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Sample records for activates von willebrand

  1. Comparison of automated von Willebrand factor activity assays

    Timm, Annette; Hillarp, Andreas; Philips, Malou;

    2015-01-01

    INTRODUCTION: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. Measurement of von Willebrand factor (VWF) activity in plasma is often based on platelet agglutination stimulated by the ristocetin cofactor activity. Novel assays, based on latex beads with recombinant...

  2. Active von Willebrand factor in thrombotic thrombocytopenic purpura and malaria

    Groot, E.

    2009-01-01

    Thrombotic thrombocytopenic purpura (TTP) and malaria are two diseases of distinct origin. TTP is a rare disorder caused by a deficiency of the von Willebrand factor (VWF) cleaving protease ADAMTS13. Malaria is a poverty-related disease caused by protozoan parasites from the genus Plasmodium. TTP an

  3. Acquired von Willebrand Syndrome

    郭涛

    2005-01-01

    @@ Acquired von Willebrand syndrome (AvWS) is kind of bleeding disorder with laboratory findings similar to those in congenital yon Willebrand disease (vWD).AvWS doesn's have any personal or family history of bleeding, but is associated with certain diseases or abnormal conditions or drugs. Although AvWS is being stated as a rare disease, it has gained more and more attention during the past years. Not because of the severity of the disease, but it is more common than we thought and most patients don' t have a proper diagnosis.

  4. Clearance of von Willebrand factor. : Clearance of von Willebrand factor

    Denis, Cécile; Christophe, Olivier; Oortwijn, Beatrijs,; Lenting, Peter,

    2008-01-01

    The life cycle of von Willebrand factor (VWF) comprises a number of distinct steps, ranging from the controlled expression of the VWF gene in endothelial cells and megakaryocytes to the removal of VWF from the circulation. The various aspects of VWF clearance have been the objects of intense research in the last few years, stimulated by observations that VWF clearance is a relatively common component of the pathogenesis of type 1 von Willebrand disease (VWD). Moreover, improving the survival ...

  5. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin

    Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A. It is isolated as a mixture of heterodimers that contain a variably sized heavy chain and a common light chain. Thrombin catalyzes the activation of fVIII in a reaction that is associated with cleavages in both types of chain. The authors isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO4/PAGE and N-terminal sequence analysis. Using a plasma-free assay of the ability of activated 125I-fVIII to function as a cofactor in the activation of factor X by factor IXa, they found that fVIII is activated by the venom enzyme. The venom enzyme-activated fVIII was isolated in stable form by cation-exchange HPLC. von Willebrand factor inhibited venom enzyme-activated fVIII but not thrombin-activated fVIII. These results suggest that the binding of fVIII to von Willebrand factor depends on the presence of an intact light chain and that activated fVIII must dissociate from von Willebrand factor to exert its cofactor effect. Thus, proteolytic activation of fVIII-von Willebrand factor complex appears to be differentially regulated by light-chain cleavage to dissociate the complex and heavy-chain cleavage to activate the cofactor function

  6. Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis

    Baldauf, Carsten; Stacklies, Wolfram; Obser, Tobias; Pieconka, Antje; Schneppenheim, Sonja; Budde, Ulrich; Graeter, Frauke

    2009-01-01

    To avoid pathological platelet aggregation by von Willebrand factor (VWF), VWF multimers are regulated in size and reactivity for adhesion by ADAMTS13-mediated proteolysis in a shear flow dependent manner. We examined if tensile stress in VWF under shear flow activates the VWF A2 domain for cleavage by ADAMTS13 using molecular dynamics simulations. We indeed observed stepwise unfolding of A2 and exposure of its deeply buried ADAMTS13 cleavage site. Interestingly, disulfide bonds in the adjacent and highly homologous VWF A1 and A3 domains obstruct their mechanical unfolding. We generated a full length mutant VWF featuring a homologous disulfide bond in A2 (N1493C and C1670S), in an attempt to lock A2 against unfolding. We find this mutant to feature ADAMTS13-resistant behavior in vitro. Our results yield molecular-detail evidence for the force-sensoring function of VWF A2, by revealing how tension in VWF due to shear flow selectively exposes the A2 proteolysis site to ADAMTS13 for cleavage while keeping the fo...

  7. How Is von Willebrand Disease Diagnosed?

    ... of your von Willebrand factor. The test helps your doctor diagnose what type of VWD you have. Platelet function test. This test measures how well your platelets are working. You may have these tests ...

  8. Differential surface activation of the A1 domain of von Willebrand factor.

    Tronic, Elaine H; Yakovenko, Olga; Weidner, Tobias; Baio, Joe E; Penkala, Rebecca; Castner, David G; Thomas, Wendy E

    2016-06-01

    The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibα (GPIbα) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbα-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF-SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID:26968213

  9. Doença de von Willebrand e anestesia Enfermedad de von Willebrand y anestesia Von Willebrand's disease and anesthesia

    Fabiano Timbó Barbosa

    2007-06-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: A doença de von Willebrand ocorre devido à mutação no cromossomo 12 e é caracterizada por deficiência qualitativa ou quantitativa do fator de von Willebrand. A diversidade de mutações leva ao aparecimento das mais variadas manifestações clínicas possibilitando a divisão dos pacientes em vários tipos e subtipos clínicos. A coagulopatia se manifesta basicamente através da disfunção plaquetária associada à diminuição dos níveis séricos do fator VIII coagulante. O objetivo dessa revisão foi mostrar os cuidados relacionados aos pacientes portadores da doença de von Willebrand durante o período perioperatório. CONTEÚDO: Foram definidas as características da doença de von Willebrand quanto à fisiopatologia, à classificação, ao diagnóstico laboratorial, ao tratamento atual e aos cuidados com o manuseio do paciente no período perioperatório. CONCLUSÕES: A doença de von Willebrand é o distúrbio hemorrágico hereditário mais comum, porém ela é subdiagnosticada pela complexidade da própria doença. A correta classificação do paciente, o uso apropriado da desmopressina e a transfusão do fator de von Willebrand são medidas fundamentais para a realização do procedimento anestésico bem-sucedido.JUSTIFICATIVA Y OBJETIVOS: La enfermedad de von Willebrand ocurre debido a la mutación en el cromosoma 12 y se caracteriza por la deficiencia cualitativa o cuantitativa del factor de von Willebrand. La diversidad de mutaciones conlleva al aparecimiento de las más variadas manifestaciones clínicas posibilitando la división de los pacientes en varios tipos y subtipos clínicos. La coagulopatía se manifiesta básicamente a través de la disfunción plaquetaria asociada con la disminución de los niveles séricos del factor VIII coagulante. El objetivo de esa revisión fue mostrar los cuidados relacionados con las pacientes portadoras de la enfermedad de von Willebrand durante el per

  10. Defective von willebrand factor activity detected by the filterometer in three clinical conditions.

    O'Brien, J R; Tsai, H M; Etherington, M D

    2000-11-01

    When exposed to high levels of shear in a filterometer, platelets bind to von Willebrand factor (vWF) via receptors Ib and IIb/IIIa, forming aggregates that block the filteromer. In this study we used the filterometer to explore the mechanisms by which abnormal vWF-platelet interaction might occur. In the first phase of the study, the global vWF-platelet interaction in native blood was investigated. In the second phase, to eliminate the difference that platelets might contribute, samples of platelet-poor plasma from test individuals were added to normal control blood and the mixtures were investigated by the filterometer. The filterometer results were adjusted for the antigen concentrations to obtain vWF potency ratios. Sodium dodecyl sulphate (SDS) agarose gel electrophoresis and SDS-Polyacylamide gel electrophoresis (PAGE) were used to analyze multimeric size and proteolytic profiles of vWF. Pregnancy was associated with high platelet retention, high vWF antigen concentration, normal multimeric size distribution, but decreased vWF potency ratios. The plasma samples of pregnancy contained one 183-kDa fragment not detected in normal plasma. These results suggested that in pregnancy, platelets were highly active. However, presumably due to abnormal proteolytic cleavage, vWF potency was decreased. This decrease in vWF potency might minimize the risk of thrombosis in association with highly active platelets. Renal transplant patients had normal platelet retention but high vWF levels. The plasma vWF contained normal multimers. A decrease in vWF potency, presumably caused by toxic inhibitors in the plasma, was detected. Aortic valve stenosis patients had decreased platelet retention, normal or slightly increased vWF antigen concentration and a decrease in large multimers. As a result, the vWF potency was markedly decreased. However, the results obtained with the filterometer became normal when the studies were repeated 3 months postpartum, when renal function had

  11. Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands

    Zhang, Z.P.; Blombaeck, M.; Anvret, M. (Karolinska Hospital, Stockholm (Sweden)); Nyman, D. (Aland Central Hospital (France))

    1993-09-01

    Patients with von Willebrand disease in four families in the Aland Islands, including the original family that was described in 1926 by the Finnish physician von Willebrand, were screened for mutations in the Swedish hot-spot' regions (exons 18, 28, 32, 43, and 45) of the von Willebrand factor gene. One cytosine deletion in exon 18 was detected in each of these families. Linkage analysis and genealogical studies suggest that the deletion present in these four families probably has an origin in common with the mutations in the Swedish patients. Apart from the deletion in exon 18, two close transitions (G [yields] A at S1263 and C [yields] T at P1266) in exon 28 on the same chromosome were identified in one individual who married into the original family and in his two children. The transitions could be due to a recombination between the von Willebrand factor gene and its pseudogene. 24 refs., 3 figs., 3 tabs.

  12. Intracellular Storage and Regulated Secretion of Von Willebrand Factor in Quantitative Von Willebrand Disease*

    Wang, Jiong-Wei; Valentijn, Karine M.; de Boer, Hetty C.; Dirven, Richard J.; van Zonneveld, Anton Jan; Koster, Abraham J.; Voorberg, Jan; Reitsma, Pieter H.; Eikenboom, Jeroen

    2011-01-01

    Several missense mutations in the von Willebrand Factor (VWF) gene of von Willebrand disease (VWD) patients have been shown to cause impaired constitutive secretion and intracellular retention of VWF. However, the effects of those mutations on the intracellular storage in Weibel-Palade bodies (WPBs) of endothelial cells and regulated secretion of VWF remain unknown. We demonstrate, by expression of quantitative VWF mutants in HEK293 cells, that four missense mutations in the D3 and CK-domain ...

  13. Significance of plasma von Willebrand factor level and von Willebrand factor-cleaving protease activity in patients with chronic renal diseases

    LU Guo-yuan; SHEN Lei; WANG Zhao-yue; GUO Xiao-fang; BAI Xia; SU Jian; RUAN Chang-geng

    2008-01-01

    Background yon Willebrand factor(vWF)mediates the initial capture of platelets to vascular subendothelium and is essential for platelet aggregation under high fluid shear stress as in arteriaI stenosis.On release frOm endothelial cells,vWF is rapidly cleaved by ADAMTSl 3/vWF-cleaving protease (vWF-CP).We investigated the clinical significance of changes in plasma vWF and vWF-CP activities in chronic renal disease.Methods Plasma vWF and vWF-CP activities were measured using enzyme-linked immunosorbent assay(ELISA)and residual collagen binding assay respectively in patients with lupus nephritis(n=31),primary nephritic syndrome(n=25),diabetic nephropathy(n=45),chronic glomerulonephritis(n=38)and 40 normal controls.The reIation of their levels with pathological and renal status was analyzed.Results In all diseased patients the levels of vWF were significantly higher and vWF-CP activity significantly lower than the controls(both P<0.01).vWF in the four subgroups did not correlate with the stage of disease but correlated negatively with vWF-CP activity.vWF-CP activity was not changed two weeks after renal transplantation.Renal biopsy demonstrated that the vWF level in stage Ⅳ was higher than in stages Ⅱ and Ⅲ while vWF-CP activity was lower in patients with lupus nephritis.After eight-week treatment,the vWF level significantly decreased and the vWF-CP activity significantly increased in systemic lupus erythema,disease activity index<9,but not with index≥9.Even though the vWF-CP activity was significantly lower in membranous nephropathy than in minimal change disease,mesangial proliferative glomerulonephritis or IgA glomerulonephritis,the vWF level was not significantly different.Conclusions The alterations of plasma vWF and vWF-CP activities were associated with different renal pathologies.Injury to endothelial cells and autoantibodies against vWF-CP activity may result in higher vWF Ievel and Iower vWF-CP activity in chronic renaI disease and thus a

  14. Von Willebrand factor durino left venricular assist device support

    Corno, A.R.; REDAELLI, R.; Somaini, G.M.; Caimi, T.M.; Caruso, R.; M. Frigerio; Trivella, M.G.; O. Parodi

    2012-01-01

    Von Willebrand factor (VWF) plays a pivotal role in the hemostatic process especially in high shear rate conditions. A reduction in high molecular weight multimers resulting in acquired von Willebrand syndrome and bleeding tendency has been reported during left ventricular support with continuous flow devices (LVAD).

  15. Report on von Willebrand Disease in Malaysia

    Mercy Halleluyah Periayah; Ahmad Sukari Halim; Arman Zaharil Mat Saad; Nik Soriani Yaacob; Faraizah Abdul Karim

    2016-01-01

    BACKGROUND: Von Willebrand disease (vWD) is an inherited hemostatic disorder that affects the hemostasis pathway. The worldwide prevalence of vWD is estimated to be 1% of the general population but only 0.002% in Malaysia. AIM: Our present paper has been written to disclose the statistical counts on the number of vWD cases reported from 2011 to 2013. MATERIAL AND METHODS: This article is based on sociodemographic data, diagnoses and laboratory findings of vWD in Malaysia. A total of 9...

  16. Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada.

    1995-01-01

    OBJECTIVE: To present current strategies for the treatment of hemophilia and von Willebrand's disease. OPTIONS: Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity...

  17. Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity.

    Gorica G Ristić

    Full Text Available To evaluate association between von Willebrand factor (vWF activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA and low cardiovascular risk.Above mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3±10.0 vs. 45.2±9.8 years. Intima-media thickness (IMT was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%, none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately.RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, p<0.05. Predictive value of vWF activity for subclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP, modified Health Assessment Questionnaire (p<0.01 for all, duration of smoking, number of cigarettes/day, rheumatoid factor concentration (p<0.05 for all, and anti-CCP antibodies (p<0.01. In the entire study population, vWF activity was higher in participants with subclinical atherosclerosis (130±68% vs. 97±38%, p<0.05 or atherosclerotic plaques (123±57% vs. 99±45%, p<0.05 than in those without. Duration of smoking was significantly associated with vWF activity (β 0.026, p = 0.039.We demonstrated association of vWF activity and subclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of

  18. Molecular basis of human von Willebrand disease: Analysis of platelet von Willebrand factor mRNA

    von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, can result from either a quantitative or a qualitative defect in the adhesive glycoprotein, von Willebrand factor (vWF). Molecular studies of vWD have been limited by the large size of the vWF gene and difficulty in obtaining the vWF mRNA from patients. By use of an adaptation of the polymerase chain reaction, vWF mRNA was amplified and sequenced from peripheral blood platelets. A silent vWF allele was identified, resulting from a cis defect in vWF mRNA transcription or processing. In two type IIA vWD patients, two different but adjacent missense mutations were identified, the locations of which may identify an important vWF functional domain. Expression in heterologous cells of recombinant vWF containing one of these latter mutations reproduced the characteristic structural abnormality seen in type IIA vWD plasma

  19. Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism.

    Hawke, Lindsey; Bowman, Mackenzie L; Poon, Man-Chiu; Scully, Mary-Frances; Rivard, Georges-Etienne; James, Paula D

    2016-07-28

    Approximately 10% of von Willebrand factor (VWF) gene mutations are thought to alter messenger RNA (mRNA) splicing through disruption of consensus splice sites. This mechanism is likely underrecognized and affected by mutations outside consensus splice sites. During VWF synthesis, splicing abnormalities lead to qualitative defects or quantitative deficiencies in VWF. This study investigated the pathologic mechanism acting in 3 von Willebrand disease (VWD) families with putative splicing mutations using patient-derived blood outgrowth endothelial cells (BOECs) and a heterologous human embryonic kidney (HEK 293(T)) cell model. The exonic mutation c.3538G>A causes 3 in-frame splicing variants (23del, 26del, and 23/26del) which cannot bind platelets, blood coagulation factor VIII, or collagen, causing VWD through dominant-negative intracellular retention of coexpressed wild-type (WT) VWF, and increased trafficking to lysosomes. Individuals heterozygous for the c.5842+1G>C mutation produce exon 33 skipping, exons 33-34 skipping, and WT VWF transcripts. Pathogenic intracellular retention of VWF lacking exons 33-34 causes their VWD. The branch site mutation c.6599-20A>T causes type 1 VWD through mRNA degradation of exon 38 skipping transcripts. Splicing ratios of aberrant transcripts and coexpressed WT were altered in the BOECs with exposure to shear stress. This study provides evidence of mutations outside consensus splice sites disrupting splicing and introduces the concept that VWF splicing is affected by shear stress on endothelial cells. PMID:27317792

  20. Pathogenesis, clinical picture and treatment of von Willebrand's disease.

    Lethagen, S R

    1995-12-01

    Von Willebrand's disease is probably the most common congenital bleeding disorder, with a prevalence close to 1% in some epidemiological studies. The disease is caused by a quantitative deficiency or a qualitative defect of the von Willebrand factor, which is a multimeric glycoprotein consisting of subunits of 2050 amino acids. The size of multimers ranges from approximately 500 kDa to 20 MDa. Each subunit consist of repeated domain structures. Several functional domains have been identified which can bind such structures as platelet receptors glycoprotein Ib or IIb/IIIA, heparin, collagen or factor VIII. The von Willebrand factor has two main functions in haemostasis, to promote normal platelet adhesion and to be a carrier protein for factor VIII. Von Willebrand's disease is divided into three major types and several subtypes depending on the quantity and quality of the von Willebrand factor in plasma and platelets. A new classification has recently been proposed. Typical symptoms are mucosal bleeding, easy bruising and increased bleeding tendency in connection with tooth extractions and other invasive procedures. Severe cases may have joint bleeding and other haemophilia-like bleeding. Desmopressin is the treatment of choice in mild cases, whereas more severe cases need treatment with factor VIII concentrates. PMID:8652143

  1. Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence

    Eikenboom, J.C.; Brieet, E.; Reitsma, P.H.; Vink, T.; Sixma, J.J. [Univ. Hospital, Utrecht (Netherlands)

    1994-03-15

    The authors have analyzed a type IIB and a type I von Willebrand disease family for the presence of mutations in the region coding for the glycoprotein Ib binding domain of the von Willebrand factor. Since this sequence is also present in the highly homologous von Willebrand factor pseudogene, the authors have studied genomic DNA as well as cDNA, which was produced from RNA isolated from endothelial cells or platelets. In both families, they have detected multiple consecutive nucleotide substitutions in the 5{prime} end of exon 28 that result in a sequence identical to the von Willebrand factor pseudogene. These substitutions were also found in cDNA, which proves that they are present in the active gene. The occurrence of multiple adjacent substitutions that exactly reflect a part of the sequence of the von Willebrand factor pseudogene is difficult to reconcile with sequential single mutational events. They therefore hypothesize that each of these multiple substitutions arose from one recombinational event between gene and pseudogene. 34 refs., 4 figs., 2 tabs.

  2. Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease.

    Chen, Junmei; Hinckley, Jesse D; Haberichter, Sandra; Jacobi, Paula; Montgomery, Robert; Flood, Veronica H; Wong, Randall; Interlandi, Gianluca; Chung, Dominic W; López, José A; Di Paola, Jorge

    2015-07-01

    Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF. PMID:26019279

  3. Characterization of a novel mutation in the von Willebrand factor propeptide in a distinct subtype of recessive von Willebrand disease

    Lanke, Elsa; Kristoffersson, Ann-Charlotte; Philips, Malou; Holmberg, Lars; Lethagen, Stefan

    2008-01-01

    von Willebrand factor (VWF) is a plasma protein that consists of a series of multimers of which the high-molecular-weight VWF multimers are the most potent in platelet adhesion and aggregation. The propeptide of the VWF (VWFpp) is known to be essential in the process of multimer assembly. Genetic...... studies were performed in a patient with a phenotype of von Willebrand disease (VWD) characterized by very low plasma factor VIII and VWF levels and a VWF consisting of only a dimeric band and total absence of all multimers in plasma. The patient was found to be homozygous for the novel C570S mutation...

  4. Characterization of the interaction between von Willebrand factor and osteoprotegerin

    Shahbazi, S.; Lenting, P. J.; Fribourg, C.; Terraube, V.; Denis, C. V.; Christophe, O. D.

    2007-01-01

    Background and objective: Osteoprotegerin (OPG), a member of the tumor necrosis-factor receptor superfamily, plays an important role in bone remodeling and is also involved in vascular diseases. OPG is physically associated with von Willebrand factor (VWF), a glycoprotein involved in primary hemosta

  5. An ELISA for the quantitation of von Willebrand Factor

    Vinholt, Pernille Just; Overgaard, Martin; Diederichsen, Axel Cosmus Pyndt;

    2013-01-01

    BACKGROUND: Von Willebrand factor (VWF) is pivotal in arterial thrombosis, and osteoprotegerin (OPG) is besides being a bone protein also related to cardiovascular diseases. OPG can bind VWF, but the significance of this interaction is not known. OBJECTIVES: The aim was to develop an assay for me...

  6. Stomatološki tretman bolesnika s Morbus von Willebrand

    Cvitanić, Čedna; Raičković, Budimir

    1983-01-01

    Prikazan je slučaj bolesnika s morbus von Willebrand i problemi stomatološkog zahvata u takvih bolesnika. Istaknuto je da liječenje stomatitisa treba provoditi u više faza uz davanje svježe plazme u dva navrata. Za to vrijeme pacijenta treba hospitalizirati.

  7. No evidence for a direct effect of von Willebrand factor's ABH blood group antigens on von Willebrand factor clearance

    Groeneveld, D J; van Bekkum, T; Cheung, K L; Dirven, R J; Castaman, G; Reitsma, P H; van Vlijmen, B; Eikenboom, J

    2015-01-01

    BACKGROUND: One of the major determinants of von Willebrand factor (VWF) plasma levels is ABO blood group status, and individuals with blood group O have ~ 25% lower plasma levels. The exact mechanism behind this relationship remains unknown, although effects on clearance have been postulated. OBJEC

  8. Pseudo (Platelet-type von Willebrand disease in pregnancy: a case report

    Grover Neetu

    2013-01-01

    Full Text Available Abstract Background Pseudo (platelet-type-von Willebrand disease is a rare autosomal dominant bleeding disorder caused by an abnormal function of the glycoprotein lb protein; the receptor for von Willebrand factor. This leads to an increased removal of VWF multimers from the circulation as well as platelets and this results in a bleeding diathesis. Worldwide, less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD. Case presentation We describe the management of platelet type von Willebrand disease in pregnancy of a 26 year old Caucasian primigravida. The initial diagnosis was made earlier following a significant haemorrhage post tonsillectomy several years prior to pregnancy. The patient was managed under a multidisciplinary team which included obstetricians, haematologists, anaesthetists and neonatologists. Care plans were made for the ante- natal, intra-partum and post-partum periods in partnership with the patient. The patient’s platelet count levels dropped significantly during the antenatal period. This necessitated the active exclusion of other causes of thrombocytopenia in pregnancy. A vaginal delivery was desired and plans were made for induction of labour at 38 weeks of gestation with platelet cover in view of the progressive fall of the platelet count. The patient however went into spontaneous labour on the day of induction. She was transfused two units of platelets before delivery. She had an unassisted vaginal delivery of a healthy baby. The successful antenatal counselling has encouraged the diagnosis of the same condition in her mother and sister. We found this to be a particularly interesting case as well as challenging to manage due to its rarity. Psuedo von Willebrand disease in pregnancy can be confused with a number of other differential diagnoses, such as gestational thrombocutopenia, idiopathatic thrombocytopenia, thrombotic thrombocytopenic purpura and pre-eclampsia; all need consideration

  9. Management of von Willebrand disease type 3 during pregnancy - 2 cases reports.

    Inocêncio, G.; Braga, A; Azevedo, S.; Buchner, C

    2013-01-01

    BACKGROUND: von Willebrand disease type 3, is an extremely rare condition. It can be severe and potentially life-threatening, particularly in pregnant women during labor and subsequently during early puerperium. Due to its rarity, there is no optimal treatment/management during pregnancy. CASE: We describe two cases of pregnant women with von Willebrand disease type 3, and its successful surveillance and treatment with Haemate P FVIII (human plasma-derived von Willebrand Factor-risto...

  10. Pseudo (Platelet-type) von Willebrand disease in pregnancy: a case report

    Grover Neetu; Boama Vincent; Chou Munazzah Rifat

    2013-01-01

    Abstract Background Pseudo (platelet-type)-von Willebrand disease is a rare autosomal dominant bleeding disorder caused by an abnormal function of the glycoprotein lb protein; the receptor for von Willebrand factor. This leads to an increased removal of VWF multimers from the circulation as well as platelets and this results in a bleeding diathesis. Worldwide, less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD). Case presentation We describe the management of...

  11. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of sever von Willebrand disease

    Severe von Willebrand disease is characterized by undetectable or trace quantities of von Willebrand factor in plasma and tissue stores. The authors have studied the genomic DNA of 10 affected individuals from six families with this disorder using probes from the 5' and 3' ends of the vWF cDNA and with a probe extending from the 5' end into the central region. Southern blots of restriction endonuclease digest and gene dosage analysis measurements carried out with quantitative slot blots of undigested genomic DNA separated these patients into three groups. The first group consisted of a family with complete homozygous deletions of the vWF gene in the four probands. The second group was comprised of a family in which there was a complete heterozygous deletion of the vWF gene in the proband and one asymptomatic parent, suggesting that a different type of genetic abnormality was inherited from the other parent. Thus, the patient appeared to be doubly heterozygous for interacting genetic abnormalities affecting vWF expression. In the third group, no gene deletions could be detected. Alloantibodies developed only in the kindred with homozygous deletions. These techniques should prove useful in identifying carriers of severe von Willebrand disease and also in defining patients predictably at risk of developing alloantibodes to vWF

  12. Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

    Suva, Larry J.; Hartman, Eric; Dilley, Joshua D.; Russell, Susan; Akel, Nisreen S.; Skinner, Robert A.; Hogue, William R.; Budde, Ulrich; Varughese, Kottayil I.; Kanaji, Taisuke; Ware, Jerry

    2008-01-01

    The platelet glycoprotein Ib-IX receptor binds surface-bound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) an...

  13. Recurrent haematomas of the thigh: a case of von Willebrand's disease presenting to a sports clinic

    Owens, S.; Baglin, T

    2000-01-01

    Von Willebrand's disease is a relatively common mild form of haemophilia. It should be suspected in assessing sports injuries when excessive bleeding occurs in response to relatively mild trauma. Those with the disease should remain active but avoid contact sports. They should not take aspirin or non-steroidal anti-inflammatory drugs, which may exacerbate bleeding, and should be given supportive treatment to cover dental extraction, surgery, or significant bleeding episodes.

  14. Assembly and activation of alternative complement components on endothelial cell-anchored ultra-large von Willebrand factor links complement and hemostasis-thrombosis.

    Nancy A Turner

    Full Text Available BACKGROUND: Vascular endothelial cells (ECs express and release protein components of the complement pathways, as well as secreting and anchoring ultra-large von Willebrand factor (ULVWF multimers in long string-like structures that initiate platelet adhesion during hemostasis and thrombosis. The alternative complement pathway (AP is an important non-antibody-requiring host defense system. Thrombotic microangiopathies can be associated with defective regulation of the AP (atypical hemolytic-uremic syndrome or with inadequate cleavage by ADAMTS-13 of ULVWF multimeric strings secreted by/anchored to ECs (thrombotic thrombocytopenic purpura. Our goal was to determine if EC-anchored ULVWF strings caused the assembly and activation of AP components, thereby linking two essential defense mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We quantified gene expression of these complement components in cultured human umbilical vein endothelial cells (HUVECs by real-time PCR: C3 and C5; complement factor (CF B, CFD, CFP, CFH and CFI of the AP; and C4 of the classical and lectin (but not alternative complement pathways. We used fluorescent microscopy, monospecific antibodies against complement components, fluorescent secondary antibodies, and the analysis of >150 images to quantify the attachment of HUVEC-released complement proteins to ULVWF strings secreted by, and anchored to, the HUVECs (under conditions of ADAMTS-13 inhibition. We found that HUVEC-released C4 did not attach to ULVWF strings, ruling out activation of the classical and lectin pathways by the strings. In contrast, C3, FB, FD, FP and C5, FH and FI attached to ULVWF strings in quantitative patterns consistent with assembly of the AP components into active complexes. This was verified when non-functional FB blocked the formation of AP C3 convertase complexes (C3bBb on ULVWF strings. CONCLUSIONS/SIGNIFICANCE: AP components are assembled and activated on EC-secreted/anchored ULVWF multimeric

  15. Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells

    1982-01-01

    Immunofluorescence staining of cultured human umbilical vein endothelial cells has shown the presence of von Willebrand protein in the perinuclear region, in small rodlike structures through the cytoplasm, and on filaments of the extracellular matrix. Nonendothelial cells showed no staining with anti-von Willebrand protein antiserum. At the light microscope level, immunoperoxidase treatment of endothelial cells revealed the same pattern and antibody specificity as the fluorescence staining. T...

  16. Acquired von Willebrand disease: from theory to practice. A single center experience - three case reports

    Colită Andrei; Saguna Carmen; Costache Andra; Borsaru Gabriela; Manolache Raluca; Ivănescu Ana Maria; Lupu Anca Roxana

    2016-01-01

    Acquired von Willebrand disease (AvWD) represents a rare, potentially severe and most likely underdiagnosed category of hemorrhagic syndromes determined by quantitative, qualitative or functional, nonhereditary, alterations of von Willebrand factor (vWF) that occur in the context of various underlying diseases. It is diagnosed mainly in adults, without any personal or familial history of bleeding. The etiopathogeny of AvWD is complex, marked by the intervention of multiple mechanisms, occurin...

  17. Epidemiology, diagnosis, and management of von Willebrand disease in India.

    Ghosh, Kanjaksha; Shetty, Shrimati

    2011-07-01

    Von Willebrand disease (VWD) in all developing countries including India is considered a rare coagulation disorder, contrary to many reports from Western countries. Prevalence data based on hospital referrals identifies type 3 VWD as the most common subtype followed by type 1 and type 2. Approximately 60 to 70% cases of type 3 VWD are reportedly born of consanguineous marriages. The discriminatory diagnostic tests mainly include assays for factor (F)VIII:C and ristocetin-induced platelet agglutination and Von Willebrand factor (VWF) antigen either by immunoelectrophoresis or by enzyme-linked immunosorbent assay. VWD-type assisting tests like VWF collagen binding, VWF ristocetin cofactor assay, VWF-FVIII binding assay, and multimer analysis are occasionally used but not routinely applied in many laboratories. Among women, menorrhagia is an important presenting manifestation. Except for a handful of centers mainly in metropolitan cities, most laboratories in the remote parts of the country have no facilities for VWD-related investigations, resulting in occasional misdiagnoses of VWD as hemophilia A. Genetic diagnosis is being offered in two or three centers using the indirect linkage method in type 3 VWD, and efforts are continuing to implementing a direct mutation detection technique for routine practice in a few laboratories. Depending on the subtype or the severity of VWD, desmopressin, cryoprecipitate, fresh-frozen plasma, and factor VIII/VWF concentrates are used for management. Antifibrinolytic agents like epsilon-aminocaproic acid and tranexamic acid are widely used as an adjuvant therapy. In women with menorrhagia, oral contraceptives as a supplementary treatment are also being widely advocated to reduce bleeding. Products like danazol, ethenyl estradiol, thalidomide, and atorvastatin have been used in individual patients; acquired VWD associated with hypothyroidism has been managed successfully with thyroid hormone treatment. Both minor and major surgical

  18. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy : results from the von Willebrand Disease Prophylaxis Network

    Holm, Elena; Abshire, Thomas C; Bowen, Joel; Álvarez, M Teresa; Bolton-Maggs, Paula; Carcao, Manuel; Federici, Augusto B; Gill, Joan Cox; Halimeh, Susan; Kempton, Christine; Key, Nigel S; Kouides, Peter; Lail, Alice; Landorph, Andrea; Leebeek, Frank; Makris, Michael; Mannucci, Pier; Mauser-Bunschoten, Eveline P; Nugent, Diane; Valentino, Leonard A; Winikoff, Rochelle; Berntorp, Erik

    2015-01-01

    Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed

  19. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A

    Castaman G

    2016-06-01

    Full Text Available Giancarlo Castaman, Silvia Linari Department of Oncology, Center for Bleeding Disorders, Careggi University Hospital, Florence, ItalyAbstract: Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF and factor VIII (FVIII are currently available. The main role of these products in the management of pediatric the population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI.Keywords: von Willebrand factor, factor VIII, plasma-derived concentrates, children, von Willebrand disease, hemophilia A

  20. Evaluation of a von Willebrand factor three test panel and chemiluminescent-based assay system for identification of, and therapy monitoring in, von Willebrand disease.

    Favaloro, Emmanuel J; Mohammed, Soma

    2016-05-01

    von Willebrand disease (VWD) is reportedly the most common bleeding disorder and arises from deficiency and/or defects of von Willebrand factor (VWF). Laboratory diagnosis and typing of VWD has important management implications and requires a wide range of tests, including VWF antigen (VWF:Ag) and various activities, involving differential identification of qualitative vs quantitative VWF defects. We have assessed a new hemostasis instrument, the chemiluminescent assay based ACL AcuStar™, and an associated HemosIL AcuStar three test panel comprising VWF:Ag, VWF ristocetin cofactor (VWF:RCo) and VWF collagen binding (VWF:CB) (Instrumentation Laboratory, Bedford, Ma. USA) for ability to identify VWD, to help provisionally type VWD, and for potential use in therapy monitoring. This test system was compared to previously evaluated and validated test systems including VWF:RCo on CS-5100 and BCS analyzers, the new Siemens INNOVANCE assay (VWF Ac) on CS-5100, and VWF:Ag and VWF:CB assays performed by automated ELISA. We employed a large total sample test set (n=535) comprising plasma and platelet-lysate samples from individuals with and without VWD, some on treatment, normal plasmas, and normal and pathological controls. We also evaluated desmopressin (DDAVP) responsiveness, plus differential sensitivity to reduction in high molecular weight (HMW) VWF. The chemiluminescent test panel (VWF:Ag, VWF:RCo, VWF:CB) showed good comparability to similar assays performed by alternate methods, and broadly similar data for identification of VWD, provisional VWD type identification, DDAVP and VWD therapy, and HMW VWF sensitivity, although some notable differences were evident. The chemiluminescent system showed best low level VWF sensitivity, and lowest inter-assay variability, compared to all other systems. In conclusion, we have validated theACL AcuStar and the chemiluminescent HemosIL AcuStar VWF test panel for use in VWD diagnostics, and have identified some favorable

  1. Effect of levothyroxine administration on hemostatic analytes in Doberman Pinschers with von Willebrand disease.

    Heseltine, Johanna C; Panciera, David L; Troy, Gregory C; Monroe, William E; Brooks, Marjory B; Feldman, Bernard F

    2005-01-01

    Levothyroxine administration has been suggested to be an effective treatment for canine von Willebrand disease (vWd), but evidence supporting this treatment is lacking. Effects of levothyroxine administration were evaluated in 8 euthyroid Doberman Pinschers with plasma von Willebrand factor (vWf) concentrations 70%). Response to placebo versus levothyroxine treatment was not significantly different between groups at day 0, 2, or 30 for BMBT, vWf:Ag, vWf:CBA, and FVIII:C. Serum T4, fT4, and T3 concentrations were significantly higher and serum TSH significantly lower in the levothyroxine-treated group than in the placebo group at days 2 and 30. Administration of levothyroxine at 0.04 mg/kg caused laboratory evidence of hyperthyroidism but did not affect plasma FVIII:C and vWf:Ag concentrations or vWf-dependent collagen binding and BMBT. The results of this study failed to identify a direct action of levothyroxine supplementation on plasma vWf concentration or activity in euthyroid Doberman Pinschers with vWd. PMID:16095169

  2. [Acquired von Willebrand syndrome in a patient with immune thrombocytopenic purpura].

    Ihara, Akihiro; Suzuki, Nobuaki; Matsushita, Tadashi; Ichinose, Akitada

    2015-07-01

    Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder similar to inherited von Willebrand disease. We describe a 78-year-old woman with coexistent idiopathic thrombocytopenic purpura (ITP) and AVWS. The patient had once been admitted to our hospital because of cerebral infarction. Her platelet count had been normal at that time. Ten years later, she showed a severe bleeding tendency (platelet count 3.2×10(4)/μl). Analysis of hemostatic parameters showed very low (IgG4) to VWF was detected by enzyme linked immunosorbent assay (ELISA). Factor XIII activity was 42%. Treatment with corticosteroids did not improve the thrombocytopenia, but did correct the bleeding diathesis. Also, VWF: Rco and VIII: C showed normalization. These findings indicated that the patient had ITP associated with AVWS. All reported cases of AVWS associated with systemic lupus erythematosus were cured by appropriate treatment of the underlying autoimmune disease with prednisone or immunosuppression. This bleeding disorder occurs mainly in patients with lymphoproliferative, myeloproliferative, cardiovascular and immunologic disorders, but no patients with ITP have previously been reported. This patient had the rare presentation of AVWS complicated by ITP and factor XIII deficiency. PMID:26256928

  3. Structural basis of regulation of von Willebrand factor binding to glycoprotein Ib.

    Blenner, Mark A; Dong, Xianchi; Springer, Timothy A

    2014-02-28

    Activation by elongational flow of von Willebrand factor (VWF) is critical for primary hemostasis. Mutations causing type 2B von Willebrand disease (VWD), platelet-type VWD (PT-VWD), and tensile force each increase affinity of the VWF A1 domain and platelet glycoprotein Ibα (GPIbα) for one another; however, the structural basis for these observations remains elusive. Directed evolution was used to discover a further gain-of-function mutation in A1 that shifts the long range disulfide bond by one residue. We solved multiple crystal structures of this mutant A1 and A1 containing two VWD mutations complexed with GPIbα containing two PT-VWD mutations. We observed a gained interaction between A1 and the central leucine-rich repeats (LRRs) of GPIbα, previously shown to be important at high shear stress, and verified its importance mutationally. These findings suggest that structural changes, including central GPIbα LRR-A1 contact, contribute to VWF affinity regulation. Among the mutant complexes, variation in contacts and poor complementarity between the GPIbα β-finger and the region of A1 harboring VWD mutations lead us to hypothesize that the structures are on a pathway to, but have not yet reached, a force-induced super high affinity state. PMID:24391089

  4. Differential localization of P-selectin and von Willebrand factor during megakaryocyte maturation

    Zingariello, M; Fabucci, M E; Bosco, D;

    2010-01-01

    An important step in megakaryocyte maturation is the appropriate assembly of at least two distinct subsets of alpha-granules. The mechanism that sorts the alpha-granule components into distinct structures and mediates their release in response to specific stimuli is now emerging. P-selectin and von...... Willebrand factor are two proteins present in the alpha-granules that recognize P-selectin glycoprotein ligand on neutrophils and collagen in the subendothelial matrix. These proteins may play an important role in determining the differential release of the alpha-granule contents in response to external...... stimuli. If P-selectin and von Willebrand factor are localized in the same or different alpha-granules is not known. To clarify this question, we analyzed by immunoelectron microscopy the localization of von Willebrand factor and P-selectin during the maturation of wild-type and Gata1(low) megakaryocytes...

  5. Human von Willebrand factor gene and pseudogene: Structural analysis and differentiation by polymerase chain reaction

    Structural analysis of the von Willebrand factor gene located on chromosome 12 is complicated by the presence of a partial unprocessed pseudogene on chromosome 22q11-13. The structures of the von Willebrand factor pseudogene and corresponding segment of the gene were determined, and methods were developed for the rapid differentiation of von Willebrand factor gene and pseudogene sequences. The pseudogene is 21-29 kilobases in length and corresponds to 12 exons (exons 23-34) of the von Willebrand factor gene. Approximately 21 kilobases of the gene and pseudogene were sequenced, including the 5' boundary of the pseudogene. The 3' boundary of the pseudogene lies within an 8-kb region corresponding to intron 34 of the gene. The presence of splice site and nonsense mutations suggests that the pseudogene cannot yield functional transcripts. The pseudogene has diverged ∼3.1% in nucleotide sequence from the gene. This suggests a recent evolutionary origin ∼19-29 million years ago, near the time of divergence of humans and apes from monkeys. Several repetitive sequences were identified, including 4 Alu, one Line-1, and several short simple sequence repeats. Several of these simple repeats differ in length between the gene and pseudogene and provide useful markers for distinguishing these loci. Sequence differences between the gene and pseudogene were exploited to design oligonucleotide primers for use in the polymerase chain reaction to selectivity amplify sequences corresponding to exons 23-34 from either the von Willebrand factor gene or the pseudogene. This method is useful for the analysis of gene defects in patients with von Willebrand disease, without interference from homologous sequences in the pseudogene

  6. Interference from lupus anticoagulant on von Willebrand factor measurement in splenic marginal zone lymphoma

    Vinholt, Pernille J; Nybo, Mads

    2015-01-01

    We present a case concerning a patient with splenic marginal zone lymphoma (SMZL) and isolated prolonged activated partial thromboplastin time (aPTT) caused by lupus anticoagulant. Von Willebrand factor (VWF) activity and antigen were immeasurable by latex particle immunoturbidimetric assays, and...... several coagulation factor levels were decreased. However, VWF activity and antigen were normal when analyzed by other methods. Also, coagulation factor levels were normal if an aPTT reagent with low lupus anticoagulant sensitivity or a chromogenic method was applied. Altogether, the initial findings were...... because of lupus anticoagulant interference and in fact, the patient had normal VWF activity and coagulation status. Interference of lupus anticoagulant in clot-based assays is well known but has not previously been described in VWF assays. This is furthermore the first report in which lupus anticoagulant...

  7. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A.

    Castaman, Giancarlo; Linari, Silvia

    2016-01-01

    Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI. PMID:27445481

  8. Autosomal dominant C1149R von Willebrand disease: phenotypic findings and their implications

    Pérez-Rodríguez, Almudena; García-Rivero, Aranzazu; Lourés, Esther; López-Fernández, Maria Fernanda; Rodríguez-Trillo, Angela; Batlle, Javier

    2009-01-01

    The classification and even the diagnosis of von Willebrand disease continues to evolve. In this paper, the authors show how a detailed examination of difficult cases using clinical laboratory and molecular analyses can be used to reach a clinically useful conclusion. See related perspective article on page 610.

  9. Von Willebrand factor availability in platelet concentrates stored for 5 days.

    Cesar, J M; García-Avello, A; Monteagudo, J; Espinosa, J I; Lodos, J C; Castillo, R; Navarro, J L

    1994-02-01

    Von Willebrand factor (vWF) availability was assessed in platelet concentrates (PCs). After 5 days of storage, 82 +/- 9% of basal levels of ristocetin cofactor activity (vWF:RCo) remained in PCs. vWF antigen (vWF:Ag) increased up to 166 +/- 38% (P < 0.05) in the same period. Autoradiograph pattern of vW:Ag showed an increase in low molecular weight multimers, and fast migrating multimeric forms were visualized by crossed immunoelectrophoresis on day 5. Studies carried out in platelet free plasma stored as PCs showed similar changes in vWF:RCo but increments in vWF:Ag were not detected. These data indicate that PCs maintain vWF:RCo levels of clinical value even after 5 days of storage and suggest that vWF comes out from platelets to plasma during storage. PMID:8141116

  10. Laboratory tests used to help diagnose von Willebrand disease: an update.

    Favaloro, Emmanuel J; Pasalic, Leonardo; Curnow, Jennifer

    2016-06-01

    von Willebrand disease (VWD) is due to quantitative deficiencies and/or qualitative defects in von Willebrand factor (VWF), and is reportedly the most common inherited bleeding disorder. However, diagnosis of VWD is problematic, and is subject to over-, under-, and misdiagnosis. This is due to many factors, including limitations in current test procedures and an over-reliance on these imperfect test systems for clinical diagnosis. VWF is a complex plasma protein with multiple functions, but essentially acts to assist in the formation of a platelet thrombus to stop blood loss from sites of injury. VWF achieves this by several activities, including binding to platelets [primarily through the glycoprotein Ib (GPIb) receptor], binding to subendothelial matrix components (primarily collagen), and binding to factor VIII (FVIII), thus protecting FVIII from degradation and enabling its delivery to sites of vascular injury. Laboratory assessment of VWD entails performance of a battery of tests, some of which aim to mimic in vivo VWF activity. VWD is classified into six separate types, based on quantitative deficiencies [types 1 (partial deficiency) and 3 (total deficiency)] of VWF, or qualitative defects (type 2 VWD), which comprise four 'subtypes'. The current report briefly overviews the diagnosis of VWD, describing the currently available armamentarium of laboratory tests, as well as emerging options for laboratory-assisted diagnostics. Although some methodologies suffer from significant limitations that challenge the accurate diagnosis of VWD, newer methodologies and specific approaches can improve detection of this common bleeding disorder, and the appropriate characterisation and typing of patients. PMID:27131932

  11. Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias.

    Dicke, Christina; Schneppenheim, Sonja; Holstein, Katharina; Spath, Brigitte; Bokemeyer, Carsten; Dittmer, Rita; Budde, Ulrich; Langer, Florian

    2016-05-01

    Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that may cause life-threatening hemorrhages in patients with plasma cell dyscrasias (PCDs). Early diagnosis and treatment require a thorough understanding of its underlying pathophysiology. Two patients with IgG MGUS presented with dramatically decreased plasma von Willebrand factor (VWF) and a severe type-1 pattern on multimer analysis. A prompt response to intravenous immunoglobulins (IVIG), but not to VWF/FVIII, was consistent with accelerated immunologic clearance of plasma VWF. Another IgG MGUS patient showed a type-2 pattern and a less pronounced response to IVIG, suggesting that additional mechanism(s) contributed to AVWS evolution. In a patient with Waldenström's macroglobulinemia and severe depletion of plasma VWF, multimer analysis indicated association of the IgM paraprotein with VWF before, but not after plasmapheresis, resulting in destruction of the agarose gel and a characteristically distorted band structure of VWF multimers. A type-2 pattern with highly abnormal VWF triplets and laboratory evidence of excessive fibrinolytic activity suggested that plasmin-mediated VWF degradation contributed to AVWS in a patient with multiple myeloma (MM) and AL amyloidosis. Finally, in a patient with IgG MM, maximally prolonged PFA-100® closure times and a specific defect in ristocetin-induced platelet agglutination, both of which resolved after remission induction, indicated interference of the paraprotein with VWF binding to platelet GPIb. Importantly, in none of the six patients, circulating autoantibodies to VWF were detected by a specific in-house ELISA. In summary, when evaluating PCD patients with severe bleeding symptoms, AVWS due to various pathogenic mechanisms should be considered. PMID:27040683

  12. Cancers in Patients with von Willebrand Disease: A Survey from the Italian Association of Haemophilia Centres.

    Franchini, Massimo; Di Perna, Caterina; Santoro, Cristina; Castaman, Giancarlo; Siboni, Simona Maria; Zanon, Ezio; Linari, Silvia; Gresele, Paolo; Pasca, Samantha; Coppola, Antonio; Santoro, Rita; Napolitano, Mariasanta; Ranalli, Paola; Tagliaferri, Annarita

    2016-02-01

    Besides its essential role in hemostasis, there is growing evidence that von Willebrand factor (VWF) has an additional antitumor effect. To elucidate the clinical significance of this biological activity we conducted a retrospective study on cancers among Italian patients with von Willebrand disease (VWD) on behalf of the Italian Association of Haemophilia Centres (AICE). A questionnaire to collect demographic, clinical, and treatment data of VWD patients with cancer was sent to all the 54 Italian Haemophilia Treatment Centres (HTCs) members of AICE. Overall, 18 HTCs (33%) provided information on 92 VWD patients (61 alive and 31 deceased) with 106 cancers collected during the period 1981 to 2014. Of them, 19 (18%) were hematological cancers and 87 (82%) were solid cancers. A total of 61% of patients had type 1, 36% type 2 (12% type 2A, 14% type 2B, 9% type 2M, and 1% type 2N), and 3% type 3 VWD: this distribution was significantly different from that observed in the whole VWD population (79% type 1, 16% type 2 [8% type 2A, 4% type 2B, 2% type 2M, 2% type 2N], and 5% type 3; type 2 vs. non-type 2: p < 0.001). Overall, VWD patients with cancer underwent 52 invasive and 72 surgical procedures, were treated with VWF/factor VIII (FVIII) concentrates in 77 cases, with desmopressin (DDAVP) alone in 24 cases and with DDAVP and VWF/FVIII concentrates in 7 cases. Hemorrhagic complications were observed only rarely (2% of invasive procedures and radiotherapy and 6% of surgical interventions). The data collected by this survey document that a substantial number of cancers are recorded among VWD patients and that these patients are safely managed by HTC physicians through a multidisciplinary approach. PMID:26595151

  13. IgGG Kappa Monoclonal Gammopathy of Undetermined Significance (MGUS) Presenting as Acquired Type III Von Willebrand Syndrome

    Howard, C.; Lin, T; Cunningham, M; Lipe, B

    2014-01-01

    Acquired von Willebrand Syndrome (AVWS) is a rare bleeding disorder associated with hematoproliferative disorders, autoimmune conditions, neoplasia, and cardiovascular disorders that often presents a diagnostic challenge. Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common causes of AVWS that typically presents later in life with mucocutaneous or postsurgical bleeding and multimers consistent with type I or II von Willebrand Disease (VWD). Here we present the c...

  14. Electron microscopy of human factor VIII/Von Willebrand glycoprotein: effect of reducing reagents on structure and function

    1982-01-01

    The structure of native and progressively reduced human factor VIII/von Willebrand factor (FVIII/vWF) was examined by electron microscopy and SDS gel electrophoresis and then correlated with its biological activities. Highly resolved electron micrographs of well-spaced, rotary- shadowed FVIII/vWF molecules showed their structure to consist of a very flexible filament that contains irregularly spaced small nodules. Filaments ranged from 50 to 1,150 nm with a mean length of 478 nm and lacked fi...

  15. Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor

    Torisu, Takehiro; Torisu, Kumiko; Lee, In Hye; Liu, Jie; Malide, Daniela; Combs, Christian A.; Wu, Xufeng S.; Rovira, Ilsa I.; Fergusson, Maria M; Weigert, Roberto; Connelly, Patricia S.; Daniels, Mathew P.; Komatsu, Masaaki; Cao, Liu; Finkel, Toren

    2013-01-01

    Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here, we demonstrate that WPBs are in some cases found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy, or knockdown of the essential autophagy genes Atg5 or Atg7, inhibits the in vitro secretion of VWF. Furthermore, while mice...

  16. Biosynthesis of von Willebrand protein by human endothelial cells: processing steps and their intracellular localization

    1984-01-01

    Biosynthesis of von Willebrand protein by human umbilical vein endothelial cells involved distinct processing steps marked by the presence of several intermediate molecular species. Examination of endoglycosidase H sensitivity of these intracellular intermediates indicated that the processing steps occurred in at least two separate cellular compartments. In the pre-Golgi apparatus (most probably the endoplasmic reticulum), the high mannose carbohydrates were added onto the precursor monomer c...

  17. Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease

    DiStefano, Youmna E.; Lazar, Michael D.

    2015-01-01

    Peripheral nerve blockade (PNB) is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR). Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD). Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year...

  18. Von Willebrand factor is reversibly decreased during torpor in 13-lined ground squirrels.

    Cooper, Scott; Sell, Shawn; Nelson, Luke; Hawes, Jennifer; Benrud, Jacob A; Kohlnhofer, Bridget M; Burmeister, Bradley R; Flood, Veronica H

    2016-01-01

    During torpor in a hibernating mammal, decreased blood flow increases the risk of blood clots such as deep vein thrombi (DVT). In other animal models platelets, neutrophils, monocytes and von Willebrand factor (VWF) have been found in DVT. Previous research has shown that hibernating mammals decrease their levels of platelets and clotting factors VIII (FVIII) and IX (FIX), increasing both bleeding time and activated partial thromboplastin time. In this study, FVIII, FIX and VWF activities and mRNA levels were measured in torpid and non-hibernating ground squirrels (Ictidomys tridecemlineatus). Here, we show that VWF high molecular weight multimers, collagen-binding activity, lung mRNA and promoter activity decrease during torpor. The VWF multimers reappear in plasma within 2 h of arousal in the spring. Similarly, FIX activity and liver mRNA both dropped threefold during torpor. In contrast, FVIII liver mRNA levels increased twofold while its activity dropped threefold, consistent with a post-transcriptional decrease in FVIII stability in the plasma due to decreased VWF levels. Finally, both neutrophils and monocytes are decreased eightfold during torpor which could slow the formation of DVT. In addition to providing insight in how blood clotting can be regulated to allow mammals to survive in extreme environments, hibernating ground squirrels provide an interesting model for studying. PMID:26481634

  19. Isoelectric focusing of human von Willebrand factor in urea-agarose gels

    An analytical technique has been developed for the isoelectric focusing (IEF) of plasma von Willebrand factor (vWF) in agarose gels containing urea. Under these conditions, vWF freely enters the gel and focuses without artifact. The focused vWF is visualized by staining fixed gels with 125I-labeled affinity-purified heterologous antibody. Utilizing a pH gradient of 5.0-6.5, normal vWF in plasma or purified preparations focuses into at least three bands with apparent isoelectric points (pI) between pH 5.7 and 5.9. A reproducible difference in the IEF pattern of vWF has been established between normal plasmas and those of individuals with variant von Willebrand's disease (vWd) type IIA and type IIB. In type IIA, vWF has a distinctly lower pI than normal. This difference may be related to the presence of smaller vWF multimers in IIA plasma because forms of vWF of corresponding size contained in normal cryoprecipitate supernatant have a similar pI. Type IIB von Willebrand factor has a pI intermediate between normal and IIA. Neuraminidase treatment of plasma samples before IEF results in an increase in pI in normal, type IIA, and type IIB vWF. The data suggest that none of the 16 type IIA and 9 IIB plasmas studied here contain significantly decreased amounts of sialic acid

  20. Linkage disequilibrium patterns vary with chromosomal location: A case study from the von Willebrand factor region

    Watkins, W.S.; Zenger, R.; O' Brien, E.; Jorde, L.B. (Univ. of Utah School of Medicine, Salt Lake City, UT (United States)); Nyman, D. (Aland Central Sjukhus (Finland)); Eriksson, A.W. (Free Univ., Amsterdam (Netherlands)); Renlund, M.

    1994-08-01

    Linkage disequilibrium analysis has been used as a tool for analyzing marker order and locating disease genes. Under appropriate circumstances, disequilibrium patterns reflect recombination events that have occurred throughput a population's history. As a result, disequilibrium mapping may be useful in genomic regions of <1 cM where the number of informative meioses needed to detect recombinant individuals within pedigrees is exceptionally high. Its utility for refining target areas for candidate disease genes before initiating chromosomal walks and cloning experiments will be enhanced as the relationship between linkage disequilibrium and physical distance is better understood. To address this issue, the authors have characterized linkage disequilibrium in a 144-kb region of the von Willebrand factor gene on chromosome 12. Sixty CEPH and 12 von Willebrand disease families were genotypes for five PCR-based markers, which include two microsatellite repeats and three single-base-pair substitutions. Linkage disequilibrium and physical distance between polymorphisms are highly correlated (r[sub m] = -.76; P<.05) within this region. None of the five markers showed significant disequilibrium with the von Willebrand disease phenotype. The linkage disequilibrium/physical distance relationship was also analyzed as a function of chromosomal location for this and eight previously characterized regions. This analysis revealed a general trend in which linkage disequilibrium dissipates more rapidly with physical distance in telomeric regions than in centromeric regions. This trend is consistent with higher recombination rates near telomeres. 52 refs., 3 figs., 4 tabs.

  1. Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin

    Zhang, Z.P.; Blomback, M.; Egberg, N.; Falk, G.; Anvret, M. (Karolinska Hospital, Stockholm (Sweden))

    1994-05-01

    Twenty-four patients with von Willebrand disease type III were screened for mutations in the von Willebrand factor (VWF) gene using the PCR technique, followed by direct sequencing. More than 250 kb of genomic DNA were sequenced, including the promoter and coding regions (52 exons) of the VWF gene from 24 patients. In addition to the previously reported mutations of a single cytosine deletion in exon 18 and the nonsense mutations in exons 28, 32, and 45, nine new mutations were detected: two nonsense mutations in exons 15 and 16, one allele with a thymidine insertion in exon 14, one allele with a cytosine insertion in exon 28, one 20-bp deletion in exon 15, one mutation in the donor splice site of exon 43, and three missense mutations in exons 28, 49, and 51. Forty-two mutant chromosomes were identified (42/48); 11 probands are homozygous for the mutations, and 8 are compound heterozygous. In addition, a new subfamily of the Alu sequence in the promoter region and 10 new polymorphisms were identified. 15 refs., 3 figs., 3 tabs.

  2. Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor

    von Willebrand factor (vWF) supports platelet adhesion on thrombogenic surfaces by binding to platelet membrane glycoprotein (GP) Ib in the GP Ib-IX receptor complex. This interaction is physiologically regulated so that it does not occur between circulating vWF and platelets but, rather, only at a site of vascular injury. The abnormal vWF found in type IIB von Willebrand disease, however, has a characteristically increased affinity for GP Ib and binds to circulating platelets. The authors have analyzed the molecular basis of this abnormality by sequence analysis of a type IIB vWF cDNA and have identified a single amino acid change, Trp550 to Cys550, located in the GP IB-binding domain of the molecule comprising residues 449-728. Bacterial expression of recombinant fragments corresponding to this vWF domain yielded molecules that, whether containing a normal Trp550 or a mutant Cys550 residue, bound directly to GP Ib in the absence of modulators and with similar affinity. These results identify a region of vWF that, although not thought to be directly involved in binding to GP Ib, may modulate the interaction through conformational changes

  3. [Stable expression and characterization of the von Willebrand factor cleaving protease].

    Ma, Zhenni; Dong, Ningzheng; Zhang, Jingyu; Su, Jian; Wang, Anyou; Ruan, Changgeng

    2010-02-01

    This study was to acquire recombinant protein of von Willebrand factor cleaving protease (ADAMTS13, a disintegrin and metalloprotease with a thromboSpondin type 1 motifs 13), for further studies on its biological function in thrombosis and hemostasis. We transfected the Hela cells with the plasmid pSecTag-ADAMTS13 by lipofectamine. A positive cell cloning was selected by hygromycin-B. The recombinant protein was purified with Ni-NTA agarose column by gradient imidazole. The purity and immune activity of purified products were identified with SDS-PAGE and Western blotting respectively. We also measured the enzymatic activity of recombinant protein (rADAMTS13) by GST-His two-site ELISA assay. The results showed that we successfully constructed Hela cells ADAMTS2-4 which expressed high level of rADAMTS13. We received about 5.8 mg recombinant protein in culture supernantants per liter purified with Ni-NTA column. The protein formed a main lane at the position of 190 kDa with SDS-PAGE and reacted with polyclonal antibody against ADAMTS13 by Western blotting. The amount of rADAMTS13 activity was 6.4 U/mL, according to the normal plasma defined as 1 U/mL. In conclusion, rADAMTS13 protein had high purity, immune activity and good enzymatic activity, which could establish the experimental foundation for further research on biological function and mechanism of this unique metalloprotease. PMID:20432945

  4. Thrombomodulin and von Willebrand factor as markers of radiation-induced endothelial injury

    Cultured confluent human umbilical vein endothelial cells were irradiated in vitro by 60Co-gamma ray at doses from 0 to 50 Gy. After irradiation Thrombomodulin in the supernatants of endothelial cell culture medium, on the surface of the cells and within the cells was measured at different times over six days. At twenty-four hours after irradiation, an increase in the release of Thrombomodulin and von Willebrand factor from irradiated endothelial cells and an increase in the number of molecules and the activity of Thrombomodulin on the surface of the cells were observed, which were radiation-dose dependent. The capacity of the cells to produce and release Thrombomodulin was decreased from two to six days after exposure to 60Co-gamma ray. Our data indicate that radiation can injure endothelial cells and that Thrombomodulin may be as a marker of radiation-induced endothelial cell injury. The relationship between dysfunction of irradiated endothelial cells and the pathological mechanisms of acute radiation sickness are discussed

  5. von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor.

    Brehm, M A; Huck, V; Aponte-Santamaría, C; Obser, T; Grässle, S; Oyen, F; Budde, U; Schneppenheim, S; Baldauf, C; Gräter, F; Schneider, S W; Schneppenheim, R

    2014-07-01

    The bleeding disorder von Willebrand disease (VWD) is caused by mutations of von Willebrand factor (VWF), a multimeric glycoprotein essential for platelet-dependent primary haemostasis. VWD type 2A-associated mutations each disrupt VWF biosynthesis and function at different stages, depending on the VWF domain altered by the mutation. These effects cause considerable heterogeneity in phenotypes and symptoms. To characterise the molecular mechanisms underlying the specific VWF deficiencies in VWD 2A/IIC, IID and IIE, we investigated VWF variants with patient-derived mutations either in the VWF pro-peptide or in domains D3 or CK. Additionally to static assays and molecular dynamics (MD) simulations we used microfluidic approaches to perform a detailed investigation of the shear-dependent function of VWD 2A mutants. For each group, we found distinct characteristics in their intracellular localisation visualising specific defects in biosynthesis which are correlated to respective multimer patterns. Using microfluidic assays we further determined shear flow-dependent characteristics in polymer-platelet-aggregate formation, platelet binding and string formation for all mutants. The phenotypes observed under flow conditions were not related to the mutated VWF domain. By MD simulations we further investigated how VWD 2A/IID mutations might alter the ability of VWF to form carboxy-terminal dimers. In conclusion, our study offers a comprehensive picture of shear-dependent and shear-independent dysfunction of VWD type 2A mutants. Furthermore, our microfluidic assay might open new possibilities for diagnosis of new VWD phenotypes and treatment choice for VWD patients with shear-dependent VWF dysfunctions that are currently not detectable by static tests. PMID:24598842

  6. Plasmatic ADAMTS-13 metalloprotease and von Willebrand factor in children with cyanotic congenital heart disease

    Changes in plasma von Willebrand factor concentration (VWF:Ag) and ADAMTS-13 activity (the metalloprotease that cleaves VWF physiologically) have been reported in several cardiovascular disorders with prognostic implications. We therefore determined the level of these proteins in the plasma of children with cyanotic congenital heart disease (CCHD) undergoing surgical treatment. Forty-eight children were enrolled (age 0.83 to 7.58 years). Measurements were performed at baseline and 48 h after surgery. ELISA, collagen-binding assays and Western blotting were used to estimate antigenic and biological activities, and proteolysis of VWF multimers. Preoperatively, VWF:Ag and ADAMTS-13 activity were decreased (65 and 71% of normal levels considered as 113 (105-129) U/dL and 91 ± 24% respectively, P < 0.003) and correlated (r = 0.39, P = 0.0064). High molecular weight VWF multimers were not related, suggesting an interaction of VWF with cell membranes, followed by proteolytic cleavage. A low preoperative ADAMTS-13 activity, a longer activated partial thromboplastin time and the need for cardiopulmonary bypass correlated with postoperative bleeding (P < 0.05). Postoperatively, ADAMTS-13 activity increased but less extensively than VWF:Ag (respectively, 2.23 and 2.83 times baseline, P < 0.0001), resulting in an increased VWF:Ag/ADAMTS-13 activity ratio (1.20 to 1.54, respectively, pre- and postoperative median values, P = 0.0029). ADAMTS-13 consumption was further confirmed by decreased ADAMTS-13 antigenic concentration (0.91 ± 0.30 to 0.70 ± 0.25 µg/mL, P < 0.0001) and persistent proteolysis of VWF multimers. We conclude that, in pediatric CCHD, changes in circulating ADAMTS-13 suggest enzyme consumption, associated with abnormal structure and function of VWF

  7. Plasmatic ADAMTS-13 metalloprotease and von Willebrand factor in children with cyanotic congenital heart disease

    Soares, R.P.S. [Fundação Pró-Sangue Hemocentro de São Paulo, São Paulo, SP (Brazil); Bydlowski, S.P.; Nascimento, N.M. [Laboratório de Investigação Médica-31, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Thomaz, A.M.; Bastos, E.N.M.; Lopes, A.A. [Faculdade de Medicina, Instituto do Coração, Universidade de São Paulo, São Paulo, SP (Brazil)

    2013-04-05

    Changes in plasma von Willebrand factor concentration (VWF:Ag) and ADAMTS-13 activity (the metalloprotease that cleaves VWF physiologically) have been reported in several cardiovascular disorders with prognostic implications. We therefore determined the level of these proteins in the plasma of children with cyanotic congenital heart disease (CCHD) undergoing surgical treatment. Forty-eight children were enrolled (age 0.83 to 7.58 years). Measurements were performed at baseline and 48 h after surgery. ELISA, collagen-binding assays and Western blotting were used to estimate antigenic and biological activities, and proteolysis of VWF multimers. Preoperatively, VWF:Ag and ADAMTS-13 activity were decreased (65 and 71% of normal levels considered as 113 (105-129) U/dL and 91 ± 24% respectively, P < 0.003) and correlated (r = 0.39, P = 0.0064). High molecular weight VWF multimers were not related, suggesting an interaction of VWF with cell membranes, followed by proteolytic cleavage. A low preoperative ADAMTS-13 activity, a longer activated partial thromboplastin time and the need for cardiopulmonary bypass correlated with postoperative bleeding (P < 0.05). Postoperatively, ADAMTS-13 activity increased but less extensively than VWF:Ag (respectively, 2.23 and 2.83 times baseline, P < 0.0001), resulting in an increased VWF:Ag/ADAMTS-13 activity ratio (1.20 to 1.54, respectively, pre- and postoperative median values, P = 0.0029). ADAMTS-13 consumption was further confirmed by decreased ADAMTS-13 antigenic concentration (0.91 ± 0.30 to 0.70 ± 0.25 µg/mL, P < 0.0001) and persistent proteolysis of VWF multimers. We conclude that, in pediatric CCHD, changes in circulating ADAMTS-13 suggest enzyme consumption, associated with abnormal structure and function of VWF.

  8. Ku Regulates Signaling to DNA Damage Response Pathways through the Ku70 von Willebrand A Domain

    Fell, Victoria L.; Schild-Poulter, Caroline

    2012-01-01

    The Ku heterodimer (Ku70/Ku80) is a main component of the nonhomologous end-joining (NHEJ) pathway that repairs DNA double-strand breaks (DSBs). Ku binds the broken DNA end and recruits other proteins to facilitate the processing and ligation of the broken end. While Ku interacts with many proteins involved in DNA damage/repair-related functions, few interactions have been mapped to the N-terminal von Willebrand A (vWA) domain, a predicted protein interaction domain. The mutagenesis of Ku70 v...

  9. Leukocyte telomere length is inversely correlated with plasma Von Willebrand factor

    Hjelmborg, Jacob V B; Nzietchueng, Rosine; Kimura, Masayuki;

    2010-01-01

    INTRODUCTION: Leukocyte telomere length (LTL) is short, while the plasma level of Von Willebrand (VWF) is high in persons with atherosclerosis. Moreover, both short LTLs and high VWF levels are observed in individuals who display risks for atherosclerosis, including hypertension, obesity, insulin...... resistance, cigarette smoking and low socio-economic status. We examined the association between LTL and VWF plasma levels to test the hypothesis that high levels of VWF promote an increase in the turnover of blood cells, including leukocytes. Such a process would heighten the rate of age-dependent LTL...

  10. Third Åland islands conference on von Willebrand disease, 26–28 September 2012: meeting report

    Berntorp, E; Fuchs, B.; Makris, M; Montgomery, R.; FLOOD, V.; O’DONNELL, J. S.; Federici, A. B.; LILLICRAP, D.; James, P; Budde, U; M. Morfini; P. Petrini; Austin, S; KANNICHT, C.; JIMÉNEZ-YUSTE, V.

    2013-01-01

    The first meeting of international specialists in the field of von Willebrand disease (VWD) was held in the Åland islands in 1998 where Erik von Willebrand had first observed a bleeding disorder in some members of a family from Föglö and a summary of the meeting was published in 1999. The second meeting was held in 2010 and a report of the meeting was published in 2012. Topics covered included progress in understanding of VWD over the last 50 years; multimers; classification of VWD; pharmacok...

  11. Complex changes in von Willebrand factor-associated parameters are acquired during uncomplicated pregnancy.

    Danielle N Drury-Stewart

    Full Text Available BACKGROUND: The coagulation protein von Willebrand Factor (VWF is known to be elevated in pregnancy. However, the timing and nature of changes in VWF and associated parameters throughout pregnancy are not well understood. OBJECTIVES: To better understand the changes in VWF provoked by pregnancy, we studied VWF-associated parameters in samples collected over the course of healthy pregnancies. METHODS: We measured VWF antigen (VWF:Ag, VWF propeptide (VWFpp, Factor VIII (FVIII, and ADAMTS13 activity in samples collected from 46 women during pregnancy and at non-pregnant baseline. We also characterized pregnant vs. non-pregnant VWF multimer structure in 21 pregnancies, and performed isoelectric focusing (IEF of VWF in two pregnancies which had samples from multiple trimesters. RESULTS: VWF:Ag and FVIII levels were significantly increased during pregnancy. ADAMTS13 activity was unchanged. VWFpp levels increased much later in pregnancy than VWF:Ag, resulting in a progressive decrease in VWFpp:Ag ratios. FVIII:VWF ratios also decreased in pregnancy. Most pregnancies exhibited a clear loss of larger VWF multimers and altered VWF triplet structure. Further evidence of acquired VWF qualitative changes in pregnancy was found in progressive, reversible shifts in VWF IEF patterns over gestation. CONCLUSIONS: These data support a new view of pregnancy in which VWF can acquire qualitative changes associated with advancing gestational age. Modeling supports a scenario in which both increased VWF production and doubling of the VWF half-life would account for the data observed. We propose that gestation induces a prolongation in VWF survival, which likely contributes to increased total VWF levels and altered VWF structure.

  12. Towards personalised therapy for von Willebrand disease: a future role for recombinant products.

    Favaloro, Emmanuel J

    2016-05-01

    von Willebrand disease (VWD) is reportedly the most common bleeding disorder and is caused by deficiencies and/or defects in the adhesive plasma protein von Willebrand factor (VWF). Functionally, normal VWF prevents bleeding by promoting both primary and secondary haemostasis. In respect to primary haemostasis, VWF binds to both platelets and sub-endothelial matrix components, especially collagen, to anchor platelets to damaged vascular tissue and promote thrombus formation. VWF also stabilises and protects factor VIII in the circulation, delivering FVIII to the site of injury, which then facilitates secondary haemostasis and fibrin formation/thrombus stabilisation. As a result of this, patients with VWD suffer a bleeding diathesis reflective of a primary defect caused by defective/deficient VWF, which in some patients is compounded by a reduction in FVIII. Management of VWD, therefore, chiefly entails replacement of VWF, and sometimes also FVIII, to protect against bleeding. The current report principally focuses on the future potential for "personalised" management of VWD, given the emerging options in recombinant therapies. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may soon change the way in which VWD is managed. In particular, we can envisage a personalised treatment approach using recombinant VWF, with or without recombinant FVIII, depending on the type of VWD, the extent of deficiencies, and the period and duration of treatment. PMID:27136426

  13. Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage

    Arunima Ghosh

    2012-01-01

    Full Text Available von Willebrand disease (VWD is the most common inherited human bleeding disorder and is caused by quantitative or qualitative defects in von Willebrand factor (VWF. VWF is a secreted glycoprotein that circulates as large multimers. While reduced VWF is associated with bleeding, elevations in overall level or multimer size are implicated in thrombosis. The zebrafish is a powerful genetic model in which the hemostatic system is well conserved with mammals. The ability of this organism to generate thousands of offspring and its optical transparency make it unique and complementary to mammalian models of hemostasis. Previously, partial clones of zebrafish vwf have been identified, and some functional conservation has been demonstrated. In this paper we clone the complete zebrafish vwf cDNA and show that there is conservation of domain structure. Recombinant zebrafish Vwf forms large multimers and pseudo-Weibel-Palade bodies (WPBs in cell culture. Larval expression is in the pharyngeal arches, yolk sac, and intestinal epithelium. These results provide a foundation for continued study of zebrafish Vwf that may further our understanding of the mechanisms of VWD.

  14. Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor.

    Tischer, Alexander; Campbell, James C; Machha, Venkata R; Moon-Tasson, Laurie; Benson, Linda M; Sankaran, Banumathi; Kim, Choel; Auton, Matthew

    2016-02-19

    Unusually large von Willebrand factor (VWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease, two rare mutations (G1324A and G1324S) within the platelet GPIbα binding interface of the VWF A1 domain impair the hemostatic function of VWF. We investigate structural and conformational effects of these mutations on the A1 domain's efficacy to bind collagen and adhere platelets under shear flow. These mutations enhance the thermodynamic stability, reduce the rate of unfolding, and enhance the A1 domain's resistance to limited proteolysis. Collagen binding affinity is not significantly affected indicating that the primary stabilizing effect of these mutations is to diminish the platelet binding efficiency under shear flow. The enhanced stability stems from the steric consequences of adding a side chain (G1324A) and additionally a hydrogen bond (G1324S) to His(1322) across the β2-β3 hairpin in the GPIbα binding interface, which restrains the conformational degrees of freedom and the overall flexibility of the native state. These studies reveal a novel rheological strategy in which the incorporation of a single glycine within the GPIbα binding interface of normal VWF enhances the probability of local unfolding that enables the A1 domain to conformationally adapt to shear flow while maintaining its overall native structure. PMID:26677223

  15. Exercise induced von Willebrand Factor release -- new model for routine endothelial testing.

    Balen, Sanja; Ruzić, Alen; Mirat, Jure; Persić, Viktor

    2007-01-01

    Endothelial dysfunction (ED) is actively involved in the mechanism of occurrence, development and progression of all the degrees of atherosclerosis. The established impact of ED on the progress and outcome of cardiovascular diseases, together with convincing indications of a possible successful therapeutic modification, necessitate the changeover of ED assessment from experimental to a routine practice. As there is no appropriate method for a clinical practice, scientists anticipate significant research efforts in the further development. Among numerous methods already available, von Willebrand Factor (vWF) stands out significantly. In accordance with the accepted leading diagnostic role of vWF baseline levels in the group of peripheral endothelial markers, and earlier scientific observations on the absence of its expected reactivation during physical exercise, we hypothesised this promising theory. We believe that a constant stronger release of vWF in endothelial cell injury leads to the exhaustion of its stores in Weibel-Palade bodies with the consequent absence of the expected rise of concentration during the exercise. Therefore, we hypothesised that ED could be exhaustible vWF endothelopathy and the exercise induced release of vWF a new, simple, safe and reliable test for the detection of ED and monitoring of the expected therapeutic effect. In order to have a final clinical usability of the proposed diagnostic model, it is necessary to test its reliability in different pathological and risk states, and establish susceptibility in therapeutic procedures. The correlation with invasive functional angiographic tests and the flow mediated dilatation test of peripheral arteries also needs to be validated. We expect the proposed test of vWF inducibility to find its place in clinical practice, i.e. in prevention, prediction and therapy of cardiovascular diseases. PMID:17507174

  16. Identification of a Small Molecule That Modulates Platelet Glycoprotein Ib-von Willebrand Factor Interaction*

    Broos, Katleen; Trekels, Mieke; Jose, Rani Alphonsa; Demeulemeester, Jonas; Vandenbulcke, Aline; Vandeputte, Nele; Venken, Tom; Egle, Brecht; De Borggraeve, Wim M.; Deckmyn, Hans; De Maeyer, Marc

    2012-01-01

    The von Willebrand factor (VWF) A1-glycoprotein (GP) Ibα interaction is of major importance during thrombosis mainly at sites of high shear stress. Inhibitors of this interaction prevent platelet-dependent thrombus formation in vivo, without major bleeding complications. However, the size and/or protein nature of the inhibitors currently in development limit oral bioavailability and clinical development. We therefore aimed to search for a small molecule protein-protein interaction inhibitor interfering with the VWF-GPIbα binding. After determination of putative small molecule binding pockets on the surface of VWF-A1 and GPIbα using site-finding algorithms and molecular dynamics, high throughput molecular docking was performed on both binding partners. A selection of compounds showing good in silico docking scores into the predicted pockets was retained for testing their in vitro effect on VWF-GPIbα complex formation, by which we identified a compound that surprisingly stimulated the VWF-GPIbα binding in a ristocetin cofactor ELISA and increased platelet adhesion in whole blood to collagen under arterial shear rate but in contrast inhibited ristocetin-induced platelet aggregation. The selected compound adhering to the predicted binding partner GPIbα could be confirmed by saturation transfer difference NMR spectroscopy. We thus clearly identified a small molecule that modulates VWF-GPIbα binding and that will now serve as a starting point for further studies and chemical modifications to fully characterize the interaction and to manipulate specific activity of the compound. PMID:22232560

  17. von Willebrand factor A1 domain can adequately substitute for A3 domain in recruitment of flowing platelets to collagen

    Bonnefoy, A.; Romijn, R. A.; Vandervoort, P. A. H.; Van Rompaey, I.; Vermylen, J.; Hoylaerts, M. F.

    2006-01-01

    Background: Binding of von Willebrand factor (VWF) to platelet GPIb alpha and to collagen is attributed to VWF A1 and A3 domains, respectively. Objectives: Using VWF, VWF lacking A1 (Delta A1-VWF) or A3 (Delta A3-VWF) and VWF with defective A3 (H1786A-VWF), in combination with recombinant A1 (residu

  18. Von Willebrand factor in patients on mechanical circulatory support – a double-edged sword between bleeding and thrombosis

    Kaczmarski, Jacek; Pacholewicz, Jerzy; Zakliczynski, Michal; Gasior, Mariusz; Zembala, Marian

    2015-01-01

    Mechanical circulatory support (MCS) is an umbrella term describing the various technologies used in both short- and long-term management of patients with either end-stage chronic heart failure (HF) or acute HF. Most often, MCS has emerged as a bridge to transplantation, but more recently it is also used as a destination therapy. Mechanical circulatory support includes left ventricular assist device (LVAD) or bi-ventricular assist device (Bi-VAD). Currently, 2- to 3-year survival in carefully selected patients is much better than with medical therapy. However, MCS therapy is hampered by sometimes life-threatening complications including bleeding and device thrombosis. Von Willebrand factor (vWF) has two major functions in haemostasis. First, it plays a crucial role in platelet-subendothelium adhesion and platelet-platelet interactions (aggregation). Second, it is the carrier of factor VIII (FVIII) in plasma. Von Willebrand factor prolongs FVIII half-time by protecting it from proteolytic degradation. It delivers FVIII to the site of vascular injury thus enhancing haemostatic process. On one hand, high plasma levels of vWF have been associated with an increased risk of thrombosis. On the other, defects or deficiencies of vWF underlie the inherited von Willebrand disease or acquired von Willebrand syndrome. Here we review the pathophysiology of thrombosis and bleeding associated with vWF. PMID:26702279

  19. Diagnosis of congenital von Willebrand disease during a preoperative assessment in a multiple myeloma patient without bleeding history.

    El Ouaaliti, Malika; Li, Rong; Gobin, Delphine; Bron, Dominique; Cantinieaux, Brigitte

    2016-07-01

    We report a rare case of type 2M von Willebrand disease diagnosed in an elderly multiple myeloma patient who had no personal and family bleeding history. This case report emphasis the importance to not systematically exclude a congenital vWD in adult patients when coagulation screening tests indicate toward a vWD. PMID:27386134

  20. Cerebral venous thrombosis associated with thyrotoxicosis, the use of desmopressin and elevated factor VIII/von Willebrand factor.

    Waheed, Waqar; Aljerdi, Salman; Decker, Barbara; Cushman, Mary; Hamill, Robert W

    2016-01-01

    Cerebral venous thrombosis (CVT) is an uncommon disorder associated with diverse processes. We report a patient who, while receiving desmopressin and contraceptive pills (OCP), developed straight sinus thrombosis. Clinical assessment and laboratory investigations revealed untreated hyperthyroidism and a hypercoagulable state, characterised by high levels of von Willebrand factor, factor VIII coagulant activity and IgM cardiolipin antibody. The clinical picture improved with anticoagulation, treatment of hyperthyroidism and discontinuation of OCP and desmopressin. To the best of our knowledge, the association between the use of oral desmopressin and CVT has not been described. The multiple risk factors present in our case were probably additive in increasing the risk of CVT. Although this case represents a rare occurrence, practitioners should be alerted to the possible associations of desmopressin, oral contraceptives and Graves' disease with venous thrombosis. PMID:27503942

  1. Fluid-phase immunoradiometric assay for the detection of qualitative abnormalities of factor VIII/von Willebrand factor in variants of von Willebrand's disease

    Antigenic reactivity of F.VIII/WF in variants of von Willebrand's disease (vWd) was studied with both fluid-phase and solid-phase immunoradiometric assays. Two different (rabbit and goat) 125I-labeled specific antibodies against purified F.VIII/WF were used in both their divalent (lgG) and their monovalent (Fab fragment) forms. Dose-response curves obtained by reacting a constant amount of antibody with serial dilutions of plasmas from normal or homozygous vWd demonstrated the specificity of the test. The accuracy was significantly higher with 125I-Fab fragments of goat anti-F.VIII/WF antiserum than intact goat lgG or rabbit lgG or Fab fragments. The significant decrease of the slope of the dose-response curves obtained with plasma from variants of vWd has been interpreted as due to the presence of abnormal F.VIII/WF molecules with decreased antigenic reactivity. A similar anomaly was found in cryosupernatant prepared from normal plasma, paralleling similarities demonstrated between variants of vWd and cryosupernatant. Results of experiments performed by reacting constant plasma dilutions from control or variants of vWd and varying concentrations of anti-F.VIII/WF Fab fragments (rabbit or goat) confirmed the decreased antigenic reactivity of variant F.VIII/WF

  2. A novel ELISA-based diagnosis of acquired von Willebrand disease with increased VWF proteolysis.

    Rauch, Antoine; Caron, Claudine; Vincent, Flavien; Jeanpierre, Emmanuelle; Ternisien, Catherine; Boisseau, Pierre; Zawadzki, Christophe; Fressinaud, Edith; Borel-Derlon, Annie; Hermoire, Sylvie; Paris, Camille; Lavenu-Bombled, Cécile; Veyradier, Agnès; Ung, Alexandre; Vincentelli, André; van Belle, Eric; Lenting, Peter J; Goudemand, Jenny; Susen, Sophie

    2016-05-01

    Von Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speed-dependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWD-patients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWF-proteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis. PMID:26791163

  3. Analysis of the complexity of the multimeric structure of factor VIII related antigen/von Willebrand protein using a modified electrophoretic technique.

    Enayat, M S; Hill, F G

    1983-01-01

    A method for multimeric analysis of factor VIII related antigen/von Willebrand protein is described. By modifying an existing method the technique has been simplified and optimised so that the different molecular forms of factor VIII related antigen and their triplet structure can be visualised. Clear differences can be seen between patterns in normals and type IIA von Willebrand's disease variants in that the latter lack high and intermediate multimers and also have a different configuration...

  4. The markers of platelet functions and Von Willebrand factor serum content from patients with type 2 diabetes mellitus and ishemic stroke

    Tetiana Tsarenko

    2016-03-01

    Full Text Available Introduction: The est and #1110;mated number of people with diabetes worldwide in 2015 is 415 million persons, up to 91% of adults hadtype 2 diabetes and the crude incidence of stroke among patients with diabetes of the 2ndtype can be more than 3 times that in the general population. It is known platelet activation and aggregation are critical in the pathogenesis of acute ischemic cerebrovascular diseases. Thus to examine the evidence of platelet functioning such as platelet count,aggregation in response to ADP, coagulation von Willebrand factor and serotonin content, monoamine oxidase (MAO activity in the blood of patients with ischemic stroke and with ischemic stroke complicated with the 2ndtype diabetes are the aim of the present study. Methods: The platelet aggregation was assayed for photo-optical aggregometer, von Willebrand factor was determined by Elisa, serotonin determination included ion-exchange chromatography and fluorescence spectrophotometry. Determination of monoamine-oxidase serum activity was spectophotometry. Results: The investigation has shown an increase of serotonin and Von Willebrand factor blood content in both groups of patients with ischemic stroke andtype 2 diabetes and stroke alone compared with the values of the control group. The monoamine oxidase activity and platelet count were reduced in blood of patients with diabetes of the 2ndtype with ischemic stroke against to the values from the group of healthy donors. Platelet aggregation in response to ADP increased under the investigated pathologies. Conclusions: These obtained data suggested a significant imbalance in vascular platelet element of hemostasis under the ischemic stroke and amplification of negative changes under the stroke with the 2ndtype diabetes. [Biomed Res Ther 2016; 3(3.000: 542-547

  5. Hemophilia and von Willebrand's disease: 1. Diagnosis, comprehensive care and assessment. Association of Hemophilia Clinic Directors of Canada.

    1995-01-01

    OBJECTIVE: To present current strategies for the assessment and comprehensive care of patients with hemophilia and von Willebrand's disease. OPTIONS: Hospital care, home care, single-provider care and multidisciplinary care. OUTCOMES: Morbidity and quality of life associated with bleeding and treatment. EVIDENCE: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of own reprint files, MEDLINE, citations in the articles reviewed and referenc...

  6. Domain-and species-specific monoclonal antibodies recognize the Von Willebrand Factor-C domain of CCN5

    Wei, Lan; McKeon, Frank; Russo, Joshua W.; Lemire, Joan; Castellot, John

    2009-01-01

    The CCN family of proteins typically consists of four distinct peptide domains: an insulin-like growth factor binding protein-type (IGFBP) domain, a Von Willebrand Factor C (VWC) domain, a thrombospondin type 1 repeat (TSP1) domain, and a carboxy-terminal (CT) domain. The six family members participate in many processes, including proliferation, motility, cell-matrix signaling, angiogenesis, and wound healing. Accumulating evidence suggests that truncated and alternatively spliced isoforms ar...

  7. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans.

    Bauer, Alexander T; Suckau, Jan; Frank, Kathrin; Desch, Anna; Goertz, Lukas; Wagner, Andreas H; Hecker, Markus; Goerge, Tobias; Umansky, Ludmila; Beckhove, Philipp; Utikal, Jochen; Gorzelanny, Christian; Diaz-Valdes, Nancy; Umansky, Viktor; Schneider, Stefan W

    2015-05-14

    Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation. PMID:25977583

  8. Acute hyperglycemia alters von Willebrand factor but not the fibrinolytic system in elderly subjects with normal or impaired glucose tolerance.

    Coppola, Ludovico; Coppola, Antonino; Grassia, Antonio; Mastrolorenzo, Luigia; Lettieri, Biagio; De Lucia, Domenico; De Nanzio, Annarita; Gombos, Giorgio

    2004-10-01

    To assess whether acute hyperglycemia affects fibrinolytic balance in elderly subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT), 40 non-obese elderly subjects (20 NGT, age 68 +/- 8 years; and 20 IGT, age 69 +/- 11 years) were studied. On two experimental days, randomly allocated and spaced 1 week apart, plasma concentrations of glucose, insulin, fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor type 1 and von Willebrand factor (vWF) were measured in each subject at baseline (0) and 30, 60, 90, 120 min after the ingestion of 75 g glucose or a similarly sweet dose of aspartame (250 mg) (control test). In both NGT and IGT elderly subjects, tissue plasminogen activator, plasminogen activator inhibitor type 1 and fibrinogen plasma levels did not significantly change after both oral aspartame and glucose load. In IGT subjects, vWF plasmatic levels decreased after glucose (not aspartame) oral load, reaching the minimum level at 90 min after load (82.7 +/- 7.8 versus 93.7 +/- 10.2, P <0.01). These results demonstrate that acute hyperglycemia does not modify plasma fibrinolysis in elderly subjects. The decrease of plasma concentration of vWF in IGT elderly subjects requires cautious interpretation and further extensive investigations. PMID:15613917

  9. Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease

    Youmna E. DiStefano

    2015-01-01

    Full Text Available Peripheral nerve blockade (PNB is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR. Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD. Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year-old female undergoing TKR. A Humate-P intravenous infusion was started and the patient was positioned supinely. Using sterile technique with ultrasound guidance, a Contiplex 18 Gauge Tuohy needle was advanced in plane through the fascia iliaca towards the femoral nerve. A nerve catheter was threaded through the needle and secured without complications. Postoperatively, a levobupivacaine femoral catheter infusion was maintained, and twice daily Humate-P intravenous infusions were administered for 48 hours; enoxaparin thromboprophylaxis was initiated thereafter. The patient was discharged uneventfully on postoperative day 4. Given documentation of delayed, unheralded bleeding from PNB in coagulopathic patients, we recommend individualized PNB in vWD patients. Multidisciplinary team involvement is required to guide factor supplementation and thromboprophylaxis, as is close follow-up to elicit signs of bleeding throughout the delayed postoperative period.

  10. The structure of the TFIIH p34 subunit reveals a von Willebrand factor A like fold.

    Dominik R Schmitt

    Full Text Available RNA polymerase II dependent transcription and nucleotide excision repair are mediated by a multifaceted interplay of subunits within the general transcription factor II H (TFIIH. A better understanding of the molecular structure of TFIIH is the key to unravel the mechanism of action of this versatile protein complex within these vital cellular processes. The importance of this complex becomes further evident in the context of severe diseases like xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy, that arise from single point mutations in TFIIH subunits. Here we describe the structure of the p34 subunit of the TFIIH complex from the eukaryotic thermophilic fungus Chaetomium thermophilum. The structure revealed that p34 contains a von Willebrand Factor A (vWA like domain, a fold which is generally known to be involved in protein-protein interactions. Within TFIIH p34 strongly interacts with p44, a positive regulator of the helicase XPD. Putative protein-protein interfaces are analyzed and possible binding sites for the p34-p44 interaction suggested.

  11. PROTEOLYTIC PROCESSING OF VON WILLEBRAND FACTOR BY ADAMTS13 AND LEUKOCYTE PROTEASES

    Stefano Lancellotti

    2013-09-01

    Full Text Available ADAMTS13 is a 190 kDa zinc protease encoded by a gene located on chromosome 9q34.   This protease specifically hydrolyzes von Willebrand factor (VWF multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1 repeats, a cysteine-rich domain, a spacer domain and 2 CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein domains. ADAMTS13 cleaves a single peptide bond (Tyr1605-Met1606 in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultra-large VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form with platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs. In this review, we a discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, b address the recent findings concerning proteolytic processing of VWF multimers by different proteases, such as the leukocyte-derived serine and metallo-proteases and c indicate the direction of future investigations

  12. Severe nose bleeding after intake of acetylsalicylic acid: von Willebrand disease type 2A. Case 9.

    von der Weid, N X; Mansouri Taleghani, B; Wuillemin, W A

    2003-08-01

    This case report of a school boy with a history of severe and repeated episodes of epistaxis presents a short overview of the clinical and laboratory findings which lead to confirm the suspected diagnosis of von Willebrand disease (vWD). Suspicion of defective primary haemostasis should arise when unusual (because of their number or duration) mucosal bleeds appear in an otherwise normal and healthy patient. Because of its definitive inhibitory effect on platelet aggregation, acetylsalicylic acid (more than other non-steroidal anti-inflammatory drugs exerting unselective inhibition of cyclooxygenase) is a strong factor in triggering or sustaining the bleeding disorders in these patients. Among the congenital disorder of primary haemostasis, vWD is by far the most frequent one. The difficulties of laboratory diagnosis of vWD are stressed; the promises and pitfalls of new in vitro methods for measuring primary haemostasis (PFA-100 analyzer) are discussed. An accurate diagnosis of the specific type of vWD is of critical importance for correct patient management as well as for genetic counseling. PMID:12923584

  13. The spider hemolymph clot proteome reveals high concentrations of hemocyanin and von Willebrand factor-like proteins.

    Sanggaard, Kristian W; Dyrlund, Thomas F; Bechsgaard, Jesper S; Scavenius, Carsten; Wang, Tobias; Bilde, Trine; Enghild, Jan J

    2016-02-01

    Arthropods include chelicerates, crustaceans, and insects that all have open circulation systems and thus require different properties of their coagulation system than vertebrates. Although the clotting reaction in the chelicerate horseshoe crab (Family: Limulidae) has been described in details, the overall protein composition of the resulting clot has not been analyzed for any of the chelicerates. The largest class among the chelicerates is the arachnids, which includes spiders, ticks, mites, and scorpions. Here, we use a mass spectrometry-based approach to characterize the spider hemolymph clot proteome from the Brazilian whiteknee tarantula, Acanthoscurria geniculata. We focused on the insoluble part of the clot and demonstrated high concentrations of proteins homologous to the hemostasis-related and multimerization-prone von Willebrand factor. These proteins, which include hemolectins and vitellogenin homologous, were previously identified as essential components of the hemolymph clot in crustaceans and insects. Their presence in the spider hemolymph clot suggests that the origin of these proteins' function in coagulation predates the split between chelicerates and mandibulata. The clot proteome reveals that the major proteinaceous component is the oxygen-transporting and phenoloxidase-displaying abundant hemolymph protein hemocyanin, suggesting that this protein also plays a role in clot biology. Furthermore, quantification of the peptidome after coagulation revealed the simultaneous activation of both the innate immune system and the coagulation system. In general, many of the identified clot-proteins are related to the innate immune system, and our results support the previously suggested crosstalk between immunity and coagulation in arthropods. PMID:26621385

  14. Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene

    Pena, S.D.J.; De Souza, K.T. (Nucleo de Genetica Medica de Minas Gerais, Belo Horizonte (Brazil)); De Andrade, M.; Chakraborty, R. (Univ. of Texas Graduate School of Biomedical Sciences, Houston, TX (United States))

    1994-01-18

    At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the same alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, the authors observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of cooperative changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes.

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

    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

  16. Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation

    Boerma, M.; Loenen, M.M. van; Klein, H.R.; Bart, C.I.; Wondergem, J. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Kruse, J.J.C.M. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Dept. of Experimental Therapy (H6), Netherlands Cancer Inst., Amsterdam (Netherlands); Zurcher, C. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Dept. of Pathology, Faculty of Veterinary Medicine, Univ. of Utrecht (Netherlands)

    2004-02-01

    Background and purpose: von willebrand factor (vWf), a glycoprotein involved in blood coagulation, is synthesized by endothelial cells. Increased amounts of vWf in blood plasma or tissue samples are indicative of damaged endothelium. In the present study, mRNA expression and localization of vWf were determined in irradiated rat heart tissue. Material and methods: sprague-dawley rats received local heart irradiation with a single dose of 0, 15, or 20 Gy. Hearts were dissected at different time points (up to 16 months) after irradiation. In a second experiment, rats were injected with the radioprotector amifostine (160 mg/kg, i.p.) 15-20 min before irradiation and sacrificed after 6 months. Immunohistochemistry was performed using a polyclonal anti-vWf antibody. Serial sections were subjected to a general rat endothelial cell immunostaining (RECA-1) or a collagen staining (picrosirius red). mRNA expression was determined by using PCR. Results: in control tissue, all endothelial cells lining the lumen of the endocardium and coronary arteries, but not capillary endothelial cells, were stained for vWf. 1 month after irradiation with both 15 and 20 Gy, myocardial capillaries became immunoreactive. From 3 months onward, staining was observed also within the extracellular matrix (ECM) of fibrotic areas. At mRNA level, no changes in vWf could be observed at all time points after irradiation, suggesting that vWf deposition was not due to increased biosynthesis of the protein. In sections of amifostine-treated rat hearts, vWf staining was increased to a lesser extent. Conclusion: these dose- and time-dependent increases in deposition of vWf indicate the presence of damaged endothelium in the irradiated rat heart. These increases in vWf accumulation precede development of fibrosis in the subendocardial layer and myocardium of the left ventricles, right ventricles, and atria. (orig.)

  17. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.

    Larkin, Deirdre

    2009-03-01

    Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF:Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF:CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU\\/ml versus 1.9 IU\\/ml; p<0.005). This increased VWF:CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF:Ag and VWF:CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (approximately 55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor.

  18. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.

    Deirdre Larkin

    2009-03-01

    Full Text Available Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20 and cerebral (n = 13 P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF:Ag level is associated with disproportionately increased VWF function. VWF collagen binding (VWF:CB was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU/ml versus 1.9 IU/ml; p<0.005. This increased VWF:CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF:Ag and VWF:CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (approximately 55% of normal; p<0.005. Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1. These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor.

  19. Cesariana em paciente com doença de von Willebrand associada à infecção pelo HIV: relato de caso Cesárea en paciente con enfermedad de von Willebrand asociada a la infección por el HIV: relato de caso Anesthesia for cesarean section in patient with von Willebrand's disease and HIV infection: case report

    Vanessa Rezende Balle

    2004-12-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: A doença de von Willebrand é a alteração inata da coagulação mais freqüente em mulheres jovens. A infecção por HIV tem mostrado incidência progressivamente maior em mulheres, constatando-se transmissão vertical em até 25% dos casos. O objetivo deste relato é mostrar o caso de uma paciente com doença de von Willebrand e HIV positivo submetida à cesariana. RELATO DO CASO: Paciente de 24 anos, portadora de anemia microcítica, doença de von Willebrand e HIV, chegou à emergência obstétrica em início de trabalho de parto. Não realizou pré-natal. Foi indicada cesariana a fim de diminuir os riscos de transmissão vertical em paciente com carga viral de HIV desconhecida. Apresentava hematomas pelo corpo e história de hematoma de parede abdominal em cesariana anterior. Os testes de coagulação eram pouco alterados. Após infusão de concentrado de fator VIII foi realizada anestesia geral. Mãe e recém-nascido apresentaram evolução satisfatória. CONCLUSÕES: A avaliação de manifestações clínicas em pacientes com coagulopatia é fundamental na decisão do tipo de anestesia a ser indicada para cada paciente. A avaliação deve ser individualizada, considerando os riscos e benefícios da técnica escolhida. Nestas pacientes, deve-se sempre restringir ao máximo a indicação de interrupção da gestação por via alta, optando-se sempre pelos métodos menos invasivos. A terapia com concentrado de fator VIII é atualmente a melhor opção de tratamento, corrigindo a deficiência específica e diminuindo os riscos de transmissão viral.JUSTIFICATIVA Y OBJETIVOS: La enfermedad de von Willebrand es la alteración innata de la coagulación más frecuente en mujeres jóvenes. La infección por HIV ha mostrado incidencia progresivamente mayor en mujeres, constatandose transmisión vertical en hasta 25% de los casos. El objetivo de este relato es mostrar el caso de una paciente con Enfermedad de von

  20. Plasma von Willebrand factor as a predictor of survival in pulmonary arterial hypertension associated with congenital heart disease

    A.A. Lopes

    2011-12-01

    Full Text Available Biomarkers have been identified for pulmonary arterial hypertension, but are less well defined for specific etiologies such as congenital heart disease-associated pulmonary arterial hypertension (CHDPAH. We measured plasma levels of eight microvascular dysfunction markers in CHDPAH, and tested for associations with survival. A cohort of 46 inoperable CHDPAH patients (age 15.0 to 60.2 years, median 33.5 years, female:male 29:17 was prospectively followed for 0.7 to 4.0 years (median 3.6 years. Plasma levels of von Willebrand factor antigen (VWF:Ag, tissue plasminogen activator (t-PA and its inhibitor (PAI-1, P-selectin, reactive C-protein, tumor necrosis factor alpha, and interleukin-6 and -10 were measured at baseline, and at 30, 90, and 180 days in all subjects. Levels of six of the eight proteins were significantly increased in patients versus controls (13 to 106% increase, P < 0.003. Interleukin-10 level was 2.06 times normal (P = 0.0003; Th2 cytokine response. Increased levels of four proteins (t-PA, PAI-1, P-selectin, and interleukin-6 correlated with disease severity indices (P < 0.05. Seven patients died during follow-up. An average VWF:Ag (mean of four determinations above the level corresponding to the 95th percentile of controls (139 U/dL was independently associated with a high risk of death (hazard ratio = 6.56, 95%CI = 1.46 to 29.4, P = 0.014. Thus, in CHDPAH, microvascular dysfunction appears to involve Th2 inflammatory response. Of the biomarkers studied, plasma vWF:Ag was independently associated with survival.

  1. Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis.

    Andreas Wannhoff

    Full Text Available In patients with liver cirrhosis procoagulant and anticoagulant changes occur simultaneously. During primary hemostasis, platelets adhere to subendothelial structures, via von Willebrand factor (vWF. We aimed to investigate the influence of vWF on primary hemostasis in patients with liver cirrhosis. Therefore we assessed in-vitro bleeding time as marker of primary hemostasis in cirrhotic patients, measuring the Platelet Function Analyzer (PFA-100 closure times with collagen and epinephrine (Col-Epi, upper limit of normal ≤ 165 s or collagen and ADP (Col-ADP, upper limit of normal ≤ 118 s. If Col-Epi and Col-ADP were prolonged, the PFA-100 was considered to be pathological. Effects of vWF on primary hemostasis in thrombocytopenic patients were analyzed and plasma vWF levels were modified by adding recombinant vWF or anti-vWF antibody. Of the 72 included cirrhotic patients, 32 (44.4% showed a pathological result for the PFA-100. They had mean closure times (± SD of 180 ± 62 s with Col-Epi and 160 ± 70 s with Col-ADP. Multivariate analysis revealed that hematocrit (P = 0.027 and vWF-antigen levels (P = 0.010 are the predictors of a pathological PFA-100 test in cirrhotic patients. In 21.4% of cirrhotic patients with platelet count ≥ 150/nL and hematocrit ≥ 27.0%, pathological PFA-100 results were found. In thrombocytopenic (< 150/nL patients with cirrhosis, normal PFA-100 results were associated with higher vWF-antigen levels (462.3 ± 235.9% vs. 338.7 ± 151.6%, P = 0.021. These results were confirmed by multivariate analysis in these patients as well as by adding recombinant vWF or polyclonal anti-vWF antibody that significantly shortened or prolonged closure times, respectively. In conclusion, primary hemostasis is impaired in cirrhotic patients. The effect of reduced platelet count in cirrhotic patients can at least be partly compensated by increased vWF levels. Recombinant vWF could be an alternative to platelet transfusions in the

  2. Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis.

    Wannhoff, Andreas; Müller, Oliver J; Friedrich, Kilian; Rupp, Christian; Klöters-Plachky, Petra; Leopold, Yvonne; Brune, Maik; Senner, Mirja; Weiss, Karl-Heinz; Stremmel, Wolfgang; Schemmer, Peter; Katus, Hugo A; Gotthardt, Daniel N

    2014-01-01

    In patients with liver cirrhosis procoagulant and anticoagulant changes occur simultaneously. During primary hemostasis, platelets adhere to subendothelial structures, via von Willebrand factor (vWF). We aimed to investigate the influence of vWF on primary hemostasis in patients with liver cirrhosis. Therefore we assessed in-vitro bleeding time as marker of primary hemostasis in cirrhotic patients, measuring the Platelet Function Analyzer (PFA-100) closure times with collagen and epinephrine (Col-Epi, upper limit of normal ≤ 165 s) or collagen and ADP (Col-ADP, upper limit of normal ≤ 118 s). If Col-Epi and Col-ADP were prolonged, the PFA-100 was considered to be pathological. Effects of vWF on primary hemostasis in thrombocytopenic patients were analyzed and plasma vWF levels were modified by adding recombinant vWF or anti-vWF antibody. Of the 72 included cirrhotic patients, 32 (44.4%) showed a pathological result for the PFA-100. They had mean closure times (± SD) of 180 ± 62 s with Col-Epi and 160 ± 70 s with Col-ADP. Multivariate analysis revealed that hematocrit (P = 0.027) and vWF-antigen levels (P = 0.010) are the predictors of a pathological PFA-100 test in cirrhotic patients. In 21.4% of cirrhotic patients with platelet count ≥ 150/nL and hematocrit ≥ 27.0%, pathological PFA-100 results were found. In thrombocytopenic (< 150/nL) patients with cirrhosis, normal PFA-100 results were associated with higher vWF-antigen levels (462.3 ± 235.9% vs. 338.7 ± 151.6%, P = 0.021). These results were confirmed by multivariate analysis in these patients as well as by adding recombinant vWF or polyclonal anti-vWF antibody that significantly shortened or prolonged closure times, respectively. In conclusion, primary hemostasis is impaired in cirrhotic patients. The effect of reduced platelet count in cirrhotic patients can at least be partly compensated by increased vWF levels. Recombinant vWF could be an alternative to platelet transfusions in the future

  3. Dogs with hearth diseases causing turbulent high-velocity blood flow have changes in patelet function and von Willebrand factor multimer distribution

    Tarnow, Inge; Kristensen, Annemarie Thuri; Olsen, Lisbeth Høier; Falk, Bo Torkel; Haubro, Lotte; Pedersen, Lotte Gam; Pedersen, Henrik Duelund

    2005-01-01

    echocardiography were performed in all dogs. PFA100 closure times (the ability of platelets to occlude a hole in a membrane at high shear rates), platelet activation markers (plasma thromboxane B2 concentration, platelet surface P-selectin expression), platelet aggregation (in whole blood and platelet-rich plasma......The purpose of this prospective study was to investigate platelet function using in vitro tests based on both high and low shear rates and von Willebrand factor (vWf) multimeric composition in dogs with cardiac disease and turbulent high-velocity blood flow. Client-owned asymptomatic, untreated...... with 3 different agonists), and vWf multimers were analyzed. Cavaliers with moderate to severe MR and dogs with SAS had longer closure times and a lower percentage of the largest vWf multimers than did controls. Maximal aggregation responses were unchanged in dogs with SAS but enhaned in Cavaliers with...

  4. Internal tension in a collapsed polymer under shear flow and the connection to enzymatic cleavage of von Willebrand factor.

    Radtke, Matthias; Lippok, Svenja; Rädler, Joachim O; Netz, Roland R

    2016-03-01

    By means of Brownian hydrodynamics simulations we show that the tension distribution along the contour of a single collapsed polymer in shear flow is inhomogeneous and above a threshold shear rate exhibits a double-peak structure when hydrodynamic interactions are taken into account. We argue that the tension maxima close to the termini of the polymer chain reflect the presence of polymeric protrusions. We establish the connection to shear-induced globule unfolding and determine the scaling behavior of the maximal tensile forces and the average protrusion length as a function of shear rate, globule size, and cohesive strength. A quasi-equilibrium theory is employed in order to describe the simulation results. Our results are used to explain experimental data for the shear-sensitive enzymatic degradation of von Willebrand factor. PMID:26993993

  5. Distribution and Evolution of von Willebrand/Integrin A Domains: Widely Dispersed Domains with Roles in Cell Adhesion and ElsewhereD⃞

    Whittaker, Charles A.; Hynes, Richard O.

    2002-01-01

    The von Willebrand A (VWA) domain is a well-studied domain involved in cell adhesion, in extracellular matrix proteins, and in integrin receptors. A number of human diseases arise from mutations in VWA domains. We have analyzed the phylogenetic distribution of this domain and the relationships among ∼500 proteins containing this domain. Although the majority of VWA-containing proteins are extracellular, the most ancient ones, present in all eukaryotes, are all intracellul...

  6. Anestesia para septoplastia e turbinectomia em paciente portador de doença de von Willebrand: relato de caso Anestesia para septoplastia y turbinectomia en paciente portador de enfermedad de von Willebrand: relato de caso Anesthesia for septoplasty and turbinectomy in von Willebrand disease patient: case report

    Múcio Paranhos de Abreu

    2003-06-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: Embora a doença de von Willebrand seja o mais comum dos distúrbios hemorrágicos hereditários, as publicações nacionais, relacionando esta doença e a prática anestésica, são escassas. O objetivo deste relato é apresentar um caso de anestesia geral para septoplastia e turbinectomia em paciente portador de doença de von Willebrand - Tipo I, tratado profilaticamente com desmopressina (1-deamino-8-D-arginina vasopressina, DDAVP nos períodos pré e pós-operatório. RELATO DO CASO: Paciente com 19 anos, sexo feminino, 58 kg, portadora de hipotiroidismo, controlado com L-tiroxina (75 mg, e de doença de von Willebrand, que se manifestou há três anos, após extração dentária dos sisos, com sangramento persistente no período pós-operatório. Com o objetivo de se evitar novos episódios hemorrágicos nos períodos per e pós-operatório da cirurgia de septoplastia e turbinectomia a que foi submetida, a paciente foi tratada profilaticamente com desmopressina (0,3 µg.kg-1. A indução anestésica foi realizada com midazolam (2,5 mg, fentanil (150 µg, droperidol (2,5 mg, lidocaína (60 mg, atracúrio (30 mg e metoprolol (4 mg, seguida de intubação traqueal e ventilação sob pressão positiva intermitente. A manutenção da anestesia foi realizada com mistura de oxigênio e óxido nitroso a 50% e sevoflurano a 2%. Esta técnica proporcionou um bom controle da freqüência cardíaca e dos níveis pressóricos durante a cirurgia. A paciente permaneceu com tampão nasal por 24 horas e, quando este foi retirado, não houve sangramento. A paciente recebeu alta hospitalar no dia seguinte ao da cirurgia, sem intercorrências. Não houve episódio hemorrágico no período pós-operatório imediato ou tardio. CONCLUSÕES: O tratamento profilático com DDAVP associado à técnica anestésica utilizada nesse caso, mostrou-se eficaz no controle do sangramento per e pós-operatório.JUSTIFICATIVA Y OBJETIVOS: Aun cuando

  7. Cost–consequence analysis of long-term prophylaxis in the treatment of von Willebrand disease in the Italian context

    Schinco P

    2014-12-01

    Full Text Available Piercarla Schinco,1 Dorina Cultrera,2 Federica Valeri,1 Alessandra Borchiellini,1 Michela Mantuano,3 Francesca Gorla,3 Alessia Savarese,3 Cristina Teruzzi3 1Hemostasis and Thrombosis Unit, Molinette Hospital of Turin, 2Department of Hematology, Hemophilia Regional Reference Center, University Hospital of Catania, 3HEMAR-Health Economics, Market Access and Reimbursement, Temas-A Quintiles Company, Milan, Italy Purpose: Prophylaxis with von Willebrand factor (VWF/factor VIII (FVIII concentrates is a potential approach for patients with severe von Willebrand disease (VWD. As far as we are aware, to date there have been no pharmacoeconomic analyses in order to assess the economic impact of treatments for severe VWD. The analysis presented here estimates the cost–benefit ratio of VWF with a low FVIII content when compared with VWF/FVIII concentrates currently used in Italy for long-term prophylaxis in patients with severe VWD. Methods: A cost–consequence analysis was undertaken to assess the economic impact of the treatment of severe VWD from the perspective both of the Italian National Health Service and society. The analysis was based on four case reports of long-term prophylaxis with VWD with VWF/FVIII concentrates and VWF with a low FVIII content. The costs per patient included direct and indirect costs for each treatment. Results: Considering the four case reports, health care costs (without cost of treatment and indirect costs per patient per year were lower with VWF with a low FVIII content than VWF/FVIII concentrates. The total health care costs (without cost of treatment and indirect costs avoided with VWF with a low FVIII content per patient per year ranged from €2,295 to €17,530 and from €1,867 to €4,978, respectively. Conclusion: VWF with a low FVIII content seems to be a cost-effective treatment option for patients with severe VWD. Although the drug cost per se is higher, the use of VWF with a low FVIII content is associated

  8. Limited polymorphism in Plasmodium falciparum ookinete surface antigen, von Willebrand factor A domain-related protein from clinical isolates

    Eisen Damon P

    2006-07-01

    Full Text Available Abstract Background As malaria becomes increasingly drug resistant and more costly to treat, there is increasing urgency to develop effective vaccines. In comparison to other stages of the malaria lifecycle, sexual stage antigens are under less immune selection pressure and hence are likely to have limited antigenic diversity. Methods Clinical isolates from a wide range of geographical regions were collected. Direct sequencing of PCR products was then used to determine the extent of polymorphisms for the novel Plasmodium falciparum sexual stage antigen von Willebrand Factor A domain-related Protein (PfWARP. These isolates were also used to confirm the extent of diversity of sexual stage antigen Pfs28. Results PfWARP was shown to have non-synonymous substitutions at 3 positions and Pfs28 was confirmed to have a single non-synonymous substitution as previously described. Conclusion This study demonstrates the limited antigenic diversity of two prospective P. falciparum sexual stage antigens, PfWARP and Pfs28. This provides further encouragement for the proceeding with vaccine trials based on these antigens.

  9. Analysis of von Willebrand factor A domain-related protein (WARP polymorphism in temperate and tropical Plasmodium vivax field isolates

    Zakeri Sedigheh

    2009-06-01

    Full Text Available Abstract Background The identification of key molecules is crucial for designing transmission-blocking vaccines (TBVs, among those ookinete micronemal proteins are candidate as a general class of malaria transmission-blocking targets. Here, the sequence analysis of an extra-cellular malaria protein expressed in ookinetes, named von Willebrand factor A domain-related protein (WARP, is reported in 91 Plasmodium vivax isolates circulating in different regions of Iran. Methods Clinical isolates were collected from north temperate and southern tropical regions in Iran. Primers have been designed based on P. vivax sequence (ctg_6991 which amplified a fragment of about 1044 bp with no size variation. Direct sequencing of PCR products was used to determine polymorphism and further bioinformatics analysis in P. vivax sexual stage antigen, pvwarp. Results Amplified pvwarp gene showed 886 bp in size, with no intron. BLAST analysis showed a similarity of 98–100% to P. vivax Sal-I strain; however, Iranian isolates had 2 bp mismatches in 247 and 531 positions that were non-synonymous substitution [T (ACT to A (GCT and R (AGA to S (AGT] in comparison with the Sal-I sequence. Conclusion This study presents the first large-scale survey on pvwarp polymorphism in the world, which provides baseline data for developing WARP-based TBV against both temperate and tropical P. vivax isolates.

  10. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients.

    Auerswald, Günter; Spranger, Torsten; Brackmann, Hans-Hermann

    2003-06-01

    Besides preventing bleeding episodes, common goals of the treatment of hemophilia include integrating of patients into a normal social life and optimizing their quality of life. Sufficient amounts of factor VIII (FVIII) concentrates, whether recombinant or plasma-derived, are continuously needed. Guidelines for quality assurance of treatment will be a cornerstone to maintain optimal clinical management of patients especially considering financial aspects. Advances in manufacturing technologies have made possible general availability of modern concentrates for the management of hemophilia A patients. Safety, cost and continuous supply of concentrates must be considered when deciding on a product for replacement therapy. As todays' products have reached an excellent margin of safety with regard to virus transmission, the development and treatment of inhibitors is currently the main concern for physicians and patients. The incidence of inhibitors is influenced by various patient-related factors such as mutation type or severity of the disease. Plasma-derived FVIII concentrates containing von Willebrand factor (VWF) may have clinical advantages over pure FVIII concentrates with regard to inhibitor development and inhibitor eradication. Clinical trials comparing FVIII/VWF concentrates with pure FVIII concentrates are lacking, thus a lower inhibitor incidence has not yet been proven. Data from Germany on immune tolerance induction with FVIII/VWF concentrates indicate higher success rates with these than with pure FVIII concentrates. In addition FVIII/VWF concentrates are the therapy of choice when immune tolerance therapy with pure FVIII products is not successful. PMID:12826531

  11. Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review.

    Franchini, Massimo; Lippi, Giuseppe

    2010-11-01

    The development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients. PMID:20838738

  12. Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels

    Nossent, Anne Yaël; Robben, J H; Deen, P M T; Vos, H L; Rosendaal, F R; Doggen, C J M; Hansen, J L; Sheikh, S P; Bertina, R M; Eikenboom, J C J

    2010-01-01

    -green fluorescent protein (GFP) cells, which is in accordance with increased levels of VWF propeptide associated with the 12E variant. The dissociation constant (K(D)) was 4.5 nm [95% confidence interval (CI) 3.6-5.4] for 12E-V2R-GFP and 16.5 nm (95% CI 10.1-22.9) for 12G-V2R-GFP. AVP-induced cAMP generation was......SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of VWF...... levels. The functionality of the G12E variant was studied in stably transfected MDCKII cells, expressing constructs of either 12G-V2R or 12E-V2R. Both V2R variants were fully glycosylated and expressed on the basolateral membrane. The binding affinity of V2R for AVP was increased three-fold in 12E-V2R...

  13. Changes in the pattern of distribution of von Willebrand factor in rat aortic endothelial cells following thrombin generation in vivo.

    Senis, Y A; Richardson, M; Tinlin, S; Maurice, D H; Giles, A R

    1996-04-01

    The pattern of distribution of von Willebrand factor (VWF) in relatively large sheets of rat aortic endothelial cells (EC) obtained by the Häutchen technique were analysed by immunocytochemistry and light microscopy. EC were examined pre and post administration of a procoagulant mixture of factor Xa (F.Xa) and phosphotidylcholine/phosphotidylserine (PCPS) vesicles which was demonstrated to result in the selective loss of high molecular weight multimers (HMWM) of plasma VWF in the rat. In placebo animals the pattern was heterogenous both in overall distribution and in individual cells which showed both a diffuse and granular pattern. Groups of intensely stained EC were oriented parallel to the longitudinal axis of the aorta and staining was particularly prominent around the orifices of the intercostal arteries, implicating shear-stress as a possible factor in VWF expression by EC. Changes in the pattern of distribution of staining were observed at various time points post-infusion of F.Xa/PCPS, suggesting the immediate release of VWF from EC stores followed by the recruitment of EC to synthesize and store VWF. These changes are consistent with the decrease in EC Weibel-Palade Body (WPB) content observed by EM in previously reported studies using this model. PMID:8611460

  14. Influence of atrial fibrillation on plasma von Willebrand factor, soluble E-selectin, and N-terminal pro B-type natriuretic peptide levels in systolic heart failure

    Freestone, B.; Gustasson, F.; Chong, A.Y.; Corell, P.; Kistorp, C.; Hildebrandt, P.; Lip, G.Y.H.

    2008-01-01

    Association class were similar. There were significant differences in NT-proBNP (p < 0.0001) and plasma vWF (p = 0.003) between patients and control subjects. On Tukey post hoe analysis, AF-HF patients had significantly increased NT-proBNP (p < 0.001) and vWF (p = 0.0183) but not E-selectin (p = 0.071) levels...... patients with systolic HF. Methods: We measured levels of plasma von Willebrand factor (vWF) and E-selectin (as indexes of endothelial damage/dysfunction and endothelial activation, respectively; both enzyme-linked immunosorbent assay) in patients with AF and HF (AF-HF), who were compared to patients with...... sinus rhythm and HF (SR-HF), as well as in age-matched, healthy, control subjects. We also assessed the relationship of vWF and E-selectin to plasma N-terminal pro B-type natriuretic peptide (NTpro-BNP), a marker for HF severity and prognosis. Results: One hundred ninety patients (73% men; mean age, 69...

  15. The endothelial cell markers von Willebrand Factor (vWF, CD31 and CD34 are lost in glomerulonephritis and no longer correlate with the morphological indices of glomerular sclerosis, interstitial fibrosis, activity and chronicity.

    Flaviu Bob

    2010-08-01

    Full Text Available Endothelial cells (ECs are active participants of an inflammatory process in glomeruli. EC damage has been shown to play an important role in the progression of glomerulonephritis (GN. The degree of glomerular and peritubular capillary loss in models of progressive renal disease correlates with the severity of glomerulosclerosis and interstitial fibrosis. The aim of our study was to analyze the association of vWF, CD31 and CD34 immunoreactivity with the morphological indices of glomerular sclerosis, interstitial fibrosis, activity and chronicity in GN. A cross-sectional study of 22 patients with GN was conducted. Conventional stains (hematoxylin-eosin, periodic acid Schiff and Trichrome GĂśmĂśri stains and immunohistochemistry (vWF, CD31 and CD34 were employed on kidney biopsies. Activity and chronicity of GN, as well as glomerular segmental sclerosis and interstitial fibrosis, were evaluated according to a scoring system initially used for lupus nephritis and antineutrophil-cytoplasmic-antibody-associated vasculitis. Immunohistochemistry was assessed using a semi-quantitative score. Statistical analysis was performed using EpiInfo 6.04. The mean patient age was 46.68+/-14.09; 14 patients were male, and eight were female. Performing Spearman's rank correlation test, no correlation was found between each marker and glomerular segmental sclerosis, interstitial fibrosis, activity and chronicity, which suggests a loss of these markers and microvasculature involvement.

  16. The endothelial cell markers von Willebrand Factor (vWF), CD31 and CD34 are lost in glomerulonephritis and no longer correlate with the morphological indices of glomerular sclerosis, interstitial fibrosis, activity and chronicity.

    Gluhovschi, Cristina; Gluhovschi, Gheorghe; Potencz, Elena; Herman, Diana; Trandafirescu, Virginia; Petrica, Ligia; Velciov, Silvia; Bozdog, Gheorghe; Bob, Flaviu; Vernic, Corina; Cioca, Daniel

    2010-01-01

    Endothelial cells (ECs) are active participants of an inflammatory process in glomeruli. EC damage has been shown to play an important role in the progression of glomerulonephritis (GN). The degree of glomerular and peritubular capillary loss in models of progressive renal disease correlates with the severity of glomerulosclerosis and interstitial fibrosis. The aim of our study was to analyze the association of vWF, CD31 and CD34 immunoreactivity with the morphological indices of glomerular sclerosis, interstitial fibrosis, activity and chronicity in GN. A cross-sectional study of 22 patients with GN was conducted. Conventional stains (hematoxylin-eosin, periodic acid Schiff and Trichrome Gömöri stains) and immunohistochemistry (vWF, CD31 and CD34) were employed on kidney biopsies. Activity and chronicity of GN, as well as glomerular segmental sclerosis and interstitial fibrosis, were evaluated according to a scoring system initially used for lupus nephritis and antineutrophil-cytoplasmic-antibody-associated vasculitis. Immunohistochemistry was assessed using a semi-quantitative score. Statistical analysis was performed using EpiInfo 6.04. The mean patient age was 46.68+/-14.09; 14 patients were male, and eight were female. Performing Spearman's rank correlation test, no correlation was found between each marker and glomerular segmental sclerosis, interstitial fibrosis, activity and chronicity, which suggests a loss of these markers and microvasculature involvement. PMID:20675279

  17. Domain-and species-specific monoclonal antibodies recognize the Von Willebrand Factor-C domain of CCN5.

    Wei, Lan; McKeon, Frank; Russo, Joshua W; Lemire, Joan; Castellot, John

    2009-03-01

    The CCN family of proteins typically consists of four distinct peptide domains: an insulin-like growth factor binding protein-type (IGFBP) domain, a Von Willebrand Factor C (VWC) domain, a thrombospondin type 1 repeat (TSP1) domain, and a carboxy-terminal (CT) domain. The six family members participate in many processes, including proliferation, motility, cell-matrix signaling, angiogenesis, and wound healing. Accumulating evidence suggests that truncated and alternatively spliced isoforms are responsible for the diverse functions of CCN proteins in both normal and pathophysiologic states. Analysis of the properties and functions of individual CCN domains further corroborates this idea. CCN5 is unique among the CCN family members because it lacks the CT-domain. To dissect the domain functions of CCN5, we are developing domain-specific mouse monoclonal antibodies. Monoclonal antibodies have the advantages of great specificity, reproducibility, and ease of long-term storage and production. In this communication, we injected mixtures of GST-fused rat CCN5 domains into mice to generate monoclonal antibodies. To identify the domains recognized by the antibodies, we constructed serial expression plasmids that express dual-tagged rat CCN5 domains. All of the monoclonal antibodies generated to date recognize the VWC domain, indicating it is the most highly immunogenic of the CCN5 domains. We characterized one particular clone, 22H10, and found that it recognizes mouse and rat CCN5, but not human recombinant CCN5. Purified 22H10 was successfully applied in Western Blot analysis, immunofluorescence of cultured cells and tissues, and immunoprecipitation, indicating that it will be a useful tool for domain analysis and studies of mouse-human tumor models. PMID:19401828

  18. Valor pronóstico de los niveles plasmáticos del factor de Von Willebrand en pacientes con fibrilación auricular bajo : tratamiento oral

    Muiña Juárez, Begoña

    2016-01-01

    Introducción: La fibrilación auricular (FA) no valvular es la arritmia cardiaca más común y está asociada a un riesgo de ictus y de eventos tromboembólicas cinco veces superior a la población normal. El tratamiento anticoagulante oral (ACO) es la terapia más usada y efectiva para prevenir estos eventos tromboembólicas. Otra complicación frecuente en estos pacientes son los sangrados mayores, derivados del tratamiento. Niveles elevados del biomarcador plasmático, factor von Willebrand (FvW) s...

  19. The changes of von willebrand factor/a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 balance in aneurysmal subarachnoid hemorrhage

    Tang, Qi-Feng; Lu, Shi-qi; Zhao, Yi-ming; Qian, Jin-xian

    2015-01-01

    The aim of this study was to investigate the role of Von Willebrand Factor/thrombospondin type I repeats-13 (VWF/ADAMTS13) balance in aSAH. Fifty eight patients with aSAH at the First Affiliated hospital of Soochow University, Suzhou, China, between January 2012 and January 2014 were eligible for the study. They were divided into delayed cerebral ischemia group (DCI group) and non-delayed cerebral ischemia group (no DCI group), or cerebral vasospasm group (CVS group) and no spasm group (no CV...

  20. Pif97, a von Willebrand and Peritrophin Biomineralization Protein, Organizes Mineral Nanoparticles and Creates Intracrystalline Nanochambers.

    Chang, Eric P; Evans, John Spencer

    2015-09-01

    The formation of the mollusk nacre layer involves the assembly and organization of mineral nanoparticles into fracture-toughened mesoscale-sized aragonite tablets that possess intracrystalline nanoporosities. At least one nacre protein family, known as the framework proteome, is strategically located as part of a macromolecular coating around each nacre tablet and is believed to participate in tablet formation. Here, we report new studies of a recombinant form (rPif97) of a unique Japanese pearl oyster (Pinctada fucata) nacre framework biomineralization protein, Pif97. This unique protein possesses both a von Willlebrand factor type A domain (vWA, F23-Y161) and a Peritrophin A chitin-binding domain (PAC, E234-D298). rPif97 self-associates or aggregates to form amorphous protein phases that organize both amorphous and single-crystal calcium carbonate nanoparticles in vitro. Further, in the presence of nucleating calcite crystals, rPif97 protein phases deposit onto these crystals and become occluded over time, forming nanochambers within the crystal interior. The formation of these mineral-modifying amorphous protein phases is linked to the presence of intrinsic disorder and amyloid-like cross-β-strand aggregation-prone regions, and three-dimensional modeling indicates that both the vWA and PAC domains are accessible for intermolecular interactions. Thus, the vWA- and PAC-containing Pif97 protein exhibits key functionalities that would allow its participation in mollusk nacre layer tablet assembly and porosity formation. PMID:26258941

  1. Associations Between Diabetic Retinopathy and Plasma Levels of High-sensitive C-reactive Protein or Von Willebrand Factor in Long-term Type 1 Diabetic Patients

    Laursen, Jonas Vejvad Nørskov; Hoffmann, Stine Skovbo; Green, Anders; Nybo, Mads; Sjølie, Anne Katrin; Grauslund, Jakob

    2013-01-01

    population-based cohort from Fyn County, Denmark. Plasma levels of hs-CRP and von Willebrand factor antigen were measured and related to the level of diabetic retinopathy (DR) as evaluated by dilated nine-field 45 degree monoscopic fundus photos captured by Topcon TRC-NWS6 and graded according to the Early...... Treatment Diabetic Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of DR. Results: Median age and duration of diabetes were 58.7 and 43 years, respectively. Median levels (10th-90th percentile) of hs-CRP and von Willebrand factor antigen were 1.31 mg/l (0.37-13.3 mg/l) and 1.......27 IU/ml (0.79-2.07 IU/ml), respectively. No or minimal DR (ETDRS-levels 10-20) was found in 16.4%, mild DR (ETDRS-level 35) in 19.4%, moderate DR (ETDRS-levels 43-47) in 11.0%, and 53.2% had proliferative diabetic retinopathy (PDR) corresponding to ETDRS-level 60 or more. In an age- and sex...

  2. Cuidados nos pacientes com hemofilia e doença de von Willebrand na cirurgia eletiva otorrinolaringológica

    Marques Marise P. C.

    2003-01-01

    Full Text Available FORMA DE ESTUDO Clínico prospectivo. MATERIAL E MÉTODO: Foi realizado um estudo prospectivo de 10 anos de 20 pacientes com hemofilias ou doença de von Willebrand (DvW com indicação de cirurgia otorrinolaringológica. Os pacientes foram submetidos a um total de 25 cirurgias otorrinolaringológicas eletivas. A idade média foi de 23,75 anos (2 a 62 anos. O grupo de estudo consistiu em 14 hemofílicos, 11 com hemofilia A grave (1 do sexo feminino, uma portadora com 30% de atividade de fator VIII (FVIII, um hemofílico B leve e uma com deficiência grave de fator X; 6 com DvW, 4 tinham o tipo 1 (3 mulheres, um o tipo 2A e um o tipo 3. Treze hemofílicos tinham síndrome de imunodeficiência adquirida. A duração média do procedimento foi de 1 hora e 37 minutos (15 minutos a 12 horas. O defeito da coagulação foi corrigido com desmopressina (DDAVP, com concentrado de FVIII de pureza intermediária 8Y, com criopreciptado ou com complexo protrombínico não ativado (PPSB, de acordo com os níveis plasmáticos do fator e da severidade da cirurgia. O ácido épsilon aminocapróico também foi usado em associação. Em 1 hemofílico A grave houve sangramento pós-operatório que se resolveu com a elevação do nível mínimo de FVIII para 80% e em 1 paciente com DvW do Tipo 3 houve sangramento pós-operatório pela dificuldade de identificação do melhor concentrado a ser reposto. Após o uso do concentrado de pureza intermediária 8Y, houve controle do sangramento. RESULTADO: Todos os outros pacientes apresentaram a hemostasia considerada normal ou excelente. CONCLUSÃO: Concluiu-se que pacientes com hemofilias ou DvW não apresentam um risco cirúrgico aumentado se for realizada uma terapia adequada.

  3. Von Willebrand-Faktor (vWF), Faktor VIII sowie frei und zellulär in Thrombozyten zirkulierende Wachstumsfaktoren der Angiogenese vor und nach Resektion eines kolorektalen Karzinoms

    Schmieger, Tobias

    2011-01-01

    1.1. Zusammenfassung Hintergrund und Ziele Bisherige Arbeiten über erhöhte Konzentrationen zirkulierender Wachstumsfaktoren bei Patienten mit einem kolorektalen Karzinom kranken wesentlich an schwerwiegenden präanalytischen Fehlern. Die Fragen, in welchen Konzentrationen sich der von-Willebrand-Faktor (vWF), der Blutgerinnungsfaktor VIII und die Wachstumsfaktoren VEGF, PDGF-AB und TGF-ß1, welche sich frei zirkulierend oder in Thrombozyten gespeichert befinden, im Blut von Patienten mit kolore...

  4. Insulin resistance is accompanied by increased von Willebrand factor levels in nondiabetic women: a study of offspring of type 2 diabetic subjects compared to offspring of nondiabetic subjects

    Foss, Catherine Hauerslev; Vestbo, Else; Frøland, Anders; Ingerslev, Jørgen; Gjessing, Hans; Mogensen, Carl Erik; Damsgaard, Else Marie Skjøde

    OBJECTIVES: To examine whether levels of von Willebrand factor (vWF), fibrinogen and fibronectin are related to a parental history of type 2 diabetes and to determine possible explanatory factors for high versus low vWF and fibrinogen. DESIGN: Cross-sectional study. SUBJECTS, MAIN OUTCOME MEASURES......: We compared vWF, fibrinogen and fibronectin in 88 nondiabetic offspring of type 2 diabetic subjects (relatives) and 103 offspring of nondiabetic subjects (controls). Other measurements included urinary albumin excretion rate, blood pressure, lipid profile and insulin resistance using homeostasis....... Odds ratio for high versus low insulin resistance was 18.39 (P < 0.001) for women and 1.92 (P = 0.32) for men. Body mass index (BMI) (P < 0.05), sex (P < 0.01), smoking status (P < 0.05) and IHD (P < 0.01) were significant explanatory factors for fibrinogen above the median (3.1 g x L(-1)). CONCLUSIONS...

  5. The changes of von willebrand factor/a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 balance in aneurysmal subarachnoid hemorrhage.

    Tang, Qi-Feng; Lu, Shi-Qi; Zhao, Yi-Ming; Qian, Jin-Xian

    2015-01-01

    The aim of this study was to investigate the role of Von Willebrand Factor/thrombospondin type I repeats-13 (VWF/ADAMTS13) balance in aSAH. Fifty eight patients with aSAH at the First Affiliated hospital of Soochow University, Suzhou, China, between January 2012 and January 2014 were eligible for the study. They were divided into delayed cerebral ischemia group (DCI group) and non-delayed cerebral ischemia group (no DCI group), or cerebral vasospasm group (CVS group) and no spasm group (no CVS group), or good outcome group and poor outcome group. The control group consisted of twenty healthy people. All patients underwent CT, DSA, or (and) CTA diagnosed with intracranial subarachnoid hemorrhage which is caused by aneurysm rupture. Venous blood was drawn in tubes at 3 time points: 1 day after SAH (T1), (4±1) days after SAH (T2), and (9±1) days after SAH (T3) to determine plasma concentrations of ADAMTS13, VWF, P-selectin and IL-6 via enzyme-linked immunosorbent assay (ELISA). Transcranial doppler sonography (TCD) was used to measure mean blood flow velocity of the middle cerebral artery (VMCA). Glasgow Outcome Scale (GOS) was measured before discharge. Among 58 patients, 12 (20.7%) had DCI, 40 (68.9%) had TCD evidence of CVS, and 20 (34.5%) had poor outcome. The concentrations of VWF, P-selectin and IL-6 on T1, T2 and T3 after SAH were significantly higher in DCI, CVS and poor outcome groups compared with those of the control group (P 0.05). The results of our study suggest that the increased VWF and decreased ADAMTS13 activity were associated with DCI and poor outcome. The balance of VWF/ADAMTS13 could be used to predict the clinical outcome. The deficiency of ADAMTS13 can not only induce DCI but also accelerate inflammatory reaction. Our results reported in this paper may provide new insights into the possible use of ADAMTS13 as a therapeutic agent in aneurysmal subarachnoid hemorrhage. PMID:25785135

  6. Role of von Willebrand factor levels in the prognosis of stage Ⅳ colorectal cancer: Do we have enough evidence?

    I. Gil-Bazo; J. A Díaz-González; J. Rodríguez; J. Cortés; E. Calvo; J. A. Páramo; J. García-Foncillas

    2005-01-01

    @@ TO THE EDITOR Cancer patients usually present a prothrombotic condition.Several clotting-related proteins, such as yon Willebrand factor (vWF), presenting higher plasma concentrations in these patients, may play a key role in this process. Moreover,some of those proteins are currently being characterized as response rate and overall survival markers in metastatic colorectal cancer (MCRC). In this comment article, we discuss the last piece of evidence that supports the use of vWF as a prognostic indicator in MCRC patients, provided by a paper recently published by Wang et al., in the World Journal of Gastroenterology. Summarizing, although vWF should be seriously considered as potential future prognostic and predictive indicator in colorectal cancer, more dynamic and better designed studies in longer series of patients should be conducted before standardizing its universal use among these patients.

  7. Plasma fibrinolysis is related to the degree of organ dysfunction but not to the concentration of von Willebrand Factor in critically ill patients

    Vincent Jean-Louis

    2009-06-01

    Full Text Available Abstract Background Endothelial cell dysfunction, by promoting fibrin deposition, has been implicated in the development of multiple organ failure. Altered fibrinolysis during inflammation may participate in microvascular alterations. We sought to determine whether plasma fibrinolysis was related to the severity of organ dysfunction and/or to the levels of von Willebrand factor (vWF antigen, as a marker of endothelium dysfunction, in critically ill patients. Methods Forty-nine consecutive patients admitted to an adult medico-surgical intensive care unit (ICU with (18 or without sepsis (31 were included. C-reactive protein and vWF levels were measured on ICU admission and plasma fibrinolysis was assessed by the Euglobulin Clot Lysis Time (ECLT. The sequential organ failure assessment (SOFA score and the simplified acute physiology score (SAPS II were calculated on admission. Results ECLT was significantly longer in septic than in non-septic patients [1033 min (871–1372 versus 665 min (551–862, p = 0.001]. There were significant correlations between ECLT and C-reactive protein (CRP concentrations (r = 0.78, p Conclusion ECLT measurement at admission could be a marker of organ dysfunction and a prognostic indicator in critically ill patients.

  8. Interaction of asialo von Willebrand factor with glycoprotein Ib induces fibrinogen binding to the glycoprotein IIb/IIIa complex and mediates platelet aggregation

    Von Willebrand factor (vWF) is necessary for the initial attachment of platelets to exposed subendothelium, particularly under flow conditions like those prevailing in the microcirculation. Little is known about its possible participation in subsequent events leading to formation of platelet thrombi at sites of vascular injury. The authors addressed this question by studying the mechanisms by which desialylated vWF induces platelet aggregation in the absence of any other stimulus. Asialo vWF, unlike the native molecule, does not require ristocetin to interact with platelets. They have shown here that binding of asialo vWF to platelets was accompanied by release of dense granule content and subsequent ADP-dependent fibrinogen binding to receptors on the glycoprotein (GP) IIb/IIIa complex. The initial interaction of asialo vWF with platelets was mediated by GPIb, as shown by blocking obtained with monoclonal antibody. Inhibition of this initial interaction completely abolished platelet aggregation induced by asialo vWF. This, however, did not block asialo vWF binding to platelets, but rather inhibited subsequent fibrinogen binding induced by asialo vWF. Therefore, the latter process was also essential for platelet aggregation under the conditions described. This study shows that asialo, and possibly native, vWF acts as a platelet agonist after its binding to GPIb and induces aggregation through a pathway dependent on GPIIb/IIIa-related receptors

  9. Production, crystallization and preliminary crystallographic analysis of an exosite-containing fragment of human von Willebrand factor-cleaving proteinase ADAMTS13

    A fragment of the ADAMTS13 ancillary domains (ADAMTS13-DTCS) has been expressed, purified and crystallized and the crystals have been characterized by X-ray diffraction. ADAMTS13 is a reprolysin-type metalloproteinase belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin type 1 motif) family. It specifically cleaves plasma von Willebrand factor (VWF) and regulates platelet adhesion and aggregation. ADAMTS13 is a multi-domain enzyme. In addition to the N-terminal metalloproteinase domain, the ancillary domains, including a disintegrin-like domain, a thrombospondin-1 type 1 repeat, a Cys-rich domain and a spacer domain, are required for VWF recognition and cleavage. In the present study, a fragment of the ADAMTS13 ancillary domains (ADAMTS13-DTCS; residues 287–685) was expressed using CHO Lec cells, purified and crystallized. Diffraction data sets were collected using the SPring-8 beamline. Two ADAMTS13-DTCS crystals with distinct unit-cell parameters generated data sets to 2.6 and 2.8 Å resolution, respectively

  10. Von Willebrand Factor Antigen Predicts Response to Double Dose of Aspirin and Clopidogrel by PFA-100 in Patients Undergoing Primary Angioplasty for St Elevation Myocardial Infarction

    Jacopo Gianetti

    2013-01-01

    Full Text Available Von Willebrand factor (VWF is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100 with Collagen/Epinephrine (CEPI is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR. The objective of this study was to verify the effect of double dose (DD of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, n=58 or DD of aspirin and clopidogrel (DD, n=58, maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2. At Times 1 and 2 we observed a significantly higher CEPI closure times (CT in DD as compared to SD (P<0.001. Delta of CEPI-CT (T1-T0 was significantly related to VWF (P<0.001 and inversely related to ADAMTS-13 (0.01. Responders had a significantly higher level of VWF at T0. Finally, in a multivariate model analysis, VWF and ADAMTS-13 in resulted significant predictors of CEPI-CT response (P=0.02. HRP detected by PFA-100 in acute myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF.

  11. Genetic variants associated with Von Willebrand factor levels in healthy men and women identified using the HumanCVD BeadChip.

    Zabaneh, Delilah; Gaunt, Tom R; Kumari, Meena; Drenos, Fotios; Shah, Sonia; Berry, Diane; Power, Chris; Hypponen, Elina; Shah, Tina; Palmen, Jutta; Pallas, Jacky; Talmud, Philippa J; Casas, Juan Pablo; Sofat, Reecha; Lowe, Gordon; Rumley, Ann; Morris, Richard W; Whincup, Peter H; Rodriguez, Santiago; Ebrahim, Shah; Marmot, Michael G; Smith, George Davey; Lawlor, Debbie A; Kivimaki, Mika; Whittaker, John; Hingorani, Aroon D; Day, Ian N; Humphries, Steve E

    2011-07-01

    We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels. PMID:21534939

  12. Labor management in a patient with on willebrand

    von Willebrand disease (VWD) is an inherited bleeding disorder involving a deficiency or abnormal function of a blood clotting protein called von Willebrand factor (VWF). Deficiency of VWF, therefore, shows primarily in organs with small blood vessels such as the skin, the gastrointestinal tract and the uterus. This case report describes management of a patient presenting with type II von Willebrand disease in labor. She had history of lifethreatening hemorrhage from an operation for deviated nasal septum and had a risk of severe postpartum hemorrhage (PPH) within 48 hours of delivery, which was avoided by appropriate planning and timely management. (author)

  13. Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test.

    Mathieu, Sophie; Crampe, Carine; Dargaud, Yesim; Lavigne-Lissalde, Géraldine; Escuriola-Ettingshausen, Carmen; Tardy, Brigitte; Meley, Roland; Thouvenin, Sandrine; Stephan, Jean L; Berger, Claire

    2015-12-01

    Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI. PMID:26517064

  14. Early increase precedes a depletion of endothelin-1 but not of von Willebrand factor in cutaneous microvessels of diabetic patients. A quantitative immunohistochemical study.

    Properzi, G; Terenghi, G; Gu, X H; Poccia, G; Pasqua, R; Francavilla, S; Polak, J M

    1995-02-01

    Endothelin-1 (ET-1) is a vasoconstrictor peptide which is produced by endothelial cells. The subcellular distribution of ET-1 in human skin and the variation of immunostaining for ET-1 by light microscopy in skin biopsies of diabetic patients have been analysed using immunohistochemistry and image analysis quantification. Skin biopsies were collected from 17 patients with type 1 diabetes of different durations and with presence or absence of microangiopathy in the retina; skin biopsies of healthy subjects were utilized as controls. The distribution of ET-1 immunoreactivity (IR) at both light and electron microscopy was compared to that of von Willebrand factor (vWf), a general marker of total cutaneous microvessels. Immunohistochemistry revealed that in controls the distribution of immunostaining was similar for ET-1 and vWf, being localized to microvessels in all areas of the skin. However, at the electron microscopical level ET-1-IR was localized in the endothelial cytoplasm rather than in specific organelles, while vWf immunostaining was associated with Weibel-Palade bodies. ET-1-IR was observed in 4/8 (50 per cent) biopsies from healthy subjects; this increased to 81.8 per cent in biopsies of patients affected by diabetes for less than 10 years and decreased to 16.6 per cent in patients with diabetes for more than 10 years. Quantification of ET-1 staining showed a significant decrease of ET-1-IR in patients affected by diabetes for more than 10 years compared with those affected by diabetes for less than 10 years (P < 0.05). Also, the percentage of biopsies showing positive ET-1 staining was lower in patients with retinopathy than in patients without retinopathy. On the contrary, vWf-IR was observed in all skin specimens and its quantification showed no differences between diabetic patients and controls. These changes are not related to variations in the number of blood vessels, and it is suggested that they reflect a possible functional alteration of the

  15. Effects of radiofrequency catheter ablation of atrial fibrillation on soluble P-selectin, von Willebrand factor and IL-6 in the peripheral and cardiac circulation.

    Jelena Kornej

    Full Text Available BACKGROUND: Catheter ablation (CA of atrial fibrillation (AF is associated with inflammatory response, endothelial damage and with increased risk of thrombosis. However, whether these processes differ in peripheral and cardiac circulation is unknown. METHODS: Plasma markers (von Willebrand factor (vWf, soluble P-selectin (sPsel and interleukin-6 (IL-6 were measured by ELISA at three time points in 80 patients (62±10 years, 63% males, 41% paroxysmal AF undergoing CA. These were at baseline--from femoral vein (FV and left atrium (LA before ablation; directly after ablation--from the pulmonary vein (PV, LA and FV; and 24 hours after procedure--from a cubital vein (CV. RESULTS: The levels of vWF and IL6--but not sP-sel--increased significantly 24 h after procedure (p<0.001. Baseline vWF was significantly associated with persistent AF (Beta = .303, p = 0.006 and Beta = .300, p = 0.006 for peripheral and cardiac levels, respectively, while persistent AF (Beta = .250, p = 0.031 and LAA flow pattern (Beta = .386, p<0.001 remained associated with vWF in cardiac blood after ablation. Advanced age was significantly associated with IL6 levels at baseline and after ablation in peripheral and cardiac blood. There were no clinical, procedural or anti-coagulation characteristics associated with sP-sel levels in cardiac blood, while peripheral sP-sel levels were associated with hypertension before (Beta = -.307, p = 0.007 and with persistent AF after ablation (Beta = -.262, p = 0.020. CONCLUSIONS: vWF levels are higher in persistent AF and are associated with LAA rheological pattern after AF ablation. Increase of peripheral vWF and IL6 levels after procedure supports current AF ablation management with careful control of post-procedural anticoagulation to avoid ablation-related thromboembolism.

  16. Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-κB.

    Shahidi, Minoo; Mohsen Razavi, Seyed; Hayat, Parisa

    2016-09-01

    Although certain evidence has indicated a role for angiogenesis in the pathophysiology of hematopoietic malignancies, its role in chronic lymphocytic leukemia (CLL) prognosis is yet to be defined. To our knowledge, the effects of CLL plasma on cell culture have not been addressed. Therefore, we investigated the effects of CLL plasma on cell cycle regulation and von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs). Since nuclear factor-kappa B (NF-κB) transcription factor has been a therapeutic target for treatment of cancer, we inhibited NF-κB using small interfering RNA to clarify if there is a role for this factor in probable effects. The cells were treated with the plasma of patients with CLL. Subsequently, cell cycle phase distribution, vWF secretion, expression, and storage were detected using ELISA, flow cytometry, and immunohistochemical staining. In addition, NF-κB was inhibited using small interfering RNA. Plasma treatment promoted cell cycle progression by decreasing the cell number in G1 phase, while increasing the cell number in S phase and G2M phase. A significant increase of vWF expression, secretion, and storage was found, associated with the vWF levels of patients' plasma. We found that induction of cell cycle promotion, but not vWF expression and secretion, was partially suppressed by this inhibition. We found that endothelial cell cycle and vWF expression and secretion affected by CLL plasma and NF-κB play a role in the former. These findings would be useful for understanding the prognostic importance of plasma angiogenic factor levels in CLL. PMID:27472040

  17. Genetics Home Reference: von Willebrand disease

    ... mildest and most common of the three types, accounting for 75 percent of affected individuals. Type 3 ... disorder ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific articles on PubMed (1 link) PubMed Sources for This ...

  18. Acquired Von Willebrand’s Syndrome in Systemic Lupus Erythematosus

    Sara Taveras Alam

    2014-01-01

    Full Text Available Acquired von Willebrand syndrome (AVWS is an uncommon, underdiagnosed, and heterogeneous disease which is increasingly recognized as a cause of bleeding diatheses. Systemic lupus erythematosus (SLE is an infrequent cause of AVWS. Herein, we report a case of AVWS diagnosed during the initial presentation of SLE in a previously healthy young man with no family history of bleeding diathesis who presented with worsening epistaxis, gastrointestinal bleeding, and anasarca. He was found to have severe anemia and prolonged activated partial thromboplastin time (aPTT with severely decreased levels of von Willebrand factor (VWF measurements in addition to markedly decreased factor VIII levels. Further evaluation revealed nephrotic syndrome and interstitial lung disease due to SLE. He initially received combination therapy with intravenous immunoglobulin (IVIG and von Willebrand factor/factor VIII concentrates without significant improvement. Treatment with steroids, cyclophosphamide, and rituximab was followed by clinical improvement evidenced by cessation of bleeding. The short follow-up did not allow us to definitely prove the therapeutic effect of immunosuppressive treatment on AVWS in SLE patients. This case adds to the literature supporting the relationship between AVWS and SLE and highlights the importance of combination therapy in the treatment of severe AVWS as well as the role of IVIG, cyclophosphamide, and rituximab in AVWS associated with SLE.

  19. Von Willebrand Factor and ADAMTS13 Expression in Renal Tissue in Chronic Glomerulonephritis Diseases%慢性肾脏病患者肾脏vWF和ADAMTS13表达改变及其意义

    沈蕾; 卢国元; 蒋丽琼; 董宁征; 乔青; 李明; 阮长耿

    2011-01-01

    Objective To observe the expression of von Willebrand factor (vWF) and its cleaving protease-ADAMTS13 in renal tissues of patients with different pathological and clinical types of chronic kidney diseases. Methods Thirty six cases of chronic kidney disease' patients were involved in the study. Expression of vWF and ADAMTS13 in renal tissues was analyzed by immunohistochemistry. Image J analysis software was used to measure vWF and ADAMTS13 expression. The results were expressed as positive staining area percentage of total glomerular. Results (1) The vWF/ADAMTS13 positive staining eara in the NS group was significantly higher than that in the CGN group (P < 0. 05). (2) ADAMTS13 positive staining eara was significantly lower in MN group than that in the non-MN group (P < 0.05). (3) vWF/ADAMTS13 expression level was positively correlated with proteinuria (r = 0. 512,P < 0.01). Conclusion The imbalance of local expression of vWF and ADAMTS13 in chronic kidney di sease is related to the clinical and pathological type in a certain extent, may reflect changes in renal microcirculation in some degree.%目的:观察血管性血友病因子(vWF)及其裂解酶ADAMTS13在慢性肾脏病不同病理类型中的表达以及与临床指标的相关性.方法 采用免疫组织化学分析vWF和ADAMTS13在36例不同病理类型慢性肾炎患者肾脏中的表达,Image J图象分析软件测定vWF和ADAMTS13的阳性染色面积的比例.结果 (1)肾病综合征患者肾小球阳性染色面积vWF/ADAMTS13明显高于慢性肾炎组(P<0.05);(2)膜性肾病组ADAMTS13表达明显低于非膜性肾病组(P<0.05);(3)vWF/ADAMTS13阳性染色面积比与蛋白尿呈正相关(r=0.512,P<0.01).结论 慢性肾脏病局部vWF和ADAMTS13表达间平衡失调与慢性肾脏病的临床和病理类型有关,能在一定程度上反映肾脏微循环的变化.

  20. 10周游泳运动对高血压大鼠血浆一氧化氮、血管性血友病因子、P-选择素含量的影响%Effects of 10-week swimming exercise on plasma nitric oxide, von Willebrand factor and P-selectin production in spontaneous hypertension rats

    陈华卫; 窦丽; 张钧

    2012-01-01

    Objective: To investigate the effects of exercise on endothelium function and platelet activity in spontaneous hypertension rats (SHR). Method: Seventeen male SHR were divided into 2 groups randomly, control group (8 SHR) and exercise group (9 SHR). In exercise group SHR performed swimming exercise (5 times/week) at moderate intensity (60min/time) for 10 weeks. Resting blood pressure was measured fortnightly during exercise training period. After the exercise period, plasma nitric oxide (NO), platelet-derived NO level and plasma von Willebrand factor (vWF), P-selectin production were defected. Result: Compared with control group, SHR resting blood pressure decreased significantly, plasma NO level and platelet NO level increased significantly, while plasma vWF and P-selectin production decreased in exercise group-Conclusion: This study implies that long-term regular aerobic exercise can inhibit resting blood pressure gently and continuously in SHR, and can improve endothelium function and platelet activity significantly in hypertension, which can control the occurrence of thrombosis complicated in hypertension.%目的:研究运动对自发性高血压大鼠内皮功能、血小板活化状态的影响.方法:10周龄,雄性自发性高血压大鼠(SHR) 17只,随机分为对照组(8只)和运动组(9只).运动组SHR进行为期10周,每周5次,每次60min的游泳运动训练.实验期间每两周测定SHR血压,10周运动后,测定血浆一氧化氮(NO)水平,血小板NO水平,血管性血友病因子(vWF)、P-选择素浓度的变化.结果:运动组大鼠血压较对照组显著下降,血浆和血小板NO水平显著上升,血浆vWF和p-选择素显著降低.结论:规则有氧运动能产生较平稳持续的降压效果,能明显改善高血压内皮功能和血小板活化状态,降低高血压血栓并发症的发生.

  1. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure

    Bjerre, M.; Kistorp, C.; Hansen, T.K.;

    2010-01-01

    CRP), endothelial activation (soluble E-selectin, sEsel)), endothelial damage/dysfunction (von Willebrand factor, vWf) and insulin resistance (IR) and prognosis in CHF remains unknown. Design. We investigated the association(s) between plasma sMAC, hsCRP, sEsel, vWf and IR (assessed by homeostatic model assessment...

  2. Decreased plasma ADAMTS-13 activity as a predictor of postoperative bleeding in cyanotic congenital heart disease

    Rosangela P.S. Soares

    2013-04-01

    Full Text Available OBJECTIVE: To analyze the preoperative plasma antigenic concentration and activity of von Willebrand factor and its main cleaving protease ADAMTS-13 in pediatric patients with cyanotic congenital heart disease undergoing surgical treatment and investigate possible correlations with postoperative bleeding. METHODS: Plasma antigenic concentrations (von Willebrand factor:Ag and ADAMTS-13:Ag were measured using enzyme-linked immunoassays. Collagen-binding assays were developed to measure biological activities (von Willebrand factor:collagen binding and ADAMTS-13 activity. The multimeric structure of von Willebrand factor was analyzed using Western immunoblotting. Demographic, diagnostic, and general and specific laboratory data and surgery-related variables were subjected to univariate, bivariate, and multivariate analysis for the prediction of postoperative bleeding. RESULTS: Forty-eight patients were enrolled, with ages ranging from 9 months to 7.6 years (median 2.5 years. The plasma concentrations of von Willebrand factor:Ag and ADAMTS-13:Ag were decreased by 65 and 82%, respectively, in the patients compared with the controls (p<0.001. An increased density of low-molecular-weight fractions of von Willebrand factor, which are suggestive of proteolytic degradation (p = 0.0081, was associated with decreased ADAMTS-13 activity, which was likely due to ADAMTS-13 consumption (71% of controls, p = 0.0029 and decreased von Willebrand factor:collagen binding (76% of controls, p = 0.0004. Significant postoperative bleeding occurred in 13 patients. The preoperative ADAMTS-13 activity of <64.6% (mean level for the group, preoperative activated partial thromboplastin time, and the need for cardiopulmonary bypass were characterized as independent risk factors for postoperative bleeding, with respective hazard ratios of 22.35 (95% CI 1.69 to 294.79, 1.096 (95% CI 1.016 to 1.183, and 37.43 (95% CI 1.79 to 782.73. CONCLUSION: Low plasma ADAMTS-13

  3. 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

    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

  4. The correlation study of von willebrand factor level and the occurrence of atrial ifbrillation in coronary heart disease patients with heart failure%血管性血友病因子水平与冠状动脉性心脏病合并心力衰竭患者发生心房颤动的相关性研究

    邢令; 曹秋梅; 刘易新; 马炳辰; 王大为; 刘宇欣

    2016-01-01

    目的:探讨血管性血友病因子(von willebrand factor,vWF)水平与冠状动脉性心脏病(冠心病)合并心力衰竭患者发生心房颤动(房颤)的相关性。方法选取冠心病合并心力衰竭患者106例,每3个月随访1次,至患者随访期间发生房颤或随访期满18个月中止,根据随访结果将患者分为房颤组和非房颤组。比较两组患者vWF水平的差异,分析vWF的相关因素,通过Logistic回归分析及ROC曲线分析研究vWF对冠心病心力衰竭患者发生房颤的预测价值。结果房颤组患者的vWF水平高于非房颤组(P<0.05)。vWF水平与N末端脑钠肽前体(N-terminal pro-B-type natriuretic peptide,NT-proBNP)(r=0.401,P=0.00)、超敏C反应蛋白(high-sensitivity C-reactive protein, hs-CRP)(r=0.322,P=0.00)、年龄(r=0.310,P=0.002)、心室率(r=0.202,P=0.038)、左房前后径(r=0.201,P=0.045)均存在正相关。vWF是冠心病心力衰竭患者发生房颤的独立危险因素(OR=1.002,95%CI1.001~1.004),其预测冠心病心力衰竭患者发生房颤的ROC曲线下面积为0.638(95%CI0.530~0.746)。结论 vWF水平对冠心病心力衰竭患者发生房颤有预测价值,预测的最佳截断值为3154.09ng/L。%ObjectiveTo explore the correlation of the von willebrand factor(vWF) level and occurrence of atrial fibrillation(af) in coronary heart disease patients with heart failure.Method Choose 106 coronary heart disease patients with heart failure. Once every 3 months follow-up, until they happen atrial fibrillation during the follow-up period or to expire before 18 months. According to the results divided the subject into two groups:atrial fibrillation and non atrial fibrillation group. The difference of the vWF level between the two groups was compared, and the related factors with vWF level was analyzed. To study the predictive value of VWF in the occurrence of atrial fibrillation in patients

  5. Patient with von Willebrand Disease for Gynaecologic Surgery - Perianaesthetic Concerns

    Rakesh Garg

    2008-01-01

    Patients with vWD do not carry an increased operative risk during elective procedures if appropriate prophylac-tic and corrective therapy is administered. Although the administration of cryoprecipitate and other blood products has traditionally been the cornerstone of treatment for vWD, the recent development of desmopressin(DDAVP for clinical use may provide an effective alternative to replacement therapy with blood products. Further laparaoscopic procedures, taking care during ryle′s tube and foley′s catheter insertion, in such patients are the safer alternative for all kind of gynecologic surgeries.

  6. 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

    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

  7. Membrane activation, biological sewage treatment without excess sludge production?; Membranbelebung - biologische Abwasserreinigung ohne Anfall von Ueberschussschlamm?

    Cornel, P. [Technische Univ. Darmstadt (Germany). Inst. WAR - Wasserversorgung, Abwassertechnik, Abfalltechnik, Umwelt- und Raumplanung

    2000-07-01

    About 23 million cubic meters of sewage sludge are produced in Germany every year, i.e. about 2.7 - 3 million Mg. Sewage treatment accounts for up to 30% of the investment cost of a new sewage system. The current market price for sewage sludge treatment and disposal is about 1,500 DM/mg TR, i.e. an annual cost of 4 - 4.5 thousand million DM in Germany. Operators of sewage sludge systems are therefore looking into alternative options to reduce the sludge volume, e.g. by microfiltration and low-pressure membranes for biomass separation in activation processes. [German] Der biologische Abbau von Abwasserinhaltsstoffen fuehrt bei konventionell betriebenen Belebungsanlagen zur Bildung von Ueberschussschlamm. In Deutschland fallen jaehrlich ca. 23 Mio. m{sup 3}, entsprechend 2,7 Mio. Mg bis 3 Mio. Mg an. Bis zu 30% der Investitionskosten beim Klaeranlagenneubau muessen fuer die Schlammbehandlung aufgewendet werden. Der Marktpreis fuer sachgerechte Behandlung und Entsorgung des Klaerschlamms wird mit 1.500 DM/Mg TR angegeben. Dies entspricht jaehrlichen Aufwendungen von 4 bis 4,5 Mrd. DM in der Bundesrepublik Deutschland. Es ist deshalb nicht verwunderlich, wenn sich insbesondere die Klaeranlagenbetreiber Belebungsverfahren wuenschen, die eine weitestgehende Reinigung des Abwassers ohne Schlammanfall bewerkstelligen. Die Weiterentwicklung der Mikrofiltrationstechnik und der Einsatz von Niederdruckmembranen zur Biomassenabtrennung im Belebungsverfahren, scheint die Moeglichkeit zu eroeffnen, Belebungsverfahren ohne oder nahezu ohne Ueberschussschlammanfall zu betreiben. (orig.)

  8. Effects of TSP2-8 and CUB1+2 Domains on Secretion Direction of Von Willebrand Factor-cleaving Protease%TSP2-8和CUB1+2片段对血管性血友病因子裂解酶分泌方向的影响

    高单萍; 刘琼; 陈素华; 艾继辉

    2011-01-01

    本研究旨在探讨羧基端TSP2-8和CUB1+2片段是否决定血管性血友病因子裂解酶(ADAMTS13)合成后细胞内运输的方向,以了解金属蛋白酶ADAMTS13羧基端结构与功能的关系.利用脂质体转染技术将重组质粒pcDNA3.1-ADAMTS13及peDNA3.1-de1TSP2-8CUB1+2ADAMTS13分别转染犬肾上皮极性细胞MDCK,筛选出阳性细胞克隆后传代铺到中间有特殊分子筛膜的双池培养皿内培养,待细胞生长到无空隙后收集上、下池培养液;通过Western blot检测上、下池培养液中ADAMTS13蛋白表达水平,以对比分析ADAMTS13蛋白在极性细胞内的分泌方向.结果表明,德定表达野生型ADAMTS13的MDCK细胞组,在分子筛膜的上池培养液中检测到ADAMTS13蛋白,而表达缺失TSP2-8CUB1 +2区域ADAMTS13的细胞组,在分子膜的上、下池培养液中均检测到ADAMTS13重组蛋白.结论:金属蛋白酶ADAMTS13的分泌是有极性的,且羧基端TSP2-8和CUB1+2结构域与ADAMTS13合成后细胞内的运输方向密切相关.%This study was aimed to explore if the intracellular transportation direction of von Willebrand factor-cleaving protease (ADAMTS13, vWF-CP) after synthesis is determined by the carboxyl terminal TSP2-8CUB1 + 2 domains of ADAMTS13 and to decipher the relationship between the structure and function of ADAMTS13. The recombinant plasmids pcDNA3.1-ADAMTS13 and pcDNA3. 1-delTSP2-8CUB1 + 2 ADAMTS13 were introduced into Madin-Darby canine kidney cells (MDCK) by lipofectamine-mediated DNA transfection. Positive cell clones gained after antibioticscreening were grown on 6-well transwell filter units with a zeolite membrane in the middle layer. The conditioned culture media in both apical and basolateral wells were collected when cells reached confluency and the tight cell monolayer formed. ADAMTS13 proteases in the conditioned media were determined by Western blot, and the direction of ADAMTS13 secretion in polarized cells was comparatively analyzed. The results

  9. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD)

    Budde, U.; Schneppenheim, R.; Eikenboom, J.; Goodeve, A.; Will, K.; Drewke, E.; Castaman, G.; Rodeghiero, F.; Federici, A.B.; Batlle, J.; Perez, A.; Meyer, D.; Mazurier, C.; Goudemand, J.; Ingerslev, J.; Habart, D.; Vorlova, Z.; Holmberg, L.; Lethagen, S.; Pasi, J.; Hill, F.; Peake, I.

    2008-01-01

    difficult but is a prerequisite for correct classification. OBJECTIVE: To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure. Patients and methods: Previously diagnosed type 1 VWD families and healthy controls...... were recruited by 12 expert centers in nine European countries. Phenotypic characterization comprised plasma VWF parameters and multimer analysis using low- and intermediate-resolution gels combined with an optimized visualization system. VWF genotyping was performed in all index cases (ICs). RESULTS...... diagnosed as type 1 VWD, 38% showed abnormal multimers. Depending on the classification criteria used, 22 out of these 57 cases (15% of the total cohort) may be reclassified as type 2, emphasizing the requirement for multimer analysis compared with a mere ratio of VWF functional parameters and VWF:Ag. This...

  10. The ADAMTS13 metalloprotease domain: roles of subsites in enzyme activity and specificity

    de Groot, Rens; Lane, David A.; James T.B. Crawley

    2010-01-01

    ADAMTS13 modulates von Willebrand factor (VWF) platelet-tethering function by proteolysis of the Tyr1605-Met1606 bond in the VWF A2 domain. To examine the role of the metalloprotease domain of ADAMTS13 in scissile bond specificity, we identified 3 variable regions (VR1, -2, and -3) in the ADAMTS family metalloprotease domain that flank the active site, which might be important for specificity. Eight composite sequence swaps (to residues in ADAMTS1 or ADAMTS2) and 18 single-point mutants were ...

  11. Prelabeled glycoprotein Ib/IX receptors are not cleared from exposed surfaces of thrombin-activated platelets.

    White, J. G.; Krumwiede, M. D.; Cocking-Johnson, D.; Escolar, G.

    1996-01-01

    The present investigation has re-examined the hypothesis proposing that glycoprotein (GP)Ib/IX receptors for von Willebrand factor are rapidly cleared from exposed surfaces to internal membrane systems after activation of platelets by thrombin in suspension. Platelets were prelabeled with either a polyclonal antibody to GPIb alpha, antiglycocalicin (A-Gl), or a cocktail of two monoclonal antibodies, AP1 and 6D1, exposed to 0.1 or 0.2 U/ml thrombin for 5 or 10 minutes, fixed and stained with S...

  12. Dimensioning of activation systems using submerged membranes at municipal sewage treatment plants; Bemessung von Membranbelebungsanlagen beim Einsatz zur Reinigung kommunaler Abwaesser

    Ohle, P.; Dorgeloh, E. [Technische Hochschule Aachen (DE). Inst. fuer Siedlungswasserwirtschaft (ISA)

    1999-07-01

    Dimensioning of conventional activation systems in Germany as a rule relies on instruction sheet A131 of the Abwassertechnische Vereinigung or follows the Hochschulgruppen approach (HSG). They contain recommendations as to the size of the nitrification and denitrification zones, the amount of oxygen supplied and sludge production, and the size of the final sedimentation tank. For the use of sludge activation techniques by means of submerged membranes at municipal sewage treatment plant there so far do not exist any clues to dimensioning that make allowance for the modified boundary conditions. The present paper analyses instruction sheet A131 for its suitability as a basis in the dimensioning of sludge activation systems with submerged membranes at municipal sewage treatment plant. Then the dimensioning instructions are modified to suit the changed boundary conditions, and recommendations for the dimensioning of activation systems with submerged membranes on the basis of extensive studies carried out at the Institut fuer Siedlungswasserwirtschaft ISA of Aachen Technical University RWTH are given. (orig.) [German] Die Bemessung konventioneller Belebungsverfahren erfolgt in Deutschland i.d.R. auf der Grundlage des Arbeitsblatts A 131 der Abwassertechnischen Vereinigung bzw. nach dem Hochschulgruppenansatz (HSG). Sie enthalten Empfehlungen bezueglich der Dimensionierung von Nitrifikations- und Denitrifikationszone, Sauerstoffversorgung, Schlammproduktion und Nachklaerbecken. Fuer den Einsatz von Membranbelebungsanlagen in kommunalen Klaeranlagen existieren bislang keine Bemessungshinweise, die den veraenderten Randbedingungen Rechnung tragen. Der vorliegende Beitrag analysiert das Arbeitsblatt A 131 in Hinsicht auf die Moeglichkeit zur Anwendung fuer die Bemessung von Membranbelebungsanlagen beim Einsatz zur kommunalen Abwasserreinigung. Im Weiteren erfolgt die Modifikation der Bemessungshinweise hinsichtlich der geaenderten Randbedingungen und die Angabe von

  13. Influence of heavy-metal-containing dusts on the release of plateled-activating factor (PAF) by alveolar macrophages. Final report; Einfluss von schwermetallhaltigen Staeuben auf die Freisetzung von Platelet-Activating Factor (PAF) durch Alveolarmakrophagen. Abschlussbericht

    Gercken, G.; Froemming, G.; Mueller, I.M.

    1993-05-01

    The research project investigated the possibility for activating rabbit and bovine alveolar macrophages by quartz- and heavy-metal-containing dust. The formation of platelet activating factor (PAF) was used as a biochemical parameter. For comparison, human monocytes, monocytes differentiated as macrophages and granulocytes were additionally investigated. The results permit the conclusion that the formation of PAF is linked to the particle structure of the respective dust, not so much to the chemical condition of particle surface. In the case of heavy-metal containing dust, the inhibition of PAF synthesis by the heavy metals is not to be excluded. (orig./vhe) [Deutsch] In dem Forschungsprojekt wurde die Aktivierbarkeit von Kaninchen- und Rinderalveolarmakrophagen durch Quarz- und schwermetallhaltige Staeube untersucht. Als biochemischer Parameter wurde die Platelet-Activating-Factor (PAF) - Bildung herangezogen. Zum Vergleich wurden zusaetzlich humane Monocyten, zu Makrophagen ausdifferenzierte Monocyten und Granulocyten untersucht. Aufgrund der Ergebnisse kann davon ausgegangen werden, dass die PAF-Bildung mit der Partikelstruktur der einzelnen Staeube und weniger mit der chemischen Beschaffenheit der Partikeloberflaeche zusammenhaengt. Bei schwermetallhaltigen Staeuben ist eine Inhibierung der PAF-Synthese durch die Schwermetalle nicht auszuschliessen. (orig./vhe)

  14. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress.

    Y. Ikeda; Handa, M; Kawano, K; Kamata, T; Murata, M.; Araki, Y; Anbo, H; Kawai, Y; Watanabe, K.; Itagaki, I

    1991-01-01

    Exposure of platelets to shear stress leads to aggregation in the absence of exogenous agonists. We have now found that different adhesive proteins and platelet membrane glycoproteins are involved in aggregation depending on the shear stress conditions and the concentration of divalent cations in the medium. When blood is collected with trisodium citrate as anticoagulant, which causes a decrease in the levels of external ionized calcium ([Ca2+]o), platelet aggregation can be induced under low...

  15. Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

    Westein, Erik; Meer, van der Andries D.; Kuijpers, Marijke J.E.; Frimat, Jean-Philippe; Berg, van den Albert; Heemskerk, Johan W.M.

    2013-01-01

    Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote

  16. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs

    Krogh, Anne Kirstine Havnsøe; Legind, Pernille; Kjelgaard-Hansen, Mads;

    2014-01-01

    Sled dogs performing endurance races have been reported to have a high incidence of gastric erosions or ulcerations and an increased risk of gastro intestinal bleeding leading to death in some cases. In addition, these dogs also become hypothyroid during training and exercise. Canine hypothyroidi...

  17. Activation of blood clotting and fibrinolysis in angiocardiography with ionic and non-ionic contrast medium; Aktivierung von Blutgerinnung und Fibrinolyse nach Angiokardiographie mit ionischem und nichtionischem Kontrastmittel

    Winkler, U.H. [Gerinnungsphysiologisches Lab., Zentrum fuer Frauenheilkunde, Universitaetsklinikum Essen (Germany); Park, J.W. [Herz-Zentrum Kaiser-Wilhelm-Krankenhaus, Duisburg (Germany); Weber, S. [Schering AG, Geschaeftsbereich Deutschland, Berlin (Germany); Kothe, A. [Gerinnungsphysiologisches Lab., Zentrum fuer Frauenheilkunde, Universitaetsklinikum Essen (Germany); Schnitker, J. [Inst. fuer Angewandte Statistik GmbH, Bielefeld (Germany); Behrends-Steins, B. [Schering AG, Geschaeftsbereich Deutschland, Berlin (Germany); Albring, M. [Schering AG, Geschaeftsbereich Deutschland, Berlin (Germany)

    1997-06-01

    Purpose: To study the effects of a ionic (amidotrizoate) and a nonionic X-ray contrast medium (iopromid) during routine levocardiography and coronary angiography, we employed assays that detect reaction products of thrombin and plasmin to assess the activation of the haemostatic system. Methods: Subsequent to informed consent, 20 patients were randomly assigned to receive either amidotrizoate or iopromid during standard levocardiography and coronary angiography in a double-blind comparative study. Groups were comparable in respect of age, weight, sex and severity of the disease. No anticoagulation was provided. Coronary angiography was performed according to a standardised protocol. Consumption of contrast media and duration of the examination were comparable in both groups. Results: Thrombin generation (F.1+2) and thrombin activity (TAT) were higher with the ionic contrast medium but did not attain statistical significance. Fibrin generation and degradation as expressed by D-dimer fibrin split products was significantly increased in patients who had been receiving amidotrizoate (p<0,05, U-Test). Conclusion: The non-ionic X-ray contrast medium induced significantly less haemostatic activation in vivo than did the ionic medium amidotrizoate. These data suggest that earlier in vitro observations of more pronounced anticoagulant effects of ionic X-ray contrast media are of limited significance for the evaluation of in vivo effects of X-ray contrast media on haemostatic function. (orig.) [Deutsch] Ziel: Bestimmung der Aktivitaet des haemostatischen Systems in vivo nach Gabe von ionischem und nichtionischem Roentgenkontrastmittel in der Angiokardiographie. Material und Methoden: In eine randomisierte doppelblinde Vergleichsstudie mit den Kontrastmitteln Amidotrizoat und Iopromid wurden 20 Patienten (10 pro Gruppe) einbezogen. Bei der aus medizinischen Gruenden indizierten Angiokardiographie wurden 5 repraesentative Reaktionsprodukte der thrombin- und plasmininduzierten

  18. Biogas desulfurization with doped activated carbon; Feinentschwefelung von Biogas mit dotierter Aktivkohle

    Rossow, Silvana; Goetze, Toralf [AdFiS systems GmbH, Teterow (Germany); Deerberg, Goerge [Fraunhofer Inst. fuer Umwelt-, Sicherheits- und Energietechnik UMSICHT, Oberhausen (Germany); Kanswohl, Norbert [Rostock Univ. (Germany). Lehrstuhl fuer Abfall- und Stoffstromwirtschaft; Nelles, Michael [Rostock Univ. (Germany). Lehrstuhl fuer Technologie und Verfahrenstechniken der umweltgerechten Landbewirtschaftung

    2009-07-01

    Doped activated carbon is a special developed activated carbon for the desulfurization of biogas. Because of its special properties it is able to bond a big amount of hydrogen sulfide. After many laboratory tests it was possible to demonstrate the performance of doped activated carbon for desulfurization in practical use The advantages and the specific functioning of doped activated carbon for desulfurization were here exactly as in previous laboratory studies. Despite fluctuating boundary conditions a continuous complete desulfurization was possible. By using the desulfurization system the concentration of hydrogen sulfide is lowered to less than 1 ppm. The damages or interferences that are often caused by hydrogen sulfide could not be identified. A directly visible positive impact of the full desulfurization is the doubling of oil using time. (orig.)

  19. Energy consumption of aeration systems in membrane activation systems; Energiebedarf von Belueftungseinrichtungen in Membranbelebungsanlagen

    Krause, S.; Cornel, P. [Inst. WAR, TU Darmstadt, Darmstadt (Germany)

    2003-07-01

    Owing to the necessity of aeration aggregates, membrane activation systems have higher energy consumption than conventional activation systems. The contribution investigates the energy demand of aeration systems for oxygen supply to the biomass and for control of precipitates on submerged membranes. (orig.) [German] Membranbelebungsanlagen (MBR) zeichnen sich durch einen feststofffreien Klaeranlagenablauf aus. Zudem koennen hoehere Feststoffgehalte im Belebungsbecken erzielt werden. Jedoch ist aufgrund der zusaetzlichen Belueftungsaggregate zur Deckschichtminimierung an den Membranen und reduzierter {alpha}-Werte der Energiebedarf hoeher als in konventionellen Belebungsanlagen. Nachstehend wird der Energiebedarf der Belueftungseinrichtungen zur Sauerstoffversorgung der Biomasse und zur Deckschichtkontrolle getauchter Membranen untersucht. (orig.)

  20. von Neumann Morgenstern Preferences

    Vind, Karl

    von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems......von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems...

  1. von Neumann Morgenstern Preferences

    Vind, Karl

    2000-01-01

    von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems......von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems...

  2. Active Breathing Control (ABC) : Messung und Reduktion von ateminduzierten Organbewegungen des Thorax

    Kientopf, Aline

    2009-01-01

    PURPOSE: Extensive radiotherapy volumes for tumors of the chest are partly caused by interfractional organ motion. We evaluated the feasibility of respiratory observation tools using the active breathing control (ABC) system and the effect on breathing cycle regularity and reproducibility.METHODS AND MATERIALS: Thirty-six patients with unresectable tumors of the chest were selected for evaluation of the ABC system. Computed tomography scans were performed at various respiratory phases startin...

  3. Research and development activities 1984 of KFK Institut fuer Genetik und Toxikologie von Spaltstoffen

    The annual report describes the R+D activities in 1984. Most of the projects were long-term research projects in the fields of gene repair and regulation, biological carcinogenesis, radiation toxicology of actinides, biochemistry of actinides and other heavy metals, biophysic aspects of organometallic compounds, and biochemical fundamentals of gene repair. A new research project is entitled 'Molecular genetics of eukaryontic genes'. (MG)

  4. The effects of percutaneous coronary interventional therapy on platelet activation and the systems fibrinolysis in patients with coronary artery disease

    Objective: To investigate the effects of percutaneous coronary interventional therapy on platelet activation and the systemic fibrinolysis in patients with coronary artery disease (CAD). Methods: The plasma concentration of platelet alpha-granule membrane glycoprotein-140 (GMP-140), plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), von Willebrand factor (vWF) and D-dimer (D-D) of the blood sampled from vein according to the schedule were measured by ELISA. Results: In the sixty-five patients with CAD, at 10 minutes after the procedure, plasma levels of GMP-140, t-PA and D-D were significantly higher than the previous ones; and at 24 h, plasma levels of PAI-1 and vWF were also increased significantly. Conclusions: The activation of platelet and impaired fibrinolytic activity were occurred after PCI in the patients with CAD

  5. Abnormal hemostatic function one year after orthotopic liver transplantation can be fully attributed to endothelial cell activation [v1; ref status: indexed, http://f1000r.es/3ah

    Freeha Arshad

    2014-05-01

    Full Text Available Background: The long-term risk of thrombotic and vascular complications is elevated in liver transplant recipients compared to the general population. Patients with cirrhosis are in a hypercoagulable status during and directly after orthotopic liver transplantation, but it is unclear whether this hypercoagulability persists over time. Aim: We aimed to investigate the hemostatic status of liver transplant recipients one year after transplantation. Methods: We prospectively collected blood samples of 15 patients with a functioning graft one year after orthotopic liver transplantation and compared the hemostatic status of these patients with that of 30 healthy individuals. Results: Patients one year after liver transplantation had significantly elevated plasma levels of von Willebrand factor (VWF. Thrombin generation, as assessed by the endogenous thrombin potential, was decreased in patients, which was associated with increased plasma levels of the natural anticoagulants antithrombin and tissue factor pathway inhibitor.  Plasma fibrinolytic potential was significantly decreased in patients and correlated inversely with levels of plasminogen activator inhibitor-1. Conclusion: One year after liver transplantation, liver graft recipients have a dysregulated hemostatic system characterised by elevation of plasma levels of endothelial-derived proteins. Increased levels of von Willebrand factor and decreased fibrinolytic potential may (in part be responsible for the increased risk for vascular disease seen in liver transplant recipients.

  6. Biologische Entschwefelung von Biogas

    Schneider, Ralf

    2009-01-01

    Ziel dieser Arbeit ist die Erhöhung von Abbauleistung und Stabilität des biologischen Abbaus von Schwefelwasserstoff (H2S) in Biotropfkörpern zur Entschwefelung von Biogas. Für die Nutzung von Biogas ist häufig eine Reduktion des H2S-Gehalts erforderlich. Üblicherweise wird H2S von aeroben Mikroorganismen bei Zugabe von Luft zum Biogas entweder direkt im Biogasreaktor oder in nachgeschalteten Biotropfkörpern zu Schwefel und Schwefelsäure oxidiert. In der Praxis auftretende Schwankungen der H2...

  7. Interaktive Visualisierung von Strukturmechaniksimulationen

    Sommer, Ove

    2003-01-01

    A) Motivation und Problemstellung Der Computer ist heute eines der wichtigsten Hilfsmittel beim Entwurf und der Entwicklung von Fahrzeugen. Zunächst wurde er von Konstrukteuren für das Computer Aided Design (CAD) von virtuellen Fahrzeugmodellen eingesetzt. Inzwischen ist er in vielen anderen Bereichen der Fahrzeugentwicklung unentbehrlich geworden: der Entwicklungszyklus von Automobilen ist durch die Computer-gestützte numerische Simulation substanziell verkürzt worden. An virtuellen Prot...

  8. Carl von Ossietzky

    Suhr, Elke; Ossietzky-Palm, Rosalinda von

    1988-01-01

    Ausstellung und Katalog wurden von Mitarbeitern der Universität Oldenburg anläßlich des 50. Todestages Carl von Ossietzkys erarbeitet. Diese dritte Ossietzky-Ausstellung in Oldenburg steht unter dem Thema "Republikaner ohne Republik". Der Katalog gibt zahlreiche Schautafeln der Ausstellung wieder und enthält ferner kürzere Textbeiträge verschiedener Autoren, darunter auch Erinnerungen von Zeitgenossen Carl von Ossietzkys.

  9. Effects of climate changes on microbial activity, energy and nutrient dynamics of two soils of the dike foreshores of two marsh soils. Final report; Auswirkungen von Klimaaenderungen auf Mikroorganismentaetigkeit, Energie und Stoffdynamik von Watt- und Marschboeden. Schlussbericht

    Blume, H.P.; Mueller-Thomsen, U.; Pfisterer, U.

    2000-07-01

    During two yerars the temperature, water, redox, salt, pH and nutrient dynamics (NH{sub 4}, NO{sub 3}, SO{sub 4}) as well as the gas dynamics (CO{sub 2}, CH{sub 4}, N{sub 2}O) of two soils of the dike foreshores of the Schleswig-Holstein coastal region of the North Sea have been studied. The investigation sites were a Gleyi-salic Fluvisol of a higher situated salt marsh and a silty-sandy sali-thionic Fluvisol with Salicornia and Spartina. On ten dates the emission of gases was measured on soil surface. This was carried out during 24 hours in terms of three hours. The other properties were determined in (4+5) soil depths (10, 40, 80, 140 cm, for a shorter time also in 4, 8, 12, 16 and 20 cm depth) in terms of two weeks as well as analogous to the gases. A site of 9 m{sup 2} of the Gleyi-salic Fluvisol was provided with heat by an in 3-6 cm soil depth installed heating system. Additionally on 10 dates the microbial biomass (fumigation/extraction) and the microbial activity (DMSO-reduction) of the topsoil was determined, and during one year the feeding activity of the occurring soil animals was characterised by bait stripes. The intention of the investigations was the knowledge of the effects of the for the year 2050 predicted climate scenario 2 (+2,5 K temperature, sea water table +55 cm, tidal increase +30 cm, 15% more and longer lasting storm tides, +15% winter precipitation) on the soil dynamics. The results of the heating experiment show that with the (even realistic) expectation of a compensation of the sea water table by sedimentation in the same height, soil dynamics and the action of organisms will change, but the Gleyi-salic Fluvisol will exist furthermore in a certain extent due to its morphology and its property as vegetation site and biosphere of organisms. As a consequence of increasing temperatures the microbial activity and the feeding activity of soil animals will faintly increase; more CO{sub 2} will be emitted into the atmosphere, while the actually

  10. The John von Neumann Institute for Computing (NIC): A survey of its supercomputer facilities and its Europe-wide computational science activities

    The John von Neumann Institute for Computing (NIC) at the Research Centre Juelich, Germany, is one of the leading supercomputing centres in Europe. Founded as a national centre in the mid-eighties it now provides more and more resources to European scientists. This happens within EU-funded projects (I3HP, DEISA) or Europe-wide scientific collaborations. Beyond these activities NIC started an initiative towards the new EU member states in summer 2004. Outstanding research groups are offered to exploit the supercomputers at NIC to accelerate their investigations on leading-edge technology. The article gives an overview of the organisational structure of NIC, its current supercomputer systems, and its user support. Transnational Access (TA) within I3HP is described as well as access by the initiative for new EU member states. The volume of these offers and the procedure of how to apply for supercomputer resources is introduced in detail

  11. The John von Neumann Institute for Computing (NIC): A survey of its supercomputer facilities and its Europe-wide computational science activities

    Attig, N.

    2006-03-01

    The John von Neumann Institute for Computing (NIC) at the Research Centre Jülich, Germany, is one of the leading supercomputing centres in Europe. Founded as a national centre in the mid-eighties it now provides more and more resources to European scientists. This happens within EU-funded projects (I3HP, DEISA) or Europe-wide scientific collaborations. Beyond these activities NIC started an initiative towards the new EU member states in summer 2004. Outstanding research groups are offered to exploit the supercomputers at NIC to accelerate their investigations on leading-edge technology. The article gives an overview of the organisational structure of NIC, its current supercomputer systems, and its user support. Transnational Access (TA) within I3HP is described as well as access by the initiative for new EU member states. The volume of these offers and the procedure of how to apply for supercomputer resources is introduced in detail.

  12. Einfluss von Konstruktion und Betriebsweise von Trinkwasserinstallationen auf das Wachstum von Mikroorganismen im Trinkwasser

    Astitouh, F. (Fariha)

    2013-01-01

    Das Wachstumsverhalten von Biofilmen und Krankheitserregern im Wasser aus Trinkwasserinstallationen wird durch Temperatur und Stagnation beeinflusst. Die Vermeidung von „lauwarmen“ Temperaturen, die das Legionellenwachstum begünstigt, stellt höhere Anforderungen an Konstruktion und Betriebsweise von Kaltwassersystemen. Diese Arbeit analysiert Konstruktionsprinzipien von Stockwerksinstallationen auf den Einfluss auf das Wachstum von Mikroorganismen im Trinkwasser „Kalt“. Die Versuchsanlage sim...

  13. Langzeitkultur von humanen Langerhanszellen

    Henschke, Cornelia

    2001-01-01

    Die Arbeit beschreibt das phänotypische Verhalten von kultivierten Langerhanszellen, antigenpräsentierenden Zellen der Epidermis, sowie die Art und Weise ihrer Elimination. Hierfür wurden Zellkulturen von Langerhanszellen durch Migration aus normaler menschlicher Haut gewonnen. Die Langerhanszellen durchlaufen dabei die gleiche funktionelle Entwicklung, wie nach Antigenpräsentation in situ. Ziel der Untersuchung war es, die funktionellen und zellulären Eigenschaften und die Elimination von...

  14. Neue Inschriften von Olympia

    Taeuber, Hans; Siewert, Peter

    2013-01-01

    Das Heiligtum von Olympia fasziniert die Menschen von der Antike bis in die Gegenwart. Uber seine Geschichte und den Ablauf der dort abgehaltenen Spiele erhalten wir authentische Informationen von antiken Schriftstellern wie Pausanias, durch Grabungsfunde und -befunde, vor allem aber auch durch die dort gefundenen Inschriften. Die vorliegende Publikation vereint nun die seit 1896 veröffentlichten Texte und ermoglicht somit eine vollständige Ubersicht über die epigraphischen Zeugnisse auf Stei...

  15. Statistische Besonderheiten von Finanzmarktdaten

    Krämer, Walter

    2000-01-01

    Finanzmarktdaten wie Zinsen, Aktien- oder Wechselkurse und andere spekulative Preise setzen sich durch verschiedene Besonderheiten von sonstigen ökonomischen Zeitreihendaten ab. Dieser Artikel untersucht die Konsequenzen dieser Besonderheiten für die rationale Bewertung von Finanzinstrumenten und für verschiedene, in finanzwirtschaftlichen Anwendungen angewandte statistische Schätzungen und Tests.

  16. Kointegration von Aktienkursen

    Krämer, Walter

    1997-01-01

    Die vorliegende Arbeit untersucht das gemeinsame Zeitreihenverhalten von spekulativen Preisen, speziell von Aktienkursen. Anhand ausgewählter deutscher Dividendenwerte wird gezeigt, daß dieses gemeinsame Zeitreihenverhalten zu den Markt schlagenden Anlagestrategien führen kann und in diesem Sinn mit effizienten Märkten nicht verträglich ist.

  17. Lebenszyklusbasierte Nachhaltigkeitsanalyse von Technologien

    Lehmann, Annekatrin

    2013-01-01

    ZIEL: Eine Bewertung von Technologien unter Nachhaltigkeitsgesichtspunkten erfordert die Betrachtung verschiedener Dimensionen und verschiedener Betrachtungsebenen. Das Ziel dieser Arbeit ist es, eine Antwort auf die Forschungsfrage zu geben, wie eine lebenszyklusbasierte, produktbezogene und vergleichende Nachhaltigkeitsanalyse von Technologien umgesetzt werden kann. Die Erörterung erfolgt sowohl theoretisch als auch praktisch am Beispiel einer Fallstudie zur Analyse alternativer Technologie...

  18. Mikrobieller Abbau von Iminodisuccinat

    Cokesa, Zeljko

    2004-01-01

    Iminodisuccinat (IDS) ist ein neuer synthetisch hergestellter Komplexbildner mit dem Potenzial den meistbenutzten aber schwer abbaubaren Komplexbildner Ethylendiamin-tetraacetat (EDTA) teilweise zu ersetzen. Von einem EDTA-Substitut wird neben guten Komplexierungseigenschaften insbesondere eine gute biologische Abbaubarkeit verlangt. In diesem Zusammenhang wurde die Abbaubarkeit von IDS bewertet, die initialen Abbauwege aufgeklärt und die in den Abbau involvierten Gene charakterisiert. Sta...

  19. Einfluss von Titan auf den Entwurf von Unterwasserfahrzeugen

    Malletschek, Andreas

    2011-01-01

    Die Dissertation zum „Einfluss von Titan auf den Entwurf von Unterwasserfahrzeugen“ beschäftigt sich sowohl mit der Erarbeitung der werkstoffseitigen Grundlagen für die allgemeine Integration von Titan in der Meerestechnik als auch mit der konkreten Analyse und Bewertung der Anwendung von Titan in verschiedenen schiffstechnischen Systeme eines Unterwasserfahrzeugs.

  20. Calpain Activator Dibucaine Induces Platelet Apoptosis

    Jun Liu

    2011-03-01

    Full Text Available Calcium-dependent calpains are a family of cysteine proteases that have been demonstrated to play key roles in both platelet glycoprotein Ibα shedding and platelet activation and altered calpain activity is associated with thrombotic thrombocytopenic purpura. Calpain activators induce apoptosis in several types of nucleated cells. However, it is not clear whether calpain activators induce platelet apoptosis. Here we show that the calpain activator dibucaine induced several platelet apoptotic events including depolarization of the mitochondrial inner transmembrane potential, up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-XL, caspase-3 activation and phosphatidylserine exposure. Platelet apoptosis elicited by dibucaine was not affected by the broad spectrum metalloproteinase inhibitor GM6001. Furthermore, dibucaine did not induce platelet activation as detected by P-selectin expression and PAC-1 binding. However, platelet aggregation induced by ristocetin or α-thrombin, platelet adhesion and spreading on von Willebrand factor were significantly inhibited in platelets treated with dibucaine. Taken together, these data indicate that dibucaine induces platelet apoptosis and platelet dysfunction.

  1. Classification of chemicals as endocrinally active compounds. Critical review of the classification of selected pesticides and industrial chemicals as endocrinally active chemicals; Einstufung von Schadstoffen als endokrin wirksame Substanzen. Kritische Ueberpruefung der Einstufung von ausgewaehlten Pestiziden und Industriechemikalien als endokrin wirksame Substanzen

    Bruhn, T.; Guelden, M.; Ludewig, S. [Kiel Univ. (Germany). Inst. fuer Toxikologie; Seibert, H.

    1999-10-01

    Different authors have published lists of chemicals, especially pesticides and industrial chemicals, reported to have 'reproductive and endocrine disrupting activities' or 'estrogenic/antiestrogenic' activities. The objective of this study was to examine what is the basis for and whether it is justified to classify chemical compounds as 'endocrine disrupters' that are contained in frequently cited overviews, but have not been discussed in a previous report (UBA-TEXTE 46/97). Depending on the level of evidence derived from literature data, substances are classified either as (i) endocrinally active or (ii) potentially endocrinally active or (iii) without sufficient data on endocrine activity. The criteria used for the classification are based on the definitions by US-EPA and the Weybridge conference. (orig.) [German] Von verschiedenen Autoren sind umfangreiche Listen mit Chemikalien, insbesondere Pestiziden und Industriechemikalien, veroeffentlicht worden, die als 'endokrin wirksam und reproduktionstoxisch' oder als 'oestrogen- bzw. 'antioestrogen wirksam' bezeichnet werden. Aufgabe der vorliegenden Studie ist es, zu untersuchen, auf welchen Grundlagen die Einstufung als 'endokrin wirksam' beruht, und zu ueberpruefen, ob sie gerechtfertigt ist. Je nach den Ergebnissen der Literaturrecherchen werden die Substanzen einer von drei Gruppen zugeordnet: 1. endokrin wirksam, 2. potentiell endokrin wirksam, 3. ohne ausreichende Hinweise auf endokrine Wirksamkeit. Die verwendeten Kritetien fuer die Zuordnung lehnen sich an die Definitionen der EPA und der Weybridge-Konferenz an. Schon in einem vorangegengenen Bericht (UBA-TEXTE 46/97) diskutierte Verbindungen werden nicht erneut behandelt. (orig.)

  2. Aufbau von Navigationshilfen durch Analyse von Suchanfragen

    Höchstötter, Nadine

    2007-01-01

    Nadine Höchstötter, Karlsruhe, berichtete über den letzten Stand ihrer Forschungen zum Suchverhalten in Suchmaschinen. Anhand von Datensätzen in Lycos lassen sich Muster von Suchanfragen ermitteln, aus denen Trends abgeleitet werden können. Es kann dabei zwischen vier grundsätzlichen Klassen unterschieden werden: „Eintagsfliegen“ treten im Erhebungszeitraum nur einmal auf, „Dauerbrenner“ hingegen während der Erhebungsperiode nahezu in jedem definierten Zeitintervall. Kleinere Ausschläge, bei ...

  3. The thrombospondin-1 N700S polymorphism is associated with early myocardial infarction without altering von Willebrand factor multimer size

    Zwicker, Jeffrey I.; Peyvandi, Flora; Palla, Roberta; Lombardi, Rossana; Canciani, Maria Teresa; Cairo, Andrea; Ardissino, Diego; Bernardinelli, Luisa; Bauer, Kenneth A; Lawler, Jack; Mannucci, Pier

    2006-01-01

    The N700S polymorphism of thrombospondin-1 (TSP-1) has been identified as a potential genetic risk factor for myocardial infarction (MI). In a large case-control study of 1425 individuals who survived a myocardial infarction prior to age 45, the N700S polymorphism was a significant risk factor for myocardial infarction in both homozygous (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.3, P = .01) and heterozygous carriers of the S700 allele (OR 1.4, 95% CI 1.1-3.3, P = .01). TSP-1 ha...

  4. Gruppen von quasi-Automorphismen

    Lehnert, Jörg

    2008-01-01

    Die vorliegende Arbeit beschäftigt sich mit Gruppen von quasi-Automorphismen von Graphen, genauer gesagt, von gefärbten Graphen. Ein gefärbter Graph ist ein Graph, dessen Kantenmenge in eine disjunkte Vereinigung von Mengen von Kanten einer bestimmten Farbe zerlegt ist. Ein Automorphismus eines solchen Graphen muss insbesondere die Farben der Kanten respektieren. Ein quasi-Automorphismus eines solchen Graphen ist eine Bijektion der Eckenmenge auf sich selbst, die nur endlich oft die Autmomorp...

  5. Die Messung von Vernetzung

    Kreische, Joachim

    2006-01-01

    Die Nutzungsanalyse der von Bibliotheken angebotenen Datenbanken und Volltextangebote ist bisher nicht nur stark von den Datenlieferungen der Anbieter abhängig, sondern auch sehr statisch. Mit der Einführung von Linking Resolvern, die über Statistiktools verfügen, verbessern sich die Möglichkeiten der Nutzungsanalyse deutlich. Am Beispiel der Einführung des Linking Resolvers SFX an der ULB Düsseldorf sollen verschiedene Analysemöglichkeiten vorgestellt werden. Insbesondere die über den Linkin...

  6. Carl von Clausewitz

    Højrup, Thomas

    2009-01-01

    Forskningsbaseret præsentation af Carl von Clausewitz' krigsteori og dens betydning for statsbegrebet og udviklingen af teori om statsdannelse og statssystem. Krigsbegrebets betydning for politikbegrebet ekspliciteres, og de indre relationer imellem de to begreber demonstreres med konkrete...

  7. Ellis Von Creveld Syndrome

    Afshar H

    1999-01-01

    Full Text Available One patient with Ellis Von Creveld syndrome contains: dwarfism, congenital heart"ndisease, ectodermal dysplasia, polyductyly, an abnormally wide labial frenum and maxillary"nmolars with single root.

  8. Produktentwicklung von Druckgussteilen

    Schübel, Christine

    2012-01-01

    Die Produktentwicklung von Druckgussteilen kann flexibel, wirtschaftlich und schnell durch die Herstellung von RP-Unikaten und Metallabgüssen aus Keramikschalen realisiert werden. Dieser Weg eignet sich vor allem für komplexe Bauteile und macht eine Produkterprobung mit qualitativ deutlich verbesserter Aussagekraft trotz reduzierter Entwicklungskosten möglich. In Abgrenzung zum Sandguss, muss die Konstruktion der Bauteile nicht verändert werden. 
Durch eine gezielte Wärmebehandlung wird die V...

  9. Lars von Triers film

    Nielsen, Lisbeth Overgaard

    2007-01-01

    Afhandlingen undersøger Lars von Triers filmæstetik, som den kommer til udtryk i spillefilmene fra perioden 1984-2007. Afhandlingen analyserer de enkelte films stil, virkningsstrategi og betydningsdannelse.......Afhandlingen undersøger Lars von Triers filmæstetik, som den kommer til udtryk i spillefilmene fra perioden 1984-2007. Afhandlingen analyserer de enkelte films stil, virkningsstrategi og betydningsdannelse....

  10. Photophysikalische Charakterisierung von Fluoreszenzmarkern insbesondere von Fluoreszenzproteinen

    Auerbach, Dagmar

    2015-01-01

    Die komplette Aufklärung der Vorgänge in Zellen ist von besonderer Bedeutung, da nur durch die gesamte Kenntnis dieser Mechanismen ein Nutzen im Bereich des Wirkstoffdesigns und des Wirkstofftransportes möglich ist. Für weitere Erkenntnisse im Bereich der Fluoreszenzmarker, und im Speziellen der Fluoreszenzproteine, werden in dieser Arbeit Cumarin-basierte Fluoreszenzmarker an Aminosäuren und Peptiden sowie Fluoreszenzproteine charakterisiert. Cumarin-basierte Farbstoffe sind extrinsische Mar...

  11. Maximum permissible activities of gamma-emitting radionuclides behind lead-shielding of small thickness (0,1 and 0,3 cm lead); Hoechste zulaessige Aktivitaeten von Gammastrahlern hinter Bleiabschirmungen geringer Wanddicke (0,1 und 0,3 cm Blei)

    Joerg, J. [Allgemeines Krankenhaus, Vienna (Austria). Abt. Endokrinologie und Stoffwechsel

    1998-12-31

    Maximum permissible activities of gamma-emitting radionuclides behind lead-shielding of 0,1 and 0,3 cm thickness for a dose rate of 2,5 {mu}Sv/h in 0,5 and 1 m distance are given. Values may for instance be useful in shielding containers for radioactive waste at working place. (orig.) [Deutsch] Fuer 28 ausgewaehlte Radionuklide werden die hoechstzulaessigen Aktivitaeten hinter Bleiabschirmungen von 0,1, 0,3 und 0,5 cm Wanddicke angegeben. Die Werte gelten fuer eine Dosisleistung von 25 {mu}Sv/h in 0,25 m, bzw. fuer 2,5 {mu}Sv/h in 0,5 und 1,0 m Abstand von der Strahlenquelle. Die Werte erheben keinen Anspruch auf strenge wissenschaftliche Genauigkeit, sollten jedoch zur Orientierung im praktischen Strahlenschutz - z.B. bei der Abschirmung von Sammelbehaeltern fuer radioaktiven Abfall - ausreichen. (orig.)

  12. Kontextualisierung von Queer Theory

    Anna Voigt

    2008-03-01

    Full Text Available Christine M. Klapeer legt in diesem Einführungsband dar, aus welchen politischen und theoretischen Kontexten heraus sich ‚queer‘ zu einem Begriff mit besonderem politischem und theoretischem Gehalt entwickelt hat. Wesentlich zielt sie dabei auf eine kritische Kontextualisierung von „queer theory”. Die Autorin geht zunächst auf das Gay Liberation Movement ein, grenzt die Queer Theory vom Poststrukturalismus, von feministischen Theorien und den Lesbian and Gay Studies ab, beleuchtet Eckpunkte queeren Denkens und zeichnet schließlich die Entwicklungen in Österreich sowohl politisch-rechtlich als auch bewegungsgeschichtlich und in der Wissenschaftslandschaft nach.

  13. Mein Traum von Bibliothek

    Bauer, Charlotte; Schneider, Ulrich Johannes

    2011-01-01

    Unter dem Titel „Mein Traum von Bibliothek“ wird demnächst an der Universitätsbibliothek Leipzig eine Vortragsreihe für Bibliothekare starten. Thema ist der von uns allen erlebte rasante Wandel in der Mediennutzung durch digitale Technik. Die Aufgaben der Bibliothek ändern sich, die Tätigkeiten der Bibliothekare ändern sich, die Funktionen der Bibliotheksräume ändern sich. Das hat Konsequenzen für alle wissenschaftlichen Bibliotheken, ins besondere für ein komplexes System wie das der UB Leip...

  14. Transformation von Zierpflanzen

    Börstling, Dirk

    2005-01-01

    Da die Gentechnik und die Molekularbiologie für die moderne Pflanzenzüchtung in den letzten Jahren enorm an Bedeutung gewonnen haben, besteht auch für die Züchtung von gartenbaulichen Nutzpflanzen ein Interesse am Einsatz dieser Methoden. Die erfolgreiche Veränderung der Blütenfarbe bei Petunia hybrida (Meyer et al. 1987) stellt den Anfang der Transformation von Zierpflanzen mit einem konkreten und wirtschaftlich relevanten Ziel dar. Die Ergebnisse dienen nicht nur der Grundlagenwissenschaft,...

  15. Functional magnetic resonance imaging of basal ganglia. Activation mapping with FLASH sequences for BOLD contrast and high resolution; Funktionelle Magnetresonanztomographie der Basalganglien. Einsatz von FLASH-Sequenzen zum Aktivitaetsmapping mit BOLD-Kontrast und Hochaufloesung

    Seelos, K.C. [Inst. fuer Radiologische Diagnostik, Klinikum Grosshadern, Univ. Muenchen (Germany); Bucher, S.F. [Neurologische Klinik und Poliklinik, Klinikum Grosshadern, Univ. Muenchen (Germany); Stehling, M.K. [Inst. fuer Radiologische Diagnostik, Klinikum Grosshadern, Univ. Muenchen (Germany); Oertel, W.H. [Neurologische Klinik und Poliklinik, Klinikum Grosshadern, Univ. Muenchen (Germany); Reiser, M. [Inst. fuer Radiologische Diagnostik, Klinikum Grosshadern, Univ. Muenchen (Germany)

    1995-04-01

    The activation pattern of putamen, internal and external division of globus pallidus was investigated during rapid pronation and supination of the right and left hand in 12 normal volunteers using a FLASH sequence with high resolution for functional magnetic resonance imaging (fMRI) at 1.5 T. The chosen paradigm for motor function led to a signal increase within the basal ganglia between 3 and 23%, depending on the structure and individual subject. In all cases significant activation could be found contralateral to the moving hand. In six cases activation was also found on the ipsilateral side. The activated areas within putamen, internal and external division of globus pallidus were less than 5 mm{sup 2}. These first results indicate that fMRI studies of basal ganglia are feasible and might be suitable for analyzing basal ganglia disorders. (orig.) [Deutsch] Das Aktivierungsmuster von Putamen, Globus pallidus internus und externus waehrend schneller Pronation und Supination von rechter und linker Hand wurde bei 12 normalen Probanden mit Hilfe einer fuer die funktionelle Magnetresonanztomographie (fMRT) geeigneten hochaufloesenden FLASH-Sequenz bei 1,5 Tesla untersucht. Der durch das Bewegungsparadigma verursachte Signalanstieg innerhalb der Basalganglien lag je nach Struktur und untersuchtem Individuum zwischen 3 und 23%. In allen Faellen war kontralateral zur bewegten Hand ein signifikanter Aktivitaetsanstieg nachweisbar. In 6 Faellen war auch auf der ipsilateralen Seite eine Aktivitaet nachweisbar. Die aktivierten Areale innerhalb von Putamen, Globus pallidus internus und externus waren nicht groesser als 5 mm{sup 2}. Diese ersten Ergebnisse zeigen, dass magnetresonanztomographische Funktionsuntersuchungen im Bereich der Basalganglien moeglich sind und geeignet erscheinen, um Erkrankungen dieser Systeme zu analysieren. (orig.)

  16. Insolvenzschutz von Wertguthaben

    Hanau, Peter; Rolfs, Christian

    2003-01-01

    Arbeitszeitkonten stellen einen wichtigen Bestandteil der Flexibilisierung von Arbeitszeiten in Deutschland dar. Sie dienen den Interessen der Arbeitnehmerinnen und Arbeitnehmer wie der Arbeitgeber in gleicher Weise. Die Tarifvertrags- und Betriebsparteien haben vielfältige, den spezifischen Belangen der jeweiligen Branchen und Unternehmen Rechnung tragende Modelle entwickelt. Die legislativen Rahmenbedingungen zur Fortentwicklung flexibler Arbeitszeitmodelle wurden durch den Gesetzgeber scho...

  17. Spezielle Anwendungen von EMDR

    Schubbe, Oliver; Püschel, Ines; Renssen, Monique

    2013-01-01

    Nach traumatischen Erlebnissen können sich neben der Symptomatik einer Posttraumatischen Belastungsstörung verschiedene klinische Störungsbilder entwickeln. Diese lassen sich in Abhängigkeit von der individuellen Bewältigungsform schematisch vereinfacht beschreiben.

  18. Qualitative Beschreibung von Automatisierungssoftware

    Biegert, Uwe

    1998-01-01

    Für die Entwicklung sicherer Automatisierungssysteme werden eine Reihe von konventionellen Methoden eingesetzt, die jeweils einzelne Bestandteile eines Systems separat betrachten. So wird der technische Prozeß mit Verfahren wie FMEA, PAAG oder der Fehlerbaumanalyse auf sicherheitskritische Aspekte untersucht. Bei der Automatisierungssoftware werden Validierungs- oder Verifikationsmethoden verwendet. Das Verhalten des Menschen wird auf einzelne Aktionen heruntergebrochen und ...

  19. Anpassung von individuellen Mediennutzungswahrscheinlichkeiten

    Kopp, Bruno

    2011-01-01

    Es wird eine Anpassungsmethode von Nutzungswahrscheinlichkeiten bei Umfragen zur Mediennutzung untersucht. Das Verfahren ist so angelegt, dass die Reichweiten in vorgegebenen Zielgruppen an Sollwerten justiert werden. Ein Kontrollparameter sorgt dafür, dass die ursprünglichen Nutzungswahrscheinlichkeiten möglichst wenig verändert werden.

  20. Fractal von Neumann entropy

    da Cruz, Wellington

    2002-01-01

    We consider the {\\it fractal von Neumann entropy} associated with the {\\it fractal distribution function} and we obtain for some {\\it universal classes h of fractons} their entropies. We obtain also for each of these classes a {\\it fractal-deformed Heisenberg algebra}. This one takes into account the braid group structure of these objects which live in two-dimensional multiply connected space.

  1. Qualitative Inhaltsanalyse anhand von Zielen und Problemen von Psychotherapiepatienten

    Dick, Yvonne

    2004-01-01

    Ziel der vorliegenden Arbeit war, das Vorgehen der Qualitativen Inhaltsanalyse anhand von Zielen und Problemen von Psychotherapiepatienten (Klartextangaben)zu beschreiben. Ein weiteres Ziel war es die vorherige Studie bezüglich der Probleme und Ziele von Psychotherapiepatienten zu replizieren, um die Anwendbarkeit des damals erstellten Kategoriensystems zu überprüfen. Gleichzeitig entwickelten wir das bereits existierende Kategoriensystem weiter. Dabei war es uns wichtig, der Vielgestaltigkei...

  2. Enzymkinetik von Phospholipase C und Aggregationsverhalten von Gentransfer-Komplexen

    Galneder, Reinhard Josef

    2007-01-01

    Im Rahmen dieser Arbeit wurde ein Experiment zur Laserfallen-kontrollierten Mikroelektrophorese aufgebaut und getestet, das zeitaufgelöste Messungen des Oberflächenpotentials an einzelnen kolloidalen Teilchen ermöglichte. Mit dieser Methode konnte im folgenden die Enzymkinetik von Phospholipase C mit einer bisher nicht erreichten Zeitauflösung von ca. 1 sec gemessen werden. Dazu wurden Silika-Kugeln mit einem Radius von 500 nm mit einer Lipidmembran aus neutralem Phosphatidylcholin und dem ne...

  3. Imaging of Von Meyenburg complexes.

    Pech, L; Favelier, S; Falcoz, M T; Loffroy, R; Krause, D; Cercueil, J P

    2016-04-01

    Von Meyenburg complexes, or biliary hamartomas, are frequently incidentally detected. They are usually easy to characterize with magnetic resonance imaging. However, in some occasions they are difficult to differentiate from other liver lesions, in particular from small liver metastases. Von Meyenburg complexes are developmental malformations of the ductal plate. They can be found in association with Caroli disease and Caroli syndrome. Like other ductal plate malformations, Von Meyenburg complexes associated with cholangiocarcinoma have been described and their relationship has been established. This review provides an update on the etiopathogenesis of Von Meyenburg complexes, illustrates the imaging features on ultrasound, CT and MRI of this condition and discusses the most common diagnostic pitfalls. The relationships between Von Meyenburg complexes and the various ductal plate malformations and the most recent literature data regarding the relationships between Von Meyenburg complexes and cholangiocarcinoma are presented. PMID:26522945

  4. Positive Aspekte von Erosionsprozessen

    Haffner, Willibald

    1995-01-01

    Negative Aspekte von Erosion, insbesondere der Bodenerosion, sind in der Fachliteratur vielseitig dokumentiert. Dieser Aufsatz geht der Frage nach, welche positiven Aspekte erosiven Sediment- und Bodenverlagerungen abzugewinnen sind. Folgende Beispiele aus Mitteleuropa, Nepal und dem Jemen werden diskutiert: - Entstehung edaphischer Gunsträume durch Wasser- und Winderosion - Bodenabtrag im Muschelkalk: Auf- oder Abwertung des erodierten Standortes? - Erschließung kalk- und nährstoffr...

  5. Von Kursachsen nach Europa

    Link, Ivonne; Wiegand, Peter

    2011-01-01

    Innovativer Zugriff auf raumbezogene grafische Information – unter diesem Titel erfolgte zwischen 2009 und 2011 der Ausbau des umfangreichen Rechercheportals für kartografische Fachinformationen („Kartenforum“) der Sächsischen Landesbibliothek – Staats- und Universitätsbibliothek Dresden (SLUB). Im Rahmen des von der Deutschen Forschungsgemeinschaft geförderten Projektes wurden weitere 12.000 historische Karten und Ansichten hoch aufgelöst digitalisiert, katalogisiert sowie sachlich erschloss...

  6. Semantische Adaption von Komponenten

    Söldner, Guido

    2012-01-01

    Im Bereich der Informationstechnik ist die Adaption von Software an veränderte Gegebenheiten und Umgebungen ein wichtiges Thema. Dabei bestimmen vor allem die konkret verwendete Software-Programmiersprache, die benutzten Entwurfsmuster und die der Applikation zugrundeliegende Software-Architektur, mit welchem Aufwand eine Anwendung auf neue Anforderungen eingehen kann. Darüber hinaus war und ist es interessant, Mechanismen zu entwickeln, mit denen Applikationen selbst auf spontane Änderungen ...

  7. Molekulare Mechanismen von Pankreaserkrankungen

    Ockenga, Johann

    2003-01-01

    Die Ätiologie von entzündlichen Pankreaserkrankungen, insbesondere bei den idiopathischen Pankreatitiden, ist weitgehend noch nicht verstanden. In der folgenden Arbeit sollen immunologische und molekularbiologische Aspekte zu Pankreaserkrankungen unter Berücksichtigung eigener Untersuchungen dargestellt werden. Zu Beginn unserer Arbeit haben wir untersucht inwieweit immunologische Veränderungen an der Entstehung einer chronischen Pankreatitis beteiligt sind. Wir fanden eine systemische Akti...

  8. Nutzerorientiertes Management von materiellen und immateriellen Informationsobjekten

    Hübsch, Chris

    2001-01-01

    Schaffung einer stabilen, erweiterbaren und skalierbaren Infrastruktur für die Bereitstellung von Diensten im Umfeld von Bibliotheken und ähnlichen wissensanbietenden Einrichtungen unter Verwendung von XML-RPC und Python.

  9. Tragverhalten von Textilbeton mit Kurzfasern

    Brameshuber, Wolfgang; Hinzen, Marcus

    2011-01-01

    Das Tragverhalten von Textilbeton kann durch den Einsatz von Kurzfasern erheblich verbessert werden. Untersuchungen zeigen eine Anhebung der Erstrisslast, ein dehnungsverfestigendes Verhalten, eine Verfeinerung des Rissbildes sowie eine Anhebung der maximalen Tragfähigkeit. Unklar sind bisher noch die genauen Mechanismen, die eine gezielte Einstellung des Tragverhaltens ermöglichen. Der Beitrag fasst die Untersuchungen zu den einzelnen Bereichen der Spannungs- ehnungslinie von Textilbeton mit...

  10. Dichteoptimierung und Strukturanalyse von Hartkugelpackungen

    Lochmann, Kristin

    2010-01-01

    Bei der Verwendung von Hartkugelpackungen als Modelle für verschiedene Systeme in Physik, Chemie und den Ingenieurwissenschaften kommen einige Fragen auf, z.B. nach dem Zusammenhang zwischen der Packungsdichte und der Radienverteilung der Kugeln bzw. der Packungsstruktur. Der erste Teil dieser Arbeit beschäftigt sich mit dem Problem der optimalen Packungsdichte von zufällig dichten Packungen. Es wird ein Optimierungsalgorithmus vorgestellt, der aus einer vorgegebenen Klasse von Radienverteilu...

  11. Phasenverhalten von Polyethylen in Mischsystemen

    Schnell, Matthias

    2003-01-01

    Die vorliegende Arbeit beschäftigt sich mit dem Phasenverhalten von Polyethylen (PE) in nicht-reaktiven und in reaktiven Systemen. Von drei eng verteilten Polyethylenen (Mw = 6,4, 82 bzw. 380 kg/mol) in n-Hexan sowie für das System 2,2-Dimethylbutan / PE 82 wurde die Entmischung in Abhängigkeit von der Zusammensetzung, dem Druck und der Temperatur experimentell bestimmt. Die Modellierung der Trübungskurven erfolgte nach der Theorie von Sanchez und Lacombe. Dieser Ansatz beschreibt die Ergebni...

  12. Gegenseitige Beeinflussung von Mizellaren Strukturen und Photodimerisierung von Cumarinderivaten

    Yu, Xiuling

    2004-01-01

    In dieser Arbeit wurde die gegenseitige Beeinflussung von mizellaren Strukturen und Photodimerisierung von Cumarinderivaten untersucht. Als Mizellbildner wurden das kationische Cetyltrimethylammoniumbromid (CTAB) und das nicht-ionische Triton X-100, als Solubilisate Cumarinderivaten verwendet. Es wurden rheologische, thermodynamische und photochemische Untersuchungen durchgeführt. Die Viskosität der beiden Tensidsysteme steigt mit zunehmender Solubilisatkonzentration je nach Cumarinderivat un...

  13. Aspectos ultra-sonográficos dos hamartomas dos ductos biliares (complexo de von Meyenburg: resultado de uma busca ativa de oito anos Ultrasonography findings in patients with bile duct hamartomas (von Meyenburg complex: result of an active search of eight years

    Márcio Martins Machado

    2003-06-01

    Full Text Available A correta identificação de tumores hepáticos benignos é importante, pois a maioria não necessita de conduta intervencionista. Os autores relatam os aspectos ultra-sonográficos dos hamartomas de ductos biliares (complexo de von Meyenburg em 16 pacientes estudados prospectivamente, resultados de uma busca ativa de oito anos. Em 14 pacientes foram identificadas múltiplas lesões menores ou iguais a 0,8 cm, e em dois, apenas duas lesões em cada (medindo de 0,4 cm a 1,3 cm. O aspecto ultra-sonográfico que predominou foi o de múltiplas pequenas imagens hiperecogênicas com ou sem reverberação sonora posterior e margens irregulares (14 pacientes. Menos comumente, foi encontrado o aspecto "em alvo", com centro com maior ecogenicidade que a periferia (dois pacientes com duas lesões cada e margens bem definidas.The recognition and identification of benign liver tumors is important since most of these tumors do not require any intervention. The authors report the ultrasonography findings in 16 patients with bile duct hamartomas (von Meyenburg complex that were evaluated prospectively by an active search of eight years. Multiple lesions with size equal or less than 0.8 cm were identified in 14 patients. Two other patients had only two lesions measuring 0.4 cm to 1.3 cm. The most common ultrasonographic pattern was that of multiple small hyperechogenic lesions (with or without posterior acoustic reverberation with irregular margins (14 patients. A less common finding (two patients with two lesions each was the "target" pattern with echogenic center and well defined limits.

  14. Flugmechanik und Flugregelung von Luftschiffen

    Kämpf, Bernhard G.

    2004-01-01

    In der vorliegenden Arbeit wird eine geschlossene algebraische Modellierung der Flugmechanik von Luftschiffen entwickelt und im Rahmen analytischer und numerischer Untersuchungen angewendet. Die Resultate geben eine allgemeine Einsicht in die flugmechanischen Eigenschaften von Luftschiffen und werden in den Entwurf einer Flugreglerstruktur umgesetzt. Neben der Darstellung der Gewichts- und Schubkräfte werden die aerostatischen und thermodynamischen Zusammenhänge dargestellt. Der Schwerpunk...

  15. John von Neumann

    This article is dedicated to John von Neumann, one of the most outstanding scholars of the 20th century. His life was short but bright, and his contribution to almost all branches of mathematics, as well as to physics, economics, biology, and astronomy was enormous. He constructed some of the first computers and he was among the key persons in the American atomic project. Development of his ideas will continue to play a vital part in various areas of pure and applied mathematics. (from the history of physics)

  16. Laserbasierte Ortung von Weltraumschrott

    Riede, Wolfgang; Hampf, Daniel; Wagner, Paul; Giesen, Adolf

    2014-01-01

    Raumfahrt ist heute eine der wichtigen Schlüssel- und Kernkompetenzen der modernen Industriegesellschaft. Insbesondere für Streitkräfte oder für ein effektives Katastrophenmanagement sind satellitengestützte Dienste wie z.B. Erdbeobachtung, Kommunikation und Navigation unverzichtbar. Die größte Bedrohung dieser Infrastruktur rührt aus dem Anwachsen der Population von Schrottobjekten. In den niedrigen Erdumlaufbahnen befinden sich derzeit ca. 2/3 der aktiven Satelliten und in mehreren Höhe...

  17. Verhalten von passiv betriebenen Sauggreifern unter der Krafteinwirkung von Kletterrobotern

    Simons, Florian

    2006-01-01

    Für den wirtschaftlichen Einsatz von Kletterrobotern auf Glasfassaden zur Durchführung von Wartungs- und Inspektionsaufgaben ist die Einsetzbarkeit auf einer möglichst großen Anzahl an Gebäuden notwendig. Der Roboter muss sich dafür möglichst ohne externe Energieversorgung und unabhängig von gebäudeseitigen Installationen wie Dachkränen und speziellen notwendigen Kletterstrukturen über Vakuumelemente direkt auf den Glaselementen halten und bewegen können. Dies stellt hohe Anforderungen an Gew...

  18. Contested Inclusions: Pitfalls of NGO Peace-Building Activities in Liberia Umstrittene Inklusion: Fallstricke bei peace-building-Aktivitäten von NRO in Liberia

    Veronika Fuest

    2010-01-01

    Full Text Available In post-war situations, non-governmental organizations (NGOs feature highly in peace-building processes in their (perceived capacities as both representatives of civil society and as grassroots agents to be employed in the reconstruction and transformation of society. As elsewhere, in Liberia, peace-building approaches include, first, international blueprints of representation that intend to empower groups generally perceived to be socially subordinate and, second, supporting traditional institutions considered social capital in reconciliation. Using the example of Liberia, this paper explores how in local conflict arenas, NGO workshops – the most popular mode of participatory intervention – are interpreted and appropriated by local actors; it highlights some fallacies and unintended consequences of inclusive procedures in practice and questions the support furnished to heads of gendered secret societies. Nichtregierungsorganisationen (NRO wird in Nachkriegsphasen hohe Kompetenz in Bezug auf peace-building-Prozesse zugesprochen, denn sie repräsentieren die civil society und stellen gleichzeitig Akteure, die an der Basis zum Wiederaufbau und zur gesellschaftlichen Transformation beitragen können. Auch in Liberia schließen peace-building-Konzepte an erster Stelle international erarbeitete Zielvorgaben zur Repräsentanz ein und sehen erstens eine Beteiligung von Gruppen mit niedrigem sozialen Status vor und zweitens die Unterstützung traditioneller Institutionen, die als soziales Kapital im Aussöhnungsprozess angesehen werden. Die Autorin untersucht am Beispiel Liberia, inwieweit NRO-workshops – die beliebteste Form der partizipativen Intervention – in Konfliktzonen von lokalen Akteuren interpretiert und für eigene Ziele genutzt werden; sie verweist auf irrtümliche Annahmen und unbeabsichtigte Konsequenzen der praktischen Anwendung inklusiver Verfahren und stellt die Unterstützung in Frage, die Oberhäuptern geschlechtsspezifischer

  19. Synthese und Eigenschaften von Kohlenstoffnitriden

    Horvath-Bordon, Elisabeta

    2004-01-01

    In der hier vorliegenden Arbeit über die „Synthese und Eigenschaften von Kohlenstoffnitriden“ wird im ersten Teil über die Synthese, die Strukturaufklärung, thermische Stabilität und die optischen Eigenschaften von Tri-s-triazin Derivaten (Cyamelurate, Melonate, Melem usw.) berichtet. Weil sich molekulare und polymere Tri-s-triazin Derivaten relativ einfach in reiner Form darstellen lassen, wurden sie als Precursoren zur Herstellung von harten Kohlenstoffnitriden ausgewählt. Im zweiten Teil w...

  20. Kriterien zur Beurteilung von Fahrerassistenzsystemen

    Weller, Gert; Schlag, Bernhard

    2002-01-01

    Der Markt für Fahrerassistenzsysteme wächst nach Presseinformationen von Herstellern um jährlich 15%. Die OECD (2003) geht von einem erheblichen Potential von FAS zur Reduzierung der Unfallzahlen oder zumindest der Unfallschwere aus. Ein weiterer Nutzen liegt in der angestrebten Erhöhung des Komforts und einer Optimierung der Beanspruchung des Fahrers. Andererseits können gerade diese an sich positiven Auswirkungen durch die Reaktion des Menschen auf Veränderungen im System Fahrer-Fa...

  1. Vernetzungspotential durch Nutzung von Normdaten (am Beispiel von GND / BEACON)

    Lordick, Harald

    2015-01-01

    Der Workshop-Beitrag erläutert an praktischen Beispielen, wie Online-Publikationen von ihrer Anreicherung mit IDs der Gemeinsamen Normdatei (GND) profitieren: durch bessere Sichtbarkeit und Recherchierbarkeit, durch Vernetzung mit weiteren Datenangeboten sowie durch Auflösung von Ambiguität. Skizziert wird der Einstieg in das Thema "Linked Data / Semantic Web" als niedrigschwelliger Workflow: Daten mit Ids der GND anreichern, Web-Schnittstelle einrichten, BEACON-D...

  2. Effects of the contraceptive skin patch and subdermal contraceptive implant on markers of endothelial cell activation and inflammation.

    Hernandez-Juarez, Jesus; Sanchez-Serrano, Juan Carlos; Moreno-Hernandez, Manuel; Alvarado-Moreno, Jose Antonio; Hernandez-Lopez, Jose Rubicel; Isordia-Salas, Irma; Majluf-Cruz, Abraham

    2015-07-01

    Changes in blood coagulation factors may partially explain the association between hormonal contraceptives and thrombosis. Therefore, the likely effects of the contraceptive skin patch and subdermal contraceptive implant on levels of inflammatory markers and endothelial activation were analyzed. This was an observational, prospective, longitudinal, nonrandomized study composed of 80 women between 18 and 35 years of age who made the decision to use the contraceptive skin patch or subdermal contraceptive implant. vascular cell adhesion molecule-1 (VCAM-1), endothelial cell leukocyte adhesion molecule-1 (ELAM-1), von Willebrand factor (VWF), and plasminogen activator inhibitor type 1(PAI-1) as well as high-sensitivity C-reactive protein (hsCRP) were assayed before and after 4 months of use of the contraceptive method. VCAM-1, VWF, and PAI-1 remained unchanged in the contraceptive skin patch group; however, a significant increase in hsCRP (0.29-0.50 mg/dL; P =.012) and a significant decrease in ELAM-1 (44-25 ng/mL; P =.022) were observed. A significant diminution in VCAM-1 (463-362 ng/mL; P =.022) was also found in the subdermal contraceptive implant group. Our results strongly suggest that these contraceptive methods do not induce endothelial activation after 4 months of use. Increase in hsCRP levels was unrelated to changes in markers of endothelial activation. PMID:25655356

  3. Dr. Wernher Von Braun

    1960-01-01

    On September 8, 1960 President Dwight D. Eisenhower visited Huntsville, Alabama to dedicate a new NASA field center in honor of General George C. Marshall, Eisenhower's wartime colleague and the founder of the famous Marshall Plan for European recover after World War II. The new George C. Marshall Space Flight Center was placed under the control of Dr. Wernher Von Braun shown here talking with President Eisenhower. As parto f his remarks dedicating the center, President Eisenhowe refereed to General Marshall as a 'man of yar, yet a builder of peace'. the Marshall Center's first major assignment including building the huge Saturn V rocket that launched human beings on their first journey to the surface of the moon in 1969.

  4. Die Kosmogonie Anton von Zachs.

    Brosche, P.

    In his "Cosmogenische Betrachtungen" (1804), Anton von Zach rediscovered - probably independently - some aspects of the theories of Kant and Laplace. More originally, he envisaged also the consequences of an era of heavy impacts in the early history of the Earth.

  5. Selektives Lasersintern von teilkristallinen Thermoplasten

    Rietzel, Dominik; Kühnlein, Florian; Drummer, Dietmar

    2010-01-01

    Da eine flexible Fertigung im Bereich von Losgrößen zwischen 1-1000 Stück in vielen Wirtschaftszweigen vermehrt an Bedeutung gewinnt, steigt das Interesse an Verfahren wie dem Selektiven Lasersintern. Dennoch sollen die Eigenschaften von in Serie eingesetzten Werkstoffen erreicht werden. Aufgrund der bestehenden werkstofflichen Restriktionen auf Polyamid 12 wird aktuell an der Verarbeitung anderer teilkristalliner Thermoplaste geforscht. In diesem Beitrag werden die sich in der Markteinführun...

  6. Planung von CLIL-Unterricht

    Leisen, Josef

    2015-01-01

    Der Beitrag formuliert die Sprachlernbedingungen und die Leitlinien des Sprachlernens im Fach und nennt Merkmale des guten integrierten Fach- und Sprachlehrens. Ausgehend von den Sprachproblemen, die sich im CLIL-Unterricht auftun, wird der sprachsensible CLIL-Unterricht definiert, und es werden Anregungen zur Gestaltung gegeben. Sprachliche Standardsituationen umfassen die kommunikativen Situationen im CLIL-Unterricht, die beim fachlichen Lernen auftreten und von der CLIL-Lehrkraft professio...

  7. Investitionsentscheidungen von Familien- und Nichtfamilienunternehmern

    Zellweger, Thomas

    2006-01-01

    Die wissenschaftliche Literatur zu Investitionsentscheidungen geht auf die Arbeiten von Fisher zurück, insbesondere sein Buch Theory of Interest (Fisher, 1930). Eine der zentralen Erkenntnisse wurde als "Fisher Separation" bekannt, welche eine Rechtfertigung für die "Netto-Barwert-Regel" einerseits und die Trennung von Eigentum und Management andererseits liefert. Das Separationstheorem besagt, dass in einer deterministischen Welt mit perfekten Kapitalmärkten Entscheidungen über Produktio...

  8. Von der Konzeption zur Praxis

    Emer, Wolfgang (Akad. Oberrat)

    2015-01-01

    Die kumulative Dissertation zur Projektdidaktik trägt den Titel „Von der Konzeption zur Praxis: Zur Entwicklung der Projektdidaktik am Oberstufen-Kolleg Bielefeld und ihre Impulsgebung und Modellbildung für das deutsche Regelschulwesen“. Die Dissertation versteht sich als beispielgebende Umsetzung und Implementierung der Projektdidaktik für das Regelschulsystem. Auf der Basis von 22 bereits erschienenen Publikationen und einer Monographie werden mit fünf methodischen Zugriffen (bildungshistor...

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

    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. Single-molecule kinetics under force: probing protein folding and enzymatic activity with optical tweezers

    Wong, Wesley

    2010-03-01

    Weak non-covalent bonds between and within single molecules govern many aspects of biological structure and function (e.g. DNA base-paring, receptor-ligand binding, protein folding, etc.) In living systems, these interactions are often subject to mechanical forces, which can greatly alter their kinetics and activity. My group develops and applies novel single-molecule manipulation techniques to explore and quantify these force-dependent kinetics. Using optical tweezers, we have quantified the force-dependent unfolding and refolding kinetics of different proteins, including the cytoskeletal protein spectrin in collaboration with E. Evans's group [1], and the A2 domain of the von Willebrand factor blood clotting protein in collaboration with T. Springer's group [2]. Furthermore, we have studied the kinetics of the ADAMTS13 enzyme acting on a single A2 domain, and have shown that physiolgical forces in the circulation can act as a cofactor for enzymatic cleavage, regulating hemostatic activity [2]. References: 1. E. Evans, K. Halvorsen, K. Kinoshita, and W.P. Wong, Handbook of Single Molecule Biophysics, P. Hinterdorfer, ed., Springer (2009). 2. X. Zhang, K. Halvorsen, C.-Z. Zhang, W.P. Wong, and T.A. Springer, Science 324 (5932), 1330-1334 (2009).

  11. Lewis-acid and redox-active zeolite catalysts for the activation of methane and lower hydrocarbons in the selective catalytic reduction of NO{sub x}. Subproject: structural characterization and kinetic modelling. Final report; Lewis-acide und redox-aktive Zeolith-Katalysatoren fuer die Aktivierung von Methan und Fluessiggas-Kohlenwasserstoffen in der SCR von NO{sub x}. Teilprojekt: Strukturelle Katalysatorcharakterisierung und Modellierung der Reaktionskinetik. Abschlussbericht

    Gruenert, W. [Bochum Univ. (Germany). Technische Chemie; Sowade, T.; Schmidt, C.; Stroeder, U. [Heraeus (W.C.) GmbH, Hanau (Germany)

    2001-12-01

    Zeolites (in particular ZSM-5) modified by indium and additionally promoted by ceria have been studied as catalysts for selective reduction of NO by methane. The structural properties of the catalysts have been investigated by XRD, FTIR, EXAFS, electron microscopy and XPS. The ceria promotor may be added to In-ZSM-5 by precipitation onto the external zeolite surface or by physically admixing a high surface-area powder. The preparation of the basic In-ZSM-5 system has a large influence on the properties of the catalyst. Preparation by aqueous exchange leads in most cases to a coexistence of a small amount of intra-zeolite indium species and extra-zeolite indium phases. Only at low pH, exclusively intra-zeolite indium is formed to a low extent (<10% exchange degree). Intrazeolite indium can be also obtained by dry preparations using InCl{sub 3} (solid-state ion exchange, sublimation, transport reaction). The In species formed carry Cl ligands, the stability of which depends on the indium content: after washing and calcination steps, Cl ligands could no longer be detected only in samples with low In content. Reductive solid-state ion exchange is a further method to prepare intra-zeolite In species. In mixtures containing excess indium, oligometric intra-zeolite In species are formed via this route. Intra-zeolite Cl-free In species exhibit significant SCR activity while Cl-containing In-species activate methane with low SCR selectivity. In ceria-promoted systems, the ceria provides full NO{sub 2} supply by catalysing the NO oxidation. With sufficient NO{sub 2} supply, the even Cl-containing In sites provide high SCR activities. Since the relevance of acidic sites was established e.g. by poisoning experiments, the reaction mechanism can by visualised by proceeding via methane activation over In sites, reaction of activated methane with NO{sub 2} to a volatile intermediate (e.g. nitromethane), which is then decomposed over the acidic sites. The reaction kinetics of the

  12. Ethnographische Filme und die Darstellung von Frauen

    Judith Keilbach

    2002-03-01

    Full Text Available In dieser Filmographie werden ethnographische und koloniale Filme aus dem Bestand des Nederlands Filmmuseum kommentiert, die für die Frage nach der Darstellung von Frauen und Geschlechterverhältnissen von Interesse sind.

  13. Herstellung von hohlen mineralischen Strukturen auf der Basis von Hefezellen

    Weinzierl, Daniel

    2009-01-01

    Ziel der Arbeit war die Erzeugung von hohlen Pigmenten durch die Bildung einer mineralischen, hohlen Struktur an der Oberfläche von Hefezellen. Dafür sollten großtechnisch herstellbare Hefen so modifiziert werden, dass sie als kleinzellige Kristallisationskerne für die Herstellung der mineralisierten Pigmenthohl-körper dienen. Somit sollten teure Mineralien auf günstige, hohle Strukturen aufgebracht werden, um kostengünstige Hohlpigmente herstellen zu können. Die hergestellten hohlen Pi...

  14. Bewirtschaftung und Ökobilanzierung von Kurzumtriebsplantagen

    Burger, Frank

    2011-01-01

    Die Arbeit beschreibt den kompletten Produktionszyklus von Kurzumtriebsplantagen. Alle Maßnahmen, die zur Anlage einer solchen Kultur notwendig sind, von der Vorbereitung des Ackers, der Wahl der Umtriebszeit, der Pflanzung der Balsampappeln bis zur Rodung werden aufgezeigt. Ertragskundliche Erhebungen, die seit 18 Jahren auf bayerischen Versuchsstandorten durchgeführt wurden, geben einen Eindruck von den möglichen Biomasseleistungen. Sieben Erntesysteme zur Produktion von Holzhackschnitzeln ...

  15. Langfristige Perspektiven von Anlagen in Sachwerten

    Bräuninger, Michael; Stiller, Silvia; Vöpel, Henning

    2009-01-01

    Die erheblichen Turbulenzen an den Finanzmärkten, die Talfahrten von Aktienkursen sowie die Veränderung der relativen Attraktivität unterschiedlicher Anlageformen beeinflussen die Investitionsentscheidungen von Anlegern. In der Studie untersucht das HWWI die Rentabilität von Investitionen in Sachwerte. Die Analyse zeigt besondere Chancen von Schifffahrts- und Immobilienmärkten. Dazu werden das globale Wirtschaftswachstum, der Globalisierungsprozess sowie die Finanzierungsformen über Fremdkapi...

  16. Kinematische Analyse von Schreibbewegungen im Erstschreibunterricht

    Quenzel, Irmina; Mai, Norbert

    2000-01-01

    Die Automation von Schreibbewegungen ist ein zentrales Merkmal geübten, flüssigen Schreibens. Mittels eines digitalen Schreibbrettes wurde die Schrift von 14 Grundschülern mit der von 10 routinierten erwachsenen Schreibern verglichen. Es zeigte sich, dass Kinder zu Beginn des Schreibunterrichtes bereits über die Kompetenz zu automatisierter Ausführung einfacher Schreibbewegungen verfügen, diese jedoch beim Schreiben von Buchstaben noch nicht einsetzen. Weiterhin erwies sich, dass bei der Vorg...

  17. APLF promotes the assembly and activity of non-homologous end joining protein complexes.

    Grundy, Gabrielle J; Rulten, Stuart L; Zeng, Zhihong; Arribas-Bosacoma, Raquel; Iles, Natasha; Manley, Katie; Oliver, Antony; Caldecott, Keith W

    2013-01-01

    Non-homologous end joining (NHEJ) is critical for the maintenance of genetic integrity and DNA double-strand break (DSB) repair. NHEJ is regulated by a series of interactions between core components of the pathway, including Ku heterodimer, XLF/Cernunnos, and XRCC4/DNA Ligase 4 (Lig4). However, the mechanisms by which these proteins assemble into functional protein-DNA complexes are not fully understood. Here, we show that the von Willebrand (vWA) domain of Ku80 fulfills a critical role in this process by recruiting Aprataxin-and-PNK-Like Factor (APLF) into Ku-DNA complexes. APLF, in turn, functions as a scaffold protein and promotes the recruitment and/or retention of XRCC4-Lig4 and XLF, thereby assembling multi-protein Ku complexes capable of efficient DNA ligation in vitro and in cells. Disruption of the interactions between APLF and either Ku80 or XRCC4-Lig4 disrupts the assembly and activity of Ku complexes, and confers cellular hypersensitivity and reduced rates of chromosomal DSB repair in avian and human cells, respectively. Collectively, these data identify a role for the vWA domain of Ku80 and a molecular mechanism by which DNA ligase proficient complexes are assembled during NHEJ in mammalian cells, and reveal APLF to be a structural component of this critical DSB repair pathway. PMID:23178593

  18. Reduction of homocysteine in elderly with heart failure improved vascular function and blood pressure control but did not affect inflammatory activity.

    Andersson, Sven E; Edvinsson, Marie-Louise; Edvinsson, Lars

    2005-11-01

    We have previously shown that hyperhomocysteinaemia is common in elderly heart failure patients, and is associated with endothelial dysfunction, impaired vasodilatory capacity and a low-grade inflammation. In the present study we examined if supplementation with B6, B12 and folate could normalize the hyperhomocysteinaemia and if so, in turn, would improve the associated parameters. This was an open study without placebo control on heart failure patients with plasma homocysteine > 15 microM. Measurements of cutaneous vascular reactivity, blood pressure, inflammatory activity and endothelial function were performed before and after intervention with intra-individual comparisons. The treatment reduced homocysteine to near normal values and enhanced the hyperaemic response to acetylcholine related to the response to heat. The mean arterial blood pressure and pulse rate was reduced. There was no effect on inflammatory activity, plasma levels of von Willebrand factor, subjective health quality or the hyperaemic responses to sodium nitroprusside or local warming. Hyperhomocysteinaemia in heart failure patients is multifactorial in origin. Folate deficiency, inflammatory activity and reduced renal function could be contributing. It is suggested that supplementation with B-vitamins can improve the vasodilatory capacity and reduce the blood pressure but additional studies are required to confirm this. PMID:16236143

  19. Fachspezifische Vermittlung von Informationskompetenz an Biologen

    Kristina Hartmann

    2013-01-01

    Die Vermittlung von Informationskompetenz ist an vielen Hochschulbibliotheken etabliert. Dabei existieren sowohl fachübergreifende als auch fachspezifische Vermittlungskonzepte. Dieser Artikel leistet einen Beitrag zur fachspezifischen Vermittlung von Informationskompetenz an Biologen. Hierfür wurden mittels einer Umfrage die aktuellen Angebote der deutschen Hochschulbibliotheken im Fach Biologie und ihre Verankerung im Fachbereich ermittelt. Der Schwerpunkt in der Vermittlung von Inf...

  20. Approximate double commutants in von Neumann algebras

    Hadwin, Don

    2011-01-01

    Richard Kadison showed that not every commutative von Neumann subalgebra of a factor von Neumann algebra is equal to its relative double commutant. We prove that every commutative C*-subalgebra of a centrally prime C*-algebra $B$ equals its relative approximate double commutant. If $B$ is a von Neumann algebra, there is a related distance formula.

  1. Hellmut von Glahn 1929 – 2008

    Janiesch, Peter

    2010-01-01

    Nachruf Hellmut von Glahn, Gründungsmitglied und von 1979 bis 2006 Vorsitzender des Vereins zur Förderung naturkundlicher Untersuchungen in Nordwestdeutschland e. V., der seit 1976 das Erscheinen der Zeitschrift DROSERA maßgeblich fördert, ist nach schwerer Krankheit am 25.10.2008 im Alter von 80 Jahren gestorben.

  2. Influence of glycated low density lipoprotein on the proliferation,expression of intercellular adhesion molecule-1,von Willebrand factor of human umbilical endothelial cells

    LU Jun; LIU Hui-ying; ZHANG Xiu-zhen; LEI Tao

    2009-01-01

    @@ Diabetes mellitus known as its macro-and microangiopathy has caused thousands of mortality per year.Recent researches showed that hyperglycemia,advanced glycation end products(AGEs)and some other factors acted on the process of atherogenesis.AGEs can combine with receptors of AGEs(RAGEs),which exist on the vascular endothelium,smooth muscle cells,macrophage,lymphocyte and so on.

  3. Distribution of von Willebrand factor levels in young women with and without bleeding symptoms: influence of ABO blood group and promoter haplotypes

    Lethagen, S.; Hillarp, A.; Ekholm, C.;

    2008-01-01

    . It was the objective of the present study to evaluate the distribution of VWF levels in young females with or without bleeding symptoms in this population, and the influence of ABO blood group and promoter haplotypes on VWF levels and to identify a possible increased prevalence of VWD in females with bleeding symptoms.......4%) (p = 0.017). Blood group O was found in 14/18 girls with low VWF:RCo. There was a highly significant correlation between VWF:RCo and blood group O and non-O genotypes. Two common VWF promoter haplotypes did not contribute to the VWF:RCo variation. VWF levels did not correlate with time during...... menstrual cycle, or the use of oral contraceptives. No case fulfilled the diagnostic criteria for VWD. In conclusion, low VWF:RCo was significantly more frequent in females with bleeding symptoms. However, we found no case fulfilling strict diagnostic criteria for VWD. The ABO blood group was a strong...

  4. A G{sub +3}-to-T donor splice site mutation leads to skipping of exon 50 in von Willebrand factor mRNA

    Mertes, G.; Schwaab, R.; Brackmann, H.H.; Ludwig, M. [Universitaet Bonn (Germany)] [and others

    1994-11-01

    Genomic DNA was prepared from leukocytes, and platelet-derived total mRNA was isolated by lysis of thrombocytes in 4 M guanidinium hydrochloride followed by precipitation in 2 M lithium chloride twice. PCR reactions were performed using either RT-PCR primers or genomic PCR-primers. Preferential signle-strand amplification for both PCR products was carried out with nested RT-PCR primers.

  5. Severely impaired von Willebrand factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device (HeartMate II)

    Klovaite, Jolanta; Gustafsson, Finn; Mortensen, Svend A;

    2009-01-01

    OBJECTIVES: This study investigated the influence of the mechanical blood pump HeartMate II (HMII) (Thoratec Corporation, Pleasanton, California) on blood coagulation and platelet function. BACKGROUND: HMII is an implantable left ventricular assist device used for the treatment of heart failure...

  6. Ultraproducts of von Neumann algebras

    Ando, Hiroshi; Haagerup, Uffe

    2014-01-01

    We study several notions of ultraproducts of von Neumann algebras from a unified viewpoint. In particular, we show that for a sigma-finite von Neumann algebra M  , the ultraproduct MωMω introduced by Ocneanu is a corner of the ultraproduct ∏ωM∏ωM introduced by Groh and Raynaud. Using this...... the ultrapower MωMω of a Type III0 factor is never a factor. Moreover we settle in the affirmative a recent problem by Ueda about the connection between the relative commutant of M   in MωMω and Connes' asymptotic centralizer algebra MωMω....

  7. Direktsaat von Mais im Biolandbau

    Dierauer, Hansueli; Hegglin, Django; Böhler, Daniel

    2014-01-01

    Der Mais ist für die Fütterung von Wieder- als auch Nichtwiederkäuer eine sehr wertvolle Pflanze. Im Biolandbau wird für den Maisanbau aufgrund der einfacheren Unkrautregulierung standardmässig der Pflug verwendet. Bezüglich Bodenerosion, Verdichtung und Abschwemmung ist aber gerade beim Maisanbau der Pflugeinsatz nicht optimal. Die Direktsaat von Mais löst diese Probleme weitgehend und erhöht auch im Biolandbau die Akzeptanz, da auf dem geschlossenen Boden auch die Ernte bodenschonender durc...

  8. Development of active barriers for removing heavy metals from mine water: Freiberg colliery, Sachsen; Entwicklung aktiver Barrieren fuer die Entfernung von Schwermetallen aus Grubenwaessern am Beispiel der Freiberger Grube, Sachsen

    Zoumis, T.

    2003-07-01

    Mine water treatment is costly, difficult, and requires extensive surface installations. The author explains the development of geochemical ('active') barriers of low-cost materials. The materials investigated were industrial residues (red sludge, fly ash, tinder residues, porous concrete residues), natural materials (bark, zeolite, bentonite, hydroxyl apatite), and commercial products (GEH, Ratio Pur MF-S). Investigations focused on density, specific surface, grain size, and acid neutralization capacity. In the final stage, experiments were made on heavy metal removal from a model water. [German] Einen grossen Anteil an der Schwermetallbelastung in Fluessen haben toxische Abwaesser aus Bergbaugebieten (Grubenwaesser). Die Moeglichkeit der Behandlung sind sehr aufwendig, kostenintensiv und nur 'ueber Tage' durchfuehrbar. Die vorliegende Arbeit erlaeutert die Behandlung von Grubenwaessern mit geochemischen ('aktiven') Barrieren. Es werden aktive Barrieren entwickelt, die in einen Schacht eingebracht werden koennen, um eine Schwermetallausbreitung zu unterbinden. In diesem Zusammenhang werden kostenguenstige Materialien untersucht, die Schadstoffe durch chemische und/oder physikalische Mechanismen aus Wasser entfernen koennen. Untersucht wurden industrielle Reststoffe (Rotschlamm, Flugasche, Zunderrueckstaende, Porenbetonabfall), natuerliche Materialien (Baumrinde, Zeolith, Bentonit, Hydroxylapatit) und kommerzielle Produkte (GEH, Ratio Pur MF-S). Die Materialien werden hinsichtlich der Dichte, der spezifischen Oberflaeche, der Korngroesse und der Saeureneutralisationskapazitaet charakterisiert. Anschliessend wurden Versuche zur Schwermetallentfernung aus einem Modellwasser durchgefuehrt. (orig.)

  9. Echicetin coated polystyrene beads: a novel tool to investigate GPIb-specific platelet activation and aggregation.

    Alexey Navdaev

    Full Text Available von Willebrand factor/ristocetin (vWF/R induces GPIb-dependent platelet agglutination and activation of αIIbβ3 integrin, which also binds vWF. These conditions make it difficult to investigate GPIb-specific signaling pathways in washed platelets. Here, we investigated the specific mechanisms of GPIb signaling using echicetin-coated polystyrene beads, which specifically activate GPIb. We compared platelet activation induced by echicetin beads to vWF/R. Human platelets were stimulated with polystyrene beads coated with increasing amounts of echicetin and platelet activation by echicetin beads was then investigated to reveal GPIb specific signaling. Echicetin beads induced αIIbβ3-dependent aggregation of washed platelets, while under the same conditions vWF/R treatment led only to αIIbβ3-independent platelet agglutination. The average distance between the echicetin molecules on the polystyrene beads must be less than 7 nm for full platelet activation, while the total amount of echicetin used for activation is not critical. Echicetin beads induced strong phosphorylation of several proteins including p38, ERK and PKB. Synergistic signaling via P2Y12 and thromboxane receptor through secreted ADP and TxA2, respectively, were important for echicetin bead triggered platelet activation. Activation of PKG by the NO/sGC/cGMP pathway inhibited echicetin bead-induced platelet aggregation. Echicetin-coated beads are powerful and reliable tools to study signaling in human platelets activated solely via GPIb and GPIb-triggered pathways.

  10. Von Krahl ON! / Terje Metsavas

    Metsavas, Terje

    2008-01-01

    Madli Pesti ja Terje Metsavas kohtusid Von Krahli teatri tehnilise meeskonnaga teatri black-box-saalis. Teatri tehniline meeskond on tehnikadirektor Enar Tarmo, video- ja multimeediaga tegelev Lauri Sepp, tehnikud Janno "John" Jaanus, Oliver Kulpsoo ja Allan Räim. Selles, kuidas sünnivad "tehnikaimed" ja kuidas lahendatakse lavastuslikke projekte