English)

    Liang-cai WU; Xi LIN; Hao SUN

    2012-01-01

    Aim:To evaluate the effects of tanshinone ⅡA (Tan ⅡA),a lipophilic diterpene from the Chinese herb Salvia miltiorrhiza,on lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) in rabbits.Methods:LPS-induced DIC model was made in adult male New Zealand rabbits by continuous intravenous infusion of LPS (0.5 mg/kg)via marginal ear vein for 6 h.The animals were simultaneously administered with Tan ⅡA (1,3 and 10 mg/kg) or heparin (500 000IU/kg) through continuous infusion via the contralateral marginal ear vein for 6 h.Before and 2 and 6 h after the start of LPS infusion,blood samples were taken for biochemical analyses.Results:Continuous infusion of LPS into the rabbits gradually impaired the hemostatic parameters,damaged renal and liver functions,increased the plasma TNF-α level,and led to a high mortality rate (80%).Treatment of the rabbits with Tan ⅡA dose-dependently attenuated the increase in activated partial thromboplastin time (APTT),prothrombin time (PT) and fibrin-fibrinogen degradation products (FDP); ameliorated the decrease in plasma levels of fibrinogen and platelets; and reversed the decline in activity of protein C and antithrombin Ⅲ.Meanwhile,the treatment significantly suppressed the increase in the plasma levels of aminotransferase,creatinine and TNF-α,and led to much lower mortality (46.7% and 26.7% for the medium- and high-dose groups).Treatment of the rabbits with the high dose of heparin also effectively improved the hemostatic parameters,ameliorated liver and renal injuries,and reduced the plasma level of TNF-α,and significantly reduced the mortality (33.3%).Conclusion:Tan ⅡA exerts a protective effect against DIC in rabbits.

  11. SEPSIS-ASSOCIATED DISSEMINATED INTRAVASCULAR COAGULATION AND THROMBOEMBOLIC DISEASE

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    Nicola Semeraro

    2010-08-01

    Full Text Available Sepsis is almost invariably associated with haemostatic abnormalities ranging from subclinical activation of blood coagulation (hypercoagulability, which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC, characterized by massive thrombin formation and widespread microvascular thrombosis, partly responsible of the multiple organ dysfunction syndrome (MODS, and subsequent consumption of platelets and coagulation proteins causing, in most severe cases, bleeding manifestations. There is general agreement that the key event underlying this life-threatening sepsis complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. Mechanistically, the latter, together with the micro-organism and its derivatives, causes DIC by 1 up-regulation of procoagulant molecules, primarily tissue factor (TF, which is produced mainly by stimulated monocytes-macrophages and by specific cells in target tissues; 2 impairment of physiological anticoagulant pathways (antithrombin, protein C pathway, tissue factor pathway inhibitor, which is orchestrated mainly by dysfunctional endothelial cells (ECs; and 3 suppression of fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1 by ECs and likely also to thrombin-mediated  activation of thrombin-activatable fibrinolysis inhibitor (TAFI. Notably, clotting enzymes non only lead to microvascular thrombosis but can also elicit cellular responses that amplify the inflammatory reactions. Inflammatory mediators can also cause, directly or indirectly, cell apoptosis or necrosis and recent evidence indicates that products released from dead cells, such as nuclear proteins (particularly extracellular histones, are able to propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenetic mechanisms of DIC and MODS may have important implications for the

  12. High mobility group B1 levels in sepsis and Disseminated Intravascular Coagulation.

    Science.gov (United States)

    Eskici, Zeynep M; Açıkgöz, Şerefden; Pişkin, Nihal; Mungan, Görkem; Can, Murat; Güven, Berrak; Köktürk, Fürüzan

    2012-01-01

    Cytokines trigger coagulant and fibrinolytic systems in sepsis to result in Disseminated Intravascular Coagulation (DIC) that is an important complication and leads to disseminated hemorrhages and multi-organ failure. High Mobility Group B1 DNA Binding (HMGB1) protein is a cytokine taking part in systemic inflammatory response. The objective of this study was to investigate HMGB1 levels in groups of septic patients with and without DIC.Twenty-one septic patients without DIC and 12 septic patients with DIC from the Intensive Care Unit (ICU) were included in the study. In addition, 20 patients admitted to the ICU without sepsis or DIC and 20 healthy volunteers served as controls. Levels of HMGB1, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, protein C, protein S, anti-thrombin III (ATIII), platelet (thrombocyte) and leukocyte count were determined. Levels of fibrinogen, protein C, ATIII and platelet count were significantly lower and D-dimer was significantly higher in the group with sepsis plus DIC compared to the group with sepsis without DIC. Levels of HMGB1 were higher in the group with sepsis and DIC compared to the group with sepsis; however, the difference was not statistically significant and the levels of HGMB1 of both groups were significantly higher compared to ICU and healthy control groups. HMGB1 levels were not significantly different in survivor and non survivor patients. HMGB1 levels did not differ in lower respiratory tract infection (LRTI) and urinary tract infection (UTI) in regard to the etiology of sepsis.

  13. Blood coagulation parameters and activity indices in patients with systemic lupus erythematosus

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    A. A. Arshinov

    2005-01-01

    Full Text Available Objective. To assess coagulation parameters and activity indices in pts with systemic lupus erythematosus (SLE. Material and methods . 86 pts with SLE (83 female and 3 male were examined. 12 of them had antiphospholipid syndrome. Mean age was 35,9±1,5 years (from 18 to 58 years, mean disease duration was 9,8+1,4 years. Control group consisted of 60 healthy volunteers with mean age 37,1+4,1 years. SLE activity assessment was performed with SLAM, SLEDAI and ECLAM indices. Results. SLE pts showed 5-fold (p<0,01 increase of spontaneous platelets aggregation and more than 3-fold increase of factor von Willebrand antigen (FWA concentration. Platelet activation in pts was accompanied by decrease of platelet aggregation with collagen (on 27%, p<0,01. Characteristic sign of coagulation hemostasis activation was significant increase of soluble fibrin-monomer complexes (SFMC concentration on 81 % (p<0,01 so as increase D-dimers level in 53,3% of pts. Fibrinogen concentration was increased on 29%, spontaneous fibrinolysis parameters were decreased on 20%, antithrombin (AT 111 - on 21% in comparison with control. Direct correlation between activity indiccs and SFMC(ECLAM, r=0,5, fibrinogen concentration (SLAM, r=0,34, D- dimers level (ECLAM, r=0,5, spontaneous platelet aggregation (ECLAM, r=0,5 so as inverse correlation with AT III activity (SLEDAI, r-0,73 was revealed. Conclusion. Changes of hemostasis parameters in SLE may serve as predictors of thrombotic disorders development and indication to drug correction of blood coagulation disorders. Direct correlation between blood coagulation system activity and indices of SLE activity.

  14. Factor V Leiden, FII G20210A, MTHFR C677T mutations as risk factors for venous thrombosis during pregnancy and puerperium

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    Đorđević Valentina

    2005-01-01

    Full Text Available Background. Venous thrombosis is the most common cause of obstetric morbidity and mortality during pregnancy and puerperium. The incidence of pregnancy associated venous thrombosis varies from 1 in 1000 to 1 in 2000 deliveries. Factor V G1691A (FV Leiden, FII G20210A and MTHFR C677T mutations are the most common genetic risk factors for thromboembolism. The aim of this study was to establish the presence of these risk factors in a group of women with an episode of deep venous thrombosis during pregnancy or puerperium. Methods. The study was carried in a group of 45 women with the first episode of deep venous thrombosis during pregnancy or puerperium. The patients with antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, and autoimmune and malignant diseases were excluded from the study. FV Leiden, FII G20210A, and MTHFR C677T mutations were detected by polymerase chain reaction, followed by digestion with specific restriction enzymes. Results. Twenty heterozygous carriers of the FV Leiden mutation and one homozygous carrier were detected, which represents the frequencies of 44.4% and 2.2%, respectively. For the FII G20210A mutation, six heterozygous carriers were identified, giving the frequency of 13.3%. The MTHFR C677T mutation was observed in 31 patients (22 heterozygous and 9 homozygous carriers which represents the frequencies of 48.9% and 20%, respectively. Conclusion. Our study suggested that the obligatory testing for FV Leiden and FII G20210A mutations was strongly recommended in women with history of venous thrombosis during pregnancy and puerperium. We found a slight effect of MTHFR 677T allele, but it should be considered in association with other risk factors.

  15. Single nucleotide polymorphisms other than factor V Leiden are associated with coagulopathy and osteonecrosis of the femoral head in Chinese patients.

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    Kou-Ti Peng

    Full Text Available Single nucleotide polymorphisms (SNPs of factor V Leiden have been associated with osteonecrosis of the femoral head (ONFH in Caucasians but remains controversial in Asians. We used an SNP microarray to screen 55 loci of factor V gene in patients with ONFH of Chinese. Significantly different candidate SNPs at 14 loci were analyzed in 146 patients and 116 healthy controls using MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and gene sequencing. The factor V Leiden (rs6025 was not found in all participants. Six SNP loci (rs9332595, rs6020, rs9332647, rs3766110, rs10919186, and rs12040141 were confirmed with significant differences in patients but not in controls. The rs6020 G-to-A polymorphism was found in 88.9% of the patients. In addition, a high percentage (87.6% of the patients had an abnormal coagulation profile that included hyperfibrinogen, elevated fibrinogen degradation products, elevated D-dimer, abnormal protein S, abnormal protein C, or a decrease in anti-thrombin III. Patients with the rs6020 G-to-A polymorphism (mutation had a higher risk (odds ratio: 4.62; 95% confidence interval: 1.44-14.8 of having coagulation abnormalities than did those without the mutation (wild-type (χ(2 p  =  0.006. Our findings suggested that the rs6020 polymorphism might be the genetic trait that accounts for the higher prevalence of ONFH in the Chinese population than in Westerners. Exposure to risk factors such as alcohol and steroids in patients with the rs6020 polymorphism causes coagulation abnormalities and, subsequently, thromboembolisms in the femoral head.

  16. Single Nucleotide Polymorphisms Other than Factor V Leiden Are Associated with Coagulopathy and Osteonecrosis of the Femoral Head in Chinese Patients

    Science.gov (United States)

    Peng, Kou-Ti; Huang, Kuo-Chin; Huang, Tsan-Wen; Lee, Yun-Shien; Hsu, Wei-Hsiu; Hsu, Robert W. W.; Ueng, Steve W. N.; Lee, Mel S.

    2014-01-01

    Single nucleotide polymorphisms (SNPs) of factor V Leiden have been associated with osteonecrosis of the femoral head (ONFH) in Caucasians but remains controversial in Asians. We used an SNP microarray to screen 55 loci of factor V gene in patients with ONFH of Chinese. Significantly different candidate SNPs at 14 loci were analyzed in 146 patients and 116 healthy controls using MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry and gene sequencing. The factor V Leiden (rs6025) was not found in all participants. Six SNP loci (rs9332595, rs6020, rs9332647, rs3766110, rs10919186, and rs12040141) were confirmed with significant differences in patients but not in controls. The rs6020 G-to-A polymorphism was found in 88.9% of the patients. In addition, a high percentage (87.6%) of the patients had an abnormal coagulation profile that included hyperfibrinogen, elevated fibrinogen degradation products, elevated D-dimer, abnormal protein S, abnormal protein C, or a decrease in anti-thrombin III. Patients with the rs6020 G-to-A polymorphism (mutation) had a higher risk (odds ratio: 4.62; 95% confidence interval: 1.44–14.8) of having coagulation abnormalities than did those without the mutation (wild-type) (χ2 p  =  0.006). Our findings suggested that the rs6020 polymorphism might be the genetic trait that accounts for the higher prevalence of ONFH in the Chinese population than in Westerners. Exposure to risk factors such as alcohol and steroids in patients with the rs6020 polymorphism causes coagulation abnormalities and, subsequently, thromboembolisms in the femoral head. PMID:25119470

  17. [Impact of biochemisty on the duration of treatment for pulmonary embolus].

    Science.gov (United States)

    Ferrari, E; Benhamou, M; Cerboni, P; Baudouy, M

    2003-12-01

    Can the biochemical evidence for "new thrombophilic factors" influence the duration of AVK treatment following the occurrence of a first pulmonary embolus? Certainly for the classic but very rare antithrombin defects as well as for the existence of circulating anticoagulant. Possibly for protein C and S defects. On the other hand, the existence of a heterozygotic "Leiden" mutation of factor V, or factor II, and an increase of factors VIII, IX, or XI, do not at present warrant a change in AVK prescription. In effect, in the case where the existence of a thrombogenic state implies a prolongation of AVK treatment with its significant potential complications, it is indispensable that the risk/benefit ratio is well founded, which is not the case for these "new" thrombophilic states. The coexistence of several of these new biochemical anomalies (for example the association of a factor V and factor II mutation) probably represents an excess risk of thrombosis, but in this situation the reasoning remains the same. On the other hand, faced with a confirmed recurrence, the studies in the literature tell us that very long term treatment should be debated independently from the biochemical results. It is conceivable that there are biochemical anomalies (sometimes quite frequent which should be viewed as "normal variants") which, although they have great significance for improving the understanding of venous thrombo-embolic disease, do not at present warrant a change in our therapeutic protocols. Another facet of the problem concerns the use of D-dimers following the first months of AVK treatment in order to possibly distinguish patients at low risk of recurrence. The first results of this approach are interesting, but require confirmation before they can be used in practice.

  18. Honeybee Venom Proteome Profile of Queens and Winter Bees as Determined by a Mass Spectrometric Approach

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    Ellen L. Danneels

    2015-10-01

    Full Text Available Venoms of invertebrates contain an enormous diversity of proteins, peptides, and other classes of substances. Insect venoms are characterized by a large interspecific variation resulting in extended lists of venom compounds. The venom composition of several hymenopterans also shows different intraspecific variation. For instance, venom from different honeybee castes, more specifically queens and workers, shows quantitative and qualitative variation, while the environment, like seasonal changes, also proves to be an important factor. The present study aimed at an in-depth analysis of the intraspecific variation in the honeybee venom proteome. In summer workers, the recent list of venom proteins resulted from merging combinatorial peptide ligand library sample pretreatment and targeted tandem mass spectrometry realized with a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS/MS. Now, the same technique was used to determine the venom proteome of queens and winter bees, enabling us to compare it with that of summer bees. In total, 34 putative venom toxins were found, of which two were never described in honeybee venoms before. Venom from winter workers did not contain toxins that were not present in queens or summer workers, while winter worker venom lacked the allergen Api m 12, also known as vitellogenin. Venom from queen bees, on the other hand, was lacking six of the 34 venom toxins compared to worker bees, while it contained two new venom toxins, in particularly serine proteinase stubble and antithrombin-III. Although people are hardly stung by honeybees during winter or by queen bees, these newly identified toxins should be taken into account in the characterization of a putative allergic response against Apis mellifera stings.

  19. Honeybee venom proteome profile of queens and winter bees as determined by a mass spectrometric approach.

    Science.gov (United States)

    Danneels, Ellen L; Van Vaerenbergh, Matthias; Debyser, Griet; Devreese, Bart; de Graaf, Dirk C

    2015-11-01

    Venoms of invertebrates contain an enormous diversity of proteins, peptides, and other classes of substances. Insect venoms are characterized by a large interspecific variation resulting in extended lists of venom compounds. The venom composition of several hymenopterans also shows different intraspecific variation. For instance, venom from different honeybee castes, more specifically queens and workers, shows quantitative and qualitative variation, while the environment, like seasonal changes, also proves to be an important factor. The present study aimed at an in-depth analysis of the intraspecific variation in the honeybee venom proteome. In summer workers, the recent list of venom proteins resulted from merging combinatorial peptide ligand library sample pretreatment and targeted tandem mass spectrometry realized with a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS/MS). Now, the same technique was used to determine the venom proteome of queens and winter bees, enabling us to compare it with that of summer bees. In total, 34 putative venom toxins were found, of which two were never described in honeybee venoms before. Venom from winter workers did not contain toxins that were not present in queens or summer workers, while winter worker venom lacked the allergen Api m 12, also known as vitellogenin. Venom from queen bees, on the other hand, was lacking six of the 34 venom toxins compared to worker bees, while it contained two new venom toxins, in particularly serine proteinase stubble and antithrombin-III. Although people are hardly stung by honeybees during winter or by queen bees, these newly identified toxins should be taken into account in the characterization of a putative allergic response against Apis mellifera stings. PMID:26529016

  20. Effect of smoking on regional cerebral blood flow in the normal aged volunteers

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, Kazuya; Kobayashi, Shotai; Yamaguchi, Shuhei; Kitani, Kohaku; Tsunematsu, Tokugoro

    1987-06-01

    They were divided into four groups of (1) 15 young smokers (mean age of 55 years), (2) 14 young non-smokers (mean age of 52 years), (3) 16 elderly smokers (mean age of 74 years), and (4) elderly non-smokers (mean age of 75 years). All subjects were healthy volunteers without any past history of cerebral and pulmonary diseases. The rCBF was measured by Xe/sup 133/ inhalation method using 16-ch-Novo-cerebrograph. Pulmonary functions such as FVC, FEV/sub 1.0/%, %VC, FEV/sub 1.0/, V/sub 50/ and V/sub 25/ were measured by Autospiror HI-498, and End-tidal partial pressures for carbon dioxide (PeCO/sub 2/) were monitored by capnograph (Normocap, Datex). The rCBF reduced significantly with advancing age. Although there was no significant difference in rCBF between young smokers and non-smokers, elderly smokers showed significantly lower rCBF than elderly non-smokers. There was no difference in vital capacity and FEV/sub 1.0/% between smokers and non-smokers in both young and elderly people. Smokers group, however, showed significantly lower V/sub 50/ than non-smokers group. PeCO/sub 2/ in smokers was significantly lower than that in non-smokers. No significant differences were seen in hematocrit, antithrombin III, serum lipids, and blood pressure between two groups in the young and elderly. There was a significantly positive correlation between rCBF and PeCO/sub 2/. Our finding showed smoking over a long period produces reductions in the cerebral blood flow. This was consistent with the reports by other researchers. In addition, the results of the present study suggested the possibility that the latent small airway disturbances resulting from long-term smoking also play a ole of leading to decreased PCO/sub 2/ and eventually cause reductions in rCBF.

  1. Clinical study of venous thromboembolism during pregnancy and puerperium.

    Science.gov (United States)

    Adachi, T; Hashiguchi, K; Arai, Y; Ohta, H

    2001-01-01

    We encountered 16 cases of venous thromboembolism (VTE) in women during pregnancy and/or puerperium over the past 15 years at our perinatal center, representing 0.14% of all patients who delivered babies. The present study was undertaken to analyze the risk factors, clinical course and outcomes in these 16 cases. The ages of the patients varied from 29 to 39 years. Four women had pulmonary embolism (PE), 3 of which after caesarean section (C/S) at 35 to 40 weeks, and one case after ovarian cystectomy at 13 weeks of gestation. Twelve cases had deep venous thrombosis (DVT), 4 of which during pregnancy, and the remaining 8 cases after C/S. Four patients who had DVT during a normal course of pregnancy had severe thrombophilia: antiphospholipid antibody syndrome, a history of thrombosis and antithrombin (AT) deficiency. They were treated with heparin with or without AT and had healthy babies via successful vaginal deliveries. The common risk factors in 3 cases of PE with C/S was prolonged bed rest due to threatened premature delivery with total placenta previa, uterine myoma and Ehlers-Danlos syndrome. Other risk factors were massive bleeding, and positive lupus anticoagulant. However, the case of the ovarian cystectomy had only one risk factor, which was obesity. This patient died but the remaining patients recovered with treatment. Because of the low incidence of thrombosis in the Japanese population, prophylactic anticoagulant therapy has not routinely been given to patients undergoing obstetrical operations. However, proper management including prophylactic anticoagulant therapy might be considered for risk patients, depending on the risk factors.

  2. Identification of Circulating Biomarker Candidates for Hepatocellular Carcinoma (HCC: An Integrated Prioritization Approach.

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    Faryal Mehwish Awan

    Full Text Available Hepatocellular carcinoma (HCC is the world's third most widespread cancer. Currently available circulating biomarkers for this silently progressing malignancy are not sufficiently specific and sensitive to meet all clinical needs. There is an imminent and pressing need for the identification of novel circulating biomarkers to increase disease-free survival rate. In order to facilitate the selection of the most promising circulating protein biomarkers, we attempted to define an objective method likely to have a significant impact on the analysis of vast data generated from cutting-edge technologies. Current study exploits data available in seven publicly accessible gene and protein databases, unveiling 731 liver-specific proteins through initial enrichment analysis. Verification of expression profiles followed by integration of proteomic datasets, enriched for the cancer secretome, filtered out 20 proteins including 6 previously characterized circulating HCC biomarkers. Finally, interactome analysis of these proteins with midkine (MDK, dickkopf-1 (DKK-1, current standard HCC biomarker alpha-fetoprotein (AFP, its interacting partners in conjunction with HCC-specific circulating and liver deregulated miRNAs target filtration highlighted seven novel statistically significant putative biomarkers including complement component 8, alpha (C8A, mannose binding lectin (MBL2, antithrombin III (SERPINC1, 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1, alcohol dehydrogenase 6 (ADH6, beta-ureidopropionase (UPB1 and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6. Our proposed methodology provides a swift assortment process for biomarker prioritization that eventually reduces the economic burden of experimental evaluation. Further dedicated validation studies of potential putative biomarkers on HCC patient blood samples are warranted. We hope that the use of such integrative secretome, interactome and miRNAs target filtration approach will

  3. Removal selectivity of Prometheus: A new extracorporeal liver support device

    Institute of Scientific and Technical Information of China (English)

    Kinan Rifai; Thomas Ernst; Ulrich Kretschmer; Hermann Haller; Michael Peter Manns; Danilo Fliser

    2006-01-01

    AIM: To evaluate whether treatment with the Prometheus(R) system significantly affects cytokines,coagulation factors and other plasma proteins.METHODS: We studied nine patients with acute-onchronic liver failure and accompanying renal failure.Prometheus(R) therapy was performed on 2 consecutive days for up to 6 h in all patients. Several biochemical parameters and blood counts were assessed at regular time points during Prometheus(R) treatment.RESULTS: We observed a significant decrease of both protein-bound (e.g. Bile acids) and water-soluble (e.g.ammonia) substances after Prometheus(R) therapy. Even though leukocytes increased during treatment (P< 0.01),we found no significant changes of C-reactive protein,interleukin-6, and tumor necrosis factor-α plasma levels (all P > 0.5). Further, antithrombin 3, factor Ⅱ and factor V plasma levels did not decrease during Prometheus(R)therapy (all P >0.5), and the INR remained unchanged (P =0.4). Plasma levels of total protein, albumin, and fibrinogen were also not altered during Prometheus(R)treatment (all P > 0.5). Finally, platelet count did not change significantly during therapy (P= 0.6).CONCLUSION: Despite significant removal of proteinbound and water-soluble substances, Prometheus(R)therapy did not affect the level of cytokines, coagulation factors or other plasma proteins. Thus, the filters and adsorbers used in the system are highly effective and specific for water-soluble substances and toxins bound to the albumin fraction.

  4. Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran.

    Science.gov (United States)

    Ammollo, Concetta Tiziana; Semeraro, Nicola; Carratù, Maria Rosaria; Colucci, Mario; Semeraro, Fabrizio

    2016-02-01

    The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator-mediated clot lysis by turbidimetry, and thrombin-activatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparins.

  5. C1-esterase inhibitor treatment: preclinical safety aspects on the potential prothrombotic risk.

    Science.gov (United States)

    Schürmann, Daniel; Herzog, Eva; Raquet, Elmar; Nolte, Marc W; May, Frauke; Müller-Cohrs, Jochen; Björkqvist, Jenny; Dickneite, Gerhard; Pragst, Ingo

    2014-11-01

    Human plasma-derived C1-esterase inhibitor (C1-INH) is an efficacious and safe treatment for hereditary angioedema. However, thrombotic events in subjects treated with C1-INH at recommended or off-label, high doses have been reported. In this study, we addressed the potential prothrombotic risk of C1-INH treatment in high doses using a non-clinical rabbit model. Following intravenous infusion of C1-INH to rabbits at doses up to 800 IU/kg, the exposure and the pharmacodynamic efficacy of C1-INH in rabbits were confirmed by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively. Potential prothrombotic effects were assessed following induction of venous and arterial thrombosis using in vivo models of venous and arterial stasis, complemented by various in vitro assays of coagulation markers. Administration of C1-INH at doses up to 800 IU/kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition of arterial occlusion was observed upon C1-INH administration when compared with isotonic saline treatment, indicating antithrombotic rather than prothrombotic activity of high dose C1-INH treatment in vivo. This was further confirmed in vitro by decreased thrombin generation, increased activated partial thromboplastin time, clotting time and clot formation time, and inhibition of platelet aggregation. No relevant changes in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin fragment 1+2 were observed upon high dose C1-INH treatment. The data suggest that treatment of healthy rabbits with high doses of C1-INH could potentially inhibit coagulation and thrombus formation rather than induce a prothrombotic risk.

  6. Haemostatic and inflammatory biomarkers in advanced chronic heart failure: role of oral anticoagulants and successful heart transplantation.

    Science.gov (United States)

    Cugno, Massimo; Mari, Daniela; Meroni, Pier Luigi; Gronda, Edoardo; Vicari, Francesco; Frigerio, Maria; Coppola, Raffaella; Bottasso, Bianca; Borghi, Maria Orietta; Gregorini, Luisa

    2004-07-01

    Advanced chronic heart failure (CHF) is associated with abnormal haemostasis and inflammation, but it is not known how these abnormalities are related, whether they are modified by oral anticoagulants (OAT), or if they persist after successful heart transplantation. We studied 25 patients with CHF (New York Heart Association class IV, 10 of whom underwent heart transplantation) and 25 age- and sex-matched healthy controls by measuring their plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT) complexes, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, factor VII (FVII), fibrinogen, von Willebrand factor (VWF), tumour necrosis factor (TNF), soluble TNF receptor II (sTNFRII), interleukin 6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelial-selectin (E-selectin) and thrombomodulin. CHF patients had higher plasma levels of TAT, D-dimer, t-PA, fibrinogen, VWF, TNF, IL-6, sTNFRII, sVCAM-1 (P = 0.0001), sICAM-1 (P = 0.003) and thrombomodulin (P = 0.007) than controls. There were significant correlations (r = 0.414-0.595) between coagulation, fibrinolysis, endothelial dysfunction and inflammation parameters, which were lower in those patients treated with OATs. Heart transplantation led to reductions in fibrinogen (P = 0.001), VWF (P = 0.05), D-dimer (P = 0.05) and IL-6 levels (P = 0.05), but all the parameters remained significantly higher (P = 0.01-0.0001) than in the controls. Advanced CHF is associated with coagulation activation, endothelial dysfunction and increased proinflammatory cytokine levels. Most of these abnormalities parallel each other, tend to normalize in patients treated with OATs and, although reduced, persist in patients undergoing successful heart transplantation, despite the absence of clinical signs of CHF. PMID:15198737

  7. Microparticle-Induced Coagulation Relates to Coronary Artery Atherosclerosis in Severe Aortic Valve Stenosis.

    Directory of Open Access Journals (Sweden)

    Patrick Horn

    Full Text Available Circulating microparticles (MPs derived from endothelial cells and blood cells bear procoagulant activity and promote thrombin generation. Thrombin exerts proinflammatory effects mediating the progression of atherosclerosis. Aortic valve stenosis may represent an atherosclerosis-like process involving both the aortic valve and the vascular system. The aim of this study was to investigate whether MP-induced thrombin generation is related to coronary atherosclerosis and aortic valve calcification.In a cross-sectional study of 55 patients with severe aortic valve stenosis, we assessed the coronary calcification score (CAC as indicator of total coronary atherosclerosis burden, and aortic valve calcification (AVC by computed tomography. Thrombin-antithrombin complex (TATc levels were measured as a marker for thrombin formation. Circulating MPs were characterized by flow cytometry according to the expression of established surface antigens and by measuring MP-induced thrombin generation.Patients with CAC score below the median were classified as patients with low CAC, patients with CAC Score above the median as high CAC. In patients with high CAC compared to patients with low CAC we detected higher levels of TATc, platelet-derived MPs (PMPs, endothelial-derived MPs (EMPs and MP-induced thrombin generation. Increased level of PMPs and MP-induced thrombin generation were independent predictors for the severity of CAC. In contrast, AVC Score did not differ between patients with high and low CAC and did neither correlate with MPs levels nor with MP-induced thrombin generation.In patients with severe aortic valve stenosis MP-induced thrombin generation was independently associated with the severity of CAC but not AVC indicating different pathomechanisms involved in coronary artery and aortic valve calcification.

  8. Endogenous angiogenesis inhibitors and their therapeutic implications.

    Science.gov (United States)

    Cao, Y

    2001-04-01

    A number of endogenous inhibitors targeting the tumor vasculature have recently been identified using in vitro and in vivo antiangiogenesis models. While many of these angiogenesis inhibitors display a broad spectrum of biological actions on several systems in the body, several inhibitors including angiostatin, endostatin, and serpin antithrombin seem to act specifically on the proliferating endothelial cell compartment of the newly formed blood vessels. The discovery of these specific endothelial inhibitors not only increases our understanding of the functions of these molecules in the regulation of physiological and pathological angiogenesis, but may also provide an important therapeutic strategy for the treatment of cancer and other angiogenesis dependent diseases, including diabetic retinopathy and chronic inflammations. Systemic administration of these angiogenesis inhibitors in animals significantly suppresses the growth of a variety of tumors and their metastases. However, their production as functional recombinant proteins has been proven to be difficult. In addition, high dosages of these inhibitors are required to suppress tumor growth in animal studies. Other disadvantages of the antiangiogenic protein therapy include repeated injections, prolonged treatment, transmission of toxins and infectious particles, and high cost for manufacturing large amounts of protein molecules. Thus, alternative strategies need to be developed in order to improve the clinical settings of antiangiogenic therapy. Developments of these strategies are ongoing and they include identification of more potent inhibitors, antiangiogenic gene therapy, improvement of protein/compound half-lives in the circulation, increase of their concentrations at the disease location, and combinatorial therapies with approaches including chemotherapy, radiotherapy, and immunotherapy. Despite the above-mentioned disadvantages, a few inhibitors have entered into the early stages of clinical trials and

  9. Splenectomy Improves Hemostatic and Liver Functions in Hepatosplenic Schistosomiasis Mansoni.

    Directory of Open Access Journals (Sweden)

    Luiz Arthur Calheiros Leite

    Full Text Available Schistosomiasis mansoni is a chronic liver disease, in which some patients (5-10% progress to the most severe form, hepatosplenic schistosomiasis. This form is associated with portal hypertension and splenomegaly, and often episodes of gastrointestinal bleeding, even with liver function preserved. Splenectomy is a validated procedure to reduce portal hypertension following digestive bleeding. Here, we evaluate beneficial effects of splenectomy on blood coagulation factors and liver function tests in hepatosplenic schistosomiasis mansoni compared to non-operated patients.Forty-five patients who had undergone splenectomy surgery were assessed by laboratory analyses and ultrasound examination and compared to a non-operated group (n = 55. Blood samples were obtained for liver function tests, platelet count and prothrombin time. Coagulation factors (II, VII, VIII, IX and X, protein C and antithrombin IIa, plasminogen activator inhibitor-1 were measured by routine photometric, chromogenic or enzyme-linked immunosorbent assays, while hyperfibrinolysis was defined by plasminogen activator inhibitor-1 levels. Both groups had similar age, gender and pattern of periportal fibrosis. Splenectomized patients showed significant reductions in portal vein diameter, alkaline phosphatase and bilirubin levels compared to non-operated patients, while for coagulation factors there were significant improvement in prothrombin, partial thromboplastin times and higher levels of factor VII, VIII, IX, X, protein C and plasminogen activator inhibitor-1.This study shows that the decrease of flow pressure in portal circulation after splenectomy restores the capacity of hepatocyte synthesis, especially on the factor VII and protein C levels, and these findings suggest that portal hypertension in patients with hepatosplenic schistosomiasis influences liver functioning and the blood coagulation status.

  10. Evaluation of bone marrow with particular consideration of the megakaryocyte lineage and coagulation profile in the pregnant fallow deer (Dama dama).

    Science.gov (United States)

    Snarska, A; Sobiech, P

    2016-01-01

    The aim of the study was to evaluate the megakaryocyte lineage of bone marrow and coagulation parameters in fallow deer during the last month of pregnancy. The animals were managed in the barn-feeding system. Twenty female fallow deer, aged 2-3 years, divided into 2 groups were used in the study. Group 1 comprised the females in the last month of pregnancy, and the non-pregnant females were used as the control. All the animals were clinically healthy. Coagulation parameters were measured in all the deer: thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and plasma concentrations of fibrinogen, D-dimer, and antithrombin III. A quantitative assessment of bone marrow was carried out for the erythroblastic, myeloid, lymphoid, monocyte-macrophage, and megakaryopoietic cell lines. A detailed analysis of megakaryocyte lineage was performed after whole blood and platelet count. There were no significant differences in the erythroblast, granulocyte, monocyte-macrophage and lymphoid systems between the animal groups. Thrombocyte count in the pregnant deer was lower than that found in the control group. Bone marrow smears revealed a slightly decreased megakaryocyte count, while the megakaryoblast and promegakaryocyte counts were unchanged. The analysis of coagulation parameters showed increased levels of fibrinogen, thrombin time, prothrombin time and activated partial thromboplastin time in the pregnant animals. The study suggested a hyperactivation of the coagulation system with a slight reduction in the megakaryocyte count in bone marrow, and a reduction in platelet count in peripheral blood at the end of pregnancy. PMID:27487510

  11. Molecular basis of the clotting defect in a bleeding patient missing the Asp-185 codon in the factor X gene.

    Science.gov (United States)

    Lu, Qiuya; Yang, Likui; Manithody, Chandrashekhara; Wang, Xuefeng; Rezaie, Alireza R

    2014-11-01

    Factor X (FX) is a vitamin K-dependent plasma zymogen, which following activation to factor Xa (FXa), converts prothrombin to thrombin in the blood clotting cascade. It was recently demonstrated that a natural variant of FX carrying the Asp-185 deletion (FX-D185del, chymotrypsinogen numbering) was associated with mild bleeding in a patient with severe FX deficiency. In this study, we expressed FX-D185del in mammalian cells and characterized its properties in appropriate kinetic assays in purified systems. We discovered that while the FX variant can be normally activated by physiological activators; both amidolytic and proteolytic activities of the mutant are dramatically impaired. Interestingly, factor Va (FVa) significantly improved the proteolytic defect when the mutant protease was assembled into the prothrombinase complex. Thus, in contrast to >50-fold catalytic defect in the absence of FVa, the variant activated prothrombin with only ~2.5-fold decreased catalytic efficiency in the presence of the cofactor. The FXa variant dramatically lost its susceptibility to inhibition by antithrombin and tissue factor pathway inhibitor, thus exhibiting ~2-3 orders of magnitude lower reactivity with the plasma inhibitors. Further studies revealed that Na(+) no longer activates the variant protease, suggesting that the functionally important allosteric linkage between the Na(+)-binding and the P1-binding sites of the protease has been eliminated. These results suggest that the lower catalytic efficiency of FXa-D185del in the bleeding patient may be partially compensated by the loss of its reactivity with plasma inhibitors, possibly explaining the basis for the paradoxical severe FX deficiency with only mild bleeding tendency for this mutation. PMID:25179519

  12. The M358R variant of α(1)-proteinase inhibitor inhibits coagulation factor VIIa.

    Science.gov (United States)

    Sheffield, William P; Bhakta, Varsha

    2016-02-12

    The naturally occurring M358R mutation of the plasma serpin α1-proteinase inhibitor (API) changes both its cleavable reactive centre bond to Arg-Ser and the efficacy with which it inhibits different proteases, reducing the rate of inhibition of neutrophil elastase, and enhancing that of thrombin, factor XIa, and kallikrein, by several orders of magnitude. Although another plasma serpin with an Arg-Ser reactive centre, antithrombin (AT), has been shown to inhibit factor VIIa (FVIIa), no published data are available with respect to FVIIa inhibition by API M358R. Recombinant bacterially-expressed API M358R and plasma-derived AT were therefore compared using gel-based and kinetic assays of FVIIa integrity and activity. Under pseudo-first order conditions of excess serpin over protease, both AT and API M358R formed denaturation-resistant inhibitory complexes with FVIIa in reactions accelerated by TF; AT, but not API M358R, also required heparin for maximal activity. The second order rate constant for heparin-independent API M358R-mediated FVIIa inhibition was determined to be 7.8 ± 0.8 × 10(2) M(-1)sec(-1). We conclude that API M358R inhibits FVIIa by forming inhibitory complexes of the serpin type more rapidly than AT in the absence of heparin. The likely 20-fold excess of API M358R over AT in patient plasma during inflammation raises the possibility that it could contribute to the hemorrhagic tendencies manifested by rare individuals expressing this mutant serpin. PMID:26797521

  13. Coagulation Changes During Graded Orhostatic Stress and Recovery

    Science.gov (United States)

    Goswami, Nandu; Cvirn, Gerhard; Schlagenhauf, Aaxel; Leschnik, Bettina; Koestenberger, Martin; Roessler, Andreas; Jantscher, Andreas; Waha, James Elvis; Wolf, Sabine; Vrecko, Karoline; Juergens, Guenther; Hinghofer-Szalkay, Helmut

    2013-02-01

    Background: Orthostatic stress has been introduced as a novel paradigm for activating the coagulation system. We examined whether graded orthostatic stress (using head up tilt, HUT + lower body negative pressure, LBNP) until presyncope leads to anti / pro-coagulatory changes and how rapidly they return to baseline during recovery. Methodology: Eight male subjects were enrolled in this study. Presyncopal runs were carried out using HUT + LBNP. At minute zero, the tilt table was brought from 0° (supine) to 70 ° head-up position for 4 min, after which pressure in the LBNP chamber was reduced to -15, -30, and -45 mm Hg every 4 min. At presyncope, the subjects were returned to supine position. Coagulatory responses and plasma mass density (for volume changes) were measured before, during and 20 min after the orthostatic stress. Whole blood coagulation was examined by means of thrombelastometry. Platelet aggregation in whole blood was examined by using impedance aggregometry. Thrombin generation parameters, prothrombin levels, and markers of endothelial activation were measured in plasma samples. Results: At presyncope, plasma volume was 20 % below the initial supine value. Blood cell counts, prothrombin levels, thrombin peak, endogenous thrombin potential (ETP), and tissue factor pathway inhibitor (TFPI) levels increased during the protocol, commensurate with hemoconcentration. The markers of endothelial activation (tissue factor, TF, tissue plasminogen activator, t-PA) and the markers of thrombin generation (Prothrombin fragments 1 and 2, F1+2, and thrombin-antithrombin complex, TAT) increased significantly. During recovery, all the coagulation parameters returned to initial supine values except F1 +2 and TAT. Conclusion: Head-up tilt/LBNP leads to activation of the coagulation system. Some of the markers of thrombin formation are still at higher than supine levels during recovery.

  14. A nitric oxide-releasing heparin conjugate for delivery of a combined antiplatelet/anticoagulant agent.

    Science.gov (United States)

    Suchyta, Dakota J; Handa, Hitesh; Meyerhoff, Mark E

    2014-02-01

    Heparin is a widely used anticoagulant due to its ability to inhibit key components in the coagulation cascade such as Factor Xa and thrombin (Factor IIa). Its potential to preferentially bind to antithrombin (ATIII) results in a conformational change and activation that leads to the prevention of fibrin formation from fibrinogen and ultimately obstructs a hemostatic plug from forming. Nitric oxide (NO) exhibits potent antiplatelet activity attributed to its capacity to increase the amount of cyclic guanosine monophosphate (cGMP) within platelets, which decreases the Ca(2+) concentration required for platelet activation. Currently there is no single agent that combines the functions of both antiplatelet and anticoagulant (anti-Xa and anti-IIa) activities to effectively block both the extrinsic and the intrinsic coagulation pathways. The research reported herein demonstrates the ability to combine the physiological capabilities of both heparin and NO into one functional compound via use of a spermine derivative of heparin, thus enabling formation of a novel diazeniumdiolate (NONOate). The heparin-spermine NONOate has a half-life of 85 min at 25 °C (pH 7.4). The heparin backbone of the conjugate maintains its anticoagulant activity as demonstrated via an anti-Xa assay, providing an anticoagulant conversion of 3.6 μg/mL of the heparin-spermine-NONO conjugate being equivalent to 2.5 μg/mL (0.50 IU/mL) of underivatized heparin in terms of anti-Xa activity. Using standard platelet aggregometry, it is shown that the functionality of the NO release portion of the heparin conjugate prevents (nearly 100%) platelet aggregation in the presence of adenosine diphosphate (ADP, platelet agonist). PMID:24423090

  15. Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants.

    Science.gov (United States)

    Al-Horani, Rami A; Gailani, David; Desai, Umesh R

    2015-08-01

    Recent development of sulfated non-saccharide glycosaminoglycan mimetics, especially sulfated pentagalloyl glucopyranoside (SPGG), as potent inhibitors of factor XIa (FXIa) (J. Med. Chem. 2013; 56:867-878 and J. Med. Chem. 2014; 57:4805-4818) has led to a strong possibility of developing a new line of factor XIa-based anticoagulants. In fact, SPGG represents the first synthetic, small molecule inhibitor that appears to bind in site remote from the active site. Considering that allosteric inhibition of FXIa is a new mechanism for developing a distinct line of anticoagulants, we have studied SPGG's interaction with FXIa with a goal of evaluating its pre-clinical relevance. Comparative inhibition studies with several glycosaminoglycans revealed the importance of SPGG's non-saccharide backbone. SPGG did not affect the activity of plasma kallikrein, activated protein C and factor XIIIa suggesting that SPGG-based anticoagulation is unlikely to affect other pathways connected with coagulation factors. SPGG's effect on APTT of citrated human plasma was also not dependent on antithrombin or heparin cofactor II. Interestingly, SPGG's anticoagulant potential was diminished by serum albumin as well as factor XI, while it could be reversed by protamine or polybrene, which implies possible avenues for developing antidote strategy. Studies with FXIa mutants indicated that SPGG engages Lys529, Arg530 and Arg532, but not Arg250, Lys252, Lys253 and Lys255. Finally, SPGG competes with unfractionated heparin, but not with polyphosphates and/or glycoprotein Ibα, for binding to FXIa. These studies enhance understanding on the first allosteric inhibitor of FXIa and highlight its value as a promising anticoagulant. PMID:25935648

  16. Metabolic engineering of Chinese hamster ovary cells: towards a bioengineered heparin.

    Science.gov (United States)

    Baik, Jong Youn; Gasimli, Leyla; Yang, Bo; Datta, Payel; Zhang, Fuming; Glass, Charles A; Esko, Jeffrey D; Linhardt, Robert J; Sharfstein, Susan T

    2012-03-01

    Heparin is the most widely used pharmaceutical to control blood coagulation in modern medicine. A health crisis that took place in 2008 led to a demand for production of heparin from non-animal sources. Chinese hamster ovary (CHO) cells, commonly used mammalian host cells for production of foreign pharmaceutical proteins in the biopharmaceutical industry, are capable of producing heparan sulfate (HS), a related polysaccharide naturally. Since heparin and HS share the same biosynthetic pathway, we hypothesized that heparin could be produced in CHO cells by metabolic engineering. Based on the expression of endogenous enzymes in the HS/heparin pathways of CHO-S cells, human N-deacetylase/N-sulfotransferase (NDST2) and mouse heparan sulfate 3-O-sulfotransferase 1 (Hs3st1) genes were transfected sequentially into CHO host cells growing in suspension culture. Transfectants were screened using quantitative RT-PCR and Western blotting. Out of 120 clones expressing NDST2 and Hs3st1, 2 clones, Dual-3 and Dual-29, were selected for further analysis. An antithrombin III (ATIII) binding assay using flow cytometry, designed to recognize a key sugar structure characteristic of heparin, indicated that Hs3st1 transfection was capable of increasing ATIII binding. An anti-factor Xa assay, which affords a measure of anticoagulant activity, showed a significant increase in activity in the dual-expressing cell lines. Disaccharide analysis of the engineered HS showed a substantial increase in N-sulfo groups, but did not show a pattern consistent with pharmacological heparin, suggesting that further balancing the expression of transgenes with the expression levels of endogenous enzymes involved in HS/heparin biosynthesis might be necessary. PMID:22326251

  17. Gold nanoparticles doped conducting polymer nanorod electrodes: ferrocene catalyzed aptamer-based thrombin immunosensor.

    Science.gov (United States)

    Rahman, Md Aminur; Son, Jung Ik; Won, Mi-Sook; Shim, Yoon-Bo

    2009-08-15

    Au nanoparticles-doped conducting polymer nanorods electrodes (AuNPs/CPNEs) were prepared by coating Au nanorods (AuNRs) with a conducting polymer layer. The AuNRs were prepared through an electroless deposition method using the polycarbonate membrane (pore diameter, 50 nm, pore density, 6 x 10(8) pores/cm(2)) as a template. The AuNPs/CPNEs combining catalytic activity of ferrocene to ascorbic acid were used for the fabrication of an ultrasensitive aptamer sensor for thrombin detection. The AuNPs/3D-CPNEs were characterized employing cyclic voltammetry (CV), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Sandwiched immunoassay for alpha-human thrombin with NH(2)-functionalized-thrombin binding aptamer (Apt) immobilized on AuNPs/3D-CPNEs was studied through the electrocatalytic oxidation of ascorbic acid by the ferrocene moiety that was bound with an antithrombin antibody and attached with the Apt/3D-CPNEs probe through target binding. Various experimental parameters affecting thrombin detection were optimized, and the performance of the thrombin aptamer sensor was examined. The Apt/AuNPs/3D-CPNEs based thrombin sensor exhibited a wide dynamic range of 5-2000 ng L(-1) and a low detection limit of 5 ng L(-1) (0.14 pM). The selectivity and the stability of the proposed thrombin aptamer sensor were excellent, and it was tested in a real human serum sample for the detection of spiked concentrations of thrombin. PMID:20337374

  18. Etiology and portal vein thrombosis in Budd-Chiari syndrome

    Institute of Scientific and Technical Information of China (English)

    Oguz Uskudar; Meral Akdogan; Nurgul Sasmaz; Sevinc Yilmaz; Muharrem Tola; Burhan Sahin

    2008-01-01

    AIM: To research the etiology, portal vein thrombosis and other features of Budd-Chiari syndrome (BCS)patients prospectively.METHODS: A total of 75 patients (40 female, 35 male) who were diagnosed between January 2002 and July 2004 as having BCS were studied prospectively.Findings from on physical examination, ultrasonography,duplex ultrasonography and venography were analyzed.Hemogram and blood chemistry were studied at the time of diagnosis and on each hospital visit. Bone marrow examination and immune phenotyping were performed by a hematologist when necessary. Protein C, S, antithrombin Ⅲ, activated protein C resistance,and anticardiolipin antibodies, antinuclear antibodies,and anti ds-DNA were studied twice. The presence of ascite, esophageal varices, and portal thrombosis were evaluated at admission and on every visit.RESULTS: At least one etiological factor was determined in 54 (72%) of the patients. The etiology could not be defined in 21 (28%) patients. One etiological factor was found in 39, 2 factors in 14 and 3 factors in 1 patient.The most common cause was the web (16%), the second was Hydatid disease (11%), the third was Behcet's disease (9%). Portal vein thrombosis was present in 11 patients and at least one etiology was identified in 9 of them (82%).CONCLUSION: Behcet's disease and hydatid disease are more prominent etiological factors in Turkey than in other countries. Patients with web have an excellent response to treatment without signs of portal vein thrombosis while patients having thrombofilic factors more than one are prone to develop portal vein thrombosis with worse clinical outcome.

  19. New developments in the management of moderate-to-severe hemophilia B.

    Science.gov (United States)

    Nazeef, Moniba; Sheehan, John P

    2016-01-01

    Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX) activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV) access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP) represent fusion proteins with the immunoglobulin G1 (IgG1) Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the

  20. Relevance of hemostatic risk factors on coronary morphology in patients with diabetes mellitus type 2

    Directory of Open Access Journals (Sweden)

    Peters Ansgar J

    2009-05-01

    Full Text Available Abstract Objective The influence hemostatitc parameters on the morphological extent and severity of coronary artery disease were studied in patients with and without DM type 2. Background It is known that patients with diabetes (DM have abnormal metabolic and hemostatic parameters Methods Of 150 consecutive patients with angiographically proven coronary artery disease 29 presented with DM. Additionally to parameters of lipid-metabolism fibrinogen, tissue-plasminogenactivator (t-PA, plasminogen-activator-inhibitor (PAI, plasmin-a-antiplasmin (PAP, prothrombin-fragment 1+2 (F1+2, thrombin-antithrombin (TAT, von-willebrand-factor (vWF, platelet factor 4 (PF4, glykomembranproteine 140 (GMP140 and the rheologic parameters plasma viscosity and red blood cell aggregation were evaluated. The extent and severity of CAD was evaluated according to the criteria of the American Heart Association. Results Patients with DM presented with a higher number of conventional risk factors as compared to non-diabetic patients. Additionally there were significant differences for F1+2, red blood cell aggregation and PAI. Diabetic patients showed a more severe extent of coronary arteriosclerosis, which also could be found more distally. A significant relationship between blood-glucose, thrombocyte-activation (vWF, endogenous fibrinolysis (PAI and the severity of CAD and a more distal location of stenoses could be found (r = 0.6, p Conclusion Patients with coronary artery disease and DM type 2 showed marked alterations of metabolic, hemostatic, fibrinolytic and rheologic parameters, which can produce a prothrombogenic state. A direct association of thrombogenic factors on coronary morphology could be shown. This can be the pathophysiologic mechanism of more severe and distal pronounced coronary atherosclerosis in these patients.

  1. Edoxaban: a focused review of its clinical pharmacology.

    Science.gov (United States)

    Lip, Gregory Y H; Agnelli, Giancarlo

    2014-07-21

    Long-term anticoagulation treatment with warfarin has been associated with a number of limitations in clinical practice and there is a need for more convenient long-term anticoagulation treatment. One of the non-vitamin K oral anticoagulants in development is edoxaban, a factor Xa inhibitor that is administered once daily. The pharmacological properties of edoxaban have various advantages in anticoagulant therapy. Edoxaban quickly reaches peak plasma concentrations in 1.5 h, has a half-life of 10-14 h, has relatively high bioavailability of 62% and exhibits highly selective, competitive, concentration-dependent inhibition of human factor Xa. The plasma concentrations of edoxaban are also closely correlated with suppression of thrombin generation and a range of platelet activation parameters (fragment 1+2, thrombin-antithrombin complex, and β-thromboglobulin), which edoxaban has been shown to rapidly inhibit. The anticoagulant activity of edoxaban is not affected by food intake or ethnicity and a number of drug-drug interaction studies have been performed. Co-administration of edoxaban with strong P-glycoprotein inhibitors, such as dronedarone, quinidine, and verapamil requires edoxaban dose-reduction by 50% to avoid the risk of over-exposure. The exposure of edoxaban may also increase in patients with a body weight ≤60 kg and moderate renal impairment. This meant a dose-reduction strategy in patients at risk of over-exposure was utilized in Phase III clinical studies. In conclusion, the pharmacological properties of edoxaban provide rapid and specific inhibition of factor Xa, which is closely related to plasma concentrations. Given the limitations with long-term warfarin therapy, once-daily edoxaban may provide a convenient long-term alternative for patients. PMID:24810388

  2. Determining the effect of freezing on coagulation testing: comparison of results between fresh and once frozen-thawed plasma.

    Science.gov (United States)

    Gosselin, Robert C; Dwyre, Denis W

    2015-01-01

    The accuracy of the results from coagulation testing can be affected by numerous preanalytic and analytic variables including the stability of the citrated sample at room temperature. Samples not tested within 2-4 h of collection should be processed and frozen for later analysis. As limited data exist about the impact of freezing samples on coagulation testing, we sought to evaluate the effect of freezing on coagulation testing. Plasma samples into 3.2% sodium citrate tubes, centrifuged to yield platelet-poor plasma, were evaluated for prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, D-dimer, antithrombin (AT) activity, factors V, VII, VIII, IX, lupus anticoagulant and anti-Xa measurements for both unfractionated and low-molecular-weight heparins. Samples were then frozen at -70°C for at least 1 week and testing was repeated using the same lot of material. All tests strongly correlated (R > 0.85) between fresh and frozen sample results. Using paired t test analysis, significant differences between fresh and frozen tested plasma existed for PT, APTT, factors V, VIII and AT. Significant differences existed between fresh and frozen lupus anticoagulant ratios (lupus anticoagulant screen but not lupus anticoagulant confirm), and single centrifugation process underestimated the presence of lupus anticoagulant as compared to double centrifugation processing. Freezing significantly affects the results for PT, APTT, factors V and VIII activity, and AT activity, although these differences were not considered to be clinically significant. Double centrifugation is required for accurate lupus anticoagulant testing, regardless of whether platelet-poor plasma is achieved with single centrifugation.

  3. Acquired protein C deficiency in a child with acute myelogenous leukemia, splenic, renal, and intestinal infarction.

    Science.gov (United States)

    Farah, Roula A; Jalkh, Khalil S; Farhat, Hussein Z; Sayad, Paul E; Kadri, Adel M

    2011-03-01

    We report the case of a 6-year-old boy diagnosed with acute promyelocytic leukemia (AML-M3V) when he presented with pallor, abdominal pain, anorexia, and fatigue. Induction chemotherapy was started according to the AML-BFM 98 protocol along with Vesanoid (ATRA, All-trans retinoic acid). On the sixth day of induction, he developed splenic and gallbladder infarcts. Splenectomy and cholecystectomy were performed while chemotherapy induction continued as scheduled. Four days later, he developed ischemic areas in the kidneys and ischemic colitis in the sigmoid colon. Hypercoagulation studies showed severe deficiency of protein C. Tests showed protein C 16% (reference range 70-140%), protein S 87% (reference range 70-140%), antithrombin III 122% (reference range 80-120%), prothrombin time 13.6 s (reference = 11.3), INR (international normalized ratio) 1.21, partial thromboplastin time 33 s (reference = 33), fibrinogen 214 mg/dl, D-dimer 970 μg/ml, factor II 98%, and that antinuclear antibody, antiphospholipid antibodies, mutation for factor II gene (G20210A), and mutation for Arg506 Gln of factor V were all negative (factor V Leiden). There was no evidence of clinical disseminated intravascular coagulation (DIC). He was treated with low molecular weight heparin and did well. He continues to be in complete remission 7 years later with normal protein C levels. Acquired protein C deficiency can occur in a variety of settings and has been reported in acute myelocytic leukemia. However, clinically significant thrombosis in the absence of clinical DIC, such as our case, remains extremely rare.

  4. Hemostatic problems and thromboembolic complications in nephrotic children.

    Science.gov (United States)

    Citak, A; Emre, S; Sâirin, A; Bilge, I; Nayir, A

    2000-02-01

    A hypercoagulable state and the risk of thromboembolism in both arterial and venous circulation is a relatively frequent and serious feature of nephrotic syndrome (NS) in children and adults. The aim of this study was to evaluate the coagulation states of children with NS before and after corticosteroid (CS) therapy and to compare the results with a healthy control group. The first group consisted of 49 nephrotic children (30 boys and 19 girls) with a mean age of 6. 5+/-4.9 years (range 1-16 years). The control group included 17 healthy children (9 boys and 8 girls). At the time of admission, all patients were evaluated for the presence of clinical thromboembolism, hematological and biochemical indicators of a hypercoagulative state, and renal disease. This was repeated after CS treatment. Deep vein thrombosis was observed in 2 nephrotic patients who had very low plasma antithrombin III (AT III) levels and fibrinogen levels above 750 mg/dl. Thus, the prevalence of thromboembolism was 4% in our pediatric nephrotic population. The mean AT III level of the study group was 68.2+/-23.4% at the onset of the disease, which was significantly lower than the level of the control group (84.0+/-7. 6%). Plasma AT III levels increased to 74.4+/-15.3% after CS treatment, which correlated with the serum albumin levels. However, there was no correlation with urinary protein excretion. Protein C levels were higher than controls during all stages of the disease in both steroid-responsive and -unresponsive patients. The mean protein S level was similar in both groups. Plasma fibrinogen and cholesterol levels were significantly higher in the study group but decreased to within normal limits with remission. Our study suggests that thromboembolic complications are not infrequent in children with NS, and may be related to low plasma AT III and albumin and high fibrinogen and cholesterol levels.

  5. New compounds in the management of venous thromboembolism after orthopedic surgery: focus on rivaroxaban

    Directory of Open Access Journals (Sweden)

    Lars Carl Borris

    2008-08-01

    Full Text Available Lars Carl BorrisDepartment of Orthopaedic Surgery, Åarhus University Hospital, Åarhus, DenmarkAbstract: Rivaroxaban (Xarelto® is a member of a new class of oral, direct (antithrombin-independent factor Xa inhibitors, which restrict thrombin generation both in vitro and in vivo. After oral administration the absorption is near 100%, the bioavailability is near 80%, and the elimination half-life is 5–9 hours with mixed excretion via the renal and fecal/biliary routes. The pharmacokinetics of rivaroxaban are predictable and consistent with a rapid onset of antithrombotic action within 2 hours after administration. Phase II clinical studies have been carried out in patients undergoing total hip arthroplasty (THA or total knee arthroplasty (TKA and a dose of 10 mg once daily for thromboprophylaxis was selected for further clinical development. The results of the phase III studies showed a significantly better antithrombotic efficacy of rivaroxaban compared with enoxaparin both in the short term (10–14 days in TKA patients and long term (35 ± 4 days in THA patients with a comparable safety. Symptomatic thromboembolic events were also significantly reduced with rivaroxaban. Liver enzyme elevation was seen in patients treated with rivaroxaban, but there was no indication of an increased risk of liver toxicity compared with enoxaparin. In conclusion, rivaroxaban is a potent and safe new compound for antithrombotic prophylaxis in orthopedic surgery.Keywords: deep vein thrombosis, oral direct factor Xa inhibitor, pulmonary embolism, rivaroxaban, thromboprophylaxis, total hip arthroplasty, total knee arthroplasty

  6. Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression.

    Science.gov (United States)

    Michael, Iacovos P; Sotiropoulou, Georgia; Pampalakis, Georgios; Magklara, Angeliki; Ghosh, Manik; Wasney, Greg; Diamandis, Eleftherios P

    2005-04-15

    Human kallikrein 5 (KLK5) is a member of the human kallikrein gene family of serine proteases. Preliminary results indicate that the protein, hK5, may be a potential serological marker for breast and ovarian cancer. Other studies implicate hK5 with skin desquamation and skin diseases. To gain further insights on hK5 physiological functions, we studied its substrate specificity, the regulation of its activity by various inhibitors, and identified candidate physiological substrates. After producing and purifying recombinant hK5 in yeast, we determined the k(cat)/K(m) ratio of the fluorogenic substrates Gly-Pro-Arg-AMC and Gly-Pro-Lys-AMC, and showed that it has trypsin-like activity with strong preference for Arg over Lys in the P1 position. The serpins alpha(2)-antiplasmin and antithrombin were able to inhibit hK5 with an inhibition constant (k(+2)/K(i)) of 1.0 x 10(-) (2)and 4.2 x 10(-4) m(-1) min(-1), respectively. No inhibition was observed with the serpins alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, although alpha(2)-macroglobulin partially inhibited hK5 at high concentrations. We also demonstrated that hK5 can efficiently digest the extracellular matrix components, collagens type I, II, III, and IV, fibronectin, and laminin. Furthermore, our results suggest that hK5 can potentially release (a) angiostatin 4.5 from plasminogen, (b) "cystatin-like domain 3" from low molecular weight kininogen, and (c) fibrinopeptide B and peptide beta15-42 from the Bbeta chain of fibrinogen. hK5 could also play a role in the regulation of the binding of plasminogen activator inhibitor 1 to vitronectin. Our findings suggest that hK5 may be implicated in tumor progression, particularly in invasion and angiogenesis, and may represent a novel therapeutic target. PMID:15713679

  7. Practical applications of snake venom toxins in haemostasis.

    Science.gov (United States)

    Marsh, Neville; Williams, Vaughan

    2005-06-15

    Snake venom toxins affecting haemostasis have facilitated extensively the routine assays of haemostatic parameters in the coagulation laboratory. Snake venom thrombin-like enzymes (SVTLE) are used for fibrinogen/fibrinogen breakdown product assay and for the detection of fibrinogen dysfunction. SVTLE are not inhibited by heparin and can thus can be used for assaying antithrombin III and other haemostatic variables in heparin-containing samples. Snake venoms are a rich source of prothrombin activators and these are utilised in prothrombin assays, for studying dysprothrombinaemias and for preparing meizothrombin and non-enzymic forms of prothrombin. Russell's viper (Daboia russelli) venom (RVV) contains toxins which have been used to assay blood clotting factors V, VII, X, platelet factor 3 and, importantly, lupus anticoagulants (LA). Other prothrombin activators (from the taipan, Australian brown snake and saw-scaled viper) have now been used to assay LA. Protein C and activated protein C resistance can be measured by means of RVV and Protac, a fast acting inhibitor from Southern copperhead snake venom and von Willebrand factor can be studied with botrocetin from Bothrops jararaca venom. The disintegrins, a large family of Arg-Gly-Asp (RGD)-containing snake venom proteins, show potential for studying platelet glycoprotein receptors, notably, GPIIb/IIIa and Ib. Snake venom toxins affecting haemostasis are also used in the therapeutic setting: Ancrod (from the Malayan pit viper, Calloselasma rhodostoma), in particular, has been used as an anticoagulant to achieve 'therapeutic defibrination'. Other snake venom proteins show promise in the treatment of a range of haemostatic disorders. PMID:15922782

  8. Coagulation and fibrinolytic parameters as predictors for small-vessel disease revealed by magnetic resonance imaging of the brain

    International Nuclear Information System (INIS)

    We correlated coagulation and fibrinolytic parameters with small-vessel disease revealed by magnetic resonance imaging (MRI) of the brain. One hundred and eleven patients with asymptomatic or symptomatic cerebral infarction were randomly selected for the study; 57 males and 54 females with an average age of 66.6±9.6, age range 40 to 85, years old. Among them, 76 patients had a history of symptomatic cerebral infarction; 38 patients hypertension; and 24 patients diabetes mellitus. Patients with large cortical infarction, cerebral hemorrhage, demyelinating disease or mass lesions were excluded from the present study. The MRI scans were reviewed for areas with increased signal intensity on T2-weighted images. The small infarction was defined as a lesion less than 10 mm in diameter. The activity of von Willebrand factor (vWF) correlated significantly with the grade of caps at the anterior and posterior horns of the lateral ventricle, and the number of small infarctions in the subcortical white matter and basal ganglia, suggesting vWF could be a predictor for these small-vessel disease. The grade of caps at posterior horn of the lateral ventricle and the number of small infarctions in the subcortical white matter were associated significantly with the concentration of plasma fibrinogen and reversely with the activity of antithrombin III, an inhibitory factor in coagulation system. These results indicate that hypercoagulable state may causatively relate with small-vessel disease in the territory of medullary artery branching from cortical artery. On the contrary, these coagulation parameters did not correlate significantly with small ischemic lesions in the territory of perforating artery. No correlation was observed between the level of marker proteins for platelet activation and the degree of small-vessel disease, indicating the activation of platelet could not associate with the etiology of small-vessel disease. (author)

  9. Advances of monitoring and treatment for coagulopathy induced by sepsis%脓毒症引起凝血功能异常的监测及治疗进展

    Institute of Scientific and Technical Information of China (English)

    任珊; 赵鹤龄

    2010-01-01

    凝血功能异常是引起脓毒症死亡的重要原因,凝血、抗凝和纤溶作用之间的不均衡在脓毒症的发生与发展过程中起关键作用,通过监测凝血紊乱的预警指标,如血小板计数(platelec count,PLT)、组织纤溶酶原激活物(tissue plasminogen activator,tPA)、抗凝血酶(antithrombin AT)Ⅲ等,能够评估脓毒症预后及其严重程度,近年来,活化蛋白C、血必净注射液、乌司他丁等药物能够在一定程度上改善脓毒症凝血功能,回颐总结脓毒症引起凝血功能异常的监测及治疗进展,为临床早期诊断和治疗脓毒症提供了新思路.%Coagulation function abnormality is one of the most important reason of causing death in sepsis. Disequilibrium among coagulation, anticogulation and fibrinolysis plays a critical role in the occurrence and development of sepsis. Evaluating prognosis and severity of sepsis benefits from monitoring warning indexes of coagulopathy, such as PLT,tPA,AT-Ⅲ and so on.Recently researches showed that, to some extent activated protein C, Xuebijing injection, Ulinastatin can improve coagulation function in sepsis. This review outlines related progresses in order to provide new ideas for early clinical diagnosis and treatment of sepsis.

  10. Prevalence of JAK2V617F mutation in deep venous thrombosis patients and its clinical significance as a thrombophilic risk factor: Indian perspective.

    Science.gov (United States)

    Singh, Neha; Sharma, Amit; Sazawal, Sudha; Ahuja, Ankur; Upadhyay, Ashish; Mahapatra, Manoranjan; Saxena, Renu

    2015-09-01

    Venous thromboembolism is known to be a complex interaction of genetic and acquired factors leading to thrombosis. JAK2V617F mutation is believed to contribute to a thrombophilic phenotype, possibly through enhanced leukocyte-platelet interactions in myeloproliferative neoplasms (MPNs). Several studies have focused on the importance of screening for JAK2V617F mutation in patients with splanchnic venous thrombosis (VT) for the detection of nonovert MPNs. The role of JAK2V617F mutation in VT outside the splanchnic region is still widely unsettled. The primary aim of this study was to find out the prevalence of JAK2V617F mutation in patients with deep venous thrombosis (DVT), its clinical significance as a prothrombotic risk factor, and its possible interactions with other genetic thrombophilic risk factors. A total of 148 patients with idiopathic, symptomatic DVT were evaluated. Median age of presentation was 32 years (range 15-71 years) with a sex ratio of 1.3:1. Overall, the most common genetic prothrombotic factor was factor V Leiden mutation, found in 10.8% (16 of 148) of patients who also showed strong association with increased risk of thrombosis (odds ratio 5.94, confidence interval 1.33-26.4, P = .019). Deficiencies in protein C, protein S, and antithrombin were seen in 8 (5.4%), 10 (6.7%), and 8 (5.4%) patients, respectively. It was observed that the frequency of JAK2V617F mutation was lower in Indian patients, and it also showed weaker association with risk of thrombosis, at least in cases of venous thrombosis outside the splanchnic region.

  11. Thrombin interaction with fibrin polymerization sites.

    Science.gov (United States)

    Hsieh, K

    1997-05-15

    Thrombin is central to hemostasis, and postclotting fibrinolysis and wound healing. During clotting, thrombin transforms plasma fibrinogen into polymerizing fibrin, which selectively adsorbs the enzyme into the clot. This protects thrombin from heparin-antithrombin inactivation, thus preserving the enzyme for postclotting events. To determine how the fibrin N-terminal polymerization sites of A alpha 17-23 (GPRVVER) and B beta 15-25 (GHRPLDKKREE) and their analogs may interact with thrombin, amidolysis vs. plasma- and fibrinogen-clotting assays were used to differentiate blockade of catalytic site vs. other thrombin domains. Amidolysis studies suggest GPRVVER inhibition of thrombin catalytic site through hydrophobic interaction, and GPRVVER inhibited clotting. Neither GPRP nor VVER nor the B beta 15-25 homologs inhibited amidolysis. Contrary to heparin, acyl-DKKREE promoted plasma-clotting, but inhibited fibrinogen-clotting. In addition, acyl-DKKREE reversed the anticoagulant effect of heparin (0.1 U/ml) in plasma. The results suggest fibrin B beta 15-25 interaction with thrombin, possibly by blocking the heparin-binding site. Together with the reported fibrin A alpha 27-50 binding to thrombin, polymerizing fibrin appears to initially bind to thrombin catalytic site and exosite-1 through A alpha 17-50, and to another thrombin site through B beta 15-25. As these fibrin sites are also involved in polymerization, competition of the polymerization process with thrombin-binding could subsequently dislodge thrombin from fibrin alpha-chain. This may re-expose the catalytic site and exosite-1, thus explaining the thrombogenicity of clot-bound thrombin. The implications of these findings in polymerization mechanism and anticoagulant design are discussed.

  12. Intraspecies differences in hemostatic venom activities of the South American rattlesnakes, Crotalus durissus cumanensis, as revealed by a range of protease inhibitors.

    Science.gov (United States)

    Salazar, Ana M; Aguilar, Irma; Guerrero, Belsy; Girón, María E; Lucena, Sara; Sánchez, Elda E; Rodríguez-Acosta, Alexis

    2008-09-01

    Crotalus durissus cumanensis is an endemic rattlesnake found in Venezuela and Colombia. In this study, a comparative analysis of hemorrhagic, coagulation and fibrino(geno)lytic activities in the presence or absence of protease inhibitors was performed with venoms of the same species Crotalus durissus cumanensis, from seven geographical regions of Venezuela (Lagunetica, Santa Teresa, Carrizales, Guarenas, Anzoátegui, Margarita and Maracay). Lagunetica, Carrizales and Anzoátegui venoms induced hemorrhagic activity. All venoms, except that of snakes from the Carrizales region presented thrombin-like activity, which was inhibited completely by phenylmethanesulfonyl fluoride and ethylene glycol-bis-N, N,N',N'-tetraacetic acid. This effect of the latter could be explained by the high chelant calcium effect, which is a cofactor for the fibrin polymerization process. Soybean trypsin inhibitor was effective on Santa Teresa venom. Antithrombin III/Hep complex and phenantroline partially inhibited this activity in all venoms except Margarita and Anzoátegui, respectively, which were not inhibited. Serine protease inhibitors were more effective against thrombin, kallikrein and plasmin-like amidolytic activities. Additionally, metalloprotease inhibitors significantly inhibited the t-PA-like amidolytic activity and completely the hemorrhagic and fibrino(geno)lytic activities. In conclusion, the thrombin-like activity observed in these venoms was partially reduced by serine protease inhibitors, indicating the possible presence of catalytic domains in those enzymes that do not interact with these inhibitors. Using protease inhibitors on venom hemostatic activities could contribute to our understanding of the active components of snake venom on the hemostatic system, and further reveal the intraspecies variation of venoms, which is important in the treatment of envenomation, and in addition represents an interesting model for the study of venom in hemostasis.

  13. Hyperhomocysteinemia and hypercoagulability in primary biliary cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Maria Rosa Biagini; Raffaele Manta; Rosanna Abbate; Calogero Surrenti; Alessandro Tozzi; Rossella Marcucci; Rita Paniccia; Sandra Fedi; Stefano Milani; Andrea Galli; Elisabetta Ceni; Marco Capanni

    2006-01-01

    AIM: To assess the hypercoagulability in PBC and its relationship with homocysteine (HCY) and various components of the haemostatic system.METHODS: We investigated 51 PBC patients (43F/8M;mean age: 63±13.9 yr) and 102 healthy subjects (86 women/16 men; 63±13 yr), and evaluated the haemostatic process in whole blood by the Sonoclot analysis and the platelet function by PFA-100 device. We then measured HCY (fasting and after methionine loading),tissue factor (TF), thrombin-antithrombin complexes (TAT), D-dimer (D-D), thrombomodulin (TM), folic acid,vitamin B6 and B12 plasma levels. C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism was analyzed.RESULTS: Sonoclot RATE values of patients were significantly (P< 0.001) higher than those of controls. Sonoclot time to peak values and PFA-100 closure times were comparable in patients and controls. TAT, TF and HCY levels, both in the fasting and post-methionine loading,were significantly (P<0.001) higher in patients than in controls. Vitamin deficiencies were detected in 45/51 patients (88.2%). The prevalence of the homozygous TT677 MTHFR genotype was significantly higher in patients (31.4%) than in controls (17.5%) (P<0.05). Sonodot RATE values correlated significantly with HCY levels and TF.CONCLUSION: In PBC, hyper-HCY is related to hypovitaminosis and genetic predisposing factors. Increased TF and HCY levels and signs of endothelial activation are associated with hypercoagulability and may have an important role in blood clotting activation.

  14. (S)YS-51, a novel isoquinoline alkaloid, attenuates obesity-associated non-alcoholic fatty liver disease in mice by suppressing lipogenesis, inflammation and coagulation.

    Science.gov (United States)

    Park, Eun Jung; Kim, Young Min; Kim, Hye Jung; Jang, Se-Yun; Oh, Moo Hyun; Lee, Duck-Hyung; Chang, Ki Churl

    2016-10-01

    Obesity-associated non-alcoholic fatty liver disease (NAFLD) increases coagulation and inflammation. We hypothesized that (S)YS-51, an agent found to be beneficial in animal models of sepsis, may reduce NAFLD in high-fat diet (HFD) mice by reducing coagulation and inflammation. C57BL/6 mice were fed either a chow diet or HFD and each was supplemented with or without (S)YS-51 (10mg/kg, daily, i.p.) for 16 weeks. The results showed that HFD caused significant increases in lipogenesis [CD36, fatty acid synthase (FAS) and sterol response element binding protein (SREBP)-1c mRNA and protein], inflammation [monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α, intercellular cell adhesion molecule-1 (ICAM-1), TGF-β, and procollagen type 1 mRNA, macrophage infiltration] and coagulation [tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) mRNA and thrombin antithrombin complex (TAT)] in the liver, adipose tissue and serum, which were significantly reduced by (S)YS-51. These results of (S)YS-51 were accompanied by significant reduction of weight gain, liver size, hepatic steatosis and fibrosis, blood cholesterol, hepatic triglyceride, and macrophage infiltration and inflammatory cytokines in adipose tissue without affecting food intake in HFD mice. Interestingly, (S)YS-51 increased SIRT1 mRNA and protein and AMPK expression in the liver of HFD mice by increasing both NAD(+)/NADH ratio and LKB1 phosphorylation. In HepG2 cells, (S)YS-51 activated SIRT1 followed by AMPK. Finally, (S)YS-51 improved glucose tolerance and insulin resistance in HFD mice. We concluded that (S)YS-51 attenuates NAFLD and insulin resistance in HFD mice by, at least, activation of SIRT1/AMPK signals. Thus, (S)YS-51 may be beneficial in NAFLD treatment.

  15. Risk of venous thromboembolic disease in postmenopausal women taking oral or transdermal hormone replacement therapy

    Institute of Scientific and Technical Information of China (English)

    Barbara RUSZKOWSKA; Gra(z)yna GADOMSKA; Liliana BIELIS; Marzena GRUSZKA; Barbara G(O)RALCZYK; Danuta RO(S)(C); Gra(z)yna ODROW(A)(Z)-SYPNIEWSKA

    2011-01-01

    Objective: The influence of hormone replacement therapy(HRT)on hemostasis processes depends on the type of hormone,the combination of doses,the time of taking HRT,and the route of administration(oral,transdermal,implanted).The aim of the current study was to assess some parameters of coagulation,especially tissue factor pathway inhibitor(TFPI)and tissue factor(TF)in postmenopausal women using oral or transdermal HRT.Methods: The study was conducted on 76 healthy women,including 46 women aged 44-58 years who were taking oral(26)or transdermal(20)HRT,and 30 women aged 44-54 years who did not take HRT as the control group.Plasma concentrations of TF,TFPI,thrombin-antithrombin complex(TAT),and D-dimer were performed by enzyme-linked immunosorbent assay(ELISA).Moreover,the concentration of fibrinogen and activity of protein C were measured by chromogenic and chronometric methods.Results: We observed a significantly higher concentration of TF and a significantly lower concentration of TFPI in women taking oral and transdermal HRT in comparison with the control group.We also found a significantly lower concentration of fibrinogen in women taking oral HRT vs.the control group.Moreover,no statistically significant changes in concentrations of TAT and D-dimer,or activity of protein C were noted.Conclusions: In this study,the occurrence of an increased TF concentration simultaneously with a decreased concentration of TFPI in women taking HRT indicates hypercoagulability.No significant modification of TAT or D-dimer occurred,and thus there may not be increased risk of thrombosis.

  16. Recombinant Factor IX Fc Fusion Protein Maintains Full Procoagulant Properties and Exhibits Prolonged Efficacy in Hemophilia B Mice.

    Directory of Open Access Journals (Sweden)

    Garabet G Toby

    Full Text Available Hemophilia B is an inherited X chromosome-linked disorder characterized by impaired blood clotting owing to the absence of functional coagulation factor IX. Due to the relatively short half-life of factor IX, patients with hemophilia B require frequent factor IX infusions to maintain prophylaxis. We have developed a recombinant factor IX (rFIX fused to the Fc region of IgG (rFIXFc with an extended half-life in animals and humans.Procoagulant properties of rFIXFc and rFIX (BENEFIX® were compared to determine the effect of the Fc region on rFIXFc hemostatic function. Specifically, we assessed rFIXFc activation, intermolecular interactions within the Xase complex, inactivation by antithrombin III (AT and thrombin generation potential compared with rFIX. We also assessed the acute and prophylactic efficacy profiles of rFIXFc and rFIX in vivo in hemophilia B mouse bleeding models.The activation by factor XIa or factor VIIa/tissue factor, inhibition by AT, interaction profiles with phospholipids, affinities for factor VIIIa within the context of the Xase complex, and thrombin generation profiles were similar for rFIXFc and rFIX. Xase complexes formed with either molecule exhibited similar kinetic profiles for factor Xa generation. In acute efficacy models, mice infused with rFIXFc or rFIX were equally protected from bleeding. However, in prophylactic efficacy models, protection from bleeding was maintained approximately three times longer in rFIXFc-dosed mice than in those given rFIX; this prolonged efficacy correlates with the previously observed half-life extension. We conclude that rFIXFc retains critical FIX procoagulant attributes and that the extension in rFIXFc half-life translates into prolonged efficacy in hemophilia B mice.

  17. Republication: Two Premature Neonates of Congenital Syphilis with Severe Clinical Manifestations.

    Science.gov (United States)

    Akahira-Azuma, Moe; Kubota, Mai; Hosokawa, Shinichi; Kaneshige, Masao; Yasuda, Noriko; Sato, Noriko; Matsushita, Takeji

    2015-09-01

    Congenital syphilis (CS) is a public health burden in both developing and developed countries. We report two cases of CS in premature neonates with severe clinical manifestations; Patient 1 (gestational age 31 weeks, birth weight 1423 g) had disseminated idiopathic coagulation (DIC) while Patient 2 (gestational age 34 weeks and 6 days, birth weight 2299 g) had refractory syphilitic meningitis. Their mothers were single and had neither received antenatal care nor undergone syphilis screening. Both neonates were delivered via an emergency cesarean section and had birth asphyxia and transient tachypnea of newborn. Physical examination revealed massive hepatosplenomegaly. Laboratory testing of maternal and neonatal blood showed increased rapid plasma reagin (RPR) titer and positive Treponema pallidum hemagglutination assay. Diagnosis of CS was further supported by a positive IgM fluorescent treponemal antibody absorption test and large amounts of T. pallidum spirochetes detected in the placenta. Each neonate was initially treated with ampicillin and cefotaxime for early bacterial sepsis/meningitis that coexisted with CS. Patient 1 received fresh frozen plasma and antithrombin III to treat DIC. Patient 2 experienced a relapse of CS during initial antibiotic treatment, necessitating parenteral penicillin G. Treatment was effective in both neonates, as shown by reductions in RPR. Monitoring of growth and neurological development through to age 4 showed no evidence of apparent delay or complications. Without adequate antenatal care and maternal screening tests for infection, CS is difficult for non-specialists to diagnose at birth, because the clinical manifestations are similar to those of neonatal sepsis and meningitis. Ampicillin was insufficient for treating CS and penicillin G was necessary. PMID:26543391

  18. Heparin Resistance and Anticoagulation Failure in a Challenging Case of Cerebral Venous Sinus Thrombosis.

    Science.gov (United States)

    King, Adam B; O'Duffy, Anne E; Kumar, Avinash B

    2016-07-01

    We report a challenging case of cerebral venous sinus thrombosis (multiple etiologic factors) that was complicated by heparin resistance secondary to suspected antithrombin III (ATIII) deficiency. A 20-year-old female previously healthy and currently 8 weeks pregnant presented with worsening headaches, nausea, and decreasing Glasgow Coma Scale/Score (GCS), necessitating mechanical ventilatory support. Imaging showed extensive clots in multiple cerebral venous sinuses including the superior sagittal sinus, transverse, sigmoid, jugular veins, and the straight sinus. She was started on systemic anticoagulation and underwent mechanical clot removal and catheter-directed endovascular thrombolysis with limited success. Complicating the intensive care unit care was the development of heparin resistance, with an inability to reach the target partial thomboplastin time (PTT) of 60 to 80 seconds. At her peak heparin dose, she was receiving >35 000 units/24 h, and her PTT was subtherapeutic at <50 seconds. Deficiency of ATIII was suspected as a possible etiology of her heparin resistance. Fresh frozen plasma was administered for ATIII level repletion. Given her high thrombogenic risk and challenges with conventional anticoagulation regimens, we transitioned to argatroban for systemic anticoagulation. Heparin produces its major anticoagulant effect by inactivating thrombin and factor X through an AT-dependent mechanism. For inhibition of thrombin, heparin must bind to both the coagulation enzyme and the AT. A deficiency of AT leads to a hypercoagulable state and decreased efficacy of heparin that places patients at high risk of thromboembolism. Heparin resistance, especially in the setting of critical illness, should raise the index of suspicion for AT deficiency. Argatroban is an alternate agent for systemic anticoagulation in the setting of heparin resistance. PMID:27366296

  19. Thrombin-anti-thrombin levels and patency of arterio-venous fistula in patients undergoing haemodialysis compared to healthy volunteers: a prospective analysis.

    Directory of Open Access Journals (Sweden)

    James A Milburn

    Full Text Available BACKGROUND: Patients on haemodialysis (HD are at an increased risk of sustaining thrombotic events especially to their vascular access which is essential for maintenance of HD. OBJECTIVES: To assess whether 1 markers of coagulation, fibrinolysis or endothelial activation are increased in patients on HD compared to controls and 2 if measurement of any of these factors could help to identify patients at increased risk of arteriovenous (AVF access occlusion. PATIENTS/METHODS: Venous blood samples were taken from 70 patients immediately before a session of HD and from 78 resting healthy volunteers. Thrombin-antithrombin (TAT, D-dimer, von Willebrand factor (vWF, plasminogen activator inhibitor-1 antigen (PAI-1 and soluble p-selectin were measured by ELISA. C-reactive protein (hsCRP was measured by an immunonephelometric kinetic assay. Determination of the patency of the AVF was based upon international standards and was prospectively followed up for a minimum of four years or until the AVF was non-functioning. RESULTS: A total of 70 patients were studied with a median follow-up of 740 days (range 72-1788 days. TAT, D-dimer, vWF, p-selectin and hsCRP were elevated in patients on HD compared with controls. At one year follow-up, primary patency was 66% (46 patients. In multivariate analysis TAT was inversely associated with primary assisted patency (r = -0.250, p = 0.044 and secondary patency (r = -0.267, p= 0.031. CONCLUSIONS: The novel finding of this study is that in patients on haemodialysis, TAT levels were increased and inversely correlated with primary assisted patency and secondary patency. Further evaluation is required into the possible role of TAT as a biomarker of AVF occlusion.

  20. Trypanosoma brucei modifies the tsetse salivary composition, altering the fly feeding behavior that favors parasite transmission.

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    Jan Van Den Abbeele

    Full Text Available Tsetse flies are the notorious transmitters of African trypanosomiasis, a disease caused by the Trypanosoma parasite that affects humans and livestock on the African continent. Metacyclic infection rates in natural tsetse populations with Trypanosoma brucei, including the two human-pathogenic subspecies, are very low, even in epidemic situations. Therefore, the infected fly/host contact frequency is a key determinant of the transmission dynamics. As an obligate blood feeder, tsetse flies rely on their complex salivary potion to inhibit host haemostatic reactions ensuring an efficient feeding. The results of this experimental study suggest that the parasite might promote its transmission through manipulation of the tsetse feeding behavior by modifying the saliva composition. Indeed, salivary gland Trypanosoma brucei-infected flies display a significantly prolonged feeding time, thereby enhancing the likelihood of infecting multiple hosts during the process of a single blood meal cycle. Comparison of the two major anti-haemostatic activities i.e. anti-platelet aggregation and anti-coagulation activity in these flies versus non-infected tsetse flies demonstrates a significant suppression of these activities as a result of the trypanosome-infection status. This effect was mainly related to the parasite-induced reduction in salivary gland gene transcription, resulting in a strong decrease in protein content and related biological activities. Additionally, the anti-thrombin activity and inhibition of thrombin-induced coagulation was even more severely hampered as a result of the trypanosome infection. Indeed, while naive tsetse saliva strongly inhibited human thrombin activity and thrombin-induced blood coagulation, saliva from T. brucei-infected flies showed a significantly enhanced thrombinase activity resulting in a far less potent anti-coagulation activity. These data clearly provide evidence for a trypanosome-mediated modification of the tsetse

  1. Haemostatic Parameters in Patients with Behçet’s Disease

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    Juma K. Alkaabi

    2014-05-01

    Full Text Available Objectives: This study aimed to evaluate the cause of thrombosis in Behçet’s disease (BD patients, since abnormalities in coagulation and fibrinolytic parameters have shown contradictory results. Methods: Haemostatic parameters were retrospectively evaluated in BD patients treated between January 2007 and January 2011 at Sultan Qaboos University Hospital, Oman. The blood samples of 35 Omani BD patients and 30 healthy controls were analysed for factor VIII:C levels, activated protein C resistance (APCR, von Willebrand factor (vWF antigens (Ag, collagen binding and ristocetin co-factor activity (RiCoF, antithrombin (AT, protein C (chromogenic and clotting, protein S, homocysteine, tissue plasminogen activator, plasminogen activator inhibitor, plasminogen, alpha 2-antiplasmin, lupus anticoagulant and anticardiolipin and beta2-glycoprotein-1 antibodies. Results: The mean values of factor VIII:C, vWF Ag, AT and protein S were significantly higher in the patient group (P = 0.01, 0.006, 0.04 and 0.01, respectively. There was no deficiency in protein C. Screening for APCR, anticardiolipin antibodies, anti-beta2-glycoprotein-1 antibodies and lupus anticoagulant was negative and there were no differences in homocysteine levels, nor were there differences between patients with and without thrombosis. Six patients had elevated factor VIII:C levels (>150 IU/dL, P <0.02 which normalised on repeat measurements after three months. Conclusion: The elevation of factors VIII:C, vWF Ag and AT most likely represent an acute phase phenomenon. In this study, thrombophilic factors did not seem to explain thrombotic tendency. Therefore, further mechanistic studies in a larger group of patients are needed to elucidate the basis for thrombosis in BD. We hypothesise that active BD causes vasculitic endothelial perturbation with dysfunction, leading to the observed increased propensity for thrombosis.

  2. Rabbit model of uncontrolled hemorrhagic shock and hypotensive resuscitation

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    J.B. Rezende-Neto

    2010-12-01

    Full Text Available Clinically relevant animal models capable of simulating traumatic hemorrhagic shock are needed. We developed a hemorrhagic shock model with male New Zealand rabbits (2200-2800 g, 60-70 days old that simulates the pre-hospital and acute care of a penetrating trauma victim in an urban scenario using current resuscitation strategies. A laparotomy was performed to reproduce tissue trauma and an aortic injury was created using a standardized single puncture to the left side of the infrarenal aorta to induce hemorrhagic shock similar to a penetrating mechanism. A 15-min interval was used to simulate the arrival of pre-hospital care. Fluid resuscitation was then applied using two regimens: normotensive resuscitation to achieve baseline mean arterial blood pressure (MAP, 10 animals and hypotensive resuscitation at 60% of baseline MAP (10 animals. Another 10 animals were sham operated. The total time of the experiment was 85 min, reproducing scene, transport and emergency room times. Intra-abdominal blood loss was significantly greater in animals that underwent normotensive resuscitation compared to hypotensive resuscitation (17.1 ± 2.0 vs 8.0 ± 1.5 mL/kg. Antithrombin levels decreased significantly in normotensive resuscitated animals compared to baseline (102 ± 2.0 vs 59 ± 4.1%, sham (95 ± 2.8 vs 59 ± 4.1%, and hypotensive resuscitated animals (98 ± 7.8 vs 59 ± 4.1%. Evidence of re-bleeding was also noted in the normotensive resuscitation group. A hypotensive resuscitation regimen resulted in decreased blood loss in a clinically relevant small animal model capable of reproducing hemorrhagic shock caused by a penetrating mechanism.

  3. Role of serine proteases in the regulation of interleukin-877 during the development of bronchopulmonary dysplasia in preterm ventilated infants.

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    Mallinath Chakraborty

    Full Text Available The chemokine interleukin-8 is implicated in the development of bronchopulmonary dysplasia in preterm infants. The 77-amino acid isoform of interleukin-8 (interleukin-877 is a less potent chemoattractant than other shorter isoforms. Although interleukin-877 is abundant in the preterm circulation, its regulation in the preterm lung is unknown.To study expression and processing of pulmonary interleukin-877 in preterm infants who did and did not develop bronchopulmonary dysplasia.Total interleukin-8 and interleukin-877 were measured in bronchoalveolar lavage fluid from preterm infants by immunoassay. Neutrophil serine proteases were used to assess processing. Neutrophil chemotaxis assays and degranulation of neutrophil matrix metalloproteinase-9 were used to assess interleukin-8 function.Peak total interleukin-8 and interleukin-877 concentrations were increased in infants who developed bronchopulmonary dysplasia compared to those who did not. Shorter forms of interleukin-8 predominated in the preterm lung (96.3% No-bronchopulmonary dysplasia vs 97.1% bronchopulmonary dysplasia, p>0.05. Preterm bronchoalveolar lavage fluid significantly converted exogenously added interleukin-877 to shorter isoforms (p<0.001. Conversion was greater in bronchopulmonary dysplasia infants (p<0.05. This conversion was inhibited by α-1 antitrypsin and antithrombin III (p<0.01. Purified neutrophil serine proteases efficiently converted interleukin-877 to shorter isoforms in a time- and dose-dependent fashion; shorter interleukin-8 isoforms were primarily responsible for neutrophil chemotaxis (p<0.001. Conversion by proteinase-3 resulted in significantly increased interleukin-8 activity in vitro (p<0.01.Shorter, potent, isoforms interleukin-8 predominate in the preterm lung, and are increased in infants developing bronchopulmonary dysplasia, due to conversion of interleukin-877 by neutrophil serine proteases and thrombin. Processing of interleukin-8 provides an attractive

  4. Disseminated intravascular coagulation in burn injury.

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    Lippi, Giuseppe; Ippolito, Luigi; Cervellin, Gianfranco

    2010-06-01

    Disseminated intravascular coagulation (DIC) is a complex and multifaceted disorder characterized by the activation of coagulation and fibrinolytic pathways, consumption of coagulation factors, and depletion of coagulation regulatory proteins. The introduction into the circulation of cellular debris characterized by strong thromboplastic activity due to tissue factor exposition or release (in or from burned tissues), which can thereby activate extrinsic pathway of coagulation system and trigger massive thrombin generation when present in sufficient concentration, represents the most plausible biological explanation to support the development of intravascular coagulation in patients with burn injury. Severe burns left untreated might also lead to an immunological and inflammatory response (activation of the complement cascade), which can amplify fibrinolysis and blood clotting. Overall, the real prevalence of DIC in patients with burns is as yet unclear. Postmortem, retrospective, and even longitudinal investigations are in fact biased by several factors, such as the objective difficulty to establish whether DIC might have occurred as a primary complication of burns or rather as a consequence of other superimposed pathologies (e.g., sepsis, multiple organ failure), the different diagnostic criteria for assessing DIC, and the heterogeneity of the patient samples studied. Nevertheless, the current scientific evidence is consistent with the hypothesis that biochemical changes suggestive for DIC (hypercoagulability, hypo- and hyperfibrinolysis) are commonplace in patients with burn trauma, and their severity increases exponentially with the severity of injury. Overt DIC seems to occur especially in critically ill burn patients or in those with severe burns (up to third degree) and large involvement of body surface area, in whom an appropriate therapy might be effective to prevent the otherwise fulminant course. Although early prophylaxis with antithrombin concentrates

  5. In vivo antithrombotic properties of a heparin from the oocyte test cells of the sea squirt Styela plicata(Chordata-Tunicata

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    L. Cardilo-Reis

    2006-11-01

    Full Text Available In the ascidian Styela plicata, the oocytes are surrounded by two types of accessory cells named follicle cells and test cells. A heparin-like substance with an anticoagulant activity equivalent to 10% of mammalian heparin and about 5% as potent as the mammalian counterpart for the inhibition of thrombin by antithrombin was isolated from the oocyte test cells. In the present study, we compared the antithrombotic and hemorrhagic effects of sea squirt oocyte test cell heparin with those of porcine heparin in rat models of venous thrombosis and blood loss. Intravenous administration of the oocyte test cell heparin to Wistar rats (both sexes, weighing ~300 g, N = 4 in each group at a dose of 5.0 mg/kg body weight, which produced a 1.8-fold increase in plasma activated partial thromboplastin time, inhibited thrombosis by 45 ± 13.5% (mean ± SD without any bleeding effect. The same dose of porcine heparin inhibited thrombosis by 100 ± 1.4%, but produced a blood loss three times greater than that of the saline-treated control. However, 10-fold reduction of the dose of porcine heparin to 0.5 mg/kg body weight, which produced a 5-fold increase in plasma-activated partial thromboplastin time, inhibited thrombosis by 70 ± 13% without any bleeding effect. The antithrombotic properties of a new heparin isolated from test cells of the sea squirt S. plicata, reported here for the first time, indicate that, although sea squirt oocyte test cell heparin was a poor anticoagulant compared to porcine heparin, it had a significant antithrombotic effect without causing bleeding.

  6. Topical thrombin preparations and their use in cardiac surgery

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    Brianne L Dunn

    2009-10-01

    Full Text Available Brianne L Dunn1, Walter E Uber1, John S Ikonomidis21Department of Pharmacy Services and 2Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USAAbstract: Coagulopathic bleeding may lead to increased morbidity and mortality after cardiac surgery. Topical bovine thrombin has been used to promote hemostasis after surgical procedures for over 60 years and is used frequently as a topical hemostatic agent in cardiac surgery. Recently, use of bovine thrombin has been reported to be associated with increased risk for anaphylaxis, thrombosis, and immune-mediated coagulopathy thought secondary to the production of antifactor V and antithrombin antibodies. In patients who develop bovine thrombin-induced immune-mediated coagulopathy, clinical manifestations may range from asymptomatic alterations in coagulation tests to severe hemorrhage and death. Patients undergoing cardiac surgical procedures may be at increased risk for development of antibodies to bovine thrombin products and associated complications. This adverse immunologic profile has led to the development of alternative preparations including a human and a recombinant thrombin which have been shown to be equally efficacious to bovine thrombin and have reduced antigenicity. However, the potential benefit associated with reduced antigenicity is not truly known secondary to the lack of long-term experience with these products. Given the potentially higher margin of safety and less stringent storage concerns compared to human thrombin, recombinant thrombin may be the most reasonable approach in cardiac surgery.Keywords: bovine thrombin, human thrombin, recombinant thrombin, immune-mediated coagulopathy, topical hemostatic agents, thrombin 

  7. Impact of hormone-associated resistance to activated protein C on the thrombotic potential of oral contraceptives: a prospective observational study.

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    Heiko Rühl

    Full Text Available The increased thrombotic risk of oral contraceptives (OC has been attributed to various alterations of the hemostatic system, including acquired resistance to activated protein C (APC. To evaluate to what extent OC-associated APC resistance induces a prothrombotic state we monitored plasma levels of thrombin and molecular markers specific for thrombin formation in women starting OC use. Elevated plasma levels of thrombin have been reported to characterize situations of high thrombotic risk such as trauma-induced hypercoagulability, but have not yet been studied during OC use.Blood samples were collected prospectively from healthy women (n = 21 before and during three menstruation cycles after start of OC. APC resistance was evaluated using a thrombin generation-based assay. Plasma levels of thrombin and APC were directly measured using highly sensitive oligonucleotide-based enzyme capture assay (OECA technology. Thrombin generation markers and other hemostasis parameters were measured additionally.All women developed APC resistance as indicated by an increased APC sensitivity ratio compared with baseline after start of OC (p = 0.0003. Simultaneously, plasma levels of thrombin, prothrombin fragment 1+2, and of thrombin-antithrombin complexes did not change, ruling out increased thrombin formation. APC plasma levels were also not influenced by OC use, giving further evidence that increased thrombin formation did not occur.In the majority of OC users no enhanced thrombin formation occurs despite the development of APC resistance. It cannot be ruled out, however, that thrombin formation might occur to a greater extent in the presence of additional risk factors. If this were the case, endogenous thrombin levels might be a potential biomarker candidate to identify women at high thrombotic risk during OC treatment. Large-scale studies are required to assess the value of plasma levels of thrombin as predictors of OC-associated thrombotic risk.

  8. Vascular endothelial damage as well as changes in coagulation and anticoagulation function in psoriatic patients%银屑病患者血管内皮及凝血、抗凝血功能变化的观察

    Institute of Scientific and Technical Information of China (English)

    孙小强; 王璐; 门剑龙; 周之海

    2008-01-01

    psoriasis.Methods A total of 51 patients with psoriasis(29 at active stage and 22 at stable stage)were enrolled into this study,along with 50 normal controls.Twenty Patients with active psoriasis received treatment with daily introvenous Danshen injection,topical triamcinolone acetonide cream as well as oral clarithromycin when necessary.Coagulation analyzer ACL 9000 was used to measure the parameters related to endothelial damage,coagulation and anticoagulation system in these patients and controls.Psoriasis area and severity index(PASI)was used to evaluate these patients before and after the treatment.The correlation between PASI and the tested parameters was assessed.Results Compared with the normal controls.decreased antithrombin activity as well as protein C activity and antigen were observed in patients at active stage(69.2%±17.3%,80.4%±17.3%,74.1%±23.8%respectively)and in those at stable stage (84.6%±11.9%,93.1%±15.5%,95.2%±18.3%respectively),whereas increased levels of plasminogen activator inhibitor-1 and vW factor were found in active psoriatic patients(0.6±0.5 Au/L,100.7%±25.6%respectively)and in stable psoriatic patients(0.9±0.6 Au/L,141.6%±59.1%respectively).Patients with active psoriasis had a higher level of vW factor but a lower level of antithrombin and protein C activity than those with stable psoriasis(all P<0.01).After treatment,the levels of antithrombin activity as well as protein C activity and antigen in patients with active psoriasis increased to 79.5%±13.0%,87.6%±10.9%,86.9%±20.5% respectively.while the level of plasminogen activator inhibitor-1 and vW factor decreased to 1.0±0.86 Au/L and 172.8%±44.5% respectively(all P<0.01).The activity of blood coagulation factor Ⅷ was lower in pailents with stable psoriasis than in those with active psoriasis(129.4%±33.2%VS 156.2%±67.1%,P<0.01)but higher than in the normal controls(P<0.01).No significant difierence was noticed in PASI before and after the treatment.and there was no

  9. Phage display of the serpin alpha-1 proteinase inhibitor randomized at consecutive residues in the reactive centre loop and biopanned with or without thrombin.

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    Benjamin M Scott

    Full Text Available In spite of the power of phage display technology to identify variant proteins with novel properties in large libraries, it has only been previously applied to one member of the serpin superfamily. Here we describe phage display of human alpha-1 proteinase inhibitor (API in a T7 bacteriophage system. API M358R fused to the C-terminus of T7 capsid protein 10B was directly shown to form denaturation-resistant complexes with thrombin by electrophoresis and immunoblotting following exposure of intact phages to thrombin. We therefore developed a biopanning protocol in which thrombin-reactive phages were selected using biotinylated anti-thrombin antibodies and streptavidin-coated magnetic beads. A library consisting of displayed API randomized at residues 357 and 358 (P2-P1 yielded predominantly Pro-Arg at these positions after five rounds of thrombin selection; in contrast the same degree of mock selection yielded only non-functional variants. A more diverse library of API M358R randomized at residues 352-356 (P7-P3 was also probed, yielding numerous variants fitting a loose consensus of DLTVS as judged by sequencing of the inserts of plaque-purified phages. The thrombin-selected sequences were transferred en masse into bacterial expression plasmids, and lysates from individual colonies were screening for API-thrombin complexing. The most active candidates from this sixth round of screening contained DITMA and AAFVS at P7-P3 and inhibited thrombin 2.1-fold more rapidly than API M358R with no change in reaction stoichiometry. Deep sequencing using the Ion Torrent platform confirmed that over 800 sequences were significantly enriched in the thrombin-panned versus naïve phage display library, including some detected using the combined phage display/bacterial lysate screening approach. Our results show that API joins Plasminogen Activator Inhibitor-1 (PAI-1 as a serpin amenable to phage display and suggest the utility of this approach for the selection

  10. Heparin enhances the catalytic activity of des-ETW-thrombin.

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    Goodwin, C A; Deadman, J J; Le Bonniec, B F; Elgendy, S; Kakkar, V V; Scully, M F

    1996-04-01

    The thrombin mutant, des-ETW-thrombin, lacking Glu(146), Thr(147), and Trp(148) within a unique insertion loop located at the extreme end of the primary specificity pocket, has been shown previously to exhibit reduced catalytic activity with respect to macromolecular and synthetic thrombin substrates and reduced or enhanced susceptibility to inhibition. Investigation of the hydrolysis of peptidyl p-nitroanilide substrates by des-ETW-thrombin showed increased activity in the presence of heparin and other sulphated glycosaminoglycans. No effect was observed upon the activity of wild-type thrombin. Heparin was found to decrease the K(m) for cleavage of four thrombin-specific substrates by des-ETW-thrombin by 3-4-fold. Similarly, pentosan polysulphate (PPS) decreased the K(m) with these substrates by 8-10-fold. Heparin also increased the rate of inhibition of des-ETW-thrombin by antithrombin III and D-phenylalanyl-prolyl-arginylchloromethane (PPACK). The inhibition of des-ETW-thrombin by a number of thrombin-specific peptide boronic acids also showed significant reduction in the final K(i) in the presence of heparin, due to reduction in the off-rate. A peptide analogue of a sequence of hirudin which binds thrombin tightly to exosite I (fibrinogen recognition site) potentiated the activity of des-ETW-thrombin against peptide p-nitroanilide substrates in a manner similar to heparin. The K(i) for the inhibition of des-ETW-thrombin by p-aminobenzamidine was decreased by these ligands from 9.7 mM to 7.5 mM, 5.1 mM, and 2.5 mM in the presence of heparin, hirudin peptide and PPS respectively, suggesting the increased catalytic activity is due to enhanced access to the primary specificity pocket. The positive influence of these ligands on des-ETW-thrombin was reversed in the presence of ATP or ADP; the latter has previously been shown to inhibit thrombin activity by blocking initial interaction with fibrinogen at exosite 1. Because the effect of heparin and PPS is similar to

  11. Heparin Versus Bivalirudin in Acute Myocardial Infarction: Unfractionated Heparin Monotherapy Elevated to Primary Treatment in Contemporary Percutaneous Coronary Intervention.

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    Centurión, Osmar Antonio

    2016-01-01

    Bivalirudin, a direct thrombin inhibitor, was developed as an antithrombin agent for patients undergoing percutaneous coronary interventions (PCI) with the hypothesis that it would reduce bleeding complications without compromising the rate of ischemic events compared to heparin plus GP IIb/IIIa inhibitors. Although the cumulative evidence makes a strong argument for the use of bivalirudin rather than heparin plus systematic GP IIb/IIIa inhibitors for the great majority of patients with acute myocardial infarction (AMI) undergoing PCI, the benefit observed with bivalirudin was achieved because of the major bleeding complications with the use of heparin plus GP IIb/IIIa inhibitors. When bivalirudin was compared with unfractionated heparin alone there was no benefit in ischemic complications with a decrease in major bleeding. However, in a recent large randomized controlled trial comparing bivalirudin with unfractionated heparin alone in AMI patients undergoing primary PCI, bivalirudin did not reduce bleeding complications and was associated with higher rates of stent thrombosis, myocardial reinfarction, and repeat revascularization compared with heparin. Moreover, a very recent meta-analysis shed more insights on the utilization of bivalirudin versus heparin regimens during PCI. Findings from this meta-analysis suggest that routine use of bivalirudin offers little advantage over heparin among PCI patients. In a detailed analysis of some randomized trials and observational studies with bivalirudin in AMI patients done by myself and published almost five years ago in this journal, I rendered some reflections on the future widespread use of bivalirudin. "In the setting of PCI in AMI patients, and in the absence of GP IIb/IIIa inhibitors, bivalirudin did not offer any beneficial effect in the incidence of the composite end points when compared with heparin alone. For now, in real world practice, one would probably choose a well known cheaper drug that has already passed

  12. Synthetic heparin pentasaccharide depolymerization by heparinase I: molecular and biological implications.

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    Daud, A N; Ahsan, A; Iqbal, O; Walenga, J M; Silver, P J; Ahmad, S; Fareed, J

    2001-01-01

    A synthetic pentasaccharide (SR90107/ ORG31540) representing the antithrombin III (ATIII) binding sequence in heparin is under clinical development for the prophylaxis and management of venous thromboembolism. This pentasaccharide exhibits potent anti-factor Xa (AXa) effects (>750 IU/mg) and does not exhibit any anti-factor IIa (AIIa) activity. Previous reports have suggested that synthetic heparin pentasaccharides are resistant to the digestive effects of heparinase I. To investigate the effect of heparinase I on the AXa activity of pentasaccharide SR90107/ORG31540, graded concentrations (1.25-100 microg/ml) were incubated with a fixed amount of heparinase I (0.1 U/ml). Heparinase I produced a strong neutralizing effect on this pentasaccharide, as measured by AXa activity. This observation led to further studies where high performance liquid chromatography (HPLC) analysis was employed to determine the potential breakdown products of the pentasaccharide. The experiment with the pentasaccharide included incubation (37 degrees C) at 1 mg/ml and exposure to graded concentrations of heparinase I (0.125-1 U/ml). After 30 min of incubation, the enzymatic activity was stopped by heat treatment and the mixture was analyzed using high performance size exclusion chromatography (HPSEC). Heparinase I concentration-dependent cleavage of the pentasaccharide was evident. The breakdown products exhibited a mass of 1,034 d and 743 d, respectively, suggesting the generation of a trisaccharide and a disaccharide moiety. The extinction of a disaccharide moiety in the UV region was high, indicating the presence of a double bond in this molecule. These data clearly suggest that pentasaccharide SR90107/ORG31540 is digestible by heparinase I into its two components. Furthermore, these data support the hypothesis that heparinase I can be used as a neutralizing agent for pentasaccharide overdose. Additionally, a highly methylated analog of the previously mentioned synthetic pentasaccharide

  13. Etiology of hypercoagulable state in women with recurrent fetal loss without other causes of miscarriage from Southern Italy: new clinical target for antithrombotic therapy

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    Maristella D’Uva

    2008-10-01

    Full Text Available Maristella D’Uva1, Pierpaolo Di Micco2, Ida Strina1, Antonio Ranieri1, Carlo Alviggi1, Antonio Mollo1, Francesca Fabozzi1, Lucia Cacciapuoti1, Maria Teresa Scotto di Frega1, Mariateresa Iannuzzo2, Giuseppe De Placido11Dipartimento Universitario di Scienze Ostetriche Ginecologiche e Medicina della Riproduzione, Area Funzionale di Medicina della Riproduzione ed Endoscopia Ginecologica, Università degli Studi di Napoli Federico II, via Pansini 5 Building 9, 80131, Naples, Italy; 2Internal Medicine Division, Fatebenefratelli Hospital of Naples, Naples, ItalyBackground: Recurrent fetal loss (RPL is one of the most common cause of sterility. Several studies identified thrombophilia as the principal cause of recurrent pregnancy loss. However, reported studies often do not evaluate other causes of miscarriages in their inclusion and exclusion criteria. So the aim of our study was to investigate the role of inherited thrombophilia in patients with RPL and without other causes of RPL.Patients and methods: Patients with 2 or more first trimester abortion or with 1 or more late pregnancy loss were considered for this study. In order to evaluate the causes of RPL we looked for chromosomal, endocrine, chronic inflammatory, and infectious alterations. 90 patients affected by unexplained RPL were enrolled and tested for hemostatic alterations. These women were tested for inherited and/or acquired thrombophilia by MTHFR C677T gene polymorphism, factor V Leiden gene polymorphism, PTHRA20210G gene polymorphism, protein S deficiency, protein C deficiency, antithrombin III deficiency, lupus anticoagulant, and anticardiolipin antibodies Ig G and Ig M.Results: Acquired and/or inherited thrombophilia are strongly associated with RPL when other common causes of miscarriage were excluded. 78% of tested women showed hemostatic abnormalities. Several women with combined thrombophilic defects were also identified by our data.Conclusion: After a thorough evaluation of

  14. Reperfusionsstrategien beim Myokardinfarkt: Stellenwert der interventionellen Kardiologie

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    Huber K

    2006-01-01

    , wie z. B. der Plättcheninhibitor Prasugrel (TRITON-TIMI-38-Studie oder das direkte Antithrombin Bivalirudin (HORIZON-Studie werden derzeit in klinischen Studien getestet. Es laufen derzeit auch Studien zur Untersuchung der Wertigkeit von Substanzen, die – während der PPCI verabreicht – in der Lage sein sollen, "Reperfusionsschäden" zu vermeiden (APEXAMI, DELTA-MI.

  15. The Relationship of the Factor V Leiden Mutation and Pregnancy Outcomes for Mother and Fetus

    Science.gov (United States)

    Dizon-Townson, Donna; Miller, Connie; Sibai, Baha; Spong, Catherine Y.; Thom, Elizabeth; Wendel, George; Wenstrom, Katharine; Samuels, Philip; Cotroneo, Margaret A.; Moawad, Atef; Sorokin, Yoram; Meis, Paul; Miodovnik, Menachem; O’Sullivan, Mary J.; Conway, Deborah; Wapner, Ronald J.; Gabbe, Steven G.

    2013-01-01

    Objective We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. Methods Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. Results One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0–2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02–0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were

  16. Is there a relationship between factor V Leiden and type 2 diabetes?

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    Librè Luca

    2009-06-01

    Full Text Available Abstract Background Diabetes is well known risk factor for thrombotic events. The association between diabetes and venous thromboembolism is still matter of debate. However, during diabetes an acquired thrombophilia is present and is due to the non-enzymatic glycosilation of clotting inhibitors as antithrombin thus leading to hypercoagulable state. A possibile relationship between the presence of FVL gene variant in type 1 or type 2 diabetes has been hypothysed by several reports in the Literature with non-univocal findings. Patients and methods Retrospectively we analysed nearly 7000 patients referred to our Thrombosis Center for venous thromboembolism (VTE then we selected 115 patients underwent to the screening for inherited thrombophilia. All selected patients were divided in 2 groups: the first group (group A included 64 patients with previous VTE and carriers of factor V Leiden, while the second group (group B included 51 patients with previous VTE and evetually carriers of thrombophilic defects other than factor V Leiden. Patients of group B acted as control group. 75 g oral glucose tolerance Test (OGTT recommended by WHO was perfomed to all subjects in the study in order to screen subjects with glucose reduced tolerance or subjects with inducible diabetes. Statistical analysis was performed with STATA 6 http://www.stata.com with Student t test for unpaired data, with χ2 test or with Fisher exact test where appropriated; differences were considered to be significant if p Results We did not find sifferences between glycaemia at baseline and after OGTT between patients with VTE carriers of FVL compared to non-carriers of FVL. We found a relevant increase in the prevalence of IGT and diabetes between patients with VTE carriers of FVL compared to non-carriers of FVL although this increase did not raise statistical significance. Discussion our data pointed out an interesting aspect of the linking between FVL gene variant, diabetes and

  17. Is there a relationship between factor V Leiden and type 2 diabetes?

    Science.gov (United States)

    Lodigiani, Corrado; Ferrazzi, Paola; Di Micco, Pierpaolo; Librè, Luca; Genovese, Stefano; Quaglia, Ilaria; Rota, Lidia Luciana

    2009-01-01

    Background Diabetes is well known risk factor for thrombotic events. The association between diabetes and venous thromboembolism is still matter of debate. However, during diabetes an acquired thrombophilia is present and is due to the non-enzymatic glycosilation of clotting inhibitors as antithrombin thus leading to hypercoagulable state. A possibile relationship between the presence of FVL gene variant in type 1 or type 2 diabetes has been hypothysed by several reports in the Literature with non-univocal findings. Patients and methods Retrospectively we analysed nearly 7000 patients referred to our Thrombosis Center for venous thromboembolism (VTE) then we selected 115 patients underwent to the screening for inherited thrombophilia. All selected patients were divided in 2 groups: the first group (group A) included 64 patients with previous VTE and carriers of factor V Leiden, while the second group (group B) included 51 patients with previous VTE and evetually carriers of thrombophilic defects other than factor V Leiden. Patients of group B acted as control group. 75 g oral glucose tolerance Test (OGTT) recommended by WHO was perfomed to all subjects in the study in order to screen subjects with glucose reduced tolerance or subjects with inducible diabetes. Statistical analysis was performed with STATA 6 with Student t test for unpaired data, with χ2 test or with Fisher exact test where appropriated; differences were considered to be significant if p < 0.05. Results We did not find sifferences between glycaemia at baseline and after OGTT between patients with VTE carriers of FVL compared to non-carriers of FVL. We found a relevant increase in the prevalence of IGT and diabetes between patients with VTE carriers of FVL compared to non-carriers of FVL although this increase did not raise statistical significance. Discussion our data pointed out an interesting aspect of the linking between FVL gene variant, diabetes and atherothrombosis and other vascular

  18. Thrombocytopenia in the experimental leptospirosis of guinea pig is not related to disseminated intravascular coagulation

    Directory of Open Access Journals (Sweden)

    HU Bao-Yu

    2006-02-01

    Full Text Available Abstract Background Thrombocytopenia is commonly observed in severe leptospirosis. However, previous studies on coagulation alterations during leptospirosis resulted in inconsistent conclusions. Some findings showed that the prominent levels of thrombocytopenia observed in severe leptospirosis did not reflect the occurrence of disseminated intravascular coagulation (DIC syndrome, while the others reached the conclusion that the hemorrhages observed in leptospirosis were due to DIC. The aim of this study is to elucidate whether DIC is an important feature of leptospirosis. Methods The leptospirosis model of guinea pig was established by intraperitoneal inoculation of Leptospira interrogans strain Lai. Hematoxylin and eosin (HE staining, electron microscopy and immunohistochemistry staining were used to detect the pathologic changes. Platelet thrombus or fibrin thrombus was detected by HE, Martius Scarlet Blue (MSB staining and electron microscopy. Hemostatic molecular markers such as 11-dehydrogenate thromboxane B2 (11-DH-TXB2, thrombomodulin (TM, thrombin-antithrombin III complex (TAT, D-Dimer and fibrin (ogen degradation products (FDPs in the plasma were examined by quantitative enzyme-linked immunosorbent assay (ELISA to evaluate the hematological coagulative alterations in leptospirosis models. Results Pulmonary hemorrhage appeared in the model guinea pig 24 hours after leptospires intraperitoneal inoculation, progressing to a peak at 96 hours after the infection. Leptospires were detected 24 hours post-inoculation in the liver, 48 hours in the lung and 72 hours in the kidney by immunohistochemistry staining. Spiral form of the bacteria was initially observed in the liver, lung and kidney suggestive of intact leptospires, granular form of leptospires was seen as the severity increased. Platelet aggregation in hepatic sinusoid as well as phagocytosis of erythrocytes and platelets by Kupffer cells were both observed. Neither platelet thrombus

  19. Two acidic, anticoagulant PLA2 isoenzymes purified from the venom of monocled cobra Naja kaouthia exhibit different potency to inhibit thrombin and factor Xa via phospholipids independent, non-enzymatic mechanism.

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    Ashis K Mukherjee

    Full Text Available BACKGROUND: The monocled cobra (Naja kaouthia is responsible for snakebite fatality in Indian subcontinent and in south-western China. Phospholipase A2 (PLA2; EC 3.1.1.4 is one of the toxic components of snake venom. The present study explores the mechanism and rationale(s for the differences in anticoagulant potency of two acidic PLA2 isoenzymes, Nk-PLA2α (13463.91 Da and Nk-PLA2β (13282.38 Da purified from the venom of N. kaouthia. PRINCIPAL FINDINGS: By LC-MS/MS analysis, these PLA2s showed highest similarity (23.5% sequence coverage with PLA2 III isolated from monocled cobra venom. The catalytic activity of Nk-PLA2β exceeds that of Nk-PLA2α. Heparin differentially regulated the catalytic and anticoagulant activities of these Nk-PLA2 isoenzymes. The anticoagulant potency of Nk-PLA2α was comparable to commercial anticoagulants warfarin, and heparin/antithrombin-III albeit Nk-PLA2β demonstrated highest anticoagulant activity. The anticoagulant action of these PLA2s was partially contributed by a small but specific hydrolysis of plasma phospholipids. The strong anticoagulant effect of Nk-PLA2α and Nk-PLA2β was achieved via preferential, non-enzymatic inhibition of FXa (Ki = 43 nM and thrombin (Ki = 8.3 nM, respectively. Kinetics study suggests that the Nk-PLA2 isoenzymes inhibit their "pharmacological target(s" by uncompetitive mechanism without the requirement of phospholipids/Ca(2+. The anticoagulant potency of Nk-PLA2β which is higher than that of Nk-PLA2α is corroborated by its superior catalytic activity, its higher capacity for binding to phosphatidylcholine, and its greater strength of thrombin inhibition. These PLA2 isoenzymes thus have evolved to affect haemostasis by different mechanisms. The Nk-PLA2β partially inhibited the thrombin-induced aggregation of mammalian platelets suggesting its therapeutic application in the prevention of unwanted clot formation. CONCLUSION/SIGNIFICANCE: In order to develop peptide

  20. Increased PADI4 expression in blood and tissues of patients with malignant tumors

    Science.gov (United States)

    2009-01-01

    Background Peptidylarginine deiminase type 4 (PAD4/PADI4) post-translationally converts peptidylarginine to citrulline. Recent studies suggest that PADI4 represses expression of p53-regulated genes via citrullination of histones at gene promoters. Methods Expression of PADI4 was investigated in various tumors and non-tumor tissues (n = 1673) as well as in A549, SKOV3 and U937 tumor cell lines by immunohistochemistry, real-time PCR, and western blot. Levels of PADI4 and citrullinated antithrombin (cAT) were investigated in the blood of patients with various tumors by ELISA (n = 1121). Results Immunohistochemistry detected significant PADI4 expression in various malignancies including breast carcinomas, lung adenocarcinomas, hepatocellular carcinomas, esophageal squamous cancer cells, colorectal adenocarcinomas, renal cancer cells, ovarian adenocarcinomas, endometrial carcinomas, uterine adenocarcinomas, bladder carcinomas, chondromas, as well as other metastatic carcinomas. However, PADI4 expression was not observed in benign leiomyomas of stomach, uterine myomas, endometrial hyperplasias, cervical polyps, teratomas, hydatidiform moles, trophoblastic cell hyperplasias, hyroid adenomas, hemangiomas, lymph hyperplasias, schwannomas, neurofibromas, lipomas, and cavernous hemangiomas of the liver. Additionally, PADI4 expression was not detected in non-tumor tissues including cholecystitis, cervicitis and synovitis of osteoarthritis, except in certain acutely inflamed tissues such as in gastritis and appendicitis. Quantitative PCR and western blot analysis showed higher PADI4 expression in gastric adenocarcinomas, lung adenocarcinomas, hepatocellular carcinomas, esophageal squamous cell cancers and breast cancers (n = 5 for each disease) than in the surrounding healthy tissues. Furthermore, western blot analysis detected PADI4 expression in cultured tumor cell lines. ELISA detected increased PADI4 and cAT levels in the blood of patients with various malignant tumors

  1. New developments in the management of moderate-to-severe hemophilia B

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    Nazeef M

    2016-04-01

    Full Text Available Moniba Nazeef,1,2 John P Sheehan1,2 1Department of Medicine, Division of Hematology/Oncology, 2UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Abstract: Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP represent fusion proteins with the immunoglobulin G1 (IgG1 Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin

  2. Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes.

    Science.gov (United States)

    Oberbach, Andreas; Blüher, Matthias; Wirth, Henry; Till, Holger; Kovacs, Peter; Kullnick, Yvonne; Schlichting, Nadine; Tomm, Janina M; Rolle-Kampczyk, Ulrike; Murugaiyan, Jayaseelan; Binder, Hans; Dietrich, Arne; von Bergen, Martin

    2011-10-01

    Obesity is associated with multiple adverse health effects and a high risk of developing metabolic and cardiovascular diseases. Therefore, there is a great need to identify circulating parameters that link changes in body fat mass with obesity. This study combines proteomic and metabolomic approaches to identify circulating molecules that discriminate healthy lean from healthy obese individuals in an exploratory study design. To correct for variations in physical activity, study participants performed a one hour exercise bout to exhaustion. Subsequently, circulating factors differing between lean and obese individuals, independent of physical activity, were identified. The DIGE approach yielded 126 differentially abundant spots representing 39 unique proteins. Differential abundance of proteins was confirmed by ELISA for antithrombin-III, clusterin, complement C3 and complement C3b, pigment epithelium-derived factor (PEDF), retinol binding protein 4 (RBP4), serum amyloid P (SAP), and vitamin-D binding protein (VDBP). Targeted serum metabolomics of 163 metabolites identified 12 metabolites significantly related to obesity. Among those, glycine (GLY), glutamine (GLN), and glycero-phosphatidylcholine 42:0 (PCaa 42:0) serum concentrations were higher, whereas PCaa 32:0, PCaa 32:1, and PCaa 40:5 were decreased in obese compared to lean individuals. The integrated bioinformatic evaluation of proteome and metabolome data yielded an improved group separation score of 2.65 in contrast to 2.02 and 2.16 for the single-type use of proteomic or metabolomics data, respectively. The identified circulating parameters were further investigated in an extended set of 30 volunteers and in the context of two intervention studies. Those included 14 obese patients who had undergone sleeve gastrectomy and 12 patients on a hypocaloric diet. For determining the long-term adaptation process the samples were taken six months after the treatment. In multivariate regression analyses, SAP, CLU

  3. The role of ventilation-perfusion lung scintigraphy in the diagnosis of pulmonary embolism in nephrotic syndrome patients

    International Nuclear Information System (INIS)

    Purpose: Patients with nephrotic syndrome (NS) have a high risk to develop thrombosis and even to progress to pulmonary embolism (PE). This study was performed to investigate the possible role of ventilafion-perfusion (V/Q) lung scans to evaluate PE in NS patients. Methods: 194 patients with NS (8 cases of minimal change NS (MCNS), 33 of mesangial proliferative (MsPGN), 19 of Mesangiocapillary glomerulonephritis (MCGN), 69 of membranous nephropathy, 56 of focal and segmental glomerular sclerosis (FSGS), and 9 of NS induced from purpura, SLE, diabetes mellitus or amyloidosis) were studied. In all patients, the development probability of PE was assessed based on the results of V/Q lung scans (Technegas for ventilation and Tc-99m MAA for perfusion imaging). The findings of V/Q lung scans were interrupted into high, intermediate, low or no probability of PE. The patients' clinical symptoms and signs were observed. Additional examinations included chest radiography, and serum biochemical tests such as albumin, blood urea nitrogen (BUN), creatinine (Cr), plasma fibrinogen (Fg), antithrombin III (AT III), prothrombin time (PT), and activated partial thromboplastin time (APTT). Results: Based on the findings of V/Q lung scans, 39 (20%) of the patients were categorized as having a high probability of PE and 56 (29%) as intermediate or low probability of PE. The occurrence of PE in patients with membranous nephropathy (23 cases, 33%) was significantly higher than that in those other pathological types. In the 86 patients with severe hypoalbuminemia (serum albumin concentration = 20g/L. The Fg and AT III levels were found to be correlated with the occurrence of PE. The clinical symptoms and signs, chest radiograph results and values of BUN, Cr, PT and APTT were not consistent with the occurrence of PE. Conclusion: Though usually clinically silent, PE is not a rare complication in patients with NS, especially in those with membranous nephropathy. In this study, the occurrence

  4. PROCOAGULANT EFFECTS OF THROMBOLYTIC THERAPY IN ACUTE MYOCARDIAL INFARCTION

    Institute of Scientific and Technical Information of China (English)

    王燕妮; 刘茜茜; 祝家庆; 袁祖贻; 马西

    2002-01-01

    Objective.To examine the procoagulant effects of thrombolytic agent on hemostasis and study the role of hemostatic markers as predictors of clinical outcomes.Methods.In the present study,eighteen patients with acute myocardial infarction(AMI) received 1.5 or 2.0 million U nonspecific urokinase(UK),or 70~80 mg fibrin specific recombinant tissue plasminogen activator(rt PA)and did not use heparin until 8 hours after intravenous injection of the above agents.Eight patients with AMI and without thrombolytic therapy were enrolled as controls.Coagulant and thrombolytic activity markers included thrombin antithrombin Ⅲ complex (TAT),D dimer,fibrinogen (Fg),FMPV/Amax.All markers were determined before,immediately,1,2,4 and 8 hours after the administration of thrombolytic agents respectively. Results.Molecular marker of thrombin generation- - TAT showed an activated coagulant state immediately after thrombolytic therapy.Level of TAT showed no significant changes between every two observed phases in controls.However,level of TAT increased significantly from 4.95± 1.75μ g/L ( 4.63± 1.37μ g/L) to 14.71± 3.31μ g/L ( 14.25± 2.53μ g/L) before and immediately after administration of thrombolytic agents UK(or rt PA).There was significant difference between level of serum TAT of patients with and without thrombolytic therapy (P< 0.05).Patients achieving clinical reperfusion had lower TAT level than those failing in thrombolytic therapy,and higher FMPV/Amax level than controls.D dimer,a surrogate of thrombolytic activity increased markedly and Fg significantly declined after thrombolytic therapy(P< 0.05). Conclusions.Thrombin generation occurred in plasma in response to excess fibrinolysis induced by thrombolytic therapy.Both urokinase and rt PA had procoagulant action.This transient activation of the coagulant system might contribute to early reocclusion.These data provided the theoretical support for simultaneous administration of anticoagulant therapy with thrombolytic

  5. Hemostatic dysfunction is increased in patients with hepatosplenic schistosomiasis mansoni and advanced periportal fibrosis.

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    Luiz Arthur Calheiros Leite

    Full Text Available BACKGROUND: Schistosomiasis mansoni is an endemic parasitic disease and a public health problem in Northeast Brazil. In some patients, hepatic abnormalities lead to periportal fibrosis and result in the most severe clinical form, hepatosplenic schistosomiasis. This study aimed to evaluate whether abnormal blood coagulation and liver function tests in patients with hepatosplenic schistosomiasis (n = 55 correlate with the severity of their periportal fibrosis. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were used for liver function tests, hemogram and prothrombin time (International Normalized Ratio, INR. The blood coagulation factors (II, VII, VIII, IX and X, protein C and antithrombin IIa (ATIIa, plasminogen activator inhibitor 1 (PAI-1 and D-dimer were measured by photometry or enzyme linked immunosorbent assay. Hyperfibrinolysis was defined on the basis of PAI-1 levels and a D-dimer concentration greater than a standard cut-off of 483 ng/mL. Standard liver function tests were all abnormal in the patient group compared to healthy controls (n = 29, including raised serum transaminases (p<0.001 and lower levels of albumin (p = 0.0156. Platelet counts were 50% lower in patients, while for coagulation factors there was a 40% increase in the INR (p<0.001 and reduced levels of Factor VII and protein C in patients compared to the controls (both p<0.001. Additionally, patients with more advanced fibrosis (n = 38 had lower levels of protein C compared to those with only central fibrosis (p = 0.0124. The concentration of plasma PAI-1 in patients was one-third that of the control group (p<0.001, and D-dimer levels 2.2 times higher (p<0.001 with 13 of the 55 patients having levels above the cut-off. CONCLUSION/SIGNIFICANCE: This study confirms that hemostatic abnormalities are associated with reduced liver function and increased liver fibrosis. Of note was the finding that a quarter of patients with hepatosplenic schistosomiasis and

  6. Value of the first post-transplant biopsy for predicting long-term cardiac allograft vasculopathy (CAV and graft failure in heart transplant patients.

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    Carlos A Labarrere

    Full Text Available BACKGROUND: Cardiac allograft vasculopathy (CAV is the principal cause of long-term graft failure following heart transplantation. Early identification of patients at risk of CAV is essential to target invasive follow-up procedures more effectively and to establish appropriate therapies. We evaluated the prognostic value of the first heart biopsy (median: 9 days post-transplant versus all biopsies obtained within the first three months for the prediction of CAV and graft failure due to CAV. METHODS AND FINDINGS: In a prospective cohort study, we developed multivariate regression models evaluating markers of atherothrombosis (fibrin, antithrombin and tissue plasminogen activator [tPA] and endothelial activation (intercellular adhesion molecule-1 in serial biopsies obtained during the first three months post-transplantation from 172 patients (median follow-up = 6.3 years; min = 0.37 years, max = 16.3 years. Presence of fibrin was the dominant predictor in first-biopsy models (Odds Ratio [OR] for one- and 10-year graft failure due to CAV = 38.70, p = 0.002, 95% CI = 4.00-374.77; and 3.99, p = 0.005, 95% CI = 1.53-10.40 and loss of tPA was predominant in three-month models (OR for one- and 10-year graft failure due to CAV = 1.81, p = 0.025, 95% CI = 1.08-3.03; and 1.31, p = 0.001, 95% CI = 1.12-1.55. First-biopsy and three-month models had similar predictive and discriminative accuracy and were comparable in their capacities to correctly classify patient outcomes, with the exception of 10-year graft failure due to CAV in which the three-month model was more predictive. Both models had particularly high negative predictive values (e.g., First-biopsy vs. three-month models: 99% vs. 100% at 1-year and 96% vs. 95% at 10-years. CONCLUSIONS: Patients with absence of fibrin in the first biopsy and persistence of normal tPA in subsequent biopsies rarely develop CAV or graft failure during the next 10 years and potentially could be monitored less invasively

  7. 弥散性血管内凝血的治疗%Therapy for disseminated intravascular coagulation

    Institute of Scientific and Technical Information of China (English)

    飞球; 麦惠容

    2015-01-01

    Disseminated intravascular coagulation ( DIC ) is a exceedingly complicated pathophysiological process,both pro and anti coagulation factors are activated and consumed,it is difficult to determine acute stage of the syndrome for physicians based on clinical presentations and laboratory tests,management strategy of DIC is not same due to different etiology,the dose and regimen of drug administration are uncertain. At present pediatricians usually treat children patients with DIC according to researches and guidelines for adults. The key strategies to DIC management is to treat underlying diseases aggressively so as to clear risk factors triggering extensive coagulation and resuscitate with ap-propriate blood products. No clinical trials have proved that heparin can improve clinical outcome,efficacies of activated protein C,antithrombin, tissue factor pathway inhibitor and thrombomodulin are needed to be verified by more high qua-lity clinical trials in DIC treatment.%弥散性血管内凝血( DIC)是一个非常复杂的病理生理过程,促凝和抗凝因子及血小板均有消耗,根据临床表现和实验室检查很难准确判断疾病的真实临床进程,处理上常常需要结合所在医院习惯和专家的经验。不同类型DIC的处理、用药的剂量与方案存在诸多的不确定性。有关DIC的治疗,儿科目前主要参考成人的指南。DIC最重要的处理措施是对潜在疾患进行强有力的治疗,消除触发凝血病变危险因素,同时采用恰当的血液制品进行复苏。尚无临床随机试验证实应用肝素在DIC患者能改善临床相关结果,活化蛋白C、抗凝血酶、组织因子通路抑制物和血栓调节素等抗凝因子在DIC治疗中的意义还有待于更多高质量的临床研究深入探讨。

  8. Hypercoagulability existing in the local left atrium of patient with mitral stenosis

    Institute of Scientific and Technical Information of China (English)

    王建安; 谢鑫友; 何红; 黄金文; 鲁端; 杨倩

    2003-01-01

    Objective To investigate the pathogenesis of thromboembolism in patients with mitral stenosis in a pre-thrombotic state.Methods The biochemical markers ' levels in plasma for platelet activity [soluble P-selectin (GMP-140)], states of thrombin generation [antithrombin Ⅲ (AT Ⅲ) and protein C (PC)], fibrinolysis [D-dimer (DD), plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA) and FDP] and von Willebrand factor (vWF) were determined from blood specimens obtained from the femoral veins and arteries and the right and left atria of 43 consecutive patients (20 with atrial fibrillation and 23 with sinus rhythm) with mitral stenosis (MS), undergoing percutaneous mitral valvuloplasty. The same parameters were compared with those of 15 control subjects, who had no detectable heart disease, but with paroxysmal supraventricular tachycardia undergoing radiofrequency catheter ablation of the left accessory pathway through a transseptal passage. Results Blood from the left atrium contained an excessive amount of platelet activity, thrombin generation and fibrinolysis compared with the blood from the right atrium, and the femoral veins and arteries. However blood from the right atrium was much lower in these activities when compared with those from the left atrium, and the femoral veins and arteries in both groups. Compared with those in the control subjects, GMP-140 in the left atrium was significantly higher (P<0.05) and AT Ⅲ was significantly lower (P<0.05) in patients with MS. Compared with the patients with MS and spontaneous left atrial echocontrast (LASEC)≤1, the patients with MS and LASEC≥2 had significantly higher levels of GMP-140 in plasma (P<0.05), and significantly lower levels of AT Ⅲ (P<0.05) and PC (P<0.01) levels in the left atrium. However, there were no significant differences between patients with atrial fibrillation and those with sinus rhythm regarding amounts of plasma coagulation markers in the left atrium. Univariate

  9. Different patterns of intestinal response to injury after arterial, venous or arteriovenous occlusion in rats

    Institute of Scientific and Technical Information of China (English)

    Francisco Javier Guzmán-de la Garza; Carlos Rodrigo Cámara-Lemarroy; Gabriela Alarcón-Galván; Paula Cordero-Pérez; Linda Elsa Mu(n)oz-Espinosa; Nancy Esthela Fernández-Garza

    2009-01-01

    AIM: To investigate the differences in injury patterns caused by arterial, venous or arteriovenous mesenteric occlusion.METHODS: Male Wistar rats were separated equally into four groups. Occlusion was performed by clamping the superior mesenteric artery (A), the mesenteric vein (V) or both (AV) for 30 min, followed by 60 min of reperfusion. A control group received sham surgery only. Intestinal sections were examined for histological damage and serum tumor necrosis factor-α (TNF-α), endothelin-1 (ET-1), P-selectin, antithrombin Ⅲ (ATⅢ) and soluble intracellular adhesion molecule-1 (ICAM-1) concentrations were measured.RESULTS: All groups showed significant mucosal injury compared to controls. Furthermore, mucosal injury was significantly more severe in the V and AV groups compared to the A group (3.6 ± 0.55, 3.4 ± 0.55 and 2 ± 0.71, respectively, P = 0.01). ICAM-1 was similarly elevated in all groups, with no significant differences between the groups. P-selectin levels were significantly elevated in the V and AV groups but not the A group (1.4 ± 0.5 ng/mL, 2.52 ± 0.9 ng/mL and 0.02 ± 0.01 ng/mL,respectively, P = 0.01) and ET-1 was significantly elevated in the A and V groups but not the AV group (0.32 ± 0.04 pg/mL, 0.36 ± 0.05 pg/mL and 0.29 ± 0.03 pg/mL, respectively, P = 0.01) compared to sham controls. ATⅢ levels were markedly depleted in the V and AV groups, but not in the A group (29.1 ± 5.2 pg/mL,31.4 ± 21.8 pg/mL and 55.8 ± 35.6 pg/mL ,respectively, P = 0.01), compared to controls. Serum TNF-α was significantly increased in all groups compared to sham controls (1.32 ± 0.87 ng/mL, 1.79 ± 0.20 ng/mL and 4.4 ± 0.69 ng/mL, for groups A, V and AV,respectively, P = 0.01), with higher values in the AV group.CONCLUSION: Different patterns of response to ischemia/reperfusion are associated with venous, arterial or arteriovenous occlusion. Venous and arteriovenous occlusion was associated with the most severe alterations.

  10. Increased PADI4 expression in blood and tissues of patients with malignant tumors

    Directory of Open Access Journals (Sweden)

    Zhao Yan

    2009-01-01

    Full Text Available Abstract Background Peptidylarginine deiminase type 4 (PAD4/PADI4 post-translationally converts peptidylarginine to citrulline. Recent studies suggest that PADI4 represses expression of p53-regulated genes via citrullination of histones at gene promoters. Methods Expression of PADI4 was investigated in various tumors and non-tumor tissues (n = 1673 as well as in A549, SKOV3 and U937 tumor cell lines by immunohistochemistry, real-time PCR, and western blot. Levels of PADI4 and citrullinated antithrombin (cAT were investigated in the blood of patients with various tumors by ELISA (n = 1121. Results Immunohistochemistry detected significant PADI4 expression in various malignancies including breast carcinomas, lung adenocarcinomas, hepatocellular carcinomas, esophageal squamous cancer cells, colorectal adenocarcinomas, renal cancer cells, ovarian adenocarcinomas, endometrial carcinomas, uterine adenocarcinomas, bladder carcinomas, chondromas, as well as other metastatic carcinomas. However, PADI4 expression was not observed in benign leiomyomas of stomach, uterine myomas, endometrial hyperplasias, cervical polyps, teratomas, hydatidiform moles, trophoblastic cell hyperplasias, hyroid adenomas, hemangiomas, lymph hyperplasias, schwannomas, neurofibromas, lipomas, and cavernous hemangiomas of the liver. Additionally, PADI4 expression was not detected in non-tumor tissues including cholecystitis, cervicitis and synovitis of osteoarthritis, except in certain acutely inflamed tissues such as in gastritis and appendicitis. Quantitative PCR and western blot analysis showed higher PADI4 expression in gastric adenocarcinomas, lung adenocarcinomas, hepatocellular carcinomas, esophageal squamous cell cancers and breast cancers (n = 5 for each disease than in the surrounding healthy tissues. Furthermore, western blot analysis detected PADI4 expression in cultured tumor cell lines. ELISA detected increased PADI4 and cAT levels in the blood of patients with

  11. Anticoagulation after anterior myocardial infarction and the risk of stroke.

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    Jacob A Udell

    MI there was no benefit from the use of warfarin up to 90 days post-MI to prevent ischemic stroke. Our data suggests that routine anticoagulation of patients with anterior-wall MI may not be indicated. Prospective randomized trials are needed to determine the optimal antithrombin strategy for preventing this common and serious adverse outcome.

  12. Modifications de la coagulation sanguine dans la fièvre jaune

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    J. Vellard

    1929-01-01

    Full Text Available L'étude des modifications de la coagulation sanguine à l'aide de la technique BRAZIL-VELLARD, réalisée chez 25 malades atteints de formes diverses, mortelles, graves, et bénignes, entre le lléme et le XIIIéme jour de maladie, et chez 12 convalescents, a permis d'arriver aux conclusions suivantes: 1º. Les variations du pouvoir coagulant du serum sont très irrégulières et peu différentes des celles observées chez de sujets normaux. 2º. La coagulabilité du plasma, dès le IIème jour de la maladie, présente une diminution marquée, constante chez tous les malades, atteignant son chiffre le plus bas entre le VIIème et le IXème jour et revenant progressivement á la normale pendant la convalescence. 3º. Cette diminution de la coagulabilité est due principalement á l'apparition de grandes quantités d'antithrombines dans la circulation; la diminution du fibrinogène observée dans quelques cas, est toujours peu accusée. 4º. La diminution de la coagulabilité du plasma, qui n'a jusqu'ici été observée avec cette intensité que dans la fièvre jaune, peut être d'un certain secours pour le diagnostic précoce de cette affection; elle n'a jamais été vérifiée chez des malades atteints d'autres affections fébriles. 5º. Au point de vue du pronostic, la diminution précoce et très accentuée de la coagulabilité est un symptôme grave, indiquant une lésion profonde de la cellule hépatique. 6º. Dans la fièvre jaune expérimentale du Macacus rhesus, les altérations de la coagulation sanguine sont de même nature, mais paraissent plus tardives et moins accusées que chez l'homme.

  13. Enfermedad tromboembólica venosa y cirrosis hepática Venous thromboembolism and liver cirrhosis

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    M. J. García-Fuster

    2008-05-01

    , thrombosis characteristics, and treatment complications. Results and conclusions: approximately 0.8% of all hospitalized patients with cirrhosis had a non-portal VTE despite the elevated INR and low platelet count. We found low serum albumin, acquired antithrombin III, protein C and protein S deficiency, presence of antiphospholipid antibodies, and hyperhomocisteinemia in blood tests. Many patients had hemorragic complications during anticoagulation therapy, and 35% needed blood transfusions.

  14. Plasma levels of plasminogen activator inhibitor type 1, factor VIII, prothrombin activation fragment 1+2, anticardiolipin, and antiprothrombin antibodies are risk factors for thrombosis in hemodialysis patients.

    Science.gov (United States)

    Molino, Daniela; De Santo, Natale G; Marotta, Rosa; Anastasio, Pietro; Mosavat, Mahrokh; De Lucia, Domenico

    2004-09-01

    Patients with end-stage renal disease are prone to hemorrhagic complications and simultaneously are at risk for a variety of thrombotic complications such as thrombosis of dialysis blood access, the subclavian vein, coronary arteries, cerebral vessel, and retinal veins, as well as priapism. The study was devised for the following purposes: (1) to identify the markers of thrombophilia in hemodialyzed patients, (2) to establish a role for antiphospholipid antibodies in thrombosis of the vascular access, (3) to characterize phospholipid antibodies in hemodialysis patients, and (4) to study the effects of dialysis on coagulation cascade. A group of 20 hemodialysis patients with no thrombotic complications (NTC) and 20 hemodialysis patients with thrombotic complications (TC) were studied along with 400 volunteer blood donors. Patients with systemic lupus erythematosus and those with nephrotic syndrome were excluded. All patients underwent a screening prothrombin time, activated partial thromboplastin time, fibrinogen (Fg), coagulation factors of the intrinsic and extrinsic pathways, antithrombin III (AT-III), protein C (PC), protein S (PS), resistance to activated protein C, prothrombin activation fragment 1+2 (F1+2), plasminogen, tissue type plasminogen activator (t-PA), plasminogen tissue activator inhibitor type-1 (PAI-1), anticardiolipin antibodies type M and G (ACA-IgM and ACA-IgG), lupus anticoagulant antibodies, and antiprothrombin antibodies type M and G (aPT-IgM and aPT-IgG). The study showed that PAI-1, F 1+2, factor VIII, ACA-IgM, and aPT-IgM levels were increased significantly over controls both in TC and NTC, however, they could distinguish patients with thrombotic complications from those without, being increased maximally in the former group. The novelty of the study is represented by the significant aPT increase that was observed in non-systemic lupus erythematosus hemodialysis patients, and particularly in those with thrombotic events. In addition

  15. Heparin-induced thrombocytopenia type II: Innovations in diagnostics and treatment

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    Antonijević Nebojša

    2003-01-01

    in the first four days, high-dose intravenous gammaglobulin, antiagregans, especially ADP antagonists, aspirin, dipirydamole, dextran, prostacyclin analogues thrombolytic therapy as well as thromboembolectomy. Oral anticoagulants are not administered in active HIT type II, in deep vein thrombosis with high international normalized ratio (INR and thrombin-antithrombin complexes, and low protein C levels to avoid the possibility of venous limb gangrene development. They can be administered in a stable phase, when the thrombin generation is controlled by previous administration of one of the above-mentioned alternative anticoagulants.

  16. Factor Xa generation by computational modeling: an additional discriminator to thrombin generation evaluation.

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    Kathleen E Brummel-Ziedins

    Full Text Available Factor (fXa is a critical enzyme in blood coagulation that is responsible for the initiation and propagation of thrombin generation. Previously we have shown that analysis of computationally generated thrombin profiles is a tool to investigate hemostasis in various populations. In this study, we evaluate the potential of computationally derived time courses of fXa generation as another approach for investigating thrombotic risk. Utilizing the case (n = 473 and control (n = 426 population from the Leiden Thrombophilia Study and each individual's plasma protein factor composition for fII, fV, fVII, fVIII, fIX, fX, antithrombin and tissue factor pathway inhibitor, tissue factor-initiated total active fXa generation was assessed using a mathematical model. FXa generation was evaluated by the area under the curve (AUC, the maximum rate (MaxR and level (MaxL and the time to reach these, TMaxR and TMaxL, respectively. FXa generation was analyzed in the entire populations and in defined subgroups (by sex, age, body mass index, oral contraceptive use. The maximum rates and levels of fXa generation occur over a 10- to 12- fold range in both cases and controls. This variation is larger than that observed with thrombin (3-6 fold in the same population. The greatest risk association was obtained using either MaxR or MaxL of fXa generation; with an ∼2.2 fold increased risk for individuals exceeding the 90(th percentile. This risk was similar to that of thrombin generation(MaxR OR 2.6. Grouping defined by oral contraceptive (OC use in the control population showed the biggest differences in fXa generation; a >60% increase in the MaxR upon OC use. FXa generation can distinguish between a subset of individuals characterized by overlapping thrombin generation profiles. Analysis of fXa generation is a phenotypic characteristic which may prove to be a more sensitive discriminator than thrombin generation among all individuals.

  17. Peculiarities of coagulation hemostasis disorders in patients with chronic obstructive pulmonary disease

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    Yakovlieva V.H.

    2015-09-01

    Full Text Available The violation of blood coagulation properties is observed in many diseases of the respiratory system, including chronic obstructive pulmonary disease (COPD. It is known that in a stable COPD phase release of proinflammatory cytokines in blood is observed, it leads to disturbance of hemostasis parameters toward hypercoagulation. The aim of our study was to determine possibility of coagulation disorders formation in patients with COPD in a stable phase of pathological process at different stages of disease course and identify relationship between coagulation parameters levels and degree of violation of ventilation lung function. Materials and methods. We examined 30 patients with COPD in a stable disease phase, included in the main group (FEV1 =49,5±15,5% of the due, there were 27 men (90.0%, 3 (30.0% women, mean age was 61,8±7,9 years, level of pack /years index - 34,2±15,3. The control group consisted of 10 healthy subjects matched with the patients of the main group by age and sex. All patients were divided into 2 subgroups. Subgroup 1 included 16 patients with moderate COPD, that is the level of FEV1>50% (61,8±7,4% of predicted, and subgroup 2 - 14 COPD patients with severe COPD, that is the level of FEV1 <50% (35,3±8,2% of predicted. Patients received standard treatment according to the disease stage. Main indicators of coagulation levels: prothrombin index (PI, prothrombin ratio (PR, international normalized ratio (INR, activated partial thromboplastin time (APTT, thrombin time (TT and antithrombin III (AT III were identified in all patients. Results. The levels of PI, PR and INR in the subgroup 1 differed significantly from those of in the subgroup 2, control group (p<0,05 and pointed at hypercoagulation, whereas in the subgroup 2 all indicators were absolutely identical with control group. Correlation link between the level of INR levels and FEV1 (r=-0,73; p<0.01 in patients of the main group was determined. Levels of APTT, TT and AT

  18. Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden.

    Science.gov (United States)

    Eichinger, S; Weltermann, A; Philipp, K; Hafner, E; Kaider, A; Kittl, E M; Brenner, B; Mannhalter, C; Lechner, K; Kyrle, P A

    1999-10-01

    Normal pregnancy is associated with alterations of the hemostatic system towards a hypercoagulable state and an increased risk of venous thromboembolism. The risk of venous thrombosis is higher in pregnant women with factor V Leiden (FVL) than in those with wildtype factor V. Routine laboratory assays are not useful to detect hypercoagulable conditions. A prospective and systematic evaluation of hemostatic system activation in women with and without FVL during an uncomplicated pregnancy employing more sensitive markers of hypercoagulability, such as prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), D-Dimer, or the endogenous thrombin potential (ETP), an indicator of the plasma's potential to generate thrombin, has not been performed. We prospectively followed 113 pregnant women with (n = 11) and without (n = 102) FVL and measured F1+2. TAT, D-Dimer and the ETP at the 12th, 22nd and 34th gestational week as well as 3 months after delivery (baseline) in each subject. None of the women developed clinical signs of venous thromboembolism during pregnancy or postpartum. Pregnant women with and without FVL exhibited substantial activation of the coagulation and fibrinolytic system as indicated by a gradual increase of F1+2, TAT and D-Dimer throughout uncomplicated pregnancy up to levels similar to those found in acute thromboembolic events (p < 0.0001 by analysis of variance for each parameters). Levels of F1+2 and TAT were comparable between women with and without FVL, but levels of D-Dimer were significantly higher in women with FVL than in those without the mutation (p = 0.0005). The ETP remained unchanged in both women with and without FVL at all timepoints. Our data demonstrate a substantial coagulation and fibrinolytic system activation in healthy women with and without FVL during uncomplicated pregnancy. An elevated F1+2, TAT or D-Dimer level during pregnancy is not necessarily indicative for an acute thromboembolic event. The normal ETP in both

  19. Imbalance of pro- vs. anti-coagulation factors in Chinese patients with Budd-Chiari syndrome and non-cirrhotic portal vein thrombosis.

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    Hui Chen

    Full Text Available The coagulation abnormalities in non-cirrhotic Budd-Chiari syndrome (NC-BCS and non-cirrhotic portal vein thrombosis (NC-PVT are unclear. We conducted this case-control study to investigate the coagulation profile of NC-BCS and NC-PVT in Chinese patients.We measured the levels of factors II, V, VII, VIII, IX, X, XI, XII, protein C (PC, protein S (PS and antithrombin (AT in blood samples from 37 NC-BCS patients, 74 NC-PVT patients, and 100 healthy controls. The levels and ratios of pro- and anti-coagulation factors were compared between patients with NC-BCS and healthy controls, between different types of NC-BCS and between NC-PVT and healthy controls.In patients with NC-BCS, factor VIII (P<0.001 was significantly elevated; factor V (P<0.001, VII (P<0.001, IX (P = 0.003, X (P<0.001, XI (P<0.001, XII (P<0.001, PC (P<0.001 and AT (P<0.001 were significantly decreased; and no difference was observed for factor II (P = 0.088 and PS (P = 0.199 compared with healthy controls. Factor VIII-to-PC (P = 0.008, factor VIII-to-PS (P = 0.037 and factor VIII-to-AT (P = 0.001 were significantly increased; other ratios were significantly reduced or did not show any difference. No differences were observed between different types of NC-BCS for individual pro- and anti-coagulation factors or the ratios between them. Among patients with NC-PVT, factor VIII (P<0.001 was significantly elevated and other factors were significantly decreased. Factor II-to-PC (P<0.001, factor VIII-to-PC (P<0.001, factor IX-to-PC (P<0.001, factor VIII-to-PS (P<0.001, factor II-to-AT (P<0.001, factor VIII-to-AT (P<0.001 and factor IX-to-AT (P<0.001 were significantly increased; all other ratios for NC-PVT were significantly reduced or did not show any significant difference.NC-BCS and NC-PVT are associated with elevated levels of factor VIII and the decreased levels of PC and AT were probably the most significant features of coagulation imbalance. Additionally, NC-PVT was associated with

  20. Neonatal arterial iliac thrombosis in type-I protein C deficiency: a case report

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    Capretti Maria G

    2010-03-01

    Full Text Available Abstract A male infant born by caesarean section at 38 weeks of gestational age (B.W. 4055 g; Apgar 9-10, in the first two hours of life his right leg became hypovascularizated. Normal values of leukocities, red cells, haematocrit, hemoglobin, platelets. C-Reactive Protein negative. Electrolytes and coagulation tests were normal. Normal vitamin K coagulation proteins levels. Serological tests for TORCH (IgM and Parvovirus (IgG and IgM were negative. Sonography showed a reduced blood flow in the iliac artery and reported a 1 cm long vessel thrombosis. From 8 hours of life we administred an intravenous infusion of unfractionated heparin (UFH 75 UI/Kg for the first 10 minutes then 28 UI/Kg/h. On the 2nd day tests were performed to assess absence of inhibiting-clot factors. The dosage of homocysteine, protein S and antithrombin was normal. FV Leiden and antiphospholipid antibodies were negative. The mapping of G20210A prothrombin's gene resulted normal, whereas the concentration of Protein C was lower than normal: activity 46% (68-150%, antigen 35% (70-150%. The same deficiency was also found in the father. The mother showed normal concentrations. No episodies of thrombosis events were documentated in the family. The intravenous unfractionated heparin (UFH therapy was replaced after 64 hours by subcutaneous nadroparin 600 UI twice/day, which was stopped 5 days later when the vessel sonografic images were completely normal. During the hospitalization the infant didn't show bleeding. The child was followed-up yearly until 4 years of age: he was well and had a normal body and mental development. The final diagnosis is likely to be of a permanent protein C deficiency in heterozygous form. Our case is interesting because the first manifestation was an important thrombosis of large vessel that occurred within a few hours of life in absence of perinatal risk factors, as if it was a homozygous disease, but the patient had a heterozygotic form. In literature

  1. Estudo comparativo do emprego da aprotinina em baixas doses X placebo, durante a circulação extracorpórea Comparative study of low-dose aprotinin x placebo during cardiopulmonary bypass

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    José Carlos D. V. PONTES

    2002-03-01

    damaging effects on cardiopulmonary bypass in fibrinolytic system, which may improve hemostasis. OBJECTIVE: To study the effect of low dose aprotinin in patients undergoing extracorporeal circulation. METHOD: Seventeen patients, underwent cardiopulmonary bypass to mitral valve replacement, was ramdomized in two groups: I (control -- 9 patients received placebo after anesthesia induction and each hour in the priming; II (aprotinin -- 8 patients received after anesthesia induction 30,000 KIU/kg and 7.500 KIU/kg each hour in the priming during the perfusion. The blood loss was observed through the first 24 hours postoperatively. Arterial blood samples were taken after anesthesia induction and after administration of protamina in order to analyse: prothrombin activity (PA, partial thomboplastin time (PTT, thrombin time (TT, euglobulin lysis time (ELT and to measure levels of fibrinogen (F, d-dimer (dD and antithrombin III (ATIII. RESULTS: Mean postoperative bleeding at the 24th hours was 690.67±377 in the control group and 248,.75±105 in the aprotinin group (p=0.0017. The results taken from the blood samples were shown above. CONCLUSION: It follows that aprotinin, in low dose, was able to inhibit fibrinolysis and reduced bleeding after cardiopulmonary bypass.

  2. Prevalência dos fatores trombofílicos em mulheres com infertilidade Prevalence of thrombophilic factors in infertile women

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    Adriana de Góes e Silva Soligo

    2007-05-01

    disease were evaluated. Infertility is defined as one year of unprotected sexual intercourse without conception. The acquired and/or inherited thrombophilic factors investigated were: anticardiolipin antibody (aCL, lupus anticoagulant (LA, protein C deficiency (PCD, protein S deficiency (PSD, antithrombin III deficiency (ATD, presence of the factor V Leiden, mutation G20 210A in the prothrombin gene, and C677T mutation of methylene tetrahydrofolate reductase (MTHFR. RESULTS: the prevalence values obtained for aCL and LA were 2%. The prevalence of the hereditary thrombophilic factors were: PCD=4%, PSD=6%, ATD=5%, factor V Leiden=3%, prothrombin mutation=3%, MTHFR mutation=57%. Conclusions: of the 144 patients selected, 105 women (72.9% presented at least one thrombophilic factor. This reinforces the importance and justifies the need of investigation in this group.

  3. 儿童重症肺炎凝血指标与降钙素原变化及分析%The change of coagulation indicators and procalcitonin in children with severe pneumonia

    Institute of Scientific and Technical Information of China (English)

    黄彩芝; 莫丽亚; 李爱国; 杨娟; 邓永超

    2015-01-01

    Objective To explore the changes in the levels of coagulation indicators and procalcitonin (PCT) in children with severe pneumonia. Methods A total of 76 children with severe pneumonia were selected and were divided into two groups according to the level of PCT, PCT<2.00 ng/ml group and PCT≥2.00 ng/ml group. Thirty healthy children were selected as normal controls. The levels of PCT, platelet counts (PLT), antithrombin-Ⅲ(AT-Ⅲ) activity and D-dimer (DD) were measured and compared among groups. Results Compared with control group, PCT, PLT and DD levels were signiifcantly higher and AT- Ⅲactivity was signiifcantly lower in severe pneumonia group (P<0.05). AT- Ⅲactivity and PLT were signiifcantly lower and DD level was signiifcantly higher in PCT≥2.00 ng/ml group than those in PCT<2.00 ng/ml group (P<0.05). The incidence of disseminated intravascular coagulation (DIC) in PCT≥2.00ng/ml group was signiifcantly higher than that in PCT<2.00ng/ml group (33.33%vs. 9.09%, correctedχ2=5.02, P=0.025). Conclusions There is dysfunction of coagulation in children with severe pneumonia. The higher level of PCT is, more obvious coagulation dysfunction is. The severe pneumonia children with high level of PCT are more likely to be complicated with disseminated inravascular coagulation.%目的:探讨重症肺炎患儿凝血指标与降钙素原(PCT)的变化。方法选取重症肺炎患儿76例,根据PCT升高的程度分为2组,PCT<2.00 ng/ml组和PCT≥2.00 ng/ml组;另选择30例健康儿童作为正常对照组。检测并分析比较各组的PCT、血小板计数(PLT)、抗凝血酶Ⅲ(AT-Ⅲ)活性和D-二聚体(DD)水平。结果与对照组比较,重症肺炎组PCT、PLT、DD水平明显升高,AT-Ⅲ活性明显降低,差异均有统计学意义(P<0.05);PCT≥2.00 ng/ml组的AT-Ⅲ活性和PLT水平相比PCT<2.00 ng/ml组更低,而DD水平更高,差异均有统计学意义(P<0.05);PCT≥2.00 ng/ml组的DIC发生率(33.33%)高于PCT<2.00 ng

  4. Effects of Danshensu on maternal syndrome in phosphatidyleserine/ phosphatidylcholine micro vesicle induced-mouse model: is it a candidate for preeclampsia remedy?

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    SHEN Yang; HU Ya-li; ZHANG Yan; WANG Jing-mei

    2010-01-01

    Backgroud Up to date, there is few satisfactory pharmacotherapy, except for aspirin and heparin, to stop the preeclampsia progression. Although the mechanism of preeclampsia is poorly understood, it has been proven to be associated with coagulation activation. Researches on prophylactic and therapeutic application of anticoagulants may benefit the clinical aspects of preeclampsia individuals. This study aimed to evaluate the effects of Danshensu on maternal syndrome in phosphatidylserine/phosphatidylcholine (PS/PC) microvesicle induced-mouse model. Methods Sixty-six preeclampsia-like pregnant mice, induced by PS/PC microvesicle administration, were randomly divided into six groups. From days 5.5 to 16.5 of pregnancy, each group was respectively treated as follows: a) mice in group C (n=12, control group) were injected with 100 μl of filtered phosphate-buffered saline into the tail vein every day; b) group PE (n=15, preeclampsia model group) were injected in the same way with 100 μl of filtered PS/PC vesicle suspension; c) group H (n=9, group treated with heparin) were injected with 1 unit heparin together with PS/PC vesicle suspension; d) group A (n=10, group treated with aspirin) were injected with 20 μg/g aspirin-DL lysine as well; e) group LD (n=10, group treated with low-dose Danshensu) were injected with 10 μg/g Danshensu; and f) group HD (n=10, group treated with high-dose Danshensu) were injected with 30 μg/g Danshensu. Systolic blood pressure, total urinary protein levels, blood tests for some hemostatic function parameters (mean platelet counts, plasma antithrombin III activity (AT-Ⅲ), D-D dimmer levels, and thrombin time), fibrin deposition by phosphotungstic acid hematoxylin staining, and thrombomodulin expression by immunohistochemistry staining in placentas were examined as indices for maternal syndrome. Results Heparin showed significant effects on maternal syndrome of preeclampsia such as hypertension and proteinuria, and different doses of

  5. Registro de síndrome coronariana aguda em um centro de emergências em cardiologia Acute coronary syndrome registry at a cardiology emergency center

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    Elizabete Silva dos Santos

    2006-11-01

    % with unstable angina (UA, two (0.2% with atypical manifestations of ACS and 26 (3% with non-cardiac chest pain. During hospitalization, 87.9% of patients were given a beta-blocker, 95.9% acetylsalicylic acid, 89.9% anti-thrombin therapy, 86.2% intravenous nitroglycerin, 6.4% glycoprotein (GP IIb/IIIa receptor inhibitor, 35.9% clopidogrel, 77.9% angiotensin-converting enzyme inhibitor, and 70,9% statin drugs. Coronary arteriography was performed in 72 patients (92.3% with STEMI, and in 452 (59.8% with non-STEMI ACS (p< 0.0001. Myocardial revascularization (MR surgery was indicated for 12.9% and percutaneous coronary intervention for 26.6%. In-hospital mortality was 4.8%, and no difference was recorded between the proportion of deaths among patients with STEMI and non-STEMI ACS (6.4% versus 4.8%; p = 0.578. CONCLUSION: In this registry, we provide a description of ACS patient, which allows the evaluation of the demographic characteristics, medical treatment prescribed, and in-hospital mortality. A greater awareness of our reality may help the medical community to adhere more strictly to the procedures set by guidelines.

  6. 彩超诊断小腿肌间静脉血栓对骨科手术诊疗的应用价值%The application value of color Doppler ultrasonography in diagnosis of venous plexus thrombosis of calf muscle for orthopedic operation treatment

    Institute of Scientific and Technical Information of China (English)

    张宇明; 张文云; 邓荷萍; 房勤茂; 甄景琴; 封彦凤

    2012-01-01

    thrombosis before surgery. Hypertension and hyperlipidemia were detected in 32 patients( 59. 3% ) whose age was over 50 years. After anticoagulation and thrombolytic therapy, CDFI characters were changed gradually from no blood flow to part of the blood flow visible in lumina or fluent blood flow. As respect of biochemical indicators, plasma antithrombin Ⅲ activity and prothrombin time index were increased, however, D-dimer, fibrinogen and thrombin activity index were decreased gradually. No pulmonary embolism was observed during orthopedic surgery after anticoagulation and thrombolytic treatment for 2 weeks. Conclusion Color Doppler ultrasonography is an useful method to diagnose calf muscle vein thrombosis, so as to prevent deep vein thrombosis effectively, which is valuable for diagnosis and treatment of surgical patients in clinic in order to minimize the incidence of pulmonary embolism.

  7. Circulating platelet and erythrocyte microparticles in young children and adolescents with sickle cell disease: Relation to cardiovascular complications.

    Science.gov (United States)

    Tantawy, Azza Abdel Gawad; Adly, Amira Abdel Moneam; Ismail, Eman Abdel Rahman; Habeeb, Nevin Mamdouh; Farouk, Amal

    2013-01-01

    Sickle cell disease (SCD) is characterized by a complex vasculopathy, consisting of endothelial dysfunction and increased arterial stiffness, with a global effect on cardiovascular function. The hypercoagulable state may result from chronic hemolysis and circulating cell-derived microparticles (MPs) originating mainly from activated platelets and erythrocytes. We measured the levels of platelet and erythrocyte-derived MPs (PMPs and ErMPs) in 50 young SCD patients compared with 40 age- and sex-matched healthy controls and assessed their relation to clinicopathological characteristics and aortic elastic properties. Patients were studied stressing on the occurrence of sickling crisis, transfusion history, hydroxyurea therapy, hematological, and coagulation profile as well as flow cytometric expression of PMPs (CD41b(+)) and ErMPs (glycophorin A(+)). Echocardiography was performed to assess aortic stiffness and distensibility, left ventricular function and pulmonary artery pressure. Both PMPs and ErMPs were significantly elevated in SCD patients compared with control group (p < 0.001). SCD patients had significantly elevated d-dimer and von Willebrand factor antigen (vWF Ag) levels with lower antithrombin III compared with controls (p < 0.001). Aortic stiffness index and pulmonary artery pressure were significantly higher in SCD (p < 0.001), whereas aortic strain and aortic distensibility were significantly lower (p < 0.001) compared with controls. MPs levels were significantly increased in SCD patients with pulmonary hypertension, acute chest syndrome, and stroke as well as those who had history of thrombosis or splenectomy (p < 0.001). Also, patients in sickling crisis during the study had higher PMPs and ErMPs levels than those in steady state (p < 0.001). Patients on hydroxyurea therapy had lower MPs levels than untreated patients (p < 0.001). PMPs and ErMPs were positively correlated with disease duration, transfusion index, white blood

  8. The specificity of interactions between proteins and sulfated polysaccharides

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    Barbara Mulloy

    2005-12-01

    Full Text Available Sulfated polysaccharides are capable of binding with proteins at several levels of specificity. As highly acidic macromolecules, they can bind non-specifically to any basic patch on a protein surface at low ionic strength, and such interactions are not likely to be physiologically significant. On the other hand, several systems have been identified in which very specific substructures of sulfated polysaccharides confer high affinity for particular proteins; the best-known example of this is the pentasaccharide in heparin with high affinity for antithrombin, but other examples may be taken from the study of marine invertebrates: the importance of the fine structure of dermatan sulfate (DS to its interaction with heparin cofactor II (HCII, and the involvement of sea urchin egg-jelly fucans in species specific fertilization. A third, intermediate, kind of specific interaction is described for the cell-surface glycosaminoglycan heparan sulfate (HS, in which patterns of sulfate substitution can show differential affinities for cytokines, growth factors, and morphogens at cell surfaces and in the intracellular matrix. This complex interplay of proteins and glycans is capable of influencing the diffusion of such proteins through tissue, as well as modulating cellular responses to them.Os polissacarídeos sulfatados são capazes de se ligar às proteínas com diferentes níveis de especificidade. São macromoléculas altamente ácidas que podem se ligar de forma inespecífica a qualquer domínio básico da superfície de uma proteína em soluções com baixa força iônica, contudo tais interações não parecem ser fisiologicamente significativas. Por outro lado, foram identificados vários sistemas nos quais componentes estruturais muito específicos dos polissacarídeos sulfatados conferem alta afinidade para algumas proteínas. O exemplo mais conhecido é o pentassacarídeo da heparina com alta afinidade pela antitrombina. Outros exemplos podem ser

  9. Cosmonauts' haemostasis system status before and after space flights

    Science.gov (United States)

    Kuzichkin, Dmitry; Markin, Andrey; Morukov, Boris

    Introduction. It is known that cosmonauts expose themselves to psychophysical effort in different phases of space flights as well as in pre- and post-flight period. Stress affects different body systems functioning changes including haemostasis system. It is shown that adrenalin directly activates XII coagulation cascade factor [McKay D. G., Latour I. G., Parrish M. N.,1970], initiating intrinsic clotting pathway and affects fibrinogen concentration increase in plasma [Zubairov D. M., 1978]. A post-flight increase in the fibrinogen concentration was revealed with its drop up to the pre-flight level within rehabilitation period [T. Peter Stein, Margaret D., 2006]. Stress agents influence on haemostasis system is physiologically determined and directed to body preparation before probable blood loss. One can consider this process as a function of intrinsic clotting pathway. But in case of blood loss absence the preliminary permanent coagulation activation can lead to appearance of thrombosis risk. Purpose. The purpose was to study haemostasis system main components functional activity features before and after space flights. Methods. In the citrated plasma of astronauts who performed short-term (10 to 11 days) or long-term (196 to 199 days) the following values were determined: activated partial thrombin time (APTT); prothrombin time; prothrombin index; international normalized ratio; thrombin time (TT); activity of enzymes influencing the function of proteins involved in the formation and lysis of a clot such as antithrombin III, protein C, plasminogen, antiplasmin; content of fibrinogen, as well as intermediate products of formation and degradation of fibrin such as D-dimer, soluble fibrin-monomer complexes (SFMC). Sampling of biomaterial was perfomed 30 to 45 days prior to the flight, during the 1st day of the post flight period (all the examined persons), and in the 7th and 14th day (long-term flights member only) Results. In pre-flight period cosmonauts’ APTT

  10. Interaction of peptide-bound beads with lipopolysaccharide and lipoproteins.

    Science.gov (United States)

    Suzuki, Masatsugu M; Matsumoto, Megumi; Omi, Hiroyuki; Kobayashi, Tomomi; Nakamura, Akio; Kishi, Hiroko; Kobayashi, Sei; Takagi, Takashi

    2014-05-01

    We previously reported the generation of lipopolysaccharide (LPS)-binding peptides by phage display and chemical modification. Among them, a dodecapeptide designated Li5-025 (K'YSSSISSIRAC'; K' and C' denote d-lysine and d-cysteine, respectively) showed a high binding affinity for LPS and was resistant to protease digestion (Suzuki et al., 2010). In the current study, Li5-025-bound silica beads, hereafter referred to as P-beads, were generated and found to be devoid of LPS-neutralizing activity. Thus, LPS bound to the P-beads could be directly used in the Limulus amebocyte lysate (LAL) assay. P-beads bound LPS dissolved in solutions of ethanol, pH4, pH10, and 0.5M NaCl and LPS bound to the P-beads was quantitatively assayed. The sensitivity of this assay was observed to be approximately 0.1pg/mL LPS. P-beads bound LPS dissolved in antithrombin III (AT III) solution which is a strong inhibitor of activated factors C and B as well as the clotting enzyme in the LAL assay; the inhibitory effect of AT III was completely reversed upon washing the P-beads with 25% acetonitrile. This was employed as the first step for the detection of free LPS in plasma using the LAL assay. LPS added to human plasma at 0°C followed by application to the P-beads and subsequent washing with 25% acetonitrile resulted in low LPS activity as detected by the LAL assay. However, further washing of the P-beads with 0.1% Triton X100 in 25% acetonitrile resulted in high LPS activity. This is the first instance of quantitative detection of free LPS in plasma using the LAL assay, and the sensitivity of this method was observed to be 1pg/mL of LPS. The proteins eluted in the 0.1% Triton X-100 wash were analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis. Two protein bands of 28kDa and 18kDa were predominantly observed. Mass spectrometry analysis revealed that the 28kDa and 18kDa bands corresponded to apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II), respectively. Apo

  11. Blood products and its applications for the treatment of military trauma and diseases%血液制品及其在伤病救治中的应用

    Institute of Scientific and Technical Information of China (English)

    章金刚

    2015-01-01

    The first blood product albumin was developed during World War Ⅱ.Since then, blood products began to play an irreplaceable role in military trauma and emergency cares .Currently, the supporting system of blood and blood products has become increasingly sophisticated .Development of novel blood products also improved dramatically .Universal virus inactivated freeze-dried plasma has also been purchased by the military .Albumin is used as antishock blood volume expansion for emergency treatment of military trauma .Different kinds of albumin including albumin of various concentra-tions, high purity albumin and albumin in soft packages are available .Specific immunoglobulin has become the regular stra-tegic storage of some developed countries , used for the prevention and treatment of infection in military trauma , emerging infectious diseases and against the potential threat of bioagents and bioterrorism .Local hemostatic produced upon fibrinogen and thrombin as well as coagulator Factor Ⅶperforming integral hemostasis effect have become increasingly significant for treating hemorrhage in military trauma .Development of anticoagulants including human protein C and antithrombin has got great improvement .These medicines have the potential for preventing and treating sepsis caused by military trauma .Prote-ase inhibitors including α2-macroglobulin are expected to work in the specific medicine .In conclusion , blood products will play a greater role in the future war and non war military operations .%自第二次世界大战期间第一个血液制品,即人血白蛋白问世以来,血液制品在战创伤救治与急救医学中发挥了不可替代的作用。目前,血液和血液制品的保障体系日益完善,新型血液制品的研发也取得巨大进展。病毒灭活通用型冻干血浆已有军方采购;白蛋白作为战创伤急救用理想的抗休克血容量扩张剂,出现了不同浓度、高纯及软包装产品;特异性免疫球

  12. An unusual cause of acute abdominal pain – A case presentation

    Directory of Open Access Journals (Sweden)

    Hunt Trevor M

    2006-04-01

    Full Text Available Abstract Background In 1983, Graham Hughes described a condition of Antiphospholipid Syndrome in which there was a danger of thrombosis. The condition is readily detectable by blood tests and, once diagnosed; the risk of further thrombosis can be significantly reduced by anticoagulation treatments. Affected groups of patients can be distinguished by a specific blood test – the detection of antiphospholipid antibody (Ref-1. Patients with Hughes syndrome have hypercoaguable state with a markedly increased risk of both arterial and venous thrombosis and there is temporal persistence of antibody positivity. Case presentation A 44-year-old woman was admitted under the acute surgical "take" with left sided abdominal pain radiating to her back. She had a history of borderline thyrotoxicosis in the early 1990s. She was on etonogestrel-releasing implants for contraception and there was no history of previous deep venous thrombosis. She was very tender, locally, over the left side of the abdomen. Investigations showed haemoglobin of 13.2 g/dl, white cell count of 19.9 10*9/L, and platelets 214 10*9/L with neutrophilia. Amylase and renal function tests were found to be normal. Liver function tests were deranged with Gamma GT 244 u/l (twice normal. An abdominal Ultrasound Scan suggested a possible splenic infarction, which was confirmed by a CT scan of her abdomen. Tests were carried out to investigate the possibility of a post thrombotic state. Coagulation risk factors for thrombosis were within the normal limits; Protein S 67 %(60–140, Protein C 103 % (72–146, Antithrombin 3 110 %(80–120 and Activated P C Resistance was 1.9(2.0–4.3. The Hams test was negative but the Anticardiolipin antibody test was positive. IgM level was 52 (normal is up to 10 and IgG was 18.8 (normal is up to 10. She also had border line APC Sensitivity 1.9 (2 to 4.3. Kaolin time 49 sec (70–120 Ktmix 64 sec (70–120, thyroid function test revealed TSH 0.32 mu/L, fT4 20

  13. The parameters of coagulation in craniocerebral trauma%凝血参数在颅脑外伤中的应用

    Institute of Scientific and Technical Information of China (English)

    魏云; 陈勇; 张泉

    2012-01-01

    Objective: This study aimed at analyzing the relationship of coagulation parameters with GCS ( Glasgow Coma Scale) and ISS( Injury Severity Score) in patients with exposure compound trauma. Methods: 60 patients (9 women, 51 men) with multiple traumas were included in this study. The GCS, ISS and coagulation parameter levels were measured. Presence of a correlation between GCS and ISS with coagulation parameters was analyzed. Patients exposed to multiple traumas were assessed in four categories as the patients with no significant traumas ( A) , only head traumas (B) , head trauma and other local traumas (C) , and no head traumas but other local traumas (D). Results: A marked relationship was found between ISS and international normalized ratio (INR) , activated partial thromboplastin time ( aPTT) , D - dimer, fibrin degradation product (FDP) , antithrombin (AT) ,and fibrino-gen (P <0. 05) . There was a statistically significant difference between Group C and the other groups in INR, D -dimer,fibrinogen, APTT, and AT parameters (P<0. 05). There was also a statistically significant difference between the groups with and without head trauma in INR, D - dimer and fibrinogen ( P <0.05 ) . Conclusion: The coagulation parameters were observed to diverge in patients with head trauma, but in cases with head injuries accompanying other local traumas, more coagulation parameters became abnormal. There is a necessity for prospective studies on the course of treatment and how the results are affected in patients with coagulation disorder in early stage.%目的:探讨暴露性复合外伤病人凝血功能检查中的各参数与GCS和ISS评分间的关系.方法:收集60例复合外伤病人(男:51例;女:9例)临床资料,按软组织外伤,颅脑外伤,颅脑外伤合并其他复合外伤以及复合外伤分组,分别测定病患PLT,APTT,INR,AT,PAI-1,FDP,DD,FIB水平分析不同组间差异.结果:ISS与INR,APTT,DD,FDP,AT,FIB之间差别具有统计学意义(P<0

  14. 2型糖尿病患者凝血状态研究%The study of blood coagulation status in type 2 diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    穆志静; 王立

    2013-01-01

    目的 探讨2型糖尿病患者合并血管病变对凝血状态的影响.方法 纳入2型糖尿病住院患者311例,依据有无大血管并发症分为3组,即单纯糖尿病组130例,糖尿病合并高血压组151例,糖尿病合并冠心病组30例,同时选择我院同期健康体检者30例作为健康对照组.检测抗凝血酶-III(AT-III)、蛋白C(PC)、蛋白S(PS)、活化部分凝血活酶时间(APTT)、血浆凝血酶原时间(PT)、血浆纤维蛋白原(Fib)、血浆凝血酶时间(TT))水平评价凝血功能.结果 与健康对照组相比较,糖尿病组AT-III、PC、PS活性明显降低,凝血四项中APTT、PT降低、Fib升高,2组比较差异有统计学意义(P<0.05).糖尿病合并冠心病组与单纯糖尿病组相比,PC、PS差异有统计学意义(P<0.05).糖尿病合并冠心病组Fib及PLT升高较单纯糖尿病组更为明显,差异有统计学意义(P<0.05).结论 糖尿病患者抗凝血功能紊乱,处于血栓前状态,合并心血管并发症患者尤为明显.AT-III、PC、PS及凝血四项的测定可能有利于糖尿病患者凝血状态的评估,有利于血管并发症的早期干预.%Objective To explore the changes and clinical significance in coagulation anti-coagulation and fibrinolysis system in patients with type 2 diabetes mellitus ( DM ). Methods To measure thrombin time ( TT ), activated partial thrombo-plastin time ( APTT ), prothrombin time ( PT ), and fibrinogen ( Fib ), anti-thrombin Ⅲ ( AT-Ⅲ ), protein C ( PC ), protein S ( PS ) in 311 patients with type 2 diabetes mellitus from 2010 to 2011. These patients were categorized as single DM group, DM with hypertension group, DM with coronary heart disease group. At the same time, 30 health)' people were selected as contrast group. SPSS software was used for statistic analysis. Results The activity of AT-Ⅲ,PC,PS of type 2 diabetes melli-tus were progressively lower than those of control group. There was a significant difference between single DM

  15. Revisão sobre alterações hemostáticas na doença hipertensiva específica da gravidez (DHEG Hemostatic changes revision in preeclampsia

    Directory of Open Access Journals (Sweden)

    Luci Maria Sant'Ana Dusse

    2001-01-01

    determinação de marcadores de tromboembolismo, como um parâmetro para o planejamento de futuras gestações, uma vez que a recorrência da DHEG é da ordem de 20%.Preeclampsia (PE characterises by development of hypertension, proteinuria and swelling in pregnant women around 20th pregnancy week. The hemodynamic changes observed in the normal pregnancy comprising renal and cardiovascular adaptations that did not occur in PE. The most important feature of this disease is a pronounced arteriolar vasoconstriction leading to a increase of the peripheral vascular resistance responsable to high blood pressure. Evidences of platelet consumption and endothelial cell disfunction have been observed in PE. Conflicting opinions related to the fibrinolytic system have been raised on the literature including increase, decrease or even no changes in this system preeclamptic compared to normal pregnant women. Efforts have been carried out in order to define hemostatic parameters with diagnostic and prognostic value, considering that PE diagnosis is essentially based on clinical data and often hard to be established. In this way, platelet count, thrombomodulin, thrombin-antithrombin complex and plasminogen activator inhibitor type 2 measurement were performed as helpful parameters for PE diagnosis. However, it remains to be established the usefulness of all these laboratory markers. Recently, it was suggested an association between the occurence of pregnancy complication, including PE, and the presence of genetic mutations which favors the development of thromboembolic events. It has been proposed a hemostatic the assessment in preeclamptic women, even if there was no previous thromboembolic episody, by using thrombotic markers as an useful parameter for planning future pregnancies, once PE recurrence is about 20%.

  16. Novos anticoagulantes para a profilaxia do tromboembolismo venoso em cirurgias ortopédicas de grande porte New anticoagulants for the prophylaxis of venous thromboembolism

    Directory of Open Access Journals (Sweden)

    Ricardo de Alvarenga Yoshida

    2011-06-01

    novos inibidores diretos do fator Xa e inibidores do fator IIa.After about 50 years of experience with heparin and vitamin K antagonists (VKA, research and clinical studies of new anticoagulants have recently evolved . Although traditional anticoagulants have proven to be clinically useful, they have important limitations in terms of laboratory control, complications, side effects and interactions with medications and food. .Unfractionated heparin interacts with plasma proteins and the vascular wall, may trigger thrombocytopenia, can only be administered parenterally, requires control by the laboratory test of partial thromboplastin time, may cause osteoporosis and alopecia when used for long periods and it is produced from biological sources. VKA have the advantage of being administered orally, but the control (made by the international normalized ratio can be difficult in some cases, since they have delayed onset of action and metabolism and a narrow therapeutic window. They also interact with foods and with a large number of medications, can cause skin necrosis in patients with antithrombin and protein C and S deficiencies and may induce fetal changes when prescribed in pregnancy. In the 1980´s the low-molecular-weight heparins were developed and proved to be an evolution over unfractionated heparin, because of their greater bio-availability, fixed dose per body weight, no need for laboratory control, subcutaneous administration, lower risk of heparin-induced thrombocytopenia, and efficacy and safety similar to unfractionated heparin. Over the last decade, a series of new anticoagulants have appeared in the market and shown promising results in several situations of venous thromboembolism prophylaxis and treatment. In the present review, the new low-molecular-weight heparins, ultra-low molecular weight heparin, pentasaccharides and the new direct inhibitors of factor Xa and factor IIa.are addressed.

  17. Effect of UC-MSCs on inflammation and thrombosis of the rats with collagen type Ⅱ induced arthritis%脐带间充质干细胞移植对胶原诱导型关节炎大鼠免疫相关易栓状态的干预作用

    Institute of Scientific and Technical Information of China (English)

    林传明; 顾健; 张育; 沈连军; 马莉; 倪军; 汪中强; 吴蔚

    2012-01-01

    -α) in serum and D-dimer ( D-D),antithrombin- Ⅲ ( AT- Ⅲ ),thrombomodulin (TM) in plasma were detected by ELISA.Results Obvious swellings of the feet were found in the experiment group compared with normal one.ELISA analysis showed that the concentrations of IL-6,TNF-α,D-D and TM in plasma of the experiment group as of ( 200.48 ± 15.04 ) ng/L,(450.25 ± 45.39 ) ng/L,(274.26 ±67.93) ng/L and (9.18 ±0.84) μg/L,respectively were higher than of( 167.62 ±0.97) ng/L,(371.44 ± 21.26) ng/L,( 193.95 ± 8.22 ) ng/L and ( 6.30 ± 0.32) μg/L respectively in normal group ( P < 0.05 ),but the concentration of AT- Ⅲ [( 89.57 ± 6.40 ) ng/L]was lower than normal group [( 112.82 ± 1.74) ng/L](P <0.05).The levels of cytokines through the UC-MSCs treatment were significantly different from the model group (P < 0.05 ).After 9 weeks,these cytokines in the UC-MSCs group were mostly the same as the normal group.Conclusion The thrombophilia status of the CIA rats was caused by immune injury.The UC-MSCs reduced the production of inflammatory cytokines and regulated and repaired the balance of coagulation and anticoagulation systerm of the body to cure the immune-related thrombophilia.

  18. 纤维蛋白原γ链Arg275His突变所致异常纤维蛋白原的功能研究%Functional study of abnormal fibrinogen caused by Arg275His mutation in fibrinogen γchain

    Institute of Scientific and Technical Information of China (English)

    周景艺; 王学锋; 丁秋兰; 许冠群; 张利伟; 戴菁; 陆晔玲; 奚晓东; 王鸿利

    2013-01-01

    目的 对两个遗传性异常纤维蛋白原血症家系的突变纤维蛋白原(Fg)进行功能研究.方法 常规筛查凝血功能;Fg抗原和活性分别用免疫比浊法和Clauss法测定;抽提DNA,对Fg 3个基因(FGA、FGB和FGG)以及抗凝血酶基因(AT3)所有外显子及侧翼序列进行PCR扩增、测序及分析;采用常规血栓弹力图(TEG)和功能性FgTEG检查对家系B先证者及其父亲进行凝血功能的综合评价及血浆功能性Fg评估;应用Western blot检测血浆Fg肽链分子量;采用Fg动态聚集曲线和纤维蛋白溶解曲线实验检测血浆Fg的功能.结果 2例先证者凝血酶原时间(TT)和爬虫酶凝固时间(RT)明显延长,Fg活性仅为0.5 g/L和0.6 g/L,但其抗原均正常,分别为2.32 g/L和2.66 g/L.两个家系先证者均存在γ链Arg275His杂合突变,家系B先证者的祖父和姑母同时检出AT3 g.5876T>C(Ser116Pro)杂合突变.家系B先证者及其父亲TEG检测结果中α值分别接近和低于正常参考值范围下限,但最大波幅(MA值)均为正常;在功能性Fg TEG检测中,MA值明显偏低.Fg动态聚集曲线中先证者和家系患者的起跳时间明显延长、峰值明显降低.纤维蛋白溶解曲线中多数患者的纤维蛋白在特定时间内不能被纤溶酶原完全溶解.结论 首次发现遗传性异常纤维蛋白原血症合并AT缺陷的患者.γ链Arg275 His突变使Fg在纤维蛋白单体聚合以及纤维蛋白溶解方面出现异常.联合应用常规TEG和功能性TEG检测,可以更好地评估异常纤维蛋白原血症患者Fg的功能.%Objective To investigate the function of abnormal fibrinogen in two inherited dysfibrinogenemia pedigrees.Methods Routine coagulation tests were conducted in the probands and related family members.The antigen and activity levels of fibrinogen were detected by immunoturbidimetry assay and clauss assay,respectively.All the exons and exon-intron boundaries of the three fibrinogen genes and antithrombin gene (AT3

  19. Compound heterozygous mutations of a family with inherited hypofibrinogenemia%遗传性低纤维蛋白原血症家系复合杂合基因缺陷的研究

    Institute of Scientific and Technical Information of China (English)

    姜林林; 王鸿利; 王学锋; 丁秋兰; 欧阳琦; 许冠群; 张利伟; 戴菁; 陆晔玲; 奚晓东

    2012-01-01

    .Activated partial thromboplastin time ( APTT),prothrombin time ( PT),thrombin time ( TT),reptilase time ( RT),the activities of antithrombin( AT∶ A ),protein C ( PC ∶ A ) and protein S ( PS ∶ A ) were tested.The activity and antigen of plasma fibrinogen were analyzed by Clauss method and immunoturbidimetry method,respectively.The fibrinogen peptide chain of the proband was semiquantitatively assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis(SDS-PAGE).Thrombin generation test was performed by calibrated automated thromhogram.The dynamic process of blood coagulation was evaluated by the thrombelastography (TEG).Genomic DNA was extracted from the peripheral blood.The sequences of all the exons and exon-intron boundaries of the three fibrinogen genes FGA,FGB and FGG were amplified by polymerase chain reaction ( PCR ) and analyzed by direct sequen(c)ing.Results The activity and the antigen levels of the proband' s plasma fibrinogen were reduced to 0.48 g/L and 0.68 g/L,respectively.TT prolonged to 29.2 s and RT prolonged to 75.8 s.The assays of SDS-PAGE showed no abnormal molecular weight of fibrinogen.Peak height of thrombin generation was reduced to 249.93 nmol/L and endogenous thrombin potential was reduced to 1007.0 nmol · L-1 · min.Hypocoagulability state of the whole blood was found by TEG test.The coagulation index was - 8.6.The proband was diagnosed as inherited hypofibrinogenemia by phenotype analysis.Two mutations (Gln143Pro and g.4642delC) were found in the proband's fibrinogen Aa-chain gene,Gln143Pro came from her mother and g.4642delC came form her father.Conclusion Compound Heterozygous Mutations (Gln143Pro and g.4642delC ) of fibrinogen Aa-chain causes the proband congenital hypofibrinogenemia.

  20. Changes in Coagulation Indexes of Patients with Advanced Non-Small Cell Lung Cancer before and after Chemotherapy%晚期非小细胞肺癌患者化疗前后凝血指标的变化

    Institute of Scientific and Technical Information of China (English)

    崔元生; 杨莺; 阮巧玲

    2014-01-01

    Objective To investigate the changes in coagulation indexes before and after chem-otherapy and their clinical significance in patients with advanced non-small cell lung cancer (NSCLC).Methods Prothrombin time(PT),activated partial thromboplastin time(APTT),fi-brinogen(Fib),D-dimer(D-D),platelet(PLT),antithrombin Ⅲ(AT-Ⅲ)and other coagulation in-dexes were measured before and after chemotherapy in 48 patients with advanced NSCLC(NSCLC group)and 25 healthy subjects(control group).In addition,patients with advanced NSCLC were further divided into two groups:effective group(complete remission+partial remission)and inef-fective group(stable disease+progressive disease).Results Compared with control group,levels of Fib,D-D and PLT increased and levels of AT-Ⅲ decreased in NSCLC group before chemothera-py(P0.05).Moreover,there were no significant differences in all indexes be-tween effective group and ineffective group before chemotherapy(P>0.05).In effective group, levels of Fib,D-D and PLT decreased and levels of AT-Ⅲ increased after chemotherapy (P0.05).In in-effective group,all indexes were not changed after chemotherapy(P>0.05).Conclusion Changes in coagulation indexes are valuable for the diagnosis of advanced NSCLC.Patients with advanced NSCLC have abnormal coagulation function,which can be improved by effective chemotherapy. Therefore,changes in coagulation indexes can be used as the reference for the evaluation of chem-otherapy efficacy and prognosis in patients with advanced NSCLC.%目的:探讨晚期非小细胞肺癌(NSCLC)患者化疗前后凝血指标的改变及其临床意义。方法选取48例晚期 NSCLC患者(肺癌组,按治疗效果再将完全缓解+部分缓解的患者归为有效组;稳定+进展归为无效组),选取同期健康体检者作为对照组(n=25)。测量对照组及肺癌组化疗前后的血浆凝血酶原时间(PT)、部分凝血活酶时间(APTT)、纤维蛋白原(Fib)、D-二聚体

  1. Changing characteristics of commonly used indicators in different liver diseases and the Correlation with clotting mecha-nism%肝病常用指标在不同肝病中的变化特点及与凝血机制相关性分析

    Institute of Scientific and Technical Information of China (English)

    陈静; 段钟平; 童新元; 丛玉隆

    2014-01-01

    Objective To study the changing characteristics of coagulation factors and fibrinogen degradation products in different liver disease,liver disease,blood clotting and bleeding balance between relations,to explore the balance between coagulation and bleeding of hepatic diseases.Methods Coagulation factor Ⅱ,Ⅴ,Ⅶ,Ⅷ,Ⅸ,Ⅹ,Ⅺ,Ⅻ activity was detected by one-stages clotting method.Coagulogram such as APTT,TT,PT and Fig were measured by solidification method.Antithrombin Ⅲ (AT-Ⅲ),protein C (PC)activity were measured by chromogen-ic substrate assay.FDP concentration was detected using immunoturbidimetry.Results Except for FⅧ,coagulation factors and anticoagulant proteins synthesized by the liver decreased,coagulogram extended,FDP and D-D concen-tration increased in blood.Conclusion With the progression of liver diseases,the procoagulation and anti-coagulation elements synthesized by liver were parallelly reduced.Fibrinolysis activity was enhanced,which led to the imbalance between blood clotting and anti-clotting .This might be an important cause for bleeding in the end-stage of liver dis-ease patients.%目的:研究由肝脏合成的促抗凝因子、纤维蛋白原降解产物等成分在不同肝病中的变化特点,探讨肝脏疾病凝血与出血之间的平衡关系。方法(1)凝血因子活性检测(F:C):包括 FⅡ:C、FⅤ:C、FⅦ:C、FⅧ:C、FⅨ:C、FⅩ:C、FⅪ:C、FⅫ:C 均采用一期凝固法,试剂来自德国 Simens 公司,所用仪器为美国 ACL advance;(2)活化部分凝血酶时间(APTT)、凝血酶时间(TT)、凝血酶原时间(PT)、纤维蛋白原(Fig)测定采用凝固法,仪器为美国Backman 公司 ALT TOP,试剂与仪器配套;(3)蛋白 C(PC)、抗凝血酶Ⅲ(AT-Ⅲ)活性测定采用发色底物法,仪器均为法国 stago 公司的 sta-R,试剂与仪器配套;(4)纤维蛋白原降解产物(FDP)含量检测采用免疫比浊法

  2. 达比加群酯在非瓣膜性心房颤动抗凝治疗中抗凝监测指标的研究%Anticoagulation index of dabigatran etexilate anticoagulation therapy for patients with non-valvular atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    张玉静; 李学文

    2016-01-01

    recorded and coagulation indexes [ prothrombin time ( PT ) , activated partial thromboplastin time ( APTT ) , thrombin time ( TT ) , international nomalized ratio (INR),prothrombin activity(PTA),fibrous protein(FIB),antithrombin Ⅲ(AT3)activity,D-dimer]were measuredbeforetakingdabigatranetexilateandafter1,4weeksand3months.Results ①Therewereno significant changes in INR,FIB,PTA,AT3 activity and D-dimer between pre and post treatment(P>0.05).②Before and after treatment 1 weeks[PT(10.9±0.7) s vs.(11.3±0.6) s,P=0.030;APTT(31.1±2.5) s vs.(39.3±3.0) s,P=0.024;TT(13.7±0.7) s vs.(134.6±8.2) s,P=0.001],4 weeks[PT(10.9±0.7) s vs.(11.6±0.6) s,P=0.023;APTT(31.1±2.5) s vs.(44.9±4.5) s,P=0.002;TT(13.7±0.7) s vs. (152.3±9.1) s,P=0.001],3 months[PT(10.9±0.7) s vs.(12.3±0.6) s,P=0.012;APTT(31.1±2.5) s vs.(52.4±5.0) s,P=0.001;TT(13.7±0.7) s vs.(161.9±7.8) s,P=0.001],the differences were statisti-cally significant .③No events of the embolism or big bleeding occurred in the patients after taking the drugs ,and there were slight bleeding in 5 cases with significantly extended PT ,APTT,TT,and more than 2 times of APTT compared with the normal reference value .④PT,APTT,TT growth rate showed that the area of APTT growth rate under the curve was the largest(ROC area:PT growth rate was 0.741,APTT 0.914,TT 0.891)and the bestcut-offpointofAPTTgrowthratewas101.39%.Conclusion ①ThelevelofAPTTmaybeareliablein-dex for monitoring anticoagulation intensity during NVAF patients taking dabigatran etexilate .②The level of APTT should be controlled within 2 times of the normal value .

  3. 低分子量肝素对兔创伤感染时凝血功能障碍的预防作用%Preventive effect of low molecular weight heparin on coagulative disturbance in rabbits with trauma infection

    Institute of Scientific and Technical Information of China (English)

    刘宿; 蒋耀光; 葛衡江; 刘怀琼; 唐小唪

    2011-01-01

    Objective To investigate the preventive effect of low molecular weight heparin or tranexamic acid in the rabbits with hypercoagulation induced by impact injury and intravenous infusion of the endotoxin. Methods Combination of impact injury and endotoxin was created by strike on rabbit chest with type BIM-Ⅱ biological impact machine and injection of endotoxin via vein.Thirty-two male New Zealand rabbits were divided into four groups in a completely random design as follows:impact injury combined with endotoxin without treatment group(control group),treatment with low molecular weight heparin(L group),treatment with tranexamic acid(TA group),and treatment with low molecular weight heparin and tranexamie acid(L+TA group).The changes of interleukin-1β(IL-1β)and interleukin-6(IL-6)were observed by using the enzyme-linked immunosorbent assay;changes of antithrombin-Ⅲ(AT-Ⅲ)activity,tissue factor(TF)and tissue factor pathway inhibitors(TFPI)were detected by the chromogenic substrate method chromozym P:the content of fibrinogen was observed by coagulation analyzer.The lung and kidney were removed from the experimental animals at 24 hours post impact injury forhistopathologic observation. Results In the control group,the activity of AT-Ⅲ was decreased obviously.while the content of fibrinogen and the activity of TF and TFPl were increased,with formation of the thrombosis in the kidney after injection of PLS.Compared with control group,the activity of TF and the content of IL-1β and IL-6 were reduced but the TFPI was increased in the L group,which resulted in a decrease of TF/TFPI ratio.with decrease of formation of the micro-thrombosis in the organs.The content of IL-1β and IL-6 in the TA group were reduced,which was still higher than that in tIle L group.In the TA group.the activity of IF and TFPI Was lower than that in the L group and control group,with higher TF/TFPI ratio than the L group.The frequency of thrombosis increased in pulmonary artery and other

  4. 冠心病患者肥胖与血栓前状态相关性的研究%Correlation between obesity and prethrombotic state in patients with coronary heart disease

    Institute of Scientific and Technical Information of China (English)

    郭佳佳; 胡松; 王丽娜; 毛拥军; 王仁萍

    2015-01-01

    Objective:To explore the correlation among overweight ,obesity and markers of prethrombotic state in patients with coronary heart disease (CHD) .Methods:A total of 288 patients to hospital from 2013 to 2014 and di-agnosed as CHD by coronary angiography were selected .According to body mass index (BMI) ,they were divided into CHD control group (n= 106) ,overweight group (n= 121) and obesity group (n= 61) .Levels of fibrinogen (Fg) ,plasma D dimmer (D-D) ,von Willebrand factor (vWF) ,antithrombin Ⅲ (AT-Ⅲ) and plasminogen activator inhibitor (PAI)-1 were compared among three groups ,then received correlation analysis . Results:Compared with CHD control group ,there were significant rise in levels of triglyceride ,total cholesterol ,fasting blood glucose and mean arterial pressure ,morbidity rates of hypertension and diabetes mellitus in overweight group and obesity group , P<0.05 or <0.01. Compared with CHD control group ,there were significant rise in levels of Fg [ (2.89 ± 0.60) g/L vs .(3.54 ± 0.63) g/L vs .(3.92 ± 0.94) g/L] ,D-D [ (282.13 ± 73.15) ng/ml vs .(390.04 ± 73.54) ng/ml vs . (471.92 ± 80.38) ng/ml] ,vWF [ (108.62 ± 24.66)% vs .(138.45 ± 25.96)% vs .(161.20 ± 29.39)% ] and PAI-1 [ (6.97 ± 1.28) ng/ml vs .(9.60 ± 1.73) ng/ml vs .(12.33 ± 2.16) ng/ml] in overweight group and obesity group , P<0.01 all ,and those of obesity group were significantly higher than those of overweight group , P<0.01 or <0.05 ;AT-Ⅲ level [ (89.94 ± 17.99)% vs .(69.89 ± 20.22)% ] significantly reduced in obesity group (P<0.05) . Pearson correlation analysis indicated that BMI was positively correlated with markers of prethrombotic state [Fg:r=0.536 ,P<0.001 ;D-D:r= 0.250 , P< 0.001 ;vWF :r= 0.611 , P< 0.001 ;PAI-1:r=0.788 , P< 0.001) . Conclusion:BMI is positively correlated with markers of prothrombotic state in CHD patients .%目的:探讨冠心病患者超重、肥胖与血栓前状态标志物之间的相关性。方法:选择2013~2014年来院就诊

  5. Changing characteristic of blood coagulation factors and their correlation with blood coagulation status in different hepatic diseases%不同类型肝病患者凝血因子变化规律及其与凝血状态的关系

    Institute of Scientific and Technical Information of China (English)

    陈静; 段钟平; 白丽; 赵军; 丁美; 童新元; 丛玉隆

    2012-01-01

    202.9;肝衰竭组:344.7±214.6;均高于正常对照组的12.9±8.1;F=8.619,P<0.05);FⅧ∶C检测值(慢性乙型肝炎组:157.2±53.4;肝硬化组:206.9±86.9;肝衰竭组:335.7±117.7;均高于正常对照组的105.5±46.2;F=13.418,P<0.05).结论 肝脏疾病随着病情发展,由肝实质细胞合成的促抗凝成分伴发平行减少、纤溶活性增强、肝外合成凝血相关蛋白TFPI、TM、vWF及TF释放入血增多.终末期肝病患者凝血与抗凝平衡失调,可能与以上原因有关.TFPI、TM、vWF及TF在肝病轻度阶段即发生明显变化,可作为早期监测血管内皮细胞损伤敏感指标.%Objective To investigate the correlation between procoagulation factors and anticoagulation factors synthesized by the liver,and the correlation between fibrin degradation products (FDP) and D-dimer (D-D) concentration and coagulation proteins synthesized by extra-hepatic tissues,in different liver diseases; to explore the relationship between coagulation and bleeding in hepatic diseases.Methods Chronic hepatitis B (CHB) patients,CHB-related liver cirrhosis patients,CHB-related liver failure patients and healthy (normal) controls were selected for study and provided blood samples for analysis.The activity of coagulation factors (F) Ⅱ,Ⅴ,Ⅶ ,Ⅷ , Ⅸ,Ⅹ,Ⅺ,and Ⅻ was detected using the one-stage clotting method.Coagulogram analysis,including activated partial thromboplastia time (APTT),thrombin time (TT),and prothrombin time (PT),was conducted by the solidification method.Antithrombin Ⅲ (AT-Ⅲ ) and protein C (PC) activities were measured by chromogenic substrate assay.FDP concentration was detected using immunoturbidimetry.Tissue factor pathway inhibitor (TFPI),thrombomodulin (TM),von Willebrand factor (vWF),and tissue factor (TF) concentrations were measured by enzyme-linked immunosorbent assay (ELISA).Results With the exception of FⅧ ,coagulation factors and anticoagulant proteins synthesized by the liver were decreased