Inhibitor development and mortality in non-severe hemophilia A.

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Eckhardt, C L; Loomans, J I; van Velzen, A S; Peters, M; Mauser-Bunschoten, E P; Schwaab, R; Mazzucconi, M G; Tagliaferri, A; Siegmund, B; Reitter-Pfoertner, S E; van der Bom, J G; Fijnvandraat, K

2015-07-01

The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. © 2015 International Society on Thrombosis and Haemostasis.

Patient and parent preferences for characteristics of prophylactic treatment in hemophilia

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Furlan R

2015-11-01

Full Text Available Roberto Furlan,1 Sangeeta Krishnan,2 Jeffrey Vietri3 1Advanced Methods, Kantar Health, Epsom, Surrey, UK; 2Global Health Economics and Outcomes Research, Biogen, MA, USA; 3Health Outcomes, Kantar Health, Milan, Italy Introduction: New longer-acting factor products will potentially allow for less frequent infusion in prophylactic treatment of hemophilia. However, the role of administration frequency relative to other treatment attributes in determining preferences for prophylactic hemophilia treatment regimens is not well understood. Aim: To identify the relative importance of frequency of administration, efficacy, and other treatment characteristics among candidates for prophylactic treatment for hemophilia A and B. Method: An Internet survey was conducted among hemophilia patients and the parents of pediatric hemophilia patients in Australia, Canada, and the US. A monadic conjoint task was included in the survey, which varied frequency of administration (three, two, or one time per week for hemophilia A; twice weekly, weekly, or biweekly for hemophilia B, efficacy (no bleeding or breakthrough bleeding once every 4 months, 6 months, or 12 months, diluent volume (3 mL vs 2.5 mL for hemophilia A; 5 mL vs 3 mL for hemophilia B, vials per infusion (2 vs 1, reconstitution device (assembly required vs not, and manufacturer (established in hemophilia vs not. Respondents were asked their likelihood to switch from their current regimen to the presented treatment. Respondents were told to assume that other aspects of treatment, such as risk of inhibitor development, cost, and method of distribution, would remain the same. Results: A total of 89 patients and/or parents of children with hemophilia A participated; another 32 were included in the exercise for hemophilia B. Relative importance was 47%, 24%, and 18% for frequency of administration, efficacy, and manufacturer, respectively, in hemophilia A; analogous values were 48%, 26%, and 21% in

[Study of gene mutation in 62 hemophilia A children].

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Hu, Q; Liu, A G; Zhang, L Q; Zhang, A; Wang, Y Q; Wang, S M; Lu, Y J; Wang, X

2017-11-02

Objective: To analyze the mutation type of FⅧ gene in children with hemophilia A and to explore the relationship among hemophilia gene mutation spectrum, gene mutation and clinical phenotype. Method: Sixty-two children with hemophilia A from Department of Pediatric Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology between January 2015 and March 2017 were enrolled. All patients were male, aged from 4 months to 7 years and F Ⅷ activity ranged 0.2%-11.0%. Fifty cases had severe, 10 cases had moderate and 2 cases had mild hemophilia A. DNA was isolated from peripheral blood in hemophilia A children and the target gene fragment was amplified by PCR, in combination with the second generation sequencing, 22 and 1 introns were detected. Negative cases were detected by the second generation sequencing and results were compared with those of the international FⅧ gene mutation database. Result: There were 20 cases (32%) of intron 22 inversion, 2 cases (3%) of intron 1 inversion, 18 cases (29%) of missense mutation, 5 cases (8%) of nonsense mutation, 7 cases (11%) of deletion mutation, 1 case(2%)of splice site mutation, 2 cases (3%) of large fragment deletion and 1 case of insertion mutation (2%). No mutation was detected in 2 cases (3%), and 4 cases (7%) failed to amplify. The correlation between phenotype and genotype showed that the most common gene mutation in severe hemophilia A was intron 22 inversion (20 cases), accounting for 40% of severe patients, followed by 11 cases of missense mutation (22%). The most common mutation in moderate hemophilia A was missense mutation (6 cases), accounting for 60% of moderate patients. Conclusion: The most frequent mutation type in hemophilia A was intron 22 inversion, followed by missense mutation, again for missing mutation. The relationship between phenotype and genotype: the most frequent gene mutation in severe hemophilia A is intron 22 inversion, followed by missense

Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A.

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Cannavò, Antonino; Valsecchi, Carla; Garagiola, Isabella; Palla, Roberta; Mannucci, Pier Mannuccio; Rosendaal, Frits R; Peyvandi, Flora

2017-03-09

The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors. © 2017 by The American Society of Hematology.

Understanding Hemophilia. Implications for the Physical Educator.

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Coelho, Jeffrey D.

1998-01-01

Describes hemophilia and ways to provide appropriate physical education experiences to children with hemophilia. The article focuses on what hemophilia is, how to treat hemophilia, benefits of physical activity, how to teach children with hemophilia, choosing and modifying sports and activities, and safety and emergency situations. (SM)

Impact of mild to severe hemophilia on education and work by US men, women, and caregivers of children with hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

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Cutter, Susan; Molter, Don; Dunn, Spencer; Hunter, Susan; Peltier, Skye; Haugstad, Kimberly; Frick, Neil; Holot, Natalia; Cooper, David L

2017-04-01

The psychosocial impact of hemophilia on work was recently investigated in the Hemophilia Experiences, Results and Opportunities (HERO) study. The findings revealed that hemophilia had an impact for adults with moderate/severe hemophilia and caregivers of children with hemophilia. HERO did not specifically evaluate impact on education in adults/children with mild/moderate hemophilia or the impact on employment of spouses/partners of caregivers of affected children. The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study evaluated the impact of hemophilia on the lives of adult men/women with mild-severe hemophilia B and caregivers of boys/girls with hemophilia B and their spouses/partners. Many adults with hemophilia B (94%) reported that hemophilia had a negative effect on their ability to complete a formal education, often attributed to the inability to attend or concentrate in school as a result of hemophilia-related bleeding or pain. Most adults with hemophilia B (95%) and caregivers/partners (89%/84%) indicated that hemophilia had a negative impact on employment. Most adults with hemophilia were employed (81%), with construction/manufacturing (35%) as the most frequently reported industry; many worked in jobs requiring manual labor (39%). Of those unemployed, 62% never worked, and those who stopped working reported that they left the workforce due to financial issues (59%), including insurance coverage/co-pays, or hemophilia-related issues (55%). Nearly one-third of caregivers voluntarily left the workforce to care for children with hemophilia. These results suggest a need to focus more effort on career counseling for adults with hemophilia B and caregivers of affected children, especially around mild/moderate hemophilia, as this population may not be as well informed regarding potential impact in school and the workplace. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hemophilia Data and Statistics

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... View public health webinars on blood disorders Data & Statistics Language: English (US) Español (Spanish) Recommend on Facebook ... genetic testing is done to diagnose hemophilia before birth. For the one-third ... rates and hospitalization rates for bleeding complications from hemophilia ...

The impact of extended half-life versus conventional factor product on hemophilia caregiver burden.

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Schwartz, Carolyn E; Powell, Victoria E; Su, Jun; Zhang, Jie; Eldar-Lissai, Adi

2018-05-01

Extended half-life factor products have reduced annualized bleeding rates in hemophilia patients. The impact of extended half-life versus conventional factor products on hemophilia caregiver burden has not been investigated. This study aimed to evaluate caregiver burden in extended half-life versus conventional factor products for hemophilia A and B. This cross-sectional web-based study of caregivers of people with hemophilia A or B was recruited from a panel research company and by word of mouth. Participants completed the Hemophilia Caregiver Impact measure, the PedsQL Family Impact Module (PedsQL), and the Work Productivity and Activity Impairment Questionnaire (WPAI). We also collected demographic, insurance coverage, and medical information related to the hemophilia patient(s). Burden differences were assessed using linear regression and matched cohort analyses. The sample (n = 448) included 49 people who were caring for people on extended half-life factor products. Worse caregiver burden was associated with more infusions per week and more bleeds in the past 6 months. Regression analyses suggested that caring for someone who is on a extended half-life factor product is associated with lower emotional impact (β = - 0.11, p factor product had lower Emotional Impact and Practical Impact scores (t = - 2.95 and - 2.94, respectively, p factor product infusions of extended half-life factor products appears to reduce the emotional distress and practical burden of caregiving. Future work should evaluate the longitudinal impact.

Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

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Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

2016-01-01

Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

Knee Fat Pad Volumes in Patients with Hemophilia and Their Relationship with Osteoarthritis

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Annette von Drygalski

2017-01-01

Full Text Available Hemophilic arthropathy is a progressive, disabling condition with poorly understood pathobiology. Since there is an emerging interest to study the role of intra-articular fat pad size and biology in arthritic conditions, we explored fat pad volume changes in hemophilic arthropathy and to what extent they differed from osteoarthritis. We matched a cohort of 13 adult patients with hemophilic arthropathy of the knee with age- and gender-matched cohorts without osteoarthritis (“control cohort” and with the same degree of radiographic osteoarthritis (“OA cohort” in 1 : 2 fashion. Infrapatellar fat pad (IPFP and suprapatellar fat pad (SPFP volumes were calculated based on magnetic resonance imaging and differences in fat pad volumes, demographics, height, weight, and osteoarthritis scores were evaluated. Fat pad volumes were positively associated with body size parameters in all three cohorts but were unaffected by the degree of osteoarthritis. While IPFP volumes did not differ between cohorts, SPFP volumes expanded disproportionally with weight in hemophilia patients. Our observations indicate that IPFPs and SPFPs behave biologically differently in response to different arthritic stimuli. The exaggerated expansion of the SPFP in hemophilia patients highlights the importance of further studying the implications of fat pad biology for progression of hemophilic arthropathy.

Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

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Allison M Lytle

2016-01-01

Full Text Available Immune responses to coagulation factors VIII (FVIII and IX (FIX represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study.

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Cheng, Ji; Iorio, Alfonso; Marcucci, Maura; Romanov, Vadim; Pullenayegum, Eleanor M; Marshall, John K; Thabane, Lehana

2016-01-01

Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population - patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2.3

Hemoaction game: an educational step to improve hemophilia children and nurses self-efficacy

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NOOASHIN BEHESHTIPOOR

2016-10-01

Full Text Available As hemophilia is a chronic bleeding disease and can interfere with daily performance of children, these children require continuous training to prevent bleeding and take timely action (1. Since children nurses play an important role in the education of involved children and their Selfefficacy and also due to today’s approach which is using educational computer games, the use of educational games in respect to teach hemophilia children how to have self-efficacy can be effective (2. Hemoaction game is a computerized educational game designed by the World Federation of Hemophilia to educate hemophilia disease and related procedures to the care of children with hemophilia. By the use of this game children with hemophilia (aged 8-12 and also nursing experts were educated how to increase self efficacy. Nursing School of Shiraz University of Medical Sciences has used this game for the first time after its publishing, in the world (3. The results of the mentioned study demonstrates that after the Hemophilia disease and its related procedures were instructed to children with hemophilia and nursing experts in order to know how to increase patients’ self efficacy by modern approaches, self efficacy of hemophilia children and nurses were both improved. This educational method is a novel way to enhance both Hemophilia children and nursing staff, as major participants in routine and lifelong education process, self-efficacy. Due to nurses’ important role in improving children with hemophilia self-efficacy by different instructions and world leading educational approaches towards use of modern technology in education, using Hemoaction educational game, published by World Federation of Hemophilia and used by Nursing and Midwifery College of Shiraz University of Medical Sciences for the first time, can fulfill hemophilia children needs of care.

F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

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Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

2012-01-01

Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

Animal Models of Hemophilia and Related Bleeding Disorders

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Lozier, Jay N.; Nichols, Timothy C.

2013-01-01

Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: validity of the hemophilia joint health score

NARCIS (Netherlands)

Feldman, Brian M.; Funk, Sharon M.; Bergstrom, Britt-Marie; Zourikian, Nichan; Hilliard, Pamela; van der Net, Janjaap; Engelbert, Raoul; Petrini, Pia; van den Berg, H. Marijke; Manco-Johnson, Marilyn J.; Rivard, Georges E.; Abad, Audrey; Blanchette, Victor S.

2011-01-01

Repeated hemarthrosis in hemophilia causes arthropathy with pain and dysfunction. The Hemophilia Joint Health Score (HJHS) was developed to be more sensitive for detecting arthropathy than the World Federation of Hemophilia (WFH) physical examination scale, especially for children and those using

Advances in hemophilia care: report of two symposia at the Hemophilia 2010 World Congress.

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Dolan, Gerry; Cruz, Jussara Almeida; Steinhagen-Thiessen, Elisabeth; Kessler, Craig; Haaning, Jesper; Lemm, Georg; Altisent, Carmen; Guerrero, Caesar; Hermans, Cedric; Riske, Brenda; Bolton-Maggs, Paula

2012-04-01

The World Federation of Hemophilia (WFH) 2010 World Congress held in Buenos Aires, Argentina, in July 2010, attracted more than 4,300 participants from 106 countries. This report summarizes two symposia held during the congress. The first, titled "Emerging Co-Morbidities in the Aging Hemophilia Population: Healthcare Challenges and Treatment Opportunities," chaired by Gerry Dolan, MD, and Jussara Almeida Cruz, MD, examined the co-morbidities experienced by the aging hemophilic patient population, such as cardiovascular disease, cancer, arthritis, osteoporosis, hypertension, and obesity. In addition, Bayer's products in preclinical and clinical development were reviewed, including a novel factor VIIa variant and a long-acting factor VIII molecule, i.e., one that has undergone site-specific PEGylation (attachment of polyethylene glycol [PEG] polymer chains to another molecule). The other symposium, titled "Practical Steps to Making Better Care for Hemophilia Patients a Reality," chaired by Carmen Altisent, MD, and Cesar Guerrero, RN, reviewed the steps that hemophilia caregivers can take to improve the care of their patients. Issues such as the treatment of hemarthroses, the role of the research nurse, and the management of pediatric patients transitioning to adulthood were discussed.

Defining the impact of hemophilia: the Academic Achievement in Children with Hemophilia Study.

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Shapiro, A D; Donfield, S M; Lynn, H S; Cool, V A; Stehbens, J A; Hunsberger, S L; Tonetta, S; Gomperts, E D

2001-12-01

, parents' education, and IQ. The median number of bleeding episodes experienced in the year before enrollment for the cohort as a whole was 12. The median number of bleeding episodes in children on prophylaxis at enrollment was significantly lower than in children on on-demand therapy (6 vs 25.5). The mean achievement scores were within the average range of academic performance: reading, 100.4; mathematics, 101.6; language, 108.1; writing, 95.4; and total achievement, 102.5. When children were categorized as above or below the study group median by number of bleeding episodes, those who had a low number of bleeding episodes (achievement (104.4 vs 100.6) and mathematics (103.6 vs 99.6) than children in the higher bleeding episode category (> or =12) after adjusting for child's IQ and parents' education. Treatment with prophylaxis per se was not associated with better test scores, but children who had been treated on a regimen of long-term prophylaxis (>40% of lifetime) and reported achievement (104.9 vs 100.6), mathematics (105.2 vs 99.6), and reading (104.0 vs 98.6) than all other children reporting > or =12 bleeding episodes in the same time period. Increased school absenteeism and hemophilia-related limitations in physical functioning among children with greater frequency of bleeding episodes were proposed as the mechanisms for lower scores. The number of bleeding episodes was positively correlated with school absenteeism (Spearman correlation = 0.23), and children with more school absences had lower scores in mathematics, reading, and total achievement, even after adjusting for the child's IQ and parents' education. Children with fewer bleeding episodes also had better PhS scores than children in the high bleeding episode category (48.4 vs 41.3). The mean PhS for children in the low bleeding episode group (48.4) was similar to that of the general US population (50), but the mean PhS for children in the higher bleeding episode group was almost a full standard deviation

Manual therapy in the treatment of patients with hemophilia B and inhibitor.

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Cuesta-Barriuso, Rubén; Trelles-Martínez, Roberto O

2018-01-22

The main clinical manifestations of hemophilia are muscle and joint bleeding. Recurrent bleeding leads to a degenerative process known as hemophilic arthropathy. The development of inhibitors (antibodies against FVIII/FIX concentrates) is the main complication in the treatment of hemophilia. The objective was to assess the safety and efficacy of manual therapy treatment in a patient with hemophilia and inhibitor. A 26-year-old patient with hemophilia B and inhibitor received physiotherapy treatment based on manual therapy for 3 months, with a frequency of 2 sessions per week. The joint status was evaluated using the Hemophilia Joint Health Score; pain was assessed with the Visual Analog Scale; and the range of movement was evaluated using a universal goniometer. The patient developed no joint bleeding in the knees or ankles as a result of the physiotherapy treatment. Following treatment, improvements were noted in the range of movement of knees and ankles, the perception of pain in both knees, and ankle functionality. Until now, manual therapy using joint traction was contraindicated in patients with hemophilia and inhibitor, as it was feared to cause possible joint bleeding. This is the first case study to address the safety and efficacy of manual therapy in a patient with hemophilia and an inhibitor. The results of this study may help to establish which manual therapy treatments are indicated in patients with hemophilic arthropathy and inhibitors. Thus, a physiotherapy program based on manual therapy may be safe in patients with hemophilia and inhibitor and such therapy may improve joint condition, pain, and joint range of motion in patients with hemophilia and inhibitor. Randomized clinical trials are needed to confirm the results of this case study.

Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

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Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

2017-08-31

Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (Phemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

Hemophilia Care in the Pediatric Age

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Marta Bertamino

2017-05-01

Full Text Available Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should be considered in the neonatal period in the case of unusual bleeding or in the case of positive family history. Later, hemophilia should be suspected mainly in males because of abnormal bruising/bleeding or unusual bleeding following invasive procedures—for example, tonsillectomy or circumcision. Prophylactic treatment that is started early with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the gold standard of care for hemophilia A and B in most countries with adequate resources. Central venous access catheters and arterovenous fistulas play an important role in the management of hemophilia children requiring repeated and/or urgent administration of coagulation factor concentrates. During childhood and adolescence, personalized treatment strategies that suit the patient and his lifestyle are essential to ensure optimal outcomes. Physical activity is important and can contribute to better coordination, endurance, flexibility and strength. The present article focuses also on questions frequently posed to pediatric hematologists like vaccinations, day-care/school access and dental care.

Treatment of hemophilia in the near future.

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Peyvandi, Flora; Garagiola, Isabella

2015-11-01

Advancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

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Cheng J

2016-10-01

Full Text Available Ji Cheng,1,2 Alfonso Iorio,2,3 Maura Marcucci,4 Vadim Romanov,5 Eleanor M Pullenayegum,6,7 John K Marshall,3,8 Lehana Thabane1,2 1Biostatistics Unit, St Joseph’s Healthcare Hamilton, 2Department of Clinical Epidemiology and Biostatistics, 3Department of Medicine, McMaster University, Hamilton, ON, Canada; 4Geriatrics, Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 5Baxter HealthCare, Global Medical Affairs, Westlake Village, CA, USA; 6Child Health Evaluation Sciences, Hospital for Sick Children, 7Dalla Lana School of Public Health, University of Toronto, Toronto, 8Division of Gastroenterology, Hamilton Health Science, Hamilton, ON, Canada Background: Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information.Methods: We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population – patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1 or random-effects (Case 2 and Case 3 logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical

Hemophilia Treatments Have Come a Long Way

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... Products For Consumers Home For Consumers Consumer Updates Hemophilia Treatments Have Come a Long Way Share Tweet ... tissues and even be life-threatening. Treatments for Hemophilia "We have seen shifting toward the prevention of ...

Previously undiagnosed hemophilia patient with intracerebral hemorrhage

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Eray Atalay

2015-09-01

Full Text Available Intracranial bleeding in hemophilia patients is a rare but a mortal complication. Diagnosis of hemophilia in adulthood is an uncommon occurrence. In this case report an adult patient with intracranial hemorrhage is presented.

Unraveling the genetics of inhibitors in hemophilia

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Gouw, Samantha C.; Fijnvandraat, Karin

2013-01-01

In this issue of Blood, Astermark et al have identified novel genetic markers of inhibitory antibody formation in hemophilia patients that may ultimately lead to prediction and even prevention of this severe complication of hemophilia treatment.(1)

Treatment of hemophilia: A qualitative study of mothers' perspectives.

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von der Lippe, Charlotte; Frich, Jan C; Harris, Anna; Solbraekke, Kari Nyheim

2017-01-01

In Norway, boys with hemophilia usually begin treatment after their first bleeding episode. Boys with severe hemophilia usually start prophylactic treatment around 18-24 months. Health professionals administer factor concentrate initially, but when boys are around 4 years old most parents start treating their children at home. There is a lack of research on how parents, and especially how carrier mothers, experience the medical treatment for their sons' hemophilia. Our aim was to investigate how carrier mothers experience this treatment in the hospital setting and at home. In this qualitative study, we interviewed 16 mothers of boys or men with hemophilia A or B. Data were collected via semistructured interviews and analyzed using an inductive thematic analytical approach. Mothers experienced both practical and emotional challenges in relation to their sons' treatment, and repeated venipuncture was especially difficult emotionally. Parents preferred home treatment to hospital treatment because it was less time-consuming, less disruptive to family life, and provided a greater sense of control. Encountering healthcare professionals who were unfamiliar with hemophilia was a second major stress factor, especially when parents felt that health professionals lacked competence and were unwilling to seek advice. While home treatment for hemophilia enables freedom, flexibility, and autonomy for the boys as well as for the family, mothers may experience treatment of hemophilia as a burden. Health professionals should provide tailored practical and emotional support to parents by probing into their experiences with treating their sons' hemophilia. © 2016 Wiley Periodicals, Inc.

Myelofibrosis and acquired hemophilia A: a case report.

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Wrobel, Marie; Comio, Emilie; Gay, Valerie; Baroudi, Noureddine; Meyer, Pascal; Chuniaud-Louche, Christine; Hacini, Maya; Pica, Gian Matteo

2016-05-07

Myelofibrosis and acquired hemophilia A is a rare association. To the best of our knowledge only one case of myelofibrosis and acquired hemophilia A has been previously described. A 66-year-old Caucasian man diagnosed with myelofibrosis evolving in acute myeloid leukemia was referred to us for postoperative bleeding. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer; these findings led to a diagnosis of acquired hemophilia A for which he was treated with methylprednisolone and recombinant activated factor VII on admission. Due to a lack of response he was subsequently treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he received azacytidine to treat the underlying hematological malignancies. Immunosuppressive rituximab therapy resolved acquired hemophilia A with marked efficacy. Rapid and accurate diagnosis, effective hemostatic therapy, and timely treatment for underlying disease are important in the management of acquired hemophilia A secondary to hematological malignancy.

Hemophilia A

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... PA: Elsevier; 2016:chap 476. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Haemophilia. 2013;19:e1-47. PMID: 22776238 www.ncbi.nlm.nih.gov/pubmed/ ...

The Hemophilia Games: An Experiment in Health Education Planning.

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National Heart and Lung Inst. (DHEW/PHS), Bethesda, MD.

The Hemophilia Health Education Planning Project was designed to (1) create a set of tools useful in hemophilia planning and education, and (2) create a planning model for other diseases with similar factors. The project used the game-simulations technique which was felt to be particularly applicable to hemophilia health problems, since as a…

Platelets and hemophilia: A review of the literature.

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Riedl, Julia; Ay, Cihan; Pabinger, Ingrid

2017-07-01

Hemophilia A and B are inherited bleeding disorders due to deficiencies of the clotting factors VIII and IX, respectively. The severity of the disease correlates with remaining factor levels, although individual differences in bleeding tendency are seen despite similar factor levels. While thrombin generation is severely impaired in persons with hemophilia, primary hemostasis, i.e. platelet function, has been generally considered to be normal. However, some studies reported prolonged bleeding times in hemophilia, suggesting that also primary hemostasis is affected. In several other studies different aspects of platelet function in hemophilia have been investigated in more detail and various alterations were discovered, such as increased platelet P-selectin expression, a lower number of procoagulant, so-called 'coated' platelets, lower aggregation upon co-incubation with tissue factor, or reduced platelet contractile forces during clot formation in comparison to healthy individuals. An influence of platelet function on clinical phenotype was suggested, which might contribute in part to variations in bleeding tendency in hemophilic patients with similar factor levels. However, the available evidence is currently limited and no clear correlations between platelet function parameters and clinical phenotypes have been demonstrated. The impact of alterations of platelet function in hemophilia remains to be better defined. Another interesting role of platelets in hemophilia has been reported recently by establishing a novel gene-therapeutic strategy using platelets as a delivery system for FVIII, showing promising results in animal models. This review gives an overview on the currently published literature on platelet function and the potential roles of platelets in hemophilia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Emerging drugs for hemophilia B.

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Mannucci, Pier Mannuccio; Franchini, Massimo

2014-09-01

Hemophilia B is a rare congenital bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). Hemophilia B patients experience mild-to-severe bleeding complications according to the degree of FIX defect. Prophylaxis, with regular infusion of FIX concentrates, is nowadays, the mainstay of hemophilia care. However, because the relatively short half-life of such products necessitates frequent infusions and thus makes patients' adherence difficult, a number of strategies have been implemented to improve the pharmacokinetics of FIX clotting factors. This review summarizes the main results of Phase I/II and III studies on new FIX molecules engineered to have a longer half-life. Several technologies are being applied to extend FIX half-life, including Fc fusion, recombinant (r) albumin fusion and the addition of PEG polymers. By prolonging the FIX half-life up to 5 times, long-acting FIX products are expected to substantially improve the management of hemophilia B patients, allowing less frequent infusions and improving patients' adherence to prophylactic regimens and individualized treatments. Some of them are at an advanced stage of development, such as the rFIX-Fc which has been launched in March 2014. Along with the ongoing Phase III trials, long-term post-marketing surveillance studies are needed to assess their safety and effectiveness and their impact on patients' quality of life.

Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A.

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Rodgers, Susan; Duncan, Elizabeth

2017-01-01

Hemophilia A is an inherited bleeding disorder caused by a reduced level of factor VIII coagulant activity (FVIII:C) in blood. Bleeding episodes may occur spontaneously in the severe form of hemophilia or after trauma in the milder forms. It is important that patients are diagnosed correctly, which includes placing them into the correct severity category of the disorder so that appropriate treatment can be given. Diagnosis is made by determination of the amount of FVIII:C in the blood, usually using a one-stage factor VIII:C assay. However, approximately one third of patients with mild or moderate hemophilia will have much lower results by the chromogenic assay, with some of them having normal results by the one-stage assay. The chromogenic factor VIII assay is used in some specialized hemophilia reference centers and is recommended for the diagnosis of mild hemophilia A, as this assay is considered to better reflect the severity status of hemophilia patients than the one-stage assay.

Neonatal hemophilia: a rare presentation

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Nuno Ferreira

2015-12-01

Full Text Available Hemophilia A is a X-linked hereditary condition that lead to decreased factor VIII activity, occurs mainly in males. Decreased factor VIII activity leads to increased risk of bleeding events. During neonatal period, diagnosis is made after post-partum bleeding complication or unexpected bleeding after medical procedures. Subgaleal hemorrhage during neonatal period is a rare, severe extracranial bleeding with high mortality and usually related to traumatic labor or coagulation disorders. Subgaleal hemorrhage complications result from massive bleeding. We present a neonate with unremarkable family history and uneventful pregnancy with a vaginal delivery with no instrumentation, presenting with severe subgaleal bleeding at 52 hours of life. Aggressive support measures were implemented and bleeding managed. The unexpected bleeding lead to a coagulation study and the diagnosis of severe hemophilia A. There were no known sequelae. This case shows a rare hemophilia presentation reflecting the importance of coagulation studies when faced with unexplained severe bleeding.

An examination of the symptoms of anxiety and parental attitude in children with hemophilia.

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Abali, Osman; Zülfikar, Osman Bülent; Karakoç Demirkaya, Sevcan; Ayaydin, Hamza; Kircelli, Fuat; Duman, Mehtap

2014-01-01

Hemophilia is an inherited disease with serious repercussions. Psychiatric symptoms are frequently seen in children and adolescents with hemophilia. The aim of this study was to assess symptoms of anxiety in children with hemophilia and parental attitude towards children with hemophilia. 42 boys were assessed according to child and adolescent psychiatry. Anxiety symptoms and parental attitude were obtained by the State-Trait Anxiety Scale, the Self-Report for Childhood Anxiety Related Disorders (SCARED) and the Parent Attitude Research Instrument (PARI). The mean age was 11.6 ± 2.5 (range; 7-16). State anxiety scores (44.02 ± 6.9) were higher than trait anxiety scores (32.7 + 7.5). The most interesting results were high scores related to overprotective mothering (47.9 ± 9.7) and the application of strict discipline (39.4 ± 9.1). The total SCARED scores obtained were (23.25 ± 11.3). Assuring a high quality of life is important for children and adolescents with chronic illness. Quality of life is negatively affected by psychiatric symptoms (e.g. anxiety symptoms, depression, intra-familial stress symptoms) in children with hemophilia. This study suggests that high anxiety scores and problems related to parental attitude can be seen in children and adolescents with hemophilia. These problems caused by parental attitude and anxiety symptoms should be considered in the treatment of hemophilia.

Immunobiology of inhibitor development in hemophilia A

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Fijnvandraat, Karin; Bril, Wendy S.; Voorberg, Jan

2003-01-01

After treatment with factor (F) VIII concentrate a significant number of patients with hemophilia A develop inhibitory antibodies that neutralize FVIII. Epitope mapping revealed that antibodies bind to selected regions within the A2, A3, and C2 domains of FVIII. Anti-A2 and anti-A3 antibodies

Human parvovirus B19 and parvovirus 4 among Iranian patients with hemophilia.

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Javanmard, Davod; Ziaee, Masood; Ghaffari, Hadi; Namaei, Mohammad Hasan; Tavakoli, Ahmad; Mollaei, Hamidreza; Moghoofei, Mohsen; Mortazavi, Helya Sadat; Monavari, Seyed Hamidreza

2017-12-01

Human parvovirus B19 (B19V) is one of the smallest DNA viruses and shows great resistance to most disinfectants. Therefore, it is one of the common contaminant pathogens present in blood and plasma products. Parvovirus 4 (PARV4) is a newly identified parvovirus, which is also prevalent in parenteral transmission. In this study, we aimed to evaluate the prevalence of B19V and PARV4 DNA among patients with hemophilia in Birjand County in eastern Iran. This was a cross-sectional epidemiological study comprising nearly all people with hemophilia in this region. Whole blood samples were taken after patient registration and sent for plasma isolation. After nucleic acid extraction, B19V was detected with real-time polymerase chain reaction, PARV4 DNA was then detected using sensitive semi-nested PCR. In total, there were 86 patients with hemophilia, with mean age 28.5±1.5 years. Of these, 90.7% were men and 9.3% women; 84.9% had hemophilia A and 7.0% had hemophilia B. We found 11 patients (12.8%) were positive for B19V DNA and 8 were positive (9.3%) for PARV4 DNA. The prevalence of B19V was higher in middle-aged groups rather than younger people, whereas PARV4 infection was more common in younger patients ( P B19 virus, imposing more precautionary measures for serum and blood products is recommended.

Risk Factors for High-Titer Inhibitor Development in Children with Hemophilia A: Results of a Cohort Study

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Susan Halimeh

2013-01-01

Full Text Available Among the discussed risk factors for high-titre inhibitor (HRI development in patients with hemophilia A (HA are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII. The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR, and 95% confidence intervals (CIs were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, “intensive treatment moments” and “year of birth” (proxy for different treatment periods. HRI occurred in 71/288 children (24.7%. In multivariate analysis adjusted for “year of birth”, underlying risk gene mutations (HR/CI: 2.37/1.40–3.99, FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04–1.07, and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations.

Mortality caused by intracranial bleeding in non-severe hemophilia A patients

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Loomans, Janneke I.; Eckhardt, Corien L.; Reitter-Pfoertner, Sylvia E.; Holmstrom, Mats; Van Gorkom, B. Laros; Leebeek, F. W. G.; Santoro, C.; Haya, Saturnino; Meijer, K.; Nijziel, M. R.; Van Der Bom, J. G.; Fijnvandraat, K.

Background: Non-severe hemophilia (factor VIII concentration [FVIII: C] of 2-40 IU dL(-1)) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on

Assessment of Musculoskeletal Function and its Correlation with Radiological Joint Score in Children with Hemophilia A.

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Gupta, Samriti; Garg, Kapil; Singh, Jagdish

2015-12-01

To evaluate the functional independence of children with hemophilia A and its correlation to radiological joint score. The present cross sectional study was conducted at SPMCHI, SMS Medical College, Jaipur, India. Children in the age group of 4-18 y affected with severe, moderate and mild hemophilia A and with a history of hemarthrosis who attended the OPD, emergency or got admitted in wards of SPMCHI, SMS Medical College were examined. Musculoskeletal function was measured in 98 patients using Functional Independence Score in Hemophilia (FISH) and index joints (joints most commonly affected with repeated bleeding) were assessed radiologically with plain X rays using Pettersson score. The mean FISH score was 28.07 ± 3.90 (range 17-32) with squatting, running and step climbing as most affected tasks. The mean Pettersson score was 3.8 ± 3.2. A significant correlation was found between mean Pettersson score and FISH (r = -0.875, P hemophilia A.

Role of bone marrow transplantation for correcting hemophilia A in mice

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Follenzi, Antonia; Raut, Sanj; Merlin, Simone; Sarkar, Rita

2012-01-01

To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)–derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A. PMID:22368271

Renal Abnormalities Among Egyptian Children With Hemophilia A Using Renal Scintigraphy: Relation to Risk Factors and Disease Severity.

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Hamed, Ahmed Alsaeed; Shalaby, Mennatallah Hatem; El-Kinawy, Nihal Saad; Elamawy, Alaa Adel; Abd El-Ghany, Shereen Mohamed

2017-07-01

Many risk factors may contribute to renal disease in patients with hemophilia A. We aimed to evaluate functional and structural renal abnormalities among a group of Egyptian children with severe and moderate hemophilia A using technetium-99m diethylene triamine pentaacetic acid ( 99m Tc-DTPA) and technetium-99 m dimercaptusuccinic acid ( 99m Tc-DMSA) scan. We also aimed to determine the relation between these abnormalities and different risk factors and disease severity. Forty male patients, 16 with severe and 24 with moderate hemophilia A, were enrolled in this study. Their mean age was 10.2 ± 4.3 years (range, 5-17 years). Full history taking, clinical examination, laboratory, and radionuclide investigations including serum creatinine, blood urea nitrogen (BUN), urine analysis, creatinine clearance, 24-hour urinary protein, 99m Tc-DTPA scan, and 99m Tc-DMSA scan were performed to all enrolled patients. Serum creatinine and BUN were normal in all patients, and corrected creatinine clearance was diminished in 2 patients. However, 99m Tc-DTPA results yielded 19 (47.5%) patients with diminished glomerular filtration rate (GFR). Moreover, it showed that 14 (35%) had obstructive uropathy, 15 (37.5%) had obstructive nephropathy, while 11 (27.5%) patients showed normal scan. One patient had atrophy of 1 kidney on 99m Tc-DMSA scan. Among our cohort, 5 (12.5%) patients were hypertensive. Microscopic hematuria was detected in 14 (35%) patients while 72.5% had proteinuria. We found an association between hematuria and hypertension with diminished GFR. Despite normal kidney functions (serum creatinine and BUN), we found a high rate of diminished GFR and obstructive uropathy and nephropathy as detected by 99m Tc-DTPA scan among children with hemophilia A.

Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study.

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van Velzen, A S; Eckhardt, C L; Peters, M; Leebeek, F W G; Escuriola-Ettingshausen, C; Hermans, C; Keenan, R; Astermark, J; Male, C; Peerlinck, K; le Cessie, S; van der Bom, J G; Fijnvandraat, K

2017-07-01

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg -1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians

Hemophilia and Sports: Guidelines for Participation. Case Report.

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McLain, Larry G.; Heldrich, Fred T.

1990-01-01

Presents a case report of a 15-year-old boy with severe hemophilia who played soccer 1 school year but was denied continued participation following another screening examination. Before deciding about participation, physicians must assess the type and severity of hemophilia and risk factors for injury. Appropriate sports for hemophiliacs are…

Challenges and successes in the treatment of hemophilia: the story of a patient with severe hemophilia A and high-titer inhibitors

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Saba HI

2012-05-01

Full Text Available Hussain I Saba, Duc Quang Tran, JrDepartment of Medicine, University of South Florida Medical Center, Tampa, FL, USAAbstract: In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients' physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life.Keywords: hemophilia, quality of life, factor VIII inhibitors, hemophilia treatment center, early treatment, bypassing agent

The current state of adverse event reporting in hemophilia

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van Vulpen, Lize F D; Saccullo, Giorgia; Iorio, Alfonso; Makris, Michael

INTRODUCTION: Replacement of the missing clotting factor is the mainstay of hemophilia treatment. Whilst historically many hemophilia patients were infected with blood-borne viruses transmitted via plasma-derived products, nowadays the formation of alloantibodies against the missing clotting factor

Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists.

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de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

2017-05-01

Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an ETP hemophilia patients, TG was comparable to that in patients with a therapeutic INR. In one-third of non-severe hemophilia patients, TG was higher. These results suggest that anticoagulation therapy should be considered in a substantial proportion of non-severe hemophilia patients. © 2017 International Society on Thrombosis and Haemostasis.

Causes of Death Among 379 Patients With Hemophilia: A Developing Country's Report.

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Mansouritorghabeh, Hassan; Rahimi, Hossein; Mohades, Seyed Tahereh; Behboudi, Maryam

2018-05-01

There are steps to achieve an optimum life for patients with hemophilia in developing countries, and awareness of the pattern of death in patients with hemophilia is a prerequisite for any health-care program. Owing to the lack of any data on the pattern of death in patients with hemophilia from developing countries, the current study was done to address common causes of death, and the spectrum of causes of death among individuals with hemophilia A and B. To address the pattern of death in northeast of Iran, we retrospectively collected demographic data regarding deceased patients with hemophilia A and B. Overall, among 379 people with hemophilia A and B, there were 46 deaths. Thirty-two deaths happened in the severe forms of the diseases. The obtained results show the patterns of death in the patients studied are not as parallel as some reports from the developed countries. Traumatic and spontaneous bleeding events were the main causes of death. The trend of death shows a decrease in the current decade post better therapeutic facilities. Evaluation of causes of death in hemophilia can be a useful indicator for managing the efficacy of health care in the current patients.

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

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1995-07-01

To present current strategies for the assessment and comprehensive care of patients with hemophilia and von Willebrand's disease. Hospital care, home care, single-provider care and multidisciplinary care. Morbidity and quality of life associated with bleeding and treatment. 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 references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and to a predetermined outline. The availability of treatment products in Canada was also considered. Minimizing morbidity and maximizing functional status and quality of life were given a high value. The optimal use of treatment procedures and home care offers patients the advantages of minimized disability, improved survival and financial benefit. It is also cost effective. Potential harm, including the risk of hepatitis B, hepatitis C and HIV infection, has now been minimized through viral inactivation of plasma-derived coagulation-factor concentrates and through the use of recombinant clotting factor concentrates and other non-plasma-derived hemostatic agents. Patients with hemophilia and severe von Willebrand's disease should be followed in comprehensive care centres that offer expertise in the diagnosis, assessment and management of bleeding and complications and that can meet the educational and counselling needs of patients, family members and health care providers. Eligible patients should

Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model.

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Staber, Janice M; Pollpeter, Molly J

2016-01-01

Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated. To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death. Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

78 FR 57868 - Prospective Grant of Exclusive Patent License: Oral Treatment of Hemophilia

Science.gov (United States)

2013-09-20

... Exclusive Patent License: Oral Treatment of Hemophilia AGENCY: National Institutes of Health, HHS. ACTION...), entitled respectively, ``Oral Treatment of Hemophilia'' and ``Induction of Tolerance by Oral administration of Factor VIII and Treatment of Hemophilia''. The patent rights in these inventions have been...

Pain Experience in Hemophilia Patients: A Hermeneutic Phenomenological Study

Science.gov (United States)

Rambod, Masoume; Sharif, Farkhondeh; Molazem, Zahra; Khair, Kate

2016-01-01

ABSTRACT Background: Pain, as a crucial subsequence of joint hemorrhages in hemophilia patients, is chronic, debilitating, and distracting. This study aimed to describe and interpret pain experiences of hemophilia patients in their lives. Methods: This qualitative study with hermeneutic phenomenological approach was conducted on fourteen hemophilia patients who had been referred to a hemophilia center affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The study question was “what is the meaning of pain in hemophilia patients’ lives? The data were collected through semi-structured interviews and field notes through purposeful sampling. Then, thematic analysis with van Manen’s six-step methodological framework was used. MAX.QDA qualitative software package, 2010, was used to analyze the data. Results: The three main themes that emerged in this study were “alteration in physical health”, “engagement in psychological problems”, and “impairment in social relationships”. Alteration in physical health consisted of three subthemes, namely “impairment of physical function”, “change in body physics”, and “disturbance in sleep quality”. In addition, two subthemes including “nostalgia of pain in adults with hemophilia” and “psychological distress” emerged from engagement in psychological problems. Finally, “loss of social activity” and “change in relationships” were related to impairment in social relationships. Conclusion: The present study highlighted alteration in physical health, engagement in psychological problems, and impairment in social relationship as a result of pain in hemophilia patients. Thus, healthcare providers and family members have to pay special attention to these problems. Besides, providing complementary therapy interventions is suggested for reducing these issues. PMID:27713894

Prevalent Inhibitors in Hemophilia B Subjects Enrolled in the Universal Data Collection Database

Science.gov (United States)

Puetz, John; Soucie, J. Michael; Kempton, Christine L.; Monahan, Paul E.

2015-01-01

Summary Background Several risk factors for inhibitors have recently been described for hemophilia A. It has been assumed that similar risk factors are also relevant for hemophilia B, but there is limited data to confirm this notion. Objectives To determine the prevalence of and risk factors associated with inhibitors in hemophilia B Methods The database of the Universal Data Collection (UDC) project of the Centers for Disease Control for the years 1998 – 2011 was queried to determine the prevalence of inhibitors in hemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure, and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Results Of the 3800 male subjects with hemophilia B enrolled in the UDC database, 75 (2%) were determined to have an inhibitor at some point during the study period. Severe disease (OR 13.1, 95% CI 6.2-27.7), black race (OR 2.2, 95% CI 1.2-4.1), and age less than 11 (OR 2.5, 95% CI 1.5-4.0) were found to be significantly associated with having an inhibitor. There was insufficient data to determine if type of factor used and prophylaxis were associated with inhibitors. Conclusions Inhibitors in hemophilia B are much less prevalent than hemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in hemophilia A also seem to be present for hemophilia B. The information collected by this large surveillance project did not permit evaluation of potential risk factors related to treatment approaches and exposures, and additional studies will be required. PMID:23855900

MR imaging of arthropathies of juvenile arthritis and hemophilia

International Nuclear Information System (INIS)

Yulish, B.S.; Lieberman, J.; Mulopoulos, G.P.; Strandjord, S.; Newman, A.; Goodfellow, D.; Bryan, P.J.; Modic, M.T.

1986-01-01

The arthropathies of juvenile arthritis and hemophilia have in common abnormal hyperplastic synovium leading to marginal bone erosion, articular cartilage destruction, subchondral bone exposure, and dissolution and ultimately collapse of the affected joint. The authors examined children and young adults with juvenile arthritis and hemophilia by MR imaging and found that they could identify hyperplastic synovium, articular cartilage lesions, bone erosions, and joint effusions. This has therapeutic implications since identification of progressive synovial hyperplasia and/or early cartilage or marginal bone erosion may lead to earlier synovectomy in patients with hemophilia or switch to second line drugs in patients with juvenile arthritis, in an attempt to prevent progressive joint destruction

4 cases of iliopsoas hematoma associated with hemophilia

Energy Technology Data Exchange (ETDEWEB)

Oishi, Yukiyoshi; Iwata, Hisashi; Inoda, Kunio (Nagoya Univ. (Japan). Faculty of Medicine)

1984-03-01

Four patients were diagnosed as having iliopsoas hematoma associated with hemophilia by CT scanning. The site and disappearance of hematoma were observed on CT. It was suggested that hematoma occurs inside the iliacus or posoas muscle in cases of iliopsoas hematoma complicated by hemophilia or coagulation and that it occurs in the pelvic wall of the iliacus muscle in cases of iliopsoas hematoma uncomplicated by coagulation abnormality.

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

Science.gov (United States)

Johnsen, Jill M.; Fletcher, Shelley N.; Huston, Haley; Roberge, Sarah; Martin, Beth K.; Kircher, Martin; Josephson, Neil C.; Shendure, Jay; Ruuska, Sarah; Koerper, Marion A.; Morales, Jaime; Pierce, Glenn F.; Aschman, Diane J.

2017-01-01

Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using next-generation sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years. Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel. Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild–moderate disease. Novel DNA variants accounted for ∼30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected >1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia. PMID:29296726

Validation of the VERITAS-Pro treatment adherence scale in a Spanish sample population with hemophilia

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Cuesta-Barriuso R

2017-03-01

Full Text Available Rubén Cuesta-Barriuso,1–3 Ana Torres-Ortuño,4 Pilar Galindo-Piñana,4 Joaquín Nieto-Munuera,4 Natalie Duncan,5 José Antonio López-Pina6 1Department of Physiotherapy, School of Biomedical and Health Sciences, European University of Madrid, 2Fishemo, Centro Especial de Empleo, Spanish Federation of Hemophilia, 3Royal Foundation Victoria Eugenia, Madrid, 4Department of Psychiatry and Social Psychology, Faculty of Medicine, University of Murcia, Murcia, Spain; 5Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 6Department of Basic Psychology and Methodology, Faculty of Psychology, University of Murcia, Murcia, Spain Purpose: We aimed to conduct a validation in Spanish of the Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-Pro questionnaire for use in patients with hemophilia under prophylactic treatment.Patients and methods: The VERITAS-Pro scale was adapted through a process of back translation from English to Spanish. A bilingual native Spanish translator translated the scale from English to Spanish. Subsequently, a bilingual native English translator translated the scale from Spanish to English. The disagreements were resolved by agreement between the research team and translators. Seventy-three patients with hemophilia, aged 13–62 years, were enrolled in the study. The scale was applied twice (2 months apart to evaluate the test–retest reliability.Results: Internal consistency reliability was lower on the Spanish VERITAS-Pro than on the English version. Test–retest reliability was high, ranging from 0.83 to 0.92. No significant differences (P>0.05 were found between test and retest scores in subscales of VERITAS-Pro. In general, Spanish patients showed higher rates of nonadherence than American patients in all subscales.Conclusion: The Spanish version of the VERITAS-Pro has high levels of consistency and empirical validity. This scale can be administered to assess the degree of

Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists

NARCIS (Netherlands)

de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

Essentials: It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In

4 cases of iliopsoas hematoma associated with hemophilia

International Nuclear Information System (INIS)

Oishi, Yukiyoshi; Iwata, Hisashi; Inoda, Kunio

1984-01-01

Four patients were diagnosed as having iliopsoas hematoma associated with hemophilia by CT scanning. The site and disappearance of hematoma were observed on CT. It was suggested that hematoma occurs inside the iliacus or posoas muscle in cases of iliopsoas hematoma complicated by hemophilia or coagulation and that it occurs in the pelvic wall of the iliacus muscle in cases of iliopsoas hematoma uncomplicated by coagulation abnormality. (Namekawa, K.)

Thirty years of hemophilia treatment in the Netherlands, 1972-2001

NARCIS (Netherlands)

Plug, Iris; van der Bom, Johanna G.; Peters, Marjolein; Mauser-Bunschoten, Evelien P.; de Goede-Bolder, Arja; Heijnen, Lily; Smit, Cees; Zwart-van Rijkom, Jeannette E. F.; Willemse, José; Rosendaal, Frits R.

2004-01-01

Since the introduction of replacement therapy in the early 1960s by the infusion of plasma-derived factor VIII and IX preparations, important changes have occurred for hemophilia patients. We studied the medical and social developments over 30 years of hemophilia treatment. Since 1972, 5

Hemodialysis in a patient with severe hemophilia A and factor VIII inhibitor.

Science.gov (United States)

Gopalakrishnan, Natarajan; Usha, Thiruvengadam; Thopalan, Balasubramaniyan; Dhanapriya, Jeyachandran; Dineshkumar, Thanigachalam; Thirumalvalavan, Kaliaperumal; Sakthirajan, Ramanathan

2016-10-01

Hemophilia A is a hereditary X-linked recessive disease caused by mutations in the gene encoding factor VIII (FVIII), occurring in 1 out of 10,000 persons. Life expectancy and quality of life have dramatically improved recently in patients with hemophilia. Chronic kidney disease and need for renal replacement therapy in these patients are rare. The development of inhibitors to FVIII is the most serious complication of hemophilia and makes treatment of bleeds very challenging. We describe here a 28-year-old male patient with severe hemophilia A with presence of factor VIII inhibitor, who had end stage renal disease. Central venous access device was inserted along with infusion of factor eight inhibitor bypass activity before and after the procedure. He is currently on thrice weekly hemodialysis and doing well for 6 months without bleeding episodes. To our knowledge, hemophilia A with factor VIII inhibitor managed with hemodialysis has not been reported so far. © 2016 International Society for Hemodialysis.

A cohort pilot study on HIV-associated neuropsychological impairments in haemophilia patients

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Silvia eRiva

2015-06-01

Full Text Available Despite advances in the management of HIV infection with the introduction of combination antiretroviral therapy (cART, it is well known that HIV can directly infect the central nervous system (CNS and, as a result of such infection, neuropsychological impairments can be manifested. In this study we tried to determine whether seropositivity was associated with a poor neuropsychological performance in patients with hemophilia and HIV. Such a cohort of patients is very often underrepresented and understudied in the HIV literature. To amend such a gap, we carried out an extensive neuropsychological evaluation on these patients, and compared their performance with that of a group of seronegative hemophilia patients. The results revealed that HIV infection in HIV seropositive (HIV+ hemophilia patients was associated with deficits in attention, short-term memory, abstraction and visual recognition. Such results are still preliminary and explorative due to the small cohort of patients enrolled. However, the results do seem to have some important implications for day-to-day functioning, as the level of impairment detected may cause difficulties in completing common everyday tasks such as maintaining adherence to complex medication regimens, or maintaining social life activities. Continued research into the mechanisms related to HIV and neurocognitive dysfunction may provide targets for interventions that could have meaningful consequences in the real world for HIV hemophilia patients.

Understanding patient preferences and willingness to pay for hemophilia therapies

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Chaugule SS

2015-11-01

Full Text Available Shraddha S Chaugule,1 Joel W Hay,1 Guy Young2 1Department of Clinical Pharmacy, Pharmaceutical Economics and Policy, University of Southern California, 2Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Background: Despite clearly improved clinical outcomes for prophylaxis compared to on-demand therapy, on average only 56% of patients diagnosed with severe hemophilia receive prophylactic factor replacement therapy in the US. Prophylaxis rates generally drop as patients transition from childhood to adulthood, partly due to patients becoming less adherent when they reach adulthood. Assessment of patient preferences is important because these are likely to translate into increased treatment satisfaction and adherence. In this study, we assessed preferences and willingness to pay (WTP for on-demand, prophylaxis, and longer acting prophylaxis therapies in a sample of US hemophilia patients.Methods: Adult US hemophilia patients and caregivers (N=79 completed a discrete-choice survey that presented a series of trade-off questions, each including a pair of hypothetical treatment profiles. Using a mixed logit model for analysis, we compared the relative importance of five treatment characteristics: 1 out-of-pocket treatment costs (paid by patients, 2 factor dose adjustment, 3 treatment side effects, 4 availability of premixed factor, and 5 treatment effectiveness and dosing frequency. Based on these attribute estimates, we calculated patients’ WTP.Results: Out-of-pocket treatment costs (P<0.001, side effects (P<0.001, and treatment effectiveness and dosing frequency (P<0.001 were found to be statistically significant in the model. Patients were willing to pay US $410 (95% confidence interval: $164–$656 out of pocket per month for thrice-weekly prophylaxis therapy compared to on-demand therapy and $360 (95% confidence interval: $145–$575 for a switch

Molecular diagnosis of hemophilia A and B. Report of five families from Costa Rica

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Lizbeth Salazar-Sánchez

2004-09-01

Full Text Available Hemophilia Aand B are X-chromosome linked bleeding disorders caused by deficiency of the respective coagulation factor VIII and IX. Affected individuals develop a variable phenotype of hemorrhage caused by a broad range of mutations within the Factor VIII or Factor IX gene. Here, were report the results of the molecular diagnosis in a five Costa Rican families affected with Hemophilia. Methods of indirect and direct molecular diagnosis are applied in three Hemophilia A and two Hemophilia B families from Costa Rica as well as preconditions, practicability and facilities of this diagnosis. In two families with Hemophilia A and both families with Hemophilia B the causative mutation could be detected by Southern blotting, polymerase chain reaction or sequence analysis. One Hemophilia A family could only analyzed by linkage analysis using genomic markers. Rev. Biol. Trop. 52(3: 521-530. Epub 2004 Dic 15.La hemofilia A y B es una enfermedad hemorrágica hereditaria ligada al cromosoma X, producida por la deficiencia del factor VIII o IX, respectivamente. Los individuso afectados presentan un fenotipo de hemorragia variable causada por el amplio espectro de mutacionesdentro del gen del factor VIII o IX. Se reportan los resultados preliminares del diagnóstico molecular de familias hemofilicas costarricenses. Se demuestran los hallazgos obtenidos por medio de diagnóstico molecular directo e indirecto en tres familias con hemofilia A y dos con hemofilia B; así como las precondiciones y facilidad de este diagnóstico. En dos familias con hemofilia A y dos con hemofilia B, la mutación responsable pudo ser detectada por medio de Southern Blot, por la reacción en cadena de la polimerasa o por secuenciación genética. Una familia con hemofilia A pudo ser analizada solamente por medio de análisis indirecto por medio de marcadores genéticos intragénicos y extragénicos.

Biodistribution of Liver-Derived Mesenchymal Stem Cells After Peripheral Injection in a Hemophilia A Patient.

Science.gov (United States)

Sokal, Etienne M; Lombard, Catherine Anne; Roelants, Véronique; Najimi, Mustapha; Varma, Sharat; Sargiacomo, Camillo; Ravau, Joachim; Mazza, Giuseppe; Jamar, François; Versavau, Julia; Jacobs, Vanessa; Jacquemin, Marc; Eeckhoudt, Stéphane; Lambert, Catherine; Stéphenne, Xavier; Smets, Françoise; Hermans, Cédric

2017-08-01

With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers. Thus, the objectives were to evaluate the potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of the cells after intravenous injection. A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs via a peripheral vein (35 million In-oxine-labeled cells, followed by 125 million cells the next day, and 3 infusions of 250 million cells every 2 weeks thereafter; total infusion period, 50 days). After cell therapy, we found a temporary (15 weeks) decrease in the patient's FVIII requirements and severe bleeding complications, despite a lack of increase in circulating FVIII. The cells were safely administered to the patient via a peripheral vein. Biodistribution analysis revealed an initial temporary entrapment of the cells in the lungs, followed by homing to the liver and to a joint afflicted with hemarthrosis. These results suggest the potential use of ADHLSCs in the treatment of hemophilia A.

The Utilization of Rehabilitation in Patients with Hemophilia A in Taiwan: A Nationwide Population-Based Study.

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Chien-Min Chen

Full Text Available Rehabilitation plays an important role in the physical health of patients with hemophilia. However, comprehensive information regarding the utilization of rehabilitation for such patients remains scarce.This population-based study aimed to examine the characteristics, trends, and most important factors affecting rehabilitation usage in patients with hemophilia A using a nationwide database in Taiwan.Data from 777 patients with hemophilia A who were registered in the National Health Insurance Research Database between 1998 and 2008 were analyzed using SAS 9.0.Musculoskeletal or nervous system-related surgical procedures and clotting factor VIII concentrate costs were identified as factors affecting rehabilitation usage; musculoskeletal or nervous system-related surgical procedures (odds ratio = 3.788; P < 0.001 were the most important predictor of whether a patient with hemophilia A would use rehabilitation services. Joint disorders, arthropathies, bone and cartilage disorders, intracranial hemorrhage, and brain trauma were common diagnoses during rehabilitation use. The costs of physical therapy (physiotherapy comprised the majority (71.2% of rehabilitation therapy categories. Increasingly, rehabilitation therapy was performed at physician clinics. The total rehabilitation costs were <0.1% of the total annual medical costs.Musculoskeletal or nervous system-related surgical procedures and increased use of clotting factor VIII concentrate affect the rehabilitation utilization of patients with hemophilia A the most. The findings in this study could help clinicians comprehensively understand the rehabilitation utilization of patients with hemophilia A.

Pain Experience in Hemophilia Patients: A Hermeneutic Phenomenological Study

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Masoume Rambod

2016-10-01

Full Text Available Background: Pain, as a crucial subsequence of joint hemorrhages in hemophilia patients, is chronic, debilitating, and distracting. This study aimed to describe and interpret pain experiences of hemophilia patients in their lives. Methods: This qualitative study with hermeneutic phenomenological approach was conducted on fourteen hemophilia patients who had been referred to a hemophiliacenter affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The study question was “what is the meaning of pain in hemophilia patients’ lives? The data were collected through semi-structured interviews and field notes through purposeful sampling. Then, thematic analysis with van Manen’s six-step methodological framework was used. MAX.QDA qualitative software package, 2010, was used to analyze the data. Results: The three main themes that emerged in this study were “alteration in physical health”, “engagement in psychological problems”, and “impairment in social relationships”. Alteration in physical health consisted of three subthemes, namely “impairment of physical function”, “change in body physics”, and “disturbance in sleep quality”. In addition, two subthemes including “nostalgia of pain in adults with hemophilia” and “psychological distress” emerged from engagement in psychological problems. Finally, “loss of social activity” and “change in relationships” were related to impairment in social relationships. Conclusion: The present study highlighted alteration in physical health, engagement in psychological problems, and impairment in social relationship as a result of pain in hemophilia patients. Thus, healthcare providers and family members have to pay special attention to these problems. Besides, providing complementary therapy interventions is suggested for reducing these issues.

Therapeutic approaches for treating hemophilia A using embryonic stem cells.

Science.gov (United States)

Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

2016-06-01

Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

The influence of prophylactic factor VIII in severe hemophilia A

Science.gov (United States)

Gissel, Matthew; Whelihan, Matthew F; Ferris, Lauren A; Mann, Kenneth G; Rivard, Georges E; Brummel-Ziedins, Kathleen E

2013-01-01

Introduction Hemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Aim To evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)-initiated blood coagulation in severe hemophilia utilizing both empirical and computational models. Methods We investigated twenty-five clinically severe hemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact-pathway inhibited whole blood ± an anti-fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. Results Due to prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from hemophilia A. The combination of each individual's coagulation factors (outside of fVIII) determine each individual's baseline thrombin potential and may affect bleeding risk. PMID:21899664

Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A.

Science.gov (United States)

Young, G; Mahlangu, J; Kulkarni, R; Nolan, B; Liesner, R; Pasi, J; Barnes, C; Neelakantan, S; Gambino, G; Cristiano, L M; Pierce, G F; Allen, G

2015-06-01

Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of hemophilia A. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Novel, high incidence exercise-induced muscle bleeding model in hemophilia B mice

DEFF Research Database (Denmark)

Tranholm, M.; Kristensen, Annemarie Thuri; Broberg, M. L.

2015-01-01

INTRODUCTION: Muscle hematomas are the second most common complication of hemophilia and insufficient treatment may result in serious and even life-threatening complications. Hemophilic dogs and rats do experience spontaneous muscle bleeding, but currently, no experimental animal model is available...... specifically investigating spontaneous muscle bleeds in a hemophilic setting. AIM: The objective of this study was to develop a model of spontaneous muscle bleeds in hemophilia B mice. We hypothesized that treadmill exercise would induce muscle bleeds in hemophilia B mice but not in normal non-hemophilic mice...... and that treatment with recombinant factor IX (rFIX) before treadmill exercise could prevent the occurrence of pathology. METHODS: A total of 203 mice (123 F9-KO and 80 C57BL/6NTac) were included in three separate studies: (i) the model implementation study investigating the bleeding pattern in hemophilia B mice...

Optimization of prophylaxis for hemophilia A.

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Robert D Herbert

Full Text Available Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A.Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds.It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person's pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity.The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.

Hypocoagulability does not protect against atherosclerosis in hemophilia A patients with obesity

NARCIS (Netherlands)

Biere-Rafi, S.; Tuinenburg, A.; Haak, B.; Peters, M.; De Groot, E.; Verhamme, P.; Peerlinck, K.; Visseren, F.; Kruip, M.; Gorkom, B.L.-V.; Buller, H.; Gerdes, V.; Schutgens, R.; Kamphuisen, P.

Introduction: Hemophilia A patients have a 50% lower cardiovascular mortality than the general population. Whether this is caused by less atherosclerosis due to hypocoagulability is unclear. We assessed whether hemophilia A patients with obesity, a major atherosclerotic risk factor, have a lower

Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

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Raquel M. Fernández

2015-01-01

Full Text Available Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD. Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B. Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%, constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders.

Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

Science.gov (United States)

Fernández, Raquel M.; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Antiñolo, Guillermo

2015-01-01

Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders. PMID:26258137

Motivational techniques to improve self-care in hemophilia: the need to support autonomy in children.

Science.gov (United States)

Bérubé, Sarah; Mouillard, Florine; Amesse, Claudine; Sultan, Serge

2016-01-11

In pediatric hemophilia, caregivers are facing unique challenges to adherence and self-care in children and adolescents with hemophilia. Hemophilia treatment requires adequate prophylaxis and on-demand treatment, as well as a clear behavioral strategy to limit risk-taking in terms of physical exercise and diet. Medication adherence rates of hemophilia patients have been reported to decrease during late childhood and adolescence. In the developing child, moving safely from parent-care to self-care is one of the greatest challenges of integrative care within this domain. There is a clear need for initiatives designed to increase an individual's motivation for treatment and self-care activities. Among motivational approaches, the self-determination perspective offers a useful framework to explain how the transition to self-care can be facilitated. We discuss how motivation regarding hemophilia treatment may be increased through parental autonomy support and we offer examples of applied communication techniques to facilitate autonomy-supportive caregiving. Although it has not yet been tested in the context of hemophilia, these communication techniques could potentially help caregivers promote adherence and self-care in children. Confronted by unique challenges to adherence and self-care, caregivers of children with hemophilia should move from an exclusive focus on illness-management education to an integrative strategy, including motivation-enhancing communication. The self-determination perspective provides important proximal objectives (e.g. autonomy support) to maintain optimal adherence in adolescents as they move from parent-care to self-care. Future research initiatives should address the practice of these communication techniques and evaluate them in the context of hemophilia.

New developments in the management of moderate-to-severe hemophilia B

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Nazeef M

2016-04-01

Full Text Available Moniba Nazeef,1,2 John P Sheehan1,2 1Department of Medicine, Division of Hematology/Oncology, 2UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Abstract: Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP represent fusion proteins with the immunoglobulin G1 (IgG1 Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin

Hemophilia A. Considerations for dental management of pediatric patients.

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Sonia López-Villareal

2016-12-01

Full Text Available It comes to consulting the Faculty of Dentistry at the University of Nuevo León pediatric male patient of 9 years 10 months, who was admitted with a presumptive diagnosis of hemophilia due to a subsequent persistent bleeding to treatment with steel crowns made in an earlier appointment. Interconsultation is performed with the hematologist who by laboratory examinations notice decreased coagulation factor VIII confirming the diagnosis of hemophilia A. It plans and conducts comprehensive treatment dental team with the hematologist who said that patients in hospitals with the replacement of missing clotting factor is prepared by cryo precipitates or with concentrated factor VIII intravenously before and after his dental intervention. The aim of the article is to highlight that hemophilia can be a disease detected during dental surgery in some patients and for it to be successfully treated with multidisciplinary management protocol is required between hematologists and dentists.

A Case of Hemophilia A Associated with Spontaneous Hemorrhagic Pleural Effusion and Intracranial Hem

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Nuri Tutar

2014-03-01

Full Text Available Hemophilia A is a sex-linked recessive coagulation disorder almost exclusively occurring in male subjects and caused by a deficiency of factor VIII. It  is a rare disorder characterized by spontaneous hemorrhages. Spontaneous bleeding in the pleural space is very rare in hemophilia both in children and adults. Here in, we present the case of a 56-year-old hemophilia A patient with hemorrhagic pleural effusion and intracranial hematoma.

Micronucleus evaluation for determining the chromosomal breakages after radionuclide synovectomy in patients with hemophilia

International Nuclear Information System (INIS)

Kavakli, K.; Cogulu, O.; Karaca, E.

2012-01-01

To investigate the genotoxic effects of 90 Y and 186 Re in patients with hemophilia who were undergoing radionuclide synovectomy (RS) procedure in the last 3 years. Nineteen patients were enrolled in the study. Most of the patients (n=17) were hemophilia-A (mean age 20.6±10.5 years) and 18 patients (mean age 22.6±10.6 years) with hemophilia who were not exposed to RS procedure were included in the study as control group. Most cases in the control group (n=13) were hemophilia-A. 90 Y for knee joints and 186 Re for elbow or ankle joints were used to perform RS in hemophilic patients. We studied the micronucleus (MN) test on peripheral blood lymphocytes as an indicator of radiation-induced cytogenetic damage and calculated nuclear division index. There was no significant difference between the patients with and without RS with respect to MN values. However, both values obtained in RS-exposed patients and control group were much elevated than values reported in literature from healthy controls. The mean MN values of patients below 20 years old were much lower but not significant than those above 20 years old. MN frequencies between 186 Re and 90 Y groups were also analyzed, and no significant difference was observed. Hemophilia patients who were treated with 186 Re showed higher levels of MN compared to patients treated with 90 Y although the difference was not significant. Radioisotope synovectomy (RS) seems to be a safe procedure not causing a significant genotoxic effect on hemophilic patients, however, further studies including larger series of patients are needed to better understand the effects of RS on patients' health. (author)

Atherosclerotic Heart Disease: Prevalence and Risk Factors in Hospitalized Men with Hemophilia A

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Ragni, Margaret V.; Moore, Charity G.

2011-01-01

Summary Background Atherosclerotic heart disease (ASHD) is a common cause of morbidity and mortality in Western society. Few studies have determined prevalence and predictors of ASHD in hemophilia (HA), a population whose survival is improving with safer blood products and effective treatments for AIDS and hepatitis C. Objectives The purpose of this study was to determine prevalence and factors associated with ASHD in hemophilia A patients in Pennsylvania. Methods The prevalence of ASHD (myocardial infarction, angina, coronary disease), cardiac catheterization, coronary angiography, co-morbidities, and in-hospital mortality were assessed on statewide ASHD discharge data, 2001–2006, from the Pennsylvania Health Care Cost Containment Council (PHC4). Results The prevalence of hemophilia ASHD admissions fluctuated between 6.5% and 10.5% for 2001 to 2006, p=0.62. Compared to HA without ASHD, HA with ASHD were older and more likely to be hypertensive, hyperlipidemic, and diabetic, all pHemophilia patients with ASHD have similar cardiovascular risk factors, admitting diagnoses, severity of illness, and in-hospital mortality as the general population. These findings suggest cardiovascular prevention measures should be promoted in hemophilia. PMID:21371197

INSIGHT in risk factors and treatment of inhibitors in nonsevere hemophilia A

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van Velzen, A.S.

2016-01-01

Hemophilia A is an inherited X-linked bleeding disorder that occurs in male offspring of carrier females. In these individuals a mutation in the F8 gene, located on the X-chromosome, causes a deficiency of the factor VIII protein, clotting factor VIII. The worldwide prevalence of hemophilia is 1 in

Mortality caused by intracranial bleeding in non-severe hemophilia A patients: reply

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Loomans, J. I.; Fijnvandraat, K.

2017-01-01

With great interest we read the letter of Dr. Patil et al. (1) in which they present the number and percentage of hemophilia patients registered in the Mumbai hemophilia center who died from (intracranial) bleeding between 2002 and 2015. We thank Dr. Patil et al. for sharing their data and for

Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

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Franchini, Massimo; Lippi, Giuseppe

2016-12-01

Thanks to considerable progresses made over the last 30years, hemophilia benefits from the most efficacious and safe treatment among the many monogenic inherited disorders. The most challenging complication of replacement therapy in hemophilia A is the occurrence of alloantibodies against infused factor VIII (FVIII), thus predisposing the patients to increased morbidity and disability. Extensive research in this field has definitively unraveled that development of inhibitors in hemophilia A is a complex and multifactorial process, in which inherited and environmental factors dynamically interact. This narrative review, after providing a concise overview about the main genetic and non-genetic risk factors, is aimed to focus on prediction risk models and preventive strategies for minimizing the risk of developing inhibitors in hemophilia A patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity.

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El-Asrar, Mohamed Abo; Hamed, Ahmed El-Saeed; Darwish, Yasser Wagih; Ismail, Eman Abdel Rahman; Ismail, Noha Ali

2016-01-01

A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).

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Gringeri, A; Lundin, B; von Mackensen, S; Mantovani, L; Mannucci, P M

2011-04-01

Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 × week) or episodic therapy with ≥25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. © 2011 International Society on Thrombosis and Haemostasis.

Arthroscintigraphy with sup(99m)Tc in children with hemophilia

International Nuclear Information System (INIS)

Boyadzhiev, P.; Ignatov, A.; Nin'o, Sh.

1976-01-01

Recurrent haemarthroses are one of the most characteristic features of hemophilia during childhood. With the aid of sup(99m)Tc-pertechnetate arthroscintigraphy was carried out in 30 children with hemophilia between 5 and 15 years of age. The 79 articulations under investigation included 42 knee-, 13 elbow- and 24 ankle-joints. The results were compared with the scanograms of 30 normal joints, the activity of the isotope varying between 89% and 130%. Among 19 joints affected by acute haemarthrosis, 11 revealed severe changes while in chronic arthropathy, 50% of the changes proved to be slight which was disclosed with the aid of scintigraphy. There is some dependence between the severity of the changes, the grade of AHG and the frequence of haemarthroses, the latter correlating with the age factor. Arthroscintigraphy is a valuable diagnostic method above all in establishing the presence of an active inflammatory process among the destructive changes in the joints of children with hemophilia. (author)

Potential role of a new PEGylated recombinant factor VIII for hemophilia A

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Wynn TT

2016-06-01

Full Text Available Tung Thanh Wynn,1 Burak Gumuscu,2,3 1Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Florida, Gainesville, FL, 2Pediatric Hematology-Oncology, Bon Secours Health System, St. Mary’s Hospital, Richmond, VA, 3Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Virginia, Charlottesville, VA, USA Abstract: Hemophilia A, a deficiency in the activity of coagulation factor (F VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing ­activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half

Progress in the contemporary management of hemophilia: The new issue of patient aging.

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Mannucci, Pier Mannuccio; Iacobelli, Massimo

2017-09-01

The management of inherited coagulation disorders such as hemophilia A and B has witnessed dramatic progresses since the last few decades of the last century. Accordingly, persons with hemophilia (PWH) now enjoy a life expectancy at birth not different from that of males in the general population, at least in high income countries. Nowadays, a substantial proportion of PWH are aging, like their peers in the general population. This outstanding progress is accompanied by problems that are in part similar to those of any old person (multiple concomitant diseases and the resulting intake of multiple drugs other than those specific for hemophilia treatment). In addition, older PWH suffer from the consequences of the comorbidities that developed when their treatment was at the same time poorly available and unsafe. Typical hemophilia comorbidities affect the musculoskeletal system following joint and muscle bleeds, but also the liver and kidney are often impaired due to previous bloodborne infections such as viral hepatitis and HIV. Thus, the comorbidities of hemophilia superimposed on the multimorbidity and polypharmacy associated with aging create peculiar problems in the current management of these patients, that demand the coordinated holistic intervention of internists, geriatricians and clinical pharmacologists in addition to the care traditionally provided by pediatricians and hematologists. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Inhibitor development in nonsevere hemophilia A

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Eckhardt, C.L.

2014-01-01

Hemophilia A is an X-linked inherited bleeding disorder that affects approximately 1 in 5000 male live births. It is caused by a deficient plasma level of clotting factor VIII and can be treated by the intravenous administration of factor VIII concentrates. A severe complication of the treatment

Strategies to encourage physical activity in patients with hemophilia to improve quality of life

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Goto M

2016-05-01

Full Text Available Miwa Goto,1 Hideyuki Takedani,2 Kazuhiko Yokota,1 Nobuhiko Haga3 1Rehabilitation Center, The University of Tokyo Hospital, 2Department of Joint Surgery, Research Hospital of the Institute of Medical Science, The University of Tokyo, 3Department of Rehabilitation Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Abstract: Hemophilia is a bleeding disorder caused by a congenital abnormality of blood coagulation. Until the mid-1970s, patients with hemophilia (PWH were advised to refrain from physical activity (PA because of a perceived increased risk of bleeding. Since then, PA, which is recognized as being essential for health maintenance, is now recommended by the World Federation of Hemophilia. Moreover, a number of studies reported that PA can improve treatment efficacy and prevent bleeding in PWH. Physical assessment and intervention in PA are currently used in clinical practice. However, the necessity of PA is not emphasized, and many PWH generally have low- to- no PA. Therefore, a behavior change approach to encourage patient motivation is becoming ever more important. In this article, we review articles addressing PA in PWH and discuss strategies to encourage PA through a behavior change approach by focusing on factors relevant to hemophilia, such as benefits and bleeding risk of PA, risk management of bleeding, PA characteristics, and difficulty with exercise adherence. The trust relationship between clinicians and patients, a transtheoretical model of behavior change, and motivation theory as approaches to promote PA are introduced. Finally, we review a case report of the clinical success of a behavior change approach to promote PA. Many PWH find it difficult to continue PA because of aging, fear of bleeding, insufficient recognition of PA benefits, and psychological problems. Therefore, it is essential and important to perform prophylaxis with PWH and to heighten their understanding of the benefits and risks of

Antihemophilic factor (recombinant plasma/albumin-free method for the management and prevention of bleeding episodes in patients with hemophilia A

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Steven Pipe

2009-02-01

Full Text Available Steven PipeDepartment of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USAAbstract: Hemophilia is a rare genetic bleeding disorder that, if not adequately controlled, is associated with life-threatening bleeding events and serious and costly complications, primarily from joint damage. The advent of effective clotting factor replacement therapy for patients with hemophilia is considered one of the foremost medical advances of the 20th century. The last 3 decades of experience in hemophilia care have witnessed the effectiveness of the care of patients with hemophilia within specialized comprehensive care centers, advances in factor replacement therapies, the benefits of prophylaxis over on-demand replacement therapy, and the role of aggressive management of joint disease to prevent dysfunction. Ongoing challenges, including the management of inhibitors to factor therapies and the consequences of thousands of patients with hemophilia becoming infected with human immunodeficiency virus and hepatitis C virus in the 1980s from contaminated plasma-derived factor concentrates, have highlighted the need for vigilance with respect to clotting factor product safety, access to care, and a full complement of choice of factor replacement therapies. Advate® (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM] is the first recombinant factor VIII therapy manufactured without human or animal protein additives to eliminate the risk of pathogen transmission that could be carried by these additives. Preclinical studies established bioequivalence with recombinant antihemophilic factor (Recombinate®, a product with 16 years of clinical experience. Currently licensed in 44 countries worldwide, rAHF-PFM has over 7 years of clinical research within 5 global studies supporting its safety and efficacy in the treatment of patients with hemophilia A.Keywords: factor VIII, hemophilia A, recombinant proteins, clinical

DESCRIPTIVE EPIDEMIOLOGY OF HEMOPHILIA AND OTHER COAGULATION DISORDERS IN MANSOURA , EGYPT

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Rasha ElAshry

2010-08-01

–30%, moderate if 1–5% and severe if <1% of normal.

 The severe presentation represents the majority in 76.7% followed by moderate severity in 17.2%.The commonest IBDs was hemophilia A affecting 44 patients, followed by Hemophilia B affecting 15 patients. The rare types were Factor XI deficiency, Factor V deficiency, Factor VII deficiency and combined  FVIII, FIX and FX deficiency. The commonest orthopedic manifestation needing therapy was found among hemophilia A representing 8.3%. Hepatitis C viremia detected by PCR was found in 11.1% of patients. The bleeding complications as hematoma or hemarthrosis were the common complications. Nevertheless, 44.4% of patients had no complications,

 From this study we can conclude that the most common IBDs in our locality is hemophilia A followed by hemophilia B. The common presenting symptom was bleeding following male circumcision. Hepatitis C infection and arthropathy represented the main complications. The discovery of IBDs in young age children with proper supportive therapy could prevent arthropathy. Proper screening of blood and blood products reduce the risk of viral hepatitis and HIV acquisition.

Hemophilia: The Role of the School Nurse.

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Damiano, Mary Lou; And Others

1980-01-01

Care of the school student with hemophilia requires a cooperative effort by the health care team. A multidisciplinary approach is suggested for the team, whose members include a hematologist, orthopedist, oral surgeon, geneticist, physical therapist, social worker, and school nurse. (JD)

Consensus Review of the Treatment of Cardiovascular Disease in People With Hemophilia A and B

Science.gov (United States)

Boral, Leonard I.; Cohen, Alice J.; Smyth, Susan S.; White, Gilbert C.

2015-01-01

With advances in care, increasing numbers of people with hemophilia (PWH) achieve near-normal life expectancies and present with typical age-related cardiovascular conditions. Evidence-based guidelines for medical or surgical management of cardiovascular conditions in individuals with hemophilia are limited. Published recommendations exist for the management of some common cardiovascular conditions (eg, ischemic heart disease, atrial fibrillation), but identifying optimal strategies for anticoagulant or antithrombotic therapy constitutes the primary challenge of managing nonoperative cardiovascular disease (CVD) in PWH. In general, as long as factor concentrates or other hemostatic therapies maintain adequate hemostasis, the recommended medical and surgical management of CVD in PWH parallels that in individuals without hemophilia. The presence of factor inhibitors complicates hemophilia management. Published outcomes of CVD treatment in PWH are similar to those in the general population. Specific knowledge about factor replacement, factor inhibitors, and disease-specific treatment distinguishes the cardiovascular care of PWH from similar care of individuals without this rare bleeding disorder. Furthermore, a multidisciplinary approach incorporating a hematologist with an onsite coagulation laboratory, ideally associated with a hemophilia treatment center, is integral to the management of CVD in PWH. PMID:25436468

Interventions for treating acute bleeding episodes in people with acquired hemophilia A.

Science.gov (United States)

Zeng, Yan; Zhou, Ruiqing; Duan, Xin; Long, Dan; Yang, Songtao

2014-08-28

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation factor VIII (FVIII). In most cases, bleeding episodes are spontaneous and severe at presentation. The optimal hemostatic therapy is controversial. To determine the efficacy of hemostatic therapies for acute bleeds in people with acquired hemophilia A; and to compare different forms of therapy for these bleeds. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 4) and MEDLINE (Ovid) (1948 to 30 April 2014). We searched the conference proceedings of the: American Society of Hematology; European Hematology Association; International Society on Thrombosis and Haemostasis (ISTH); and the European Association for Haemophilia and Allied Disorders (EAHAD) (from 2000 to 30 April 2014). In addition to this we searched clinical trials registers. All randomised controlled trials and quasi-randomised trials of hemostatic therapies for people with acquired hemophilia A, with no restrictions on gender, age or ethnicity. No trials matching the selection criteria were eligible for inclusion. No trials matching the selection criteria were eligible for inclusion. No randomised clinical trials of hemostatic therapies for acquired hemophilia A were found. Thus, we are not able to draw any conclusions or make any recommendations on the optimal hemostatic therapies for acquired hemophilia A based on the highest quality of evidence. GIven that carrying out randomized controlled trials in this field is a complex task, the authors suggest that, while planning randomised controlled trials in which patients can be enrolled, clinicians treating the disease continue to base their choices on alternative, lower quality sources of evidence, which hopefully, in the future, will also be appraised and incorporated in a Cochrane Review.

Advanced therapies for the treatment of hemophilia: future perspectives.

Science.gov (United States)

Liras, Antonio; Segovia, Cristina; Gabán, Aline S

2012-12-13

Monogenic diseases are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in protein expression that result from genetic mutation. In hemophilia A and B such alterations affect the activity of coagulation factors VIII and IX, respectively, and are responsible for the development of the disease. Advanced therapies may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional, structural or transport protein (gene therapy); the incorporation of a full array of healthy genes and proteins through perfusion or transplantation of healthy cells (cell therapy); or tissue transplantation and formation of healthy organs (tissue engineering). For their part, induced pluripotent stem cells have recently been shown to also play a significant role in the fields of cell therapy and tissue engineering. Hemophilia is optimally suited for advanced therapies owing to the fact that, as a monogenic condition, it does not require very high expression levels of a coagulation factor to reach moderate disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy (by using viral and non-viral vectors) and cell therapy (by means of several types of target cells). Thus, although still considered a rare disorder, hemophilia is now recognized as a condition amenable to gene therapy, which can be administered in the form of lentiviral and adeno-associated vectors applied to adult stem cells, autologous fibroblasts, platelets and hematopoietic stem cells; by means of non-viral vectors; or through the repair of mutations by chimeric oligonucleotides. In hemophilia, cell therapy approaches have been based mainly on transplantation of healthy cells (adult stem cells or induced pluripotent cell-derived progenitor cells) in order to restore alterations in coagulation factor expression.

The Patient Experience of Hemophilia and Human Immunodeficiency Virus: A Systematic Review of Qualitative Evidence.

Science.gov (United States)

Omura, Kayoko; Tsuchiya, Sayaka

The objective of this review is to describe and synthesize the experiences and perspectives of illness for patients living with both hemophilia and human immunodeficiency virus (HIV). Hemophilia is an inherited bleeding disorder caused by low concentrations of specific coagulation factors. There are two major types of this condition characterized by deficiencies of factor VIII (hemophilia A) and factor IX (hemophilia B). Bleeding occurs in hemophilia owing to failure of secondary hemostasis. The bleeding tendency is related to the measured concentration of the factor and is classified as mild, moderate, or severe. Severe hemophilia A and B is classified as repeated (as often as weekly) bleeds into joints and muscles. The main treatment is to arrest spontaneous and traumatic bleeds by prophylactic injection of factor concentrates or to prevent injury by restriction of exercise. Most people with severe hemophilia are on therapy at home with intravenous infusion of the relevant missing factor. Joint bleeds are painful, and the build up of blood is irritating to the synovial lining and damages joint tissue, so that adherence to hemophilia therapy is important.Global research in 18 countries reported that compliance with therapy by patients with hemophilia was low with self-injection adherence under 75% with as few as 53-65% of adults complying with therapy. Some of the most frequently cited factors affecting patients' compliance to therapy are as follows; inability to understand potential benefits (75%); denial (67%); interference with life style (62%); and lack of time (42%).The self-injection method of administering coagulation products became popular in the 1970s. In the early 1980s, 1,432 patients with hemophilia in Japan were infected with HIV (human immunodeficiency virus) because of the use of untreated blood products contaminated with the HIV virus. In addition commercial factor concentrates, which are prepared from pools of 2 to 6000 liters of plasma obtained

Hemophilia A in Brazil – epidemiology and treatment developments

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Ferreira AA

2014-09-01

Full Text Available Adriana Aparecida Ferreira,1 Isabel Cristina Gonçalves Leite,2 Maria Teresa Bustamante-Teixeira,2 Maximiliano Ribeiro Guerra2 1Foundation and Center for Hematology and Hemotherapy of Minas Gerais (Hemominas, 2Department of Collective Health, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, BrazilAbstract: Hemophilia A is an inherited disorder characterized by deficiency of coagulation factor VIII, which predisposes patients to bleeding events. Treatment is based on replacement of the deficient factor, in a therapeutic or prophylactic manner. Brazil is the country with the third largest population of people with hemophilia, for which the public health system provides free comprehensive care. Maintaining an updated registry of patients, documenting the prevalence of complications, and assessing the effectiveness of resource use are indispensable elements in the design of a well-coordinated national program. According to sociodemographic, clinical, and laboratory data collected by the computerized Brazilian system on coagulopathies, in June 2013, there were 9,122 registered patients with hemophilia A in Brazil, of which 36.1% had a severe form of the disease. Clotting factor inhibitors were present in 7.5%, but 25.7% of records did not provide this type of data. Around 70% of the patients belonged to the economically active population, being between 15 and 59 years old. Infection by the human immunodeficiency virus was present in 23.4% of the patients tested and infection by hepatitis C virus antibodies in 59.3%. Infection by the hepatitis B virus and human T-lymphotropic virus was also reported. The high percentage of incomplete records regarding serological data shows the fragility of the information system to date. There was also no information available on the prevalence of permanent or disabling joint damage. Although few hemophiliacs receive adequate care in developing countries, and despite Brazil exhibiting great social

Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

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Nicholas B. Abt

2014-01-01

Full Text Available Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient’s plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered.

Bruising and Hemophilia: Accident or Child Abuse?

Science.gov (United States)

Johnson, Charles F.; Coury, Daniel L.

1988-01-01

Two case histories illustrate the difficulty in evaluating abuse/neglect in children with bleeding problems such as hemophilia. Discussed are guidelines for diagnosis and prevention of abuse, including: screening techniques, the need for protection from environmental trauma, parental stress, evaluation of parents' disciplinary methods, and the…

Analysis of factor VIII gene inversions in 164 unrelated hemophilia A families

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Vnencak-Jones, L.; Phillips, J.A. III; Janco, R.L. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)] [and others

1994-09-01

Hemophilia A is an X-linked recessive disease with variable phenotype and both heterogeneous and wide spread mutations in the factor VIII (F8) gene. As a result, diagnostic carrier or prenatal testing often relies upon laborious DNA linkage analysis. Recently, inversion mutations resulting from an intrachromosomal recombination between DNA sequences in one of two A genes {approximately}500 kb upstream from the F8 gene and a homologous A gene in intron 22 of the F8 gene were identified and found in 45% of severe hemophiliacs. We have analyzed banked DNA collected since 1986 from affected males or obligate carrier females representing 164 unrelated hemophilia A families. The disease was sporadic in 37%, familial in 54% and in 10% of families incomplete information was given. A unique deletion was identified in 1/164, a normal pattern was observed in 110/164 (67%), and 53/164 (32%) families had inversion mutations with 43/53 (81%) involving the distal A gene (R3 pattern) and 10/53 (19%) involving the proximal A gene (R2 pattern). While 19% of all rearrangements were R2, in 35 families with severe disease (< 1% VIII:C activity) all 16 rearrangements seen were R3. In 18 families with the R3 pattern and known activities, 16 (89%) had levels < 1%, with the remaining 2 families having {le} 2.4% activity. Further, 18 referrals specifically noted the production of inhibitors and 8/18 (45%) had the R3 pattern. Our findings demonstrate that the R3 inversion mutation patterns is (1) only seen with VIII:C activity levels of {le} 2.4%, (2) seen in 46% of families with severe hemophilia, (3) seen in 45% of hemophiliacs known to have inhibitors, (4) not correlated with sporadic or familial disease and (5) not in disequilibrium with the Bcl I or Taq I intron 18 or ST14 polymorphisms. Finally, in families positive for an inversion mutation, direct testing offers a highly accurate and less expensive alternative to DNA linkage analysis.

A Case of Heel Reconstruction with a Reverse Sural Artery Flap in a Hemophilia B Patient

Directory of Open Access Journals (Sweden)

Byung Kwon Lee

2012-03-01

Full Text Available Hemophilia B is a rare blood coagulation disorder. Complications such as bleeding and hematoma can cause necrosis of flaps, wound disruption, and the disturbance of wound healing. In particular, guidelines for flap operations in hemophilia B patients have still not been defined, and case reports are rare. We reconstructed the heel of a 41-year-old male hemophilia B patient using a reverse sural artery flap operation. The patient presented with mild hemophilia, having 27% of the normal value of coagulation factor IX. Coagulation and the changing value of the coagulation factor were regularly measured, and 70% of the normal value of coagulation factor IX was maintained through the injection of recombinant coagulation factors and antihemorrhagics. Hematoma developed twice (postoperative day [POD] 5 and POD 7 and in each case the hematoma was removed. Injections of recombinant coagulation factors and antihemorrhagics were continuously administered until postoperative week 2. When the coagulation factors were within normal ranges. In this article, a hemophilia B patient underwent reverse sural artery flap surgery and the healing progress was analyzed. We conclude that higher than baseline levels of coagulation factors are needed for successful healing in reverse sural artery flap surgery.

Using the Hemophilia Joint Health Score for assessment of children: Reliability of the Spanish version.

Science.gov (United States)

R, Cuesta-Barriuso; A, Torres-Ortuño; S, Pérez-Alenda; J, Carrasco Juan; F, Querol; J, Nieto-Munuera; Ja, López-Pina

2018-02-27

Numerous measuring instruments for the evaluation of hemophilic arthropathy have been developed. One of the most used systems is the Hemophilia Joint Health Score (HJHS) given its sensitivity to clinical changes appearing in the joints because of recurrent hemarthrosis. Assessing the interrater reliability, using the Spanish version of the HJHS (version 2.1) in children with hemophilia. Reliability study to assess the interrater reliability of the Spanish version of HJHS. A sample of 36 children aged 7-13 years diagnosed with hemophilia A or B was used. Two physiotherapists performed physical assessments with the Spanish version of the HJHS. Descriptive statistics (range, mean, standard deviation) and the analysis of interrater reliability were calculated. The interrater reliability was heterogeneous since the Kappa coefficient range (ĸ), although significant (p reliability of the Spanish population version of the HJHS is high. This scale should be used generically in evaluating musculoskeletal pediatric patients with hemophilia.

[Analysis of individualized primary prophylactic treatment of 19 cases of children with severe hemophilia A].

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Liu, G Q; Tang, L; Wu, X Y; Zhen, Y Z; Li, G; Chen, Z P; Wang, Y; Zhang, N N; Zhang, J S; Yu, G X; Wu, R H

2016-12-02

Objective: To study the current situation of primary prophylaxis in severe hemophilia A children and to explore rational regimen in order to provide evidence for the development of primary prophylaxis in China. Method: A retrospective clinical data collection and analysis was conducted for 19 severe hemophilia A children who received primary prophylaxis in Beijing Children's Hospital outpatient clinic between February 2011 and September 2015 and evaluated the regimen and efficacy. Result: (1) Primary prophylaxis regimen: the median beginning age 1.8 (range 0.5-2.9) years, the median FⅧ preparation using dosage 16.7 (8.0-23.5) U/(kg·time), the median using frequency was 1.0 (1.0-3.0) time/week. Eight cases among the patients received escalation of treatment intensity because of the poor bleeding control. (2) Efficacy: the median annual bleeding rate (ABR) was 1.9 (0-6.0) times/year, the median annual joint bleeding rate (AJBR) was 0 (0-3.3) times/year, without life threatening bleeding. All of them kept in 4th scale of Beijing Children Hospital daily activity level. The median annual factor consumption was 1 844 (840-5 040) U/kg. Conclusion: Low-dose primary prophylaxis regimen which were in low-dose /low frequencies and adjusted by bleeding frequency could decrease bleeding and joint bleeding frequency significantly, maintained the normal daily activity capacity and saved the factor consumption compared to standard regimen in severe hemophilia A children.

Molecular genetics of hemophilia A: Clinical perspectives

African Journals Online (AJOL)

Azza A.G. Tantawy

Evaluation of an individual with a suspected bleeding disorder includes: platelet count .... information for genetic counseling of at-risk family members. It is indicated for ... Patients with blood group O and a low von Willebrand antigen level have a ..... [4] Husain N. Carrier analysis for hemophilia A: ideal versus acceptable.

Neonatal Gene Therapy for Hemophilia B by a Novel Adenovirus Vector Showing Reduced Leaky Expression of Viral Genes.

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Iizuka, Shunsuke; Sakurai, Fuminori; Tachibana, Masashi; Ohashi, Kazuo; Mizuguchi, Hiroyuki

2017-09-15

Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX). An adenovirus (Ad) vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX) (Ad-E4-122aT-AHAFIX) maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.

Progress and challenges in the development of a cell-based therapy for hemophilia A.

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Fomin, M E; Togarrati, P P; Muench, M O

2014-12-01

Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review, we discuss the possibilities, progress, and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific induced pluripotent stem cells. © 2014 International Society on Thrombosis and Haemostasis.

Progress and challenges in the development of a cell-based therapy for hemophilia A

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Fomin, Marina E.; Togarrati, Padma Priya; Muench, Marcus O.

2015-01-01

Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review we discuss the possibilities, progress and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells (iPSCs) that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific iPSCs. PMID:25297648

Factoring nonviral gene therapy into a cure for hemophilia A.

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Gabrovsky, Vanessa; Calos, Michele P

2008-10-01

Gene therapy for hemophilia A has fallen short of success despite several clinical trials conducted over the past decade. Challenges to its success include vector immunogenicity, insufficient transgene expression levels of Factor VIII, and inhibitor antibody formation. Gene therapy has been dominated by the use of viral vectors, as well as the immunogenic and oncogenic concerns that accompany these strategies. Because of the complexity of viral vectors, the development of nonviral DNA delivery methods may provide an efficient and safe alternative for the treatment of hemophilia A. New types of nonviral strategies, such as DNA integrating vectors, and the success of several nonviral animal studies, suggest that nonviral gene therapy has curative potential and justifies its clinical development.

Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A

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Yoshihashi, Kazutaka; Takeda, Minako; Kitazawa, Takehisa; Soeda, Tetsuhiro; Igawa, Tomoyuki; Sampei, Zenjiro; Kuramochi, Taichi; Sakamoto, Akihisa; Haraya, Kenta; Adachi, Kenji; Kawabe, Yoshiki; Nogami, Keiji; Shima, Midori; Hattori, Kunihiro

2014-01-01

ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required. PMID:25274508

Characterization of genetic defects of hemophilia A in patients of Chinese origin

Energy Technology Data Exchange (ETDEWEB)

Lin, Shu-Wha; Lin, Shu-Rung; Shen, Ming-Ching (National Taiwan Univ., Taipei (Taiwan, Province of China))

1993-12-01

The molecular characterization of hemophilia A of Chinese origin was carried out by the polymerase chain reaction (PCR) and direct sequencing of patient's factor VIII genes. Single-strand conformation polymorphism (SSCP) and dideoxy fingerprinting (ddF) were used as screening methods to detect mutated DNAs. A total of 102 individuals from 87 different families, including 10 patients (10 families) with mild-to-moderate and 92 patients (77 families) with severe hemophilia A, were analyzed by PCR-SSCP and PCR-ddF. Of the 87 independent cases, 40 revealed a single mutation in the coding regions of their factor VIII genes. These mutations include 21 with single base changes resulting in 8 nonsense and 13 missense codons, 16 with deletion or insertion of 1-11 nucleotides, and 3 with deletion of large DNA fragments. The frequency of 8 of the identified factor VIII polymorphisms or silent mutations was also determined among Chinese. The frequencies for codons 1241, 1269, and 2223 (the numbering system follows J. Gitschier et al., 1984, Nature 312: 326-330) were found to be different from those reported for other populations. As for the 47 severe cases whose mutational events were not readily detected by PCR-SSCP and PCR-ddF, the reverse transcriptase PCR method was applied. In 24 such cases analyzed, 17 were found to be of the [open quotes]intron 22 mutations[close quotes] as described by Naylor et al. (1992, The Lancet, 342: 1066-1067), accounting for 39% of Chinese patients with hemophilia A. 31 refs., 2 figs., 6 tabs.

Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B.

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Hansson, K M; Gustafsson, D; Skärby, T; Frison, L; Berntorp, E

2015-07-01

The present study was carried out to investigate the impact of FII levels, and their increase, on the hemostatic potential in plasma from hemophilia A and B patients with and without inhibitors. Recombinant human factor (F) II (rhFII) was added ex vivo to plasma from 68 patients with hemophilia A and B, with or without inhibitors. The hemostatic potential as measured by thrombin generation (calibrated automated thrombogram [CAT]) was focused on the endogenous thrombin potential (ETP) as it has been shown to correlate with the clinical phenotype of bleeding in hemophilia patients and has also been used to guide bypassing therapy in hemophilia patients with inhibitors before elective surgery. The factor eight inhibitor bypassing agent (FEIBA(®) ) was used as a reference to the clinical situation. The study shows that rhFII concentration-dependently increased ETP by a similar magnitude in hemophilia A and B, both with and without inhibitors. Compared with FEIBA, rhFII showed a shallower concentration-response curve. In both types of hemophilia 100 mg L(-1) of rhFII roughly doubled the ETP. A corresponding response was obtained by 0.5 U mL(-1) of FEIBA. These data support the theory that FII is one of the major components responsible for the efficacy of FEIBA. The data also indicate that rhFII may be useful, alone or in combination with other coagulation factors, in some of the conditions for which FEIBA is used today, although more data are needed to substantiate this. © 2015 International Society on Thrombosis and Haemostasis.

The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China.

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Wu, Runhui; Luke, Koon Hung

2017-11-01

Currently full dose prophylaxis is the standard of care in the treatment of hemophilia (World Federation of Hemophilia). However, the high costs prevent the use of standard or intermediate dose prophylaxis in China and other developing countries. Low dose prophylaxis would be a viable alternative treatment. At present global research data on the use of low dose prophylaxis is limited. Areas covered: Since 2007, China has been developing low dose prophylaxis as a high priority (90 % of moderate and severe hemophilia boys suffer joint disease by age 6 - 9). 11 studies were successfully conducted and published results showing evidence of the benefits of low dose prophylaxis to reduce joint bleeding. This new knowledge has been implemented into clinical practice in China. However the long-term outcome of arthropathy remains unclear and obstacles in execution exist. Expert commentary: In 2016, the first phenotype-based individualized prophylaxis study using four escalating low dose regimens on severe Chinese hemophilia A boys (China Individualized Prophylaxis Study (CHIP China)) launched. Using the previously published and imminent CHIP data, the goal for China is to establish an effective escalating low dose prophylaxis protocol for use in China as a standard of care.

Child-rearing practices toward children with hemophilia: The relative importance of clinical characteristics and parental emotional reactions

NARCIS (Netherlands)

Banis, Hendrika; Suurmeijer, Th.P.B.M.; van Peer, D.R.

This study addresses the relative importance of clinical characteristics of the child and parental emotional reactions, to child-rearing practices towards children who suffer from hemophilia. The variables were assessed in a Dutch sample of 108 zero-to-twelve-year-old boys with hemophilia and their

In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia.

Science.gov (United States)

Augustsson, Cecilia; Persson, Egon

2014-11-13

Successful competition of activated factor VII (FVIIa) with zymogen factor VII (FVII) for tissue factor (TF) and loading of the platelet surface with FVIIa are plausible driving forces behind the pharmacological effect of recombinant FVIIa (rFVIIa) in hemophilia patients. Thrombin generation measurements in platelet-rich hemophilia A plasma revealed competition for TF, which potentially could reduce the effective (r)FVIIa:TF complex concentration and thereby attenuate factor Xa production. However, (auto)activation of FVII apparently counteracted the negative effect of zymogen binding; a small impact was observed at endogenous concentrations of FVII and FVIIa but was virtually absent at pharmacological amounts of rFVIIa. Moreover, corrections of the propagation phase in hemophilia A required rFVIIa concentrations above the range where a physiological level of FVII was capable to downregulate thrombin generation. These data strongly suggest that rFVIIa acts independently of TF in hemophilia therapy and that FVII displacement by rFVIIa is a negligible mechanistic component. © 2014 by The American Society of Hematology.

Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study

Directory of Open Access Journals (Sweden)

Forsyth AL

2015-10-01

Full Text Available Angela L Forsyth,1 Michelle Witkop,2 Angela Lambing,3 Cesar Garrido,4 Spencer Dunn,5 David L Cooper,6 Diane J Nugent7 1BioRx, Cincinnati, OH, USA; 2Munson Medical Center, Traverse City, MI, USA; 3Henry Ford Hospital, Detroit, MI, USA; 4Asociacion Venezolana para la Hemofilia, Caracas, Venezuela; 5Center for Inherited Blood Disorders, Orange, CA, USA; 6Novo Nordisk Inc., Plainsboro, NJ, USA; 7Children’s Hospital of Orange County, Center for Inherited Blood Disorders, Orange, CA, USA Introduction: Severe hemophilia and subsequent hemophilic arthropathy result in joint pain and impaired health-related quality of life (HRQoL. Assessment of HRQoL in persons with hemophilia (PWH, including underlying factors that drive HRQoL differences, is important in determining health care resource allocation and in making individualized clinical decisions.Aim: To examine potential associations between HRQoL, pain interference, and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center and health care professional utilization.Methods: PWH (age ≥18 years from ten countries completed a 5-point Likert scale on pain interference over the previous 4 weeks, the EQ-5D-3L scale (mobility, usual activities, self-care, pain/discomfort, anxiety/depression including a health-related visual analog scale (0–100, coded as an 11-point categorical response.Results: Pain interference (extreme/a lot was higher in PWH aged >40 years (31% compared to those aged 31–40 years (27% or ≤30 years (21%. In an analysis of eight countries with home treatment, PWH who reported EQ-5D mobility issues were less likely to be employed (53% vs 79%, with no mobility issues. Median annual bleed frequency increased with worsening EQ-5D pain or discomfort. The percentage of PWH with inhibitors reporting visual analog scale scores of 80–90–100 was lower (20% than those without inhibitors (34%. Median bleed frequency increased with pain

Social participation of patients with hemophilia in the Netherlands

NARCIS (Netherlands)

Plug, Iris; Peters, Marjolein; Mauser-Bunschoten, Eveline P.; de Goede-Bolder, Arja; Heijnen, Lily; Smit, Cees; Willemse, Jose; Rosendaal, Frits R.; van der Bom, Johanna G.

2008-01-01

The introduction of replacement therapy in the 1960s has improved medical and social circumstances gradually. The availability of prophylactic treatment has further increased the possibilities of a "normal" life for patients with hemophilia. We examined whether social participation and

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

Science.gov (United States)

Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

2017-08-31

Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Efficacy of standard prophylaxis versus on-demand treatment with bayer's sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A.

Science.gov (United States)

Zhao, Yongqiang; Xiao, Juan; Yang, Renchi; Wu, Runhui; Hu, Yu; Beckmann, Horst; Wu, Junde; Hou, Qingsong; Sun, Jing

2017-04-01

In China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2× /wk). We sought to evaluate 3× /wk, standard-dose prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2-16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study. Patients received rFVIII-FS on demand for 12 weeks followed by a 12-week prophylaxis period (25 IU/kg 3× /wk). The primary efficacy endpoint was comparison of the annualized bleeding rate (ABR) of all bleeds in the prophylaxis versus on-demand phase. Additional variables included ABR of joint bleeds, school attendance/activity, daily activity, and hemophilia Joint Health Score (HJHS). Thirty patients (median age, 12 years) were treated and analyzed. Compared with on-demand treatment, prophylaxis reduced median (quartile [Q1; Q3]) ABR of all bleeds (57.5 [44.5; 73.9] vs 0 [0; 4.0]) and joint bleeds (34.5 [26.1; 56.5] vs 0 [0; 4.0]). Median (range) total HJHS improved after both the prophylaxis and on-demand phases (8.0 [0-48.0] and 11.0 [0-55.0], respectively) compared with baseline (16.0 [0-56.0]). School attendance/activity and daily activity improved with prophylaxis versus on demand. No inhibitors or treatment-related adverse events were reported. In this first prospective, standard-dose, secondary prophylaxis study in China, rFVIII-FS prophylaxis reduced bleeding and improved health outcomes versus on-demand treatment in children with severe hemophilia A.

An intronic mutation c.6430-3C>G in the F8 gene causes splicing efficiency and premature termination in hemophilia A.

Science.gov (United States)

Xia, Zunjing; Lin, Jie; Lu, Lingping; Kim, Chol; Yu, Ping; Qi, Ming

2018-06-01

: Hemophilia A is a bleeding disorder caused by coagulation factor VIII protein deficiency or dysfunction, which is classified into severe, moderate, and mild according to factor clotting activity. An overwhelming majority of missense and nonsense mutations occur in exons of F8 gene, whereas mutations in introns can also be pathogenic. This study aimed to investigate the effect of an intronic mutation, c.6430-3C>G (IVS22-3C>G), on pre-mRNA splicing of the F8 gene. We applied DNA and cDNA sequencing in a Chinese boy with hemophilia A to search if any pathogenic mutation in the F8 gene. Functional analysis was performed to investigate the effect of an intronic mutation at the transcriptional level. Human Splicing Finder and PyMol were also used to predict its effect. We found the mutation c.6430-3C>G (IVS22-3C>G) in the F8 gene in the affected boy, with his mother being a carrier. cDNA from the mother and pSPL3 splicing assay showed that the mutation IVS22-3C>G results in a two-nucleotide AG inclusion at the 3' end of intron 22 and leads to a truncated coagulation factor VIII protein, with partial loss of the C1 domain and complete loss of the C2 domain. The in-silico tool predicted that the mutation induces altered pre-mRNA splicing by using a cryptic acceptor site in intron 22. The IVS22-3C>G mutation was confirmed to affect pre-mRNA splicing and produce a truncated protein, which reduces the stability of binding between the F8 protein and von Willebrand factor carrier protein due to the loss of an interaction domain.

Severe neonatal subgaleal hemorrhage as the first presentation of hemophilia A.

Science.gov (United States)

Radovanović, Tanja; Spasojević, Slobodan; Stojanović, Vesna; Doronjski, Aleksandra

2016-01-01

Subgaleal hemorrhage is a rare but potentially fatal birth trauma. It is caused by rupture of the emissary veins (connections between the dural sinuses and scalp veins), followed by the accumulation of blood between the epicranial aponeurosis and the periosteum. Usually, it is associated with instrumental delivery (vacuum extraction, forceps delivery), but it may also occur spontaneously, suggesting the possibility of congenital bleeding disorder. A full term male neonate was born at 40 weeks gestation by spontaneous vaginal delivery, with birth weight of 3,700 g. The Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At the age of 23 hours, the baby became pale and lethargic. Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered. Follow-up and further evaluation revealed hemophilia A as a result of a de novo mutation. This case illustrates that subgaleal hemorrhage may be the first presentation of hemophilia A. Infants without obvious risk factors for developing subgaleal hemorrhage should be evaluated for congenital bleeding disorder. Successful outcome in affected infants requires early diagnosis, careful monitoring and prompt treatment.

Molecular genetics of hemophilia A: Clinical perspectives | Tantawy ...

African Journals Online (AJOL)

Since the publication of the sequence of the factor VIII (F8) gene in 1984, a large number of mutations that cause hemophilia A have been identified and a significant progress has been made in translating this knowledge for clinical diagnostic and therapeutic purposes. Molecular genetic testing is used to determine the ...

Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

Science.gov (United States)

Mahlangu, Johnny; Powell, Jerry S.; Ragni, Margaret V.; Chowdary, Pratima; Josephson, Neil C.; Pabinger, Ingrid; Hanabusa, Hideji; Gupta, Naresh; Kulkarni, Roshni; Fogarty, Patrick; Perry, David; Shapiro, Amy; Pasi, K. John; Apte, Shashikant; Nestorov, Ivan; Jiang, Haiyan; Li, Shuanglian; Neelakantan, Srividya; Cristiano, Lynda M.; Goyal, Jaya; Sommer, Jurg M.; Dumont, Jennifer A.; Dodd, Nigel; Nugent, Karen; Vigliani, Gloria; Luk, Alvin; Brennan, Aoife

2014-01-01

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128. PMID:24227821

Hemophilia in childhood: the impact of the disease on parent's participation in their child's education

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Fabiane de Amorim Almeida

2008-09-01

Full Text Available Objectives: To identify the limitations faced by the hemophiliac child, according to his/her parents, and how they deal with these limitations, and to verify how parents approach the problem of hemophilia with the child as well as their strategies for disciplining that child and their nonhemophiliac children. Methods: An exploratory descriptive research study with a quantitative approach carried out with 20 parents of hemophiliac children seen at the ambulatory of a medium size public hospital in the city of São Paulo. The data were collected by means of a structured interview, using a form with open-ended and closed questions. Rresults: All the parents (20; 100% reported talking to their children about hemophilia, especially as to the definition of the disease (19; 46,35% and the activities that should be avoided (eight; 19.50%. Most of them (17; 85% also reported talking about hemophilia with their other children. Eighteen parents (90% restricted participation in sports and physical activities for their hemophiliac child, including at school: 11 (55% prohibit participation in physical activities, and 12 (60% ban extracurricular activities. All the parents also reported raising the subject of their child’s hemophilia with the educational professionals at their child’s school. As to discipline, half of them (ten; 50% use different strategies for disciplining their hemophiliac and non-hemophiliac children. Cconclusions: All the parents are concerned with discussing the subject of hemophilia with the child, his/her siblings, and teachers at school, imposing limitations especially as to participation in sports and/or physical activities. Differences were noted as to the strategies used by the parents for the discipline of their hemophiliac and non-hemophiliac children.

Leopold: the "bleeder prince" and public knowledge about hemophilia in Victorian Britain.

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Rushton, Alan R

2012-07-01

Hemophilia is a rare bleeding disorder inherited by males born of unaffected female carriers of the trait. British physicians became knowledgeable about this hereditary disease early in the nineteenth century as they investigated families transmitting the character through several generations. Prince Leopold (b. 1853), the fourth son of Queen Victoria, experienced recurrent bleeding episodes and was diagnosed with hemophilia during childhood. His hemorrhagic attacks were first described in the medical journals during 1868, and subsequently in the London and provincial newspapers. The royal family carefully managed news about health matters, and many newspapers reported widespread public sympathy for the travails of the queen and her children. But the republican press argued that the disaffected working classes resented the hyperbole connecting the health of royal individuals with the political future of the entire nation. Public discussion of hemophilia transformed it from a rare medical phenomenon to a matter of national news. Practicing physicians, the royal family, and the general public all came to understand the clinical features and the hereditary nature of the problem. Members of the royal family subsequently utilized this information to guide the marriages of their own children to prevent the spread of this dreaded bleeding disorder.

In Vivo Gene Therapy of Hemophilia B: Sustained Partial Correction in Factor IX-Deficient Dogs

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Kay, Mark A.; Rothenberg, Steven; Landen, Charles N.; Bellinger, Dwight A.; Leland, Frances; Toman, Carol; Finegold, Milton; Thompson, Arthur R.; Read, M. S.; Brinkhous, Kenneth M.; Woo, Savio L. C.

1993-10-01

The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done in a hemophilia B dog model. When the canine factor IX complementary DNA was transduced directly into the hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting. factor resulted in reductions of whole blood clotting and partial thromboplastin times of the treated animals. Thus, long-term treatment of hemophilia B patients may be feasible by direct hepatic gene therapy in vivo.

Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus

DEFF Research Database (Denmark)

Iversen, Astrid K N; Christiansen, Claus Bohn; Attermann, Jørn

2003-01-01

The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in approximately 2% of the Scand......The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in approximately 2...

Myositis ossificans in hemophilia

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Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

1981-10-01

A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition.

Myositis ossificans in hemophilia

International Nuclear Information System (INIS)

Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

1981-01-01

A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition. (orig.)

An innovative outcome-based care and procurement model of hemophilia management.

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Gringeri, Alessandro; Doralt, Jennifer; Valentino, Leonard A; Crea, Roberto; Reininger, Armin J

2016-06-01

Hemophilia is a rare bleeding disorder associated with spontaneous and post-traumatic bleeding. Each hemophilia patient requires a personalized approach to episodic or prophylactic treatment, but self-management can be challenging for patients, and avoidable bleeding may occur. Patient-tailored care may provide more effective prevention of bleeding, which in turn, may decrease the likelihood of arthropathy and associated chronic pain, missed time from school or work, and progressive loss of mobility. A strategy is presented here aiming to reduce or eliminate bleeding altogether through a holistic approach based on individual patient characteristics. In an environment of budget constraints, this approach would link procurement to patient outcome, adding incentives for all stakeholders to strive for optimal care and, ultimately, a bleed-free world.

Chronic spinal epidural hematoma in hemophilia A in a child

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Stanley, P.; McComb, J.G.

1983-06-01

A case of chronic spinal epidural hematoma in a thirteen-year-old male, subsequently found to have hemophilia A is reported. Following myelography, surgery was undertaken with clotting factor replacement with relief of cord compression. The patient made an uneventful recovery.

Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

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Knoebl, P; Marco, P; Baudo, F; Collins, P; Huth-Kühne, A; Nemes, L; Pellegrini, F; Tengborn, L; Lévesque, H

2012-04-01

Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA. © 2012 International Society on Thrombosis and Haemostasis.

Effect of a period of aquatic exercise therapy on the quality of life, anxiety and depression in patients with hemophilia

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Mehdi Kargarfard

2011-07-01

Full Text Available Introduction: Muscle-Skeletal disorders are the most common problems in hemophilia patients that can affect the quality of life and psychological factors in these patients. The aim of this study was to evaluate the effect of a period of aquatic exercise therapy on the quality of life, depression and anxiety in hemophilia patients. Materials and Methods: In a semi-experimental study, 20 patients who referred to Isfahan Sayedo-Shohada hospital voluntarily were selected and then randomly in two experimental (n=10 and control (n=10 groups. Subjects of aquatic exercise therapy group started their activity in water for 8 weeks, 3 sessions per week about45 to 60 minutes, while the control group was only followed-up and during this period they did not experience any exercise. The quality of life, depression and anxiety variables of patients were measured by standard questionnaires in the beginning and end of eight week aquatic exercise therapy. Results: The results showed significant improvement in quality of life, depression and anxiety variables in aquatic exercise therapy group patients, compared with the control group after 8 week aquatic exercise therapy (p<0.05. Conclusion: Results of this study showed that aquatic exercise therapy can be used as an effective and helpful method to prevent and treat hemophilia patients because it leads to improve multi-dimensional variable quality of life, depression and anxiety in hemophilia patients .

THROMBIN GENERATION AND BLEEDING IN HEMOPHILIA A

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Brummel-Ziedins, Kathleen E.; Whelihan, Matthew F.; Gissel, Matthew; Mann, Kenneth G.; Rivard, Georges E.

2012-01-01

Introduction Hemophilia A displays phenotypic heterogeneity with respect to clinical severity. Aim To determine if tissue factor (TF)-initiated thrombin generation profiles in whole blood in the presence of corn trypsin inhibitor (CTI) are predictive of bleeding risk in hemophilia A. Methods We studied factor(F) VIII deficient individuals (11 mild, 4 moderate and 12 severe) with a well-characterized five-year bleeding history that included hemarthrosis, soft tissue hematoma and annual FVIII concentrate usage. This clinical information was used to generate a bleeding score. The bleeding scores (range 0–32) were separated into three groups (bleeding score groupings: 0, 0 and ≤9.6, >9.6), with the higher bleeding tendency having a higher score. Whole blood collected by phlebotomy and contact pathway suppressed by 100μg/mL CTI was stimulated to react by the addition of 5pM TF. Reactions were quenched at 20min by inhibitors. Thrombin generation, determined by ELISA for thrombin – antithrombin was evaluated in terms of clot time (CT), maximum level (MaxL) and maximum rate (MaxR) and compared to the bleeding score. Results Data are shown as the mean±SD. MaxL was significantly different (phemophilia A. PMID:19563500

Inhibitor Risk Stratification and Individualized Treatment in Patients With Nonsevere Hemophilia A: A Single-Institution Practice Audit.

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Sun, Haowei Linda; Chan, Stella; Yenson, Paul; Jackson, Shannon

2018-03-01

Inhibitor risk in nonsevere hemophilia A increases with cumulative factor VIII (FVIII) exposure days and high-risk mutations. A standardized approach to minimize inhibitor risk is warranted. Following establishment of a systematic approach to reduce inhibitor risk in nonsevere hemophilia, we evaluated the uptake of these strategies into clinical practice. All adult males with nonsevere hemophilia A followed by British Columbia Adult Hemophilia Program from 2004 to 2016 were included in this retrospective audit. Quality-of-care indicators on inhibitor prevention were examined. Of 108 patients, 18 patients had high-risk FVIII mutations for inhibitor development. Rates of FVIII genotyping and 1-deamino-8-d-arginine-vasopressin (DDAVP) testing in mild patients without contraindications were both over 90%, although DDAVP was used for surgical prophylaxis in only 70% of procedures. Inhibitor testing and clinic visits occurred at a median interval of 22 months. Over 80% of patients with high-risk mutations had documentation and education on their inhibitor risk. Our practice audit demonstrated a high level of recognition and patient education of individual inhibitor risk. Impact of our standardized approach on the incidence of inhibitor development is yet to be determined.

Chronic spinal epidural hematoma in hemophilia A in a child

International Nuclear Information System (INIS)

Stanley, P.; McComb, J.G.; University of Southern California, Los Angeles

1983-01-01

A case of chronic spinal epidural hematoma in a thirteen-year-old male, subsequently found to have hemophilia A is reported. Following myelography, surgery was undertaken with clotting factor replacement with relief of cord compression. The patient made an uneventful recovery. (orig.)

Severe neonatal subgaleal hemorrhage as the first presentation of hemophilia A

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Radovanović Tanja

2016-01-01

Full Text Available Introduction. Subgaleal hemorrhage is a rare but potentially fatal birth trauma. It is caused by rupture of the emissary veins (connections between the dural sinuses and scalp veins, followed by the accumulation of blood between the epicranial aponeurosis and the periosteum. Usually, it is associated with instrumental delivery (vacuum extraction, forceps delivery, but it may also occur spontaneously, suggesting the possibility of congenital bleeding disorder. Case Outline. A full term male neonate was born at 40 weeks gestation by spontaneous vaginal delivery, with birth weight of 3,700 g. The Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At the age of 23 hours, the baby became pale and lethargic. Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered. Follow-up and further evaluation revealed hemophilia A as a result of a de novo mutation. Conclusion. This case illustrates that subgaleal hemorrhage may be the first presentation of hemophilia A. Infants without obvious risk factors for developing subgaleal hemorrhage should be evaluated for congenital bleeding disorder. Successful outcome in affected infants requires early diagnosis, careful monitoring and prompt treatment.

Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.

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Chao, B N; Baldwin, W H; Healey, J F; Parker, E T; Shafer-Weaver, K; Cox, C; Jiang, P; Kanellopoulou, C; Lollar, P; Meeks, S L; Lenardo, M J

2016-02-01

ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a

Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

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Callan, Mary Beth; Haskins, Mark E; Wang, Ping; Zhou, Shangzhen; High, Katherine A; Arruda, Valder R

2016-01-01

Severe hemophilia A (HA) is an inherited bleeding disorder characterized by dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A

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Sherman, Alexandra; Biswas, Moanaro; Herzog, Roland W.

2017-01-01

Hemophilia A (coagulation factor VIII deficiency) is a debilitating genetic disorder that is primarily treated with intravenous replacement therapy. Despite a variety of factor VIII protein formulations available, the risk of developing anti-dug antibodies (“inhibitors”) remains. Overall, 20–30% of patients with severe disease develop inhibitors. Current clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no prophylactic protocols to prevent the immune response. New experimental therapies, such as gene and cell therapies, show promising results in pre-clinical studies in animal models of hemophilia. Examples include hepatic gene transfer with viral vectors, genetically engineered regulatory T cells (Treg), in vivo Treg induction using immune modulatory drugs, and maternal antigen transfer. Furthermore, an oral tolerance protocol is being developed based on transgenic lettuce plants, which suppressed inhibitor formation in hemophilic mice and dogs. Hopefully, some of these innovative approaches will reduce the risk of and/or more effectively eliminate inhibitor formation in future treatment of hemophilia A. PMID:29225598

Cross-cultural adaptation of the CHO-KLAT for boys with hemophilia in rural and urban china

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Wu Runhui

2012-09-01

Full Text Available Abstract Background Quality of life (QoL is increasingly recognized as an important outcome measure in clinical trials. The Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT shows promise for use in China. Objective To adapt the CHO-KLAT version 2.0 for use in clinical trials in China. Methods Forward and back translations of the CHO-KLAT2.0 were completed in 2008. Between October 2009 and June 2010, a series of 3 focus groups were held with 20 boys and 31 parents in rural and urban China to elicit additional concepts, important to their QoL, for the Chinese CHO-KLAT2.0. All of the items identified by boys and parents were reviewed by a group of experts, resulting in a Chinese version of the CHO-KLAT2.0. This version underwent a detailed cognitive debriefing process between October 2010 and June 2011. Thirteen patient-parent pairs participated in this cognitive debriefing process until a stable and clearly understood Chinese version of the CHO-KLAT2.0 was obtained. Results The initial back translation of the Chinese CHO-KLAT2.0 was slightly discrepant from the original English version on 12 items. These were all successfully adjudicated. The focus groups identified 9 new items that formed an add-on Socio-Economic Context (SEC module for China. Linguistic improvements were made after the 2nd, 5th, 7th and 13th cognitive debriefings pairs and affected a total of 18 items. The result was a 35 item CHO-KLAT2.0 and a SEC module in Simplified Chinese, both of which have good content validity. Conclusion This detailed process proved to be extremely valuable in ensuring the items were accurately interpreted by Chinese boys with hemophilia ages ≤18 years. The need for the additional SEC module highlighted the different context that currently exists in China with regard to hemophilia care as compared to many Western countries, and will be important in tracking progress within both rural and urban China over time. Changes based on the

Reliability of patient-reported outcome instruments in US adults with hemophilia: the Pain, Functional Impairment and Quality of life (P-FiQ study

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Kempton CL

2017-09-01

Full Text Available Christine L Kempton,1 Michael Wang,2 Michael Recht,3 Anne Neff,4 Amy D Shapiro,5 Amit Soni,6 Roshni Kulkarni,7 Tyler W Buckner,2 Katharine Batt,8 Neeraj N Iyer,9 David L Cooper9 1Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 2Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, USA; 3The Hemophilia Center, Oregon Health & Science University, Portland, OR, USA; 4Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA; 5Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 6Center for Inherited Blood Disorders and CHOC Children’s Hospital/UC Irvine, Orange, CA, USA; 7MSU Center for Bleeding and Clotting Disorders, Michigan State University, East Lansing, MI, USA; 8Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 9Clinical, Medical and Regulatory Affairs, Novo Nordisk Inc., Plainsboro, NJ, USA Background: Hemophilia is marked by frequent joint bleeding, resulting in pain and functional impairment.Objective: This study aimed to assess the reliability of five patient-reported outcome (PRO instruments in people with hemophilia (PWH in a non-bleeding state.Methods: Adult male PWH of any severity and inhibitor status, with a history of joint pain or bleeding, completed a pain history and five PRO instruments (EQ-5D-5L, Brief Pain Inventory v2 [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL] during their routine comprehensive care visit. Patients were approached to complete the PRO instruments again at the end of their visit while in a similar non-bleeding state. Concordance of individual questionnaire items and correlation between domain scores were assessed using intra-class correlation coefficient (ICC.Results: Participants completing the retest (n=164 had a median age of 33.9 years. Median time for

An extra X does not prevent acquired hemophilia - Pregnancy-associated acquired hemophilia A.

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Barg, Assaf A; Livnat, Tami; Kenet, Gili

2017-03-01

Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). With an estimated annual incidence of 1.3 to 1.5 per million, AHA is a rare disease. An extremely rare form of AHA has been described among women in the peripartum period, and may present with peripartum hemorrhage. Notably, although hemorrhagic symptoms commonly present 1-4 months around delivery, they may occur up to 1 year after parturition. When caring for a mother with AHA it is important to note that Factor VIII inhibitor may be transferred via the placenta from the mother to the fetus. Hence the newborn may also be affected. It is important to increase the awareness of Gynecologists for clinical symptoms and laboratory signs of AHA in order to avoid delayed diagnosis. Treatment may involve use of bypass agents to control hemorrhage, despite the risk of thrombosis, while immunomodulation (with increasing role for Rituximab) may be required to eradicate the inhibiting antibodies. Our review will evaluate the epidemiology, diagnosis, clinical course and treatment of peripartum AHA, focusing upon mother and infant care. © 2017 Elsevier Ltd. All rights reserved.

Declining trends in invasive orthopedic interventions for people with hemophilia enrolled in the Universal Data Collection program (2000–2010)

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TOBASE, P.; LANE, H.; SIDDIQI, A.-E-A.; INGRAM-RICH, R.; WARD, R. S.

2016-01-01

Introduction Recurrent joint hemarthroses due to hemophilia (Factor VIII and Factor IX deficiency) often lead to invasive orthopedic interventions to decrease frequency of bleeding and/or to alleviate pain associated with end-stage hemophilic arthropathy. Aim Identify trends in invasive orthopedic interventions among people with hemophilia who were enrolled in the Universal Data Collection (UDC) program during the period 2000–2010. Methods Data were collected from 130 hemophilia treatment centers in the United States annually during the period 2000–2010, in collaboration with the Centers for Disease Control and Prevention (CDC). The number of visits in which an invasive orthopedic intervention was reported was expressed as a proportion of the total visits in each year of the program. Invasive orthopedic interventions consisted of arthroplasty, arthrodesis, and synovectomy. Joints included in this study were the shoulder, elbow, hip, knee, and ankle. Results A 5.6% decrease in all invasive orthopedic interventions in all joints of people with hemophilia enrolled in the UDC program over the 11-year study period was observed. Conclusions These data reflect a declining trend in invasive orthopedic interventions in people with hemophilia. Further research is needed to understand the characteristics that may influence invasive orthopedic interventions. PMID:27030396

Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce.

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Herzog, Roland W; Nichols, Timothy C; Su, Jin; Zhang, Bei; Sherman, Alexandra; Merricks, Elizabeth P; Raymer, Robin; Perrin, George Q; Häger, Mattias; Wiinberg, Bo; Daniell, Henry

2017-02-01

Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds, and pentamer assembly after 30-month storage at ambient temperature. Robust suppression of immunoglobulin G (IgG)/inhibitor and IgE formation against intravenous FIX was observed in three of four hemophilia B dogs fed with lyophilized lettuce cells expressing CTB-FIX. No side effects were detected after feeding CTB-FIX-lyophilized plant cells for >300 days. Coagulation times were markedly shortened by intravenous FIX in orally tolerized treated dogs, in contrast to control dogs that formed high-titer antibodies to FIX. Commercial-scale production, stability, prolonged storage of lyophilized cells, and efficacy in tolerance induction in a large, non-rodent model of human disease offer a novel concept for oral tolerance and low-cost production and delivery of biopharmaceuticals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Problems of Hemophilia and the Role of the Rehabilitation Counselor.

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Carrai, Edward B.; Handford, H. Allen

1983-01-01

Because of the multiple problems associated with hemophilia, optimal treatment is usually provided in a comprehensive care setting by a team of medical and nonmedical professionals. The rehabilitation counselor contributes expertise to that of other team members in development and implementation of an individual rehabilitation plan for…

Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

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Stasyshyn, O; Djambas Khayat, C; Iosava, G; Ong, J; Abdul Karim, F; Fischer, K; Veldman, A; Blackman, N; St Ledger, K; Pabinger, I

2017-04-01

Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children hemophilia A. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and

Patient preferences in the treatment of hemophilia A: impact of storage conditions on product choice

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Tischer B

2018-03-01

Full Text Available Bernd Tischer,1 Renato Marino,2 Mariasanta Napolitano3 1Kantar Health, Munich, Germany; 2Haemophilia and Thrombosis Centre, University Hospital of Bari, Apulia, Italy; 3University of Palermo, Reference Regional Center for Thrombosis and Hemostasis Hematology Unit, Palermo, Italy Objectives: To gain insights into the usage of factor VIII (FVIII products by patients diagnosed with moderate/severe hemophilia A, and to assess the impact and perceived importance of product storage.Methods: In this study, 200 patients diagnosed with moderate or severe hemophilia A across seven countries participated. Data were collected via a 30-minute, face-to-face interview in six countries and via a web-based survey in the seventh country. The questionnaire evaluated the effect of six features associated with FVIII products on the choice of the product; the structure and flow of data collection was designed to eliminate potential bias.Results: Two-thirds of the respondents were using recombinant FVIII products. Only 17% were generally dissatisfied with current FVIII products, whereas >40% of the respondents were dissatisfied with frequency of administration and storage issues when traveling. The majority noted restrictions in their daily activities, particularly travel and sports. Most of them (85%, stored their product in the refrigerator and of these, 88% believed that it should always be stored there. These patients were also less satisfied with the product overall, more concerned about storage temperature, more restricted in daily activities, and spent more time on preparation and injection compared with patients who stored their product at room temperature. Conjoint analysis revealed that origin of FVIII (plasma-derived vs recombinant was the strongest driver of product choice among all respondents, followed by storage flexibility (temperature, reconstitution device, and administration frequency. In this study, we did not investigate the efficacy and safety of

Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

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Mary Beth Callan

Full Text Available Severe hemophilia A (HA is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII

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Lozier, Jay N; Kloos, Mark T; Merricks, Elizabeth P; Lemoine, Nathaly; Whitford, Margaret H; Raymer, Robin A; Bellinger, Dwight A; Nichols, Timothy C

2016-01-01

Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons. Comparing the results with the normal canine factor VIII sequence revealed a C→T transition in exon 12 of the factor VIII gene that created a premature stop codon at amino acid 577 in the A2 domain of the protein. In addition, 2 previously described polymorphisms that do not cause hemophilia were present at amino acids 909 and 1184. The hemophilia mutation creates a new TaqI site that facilitates rapid genotyping of affected offspring by PCR and restriction endonuclease analyses. This mutation is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12. Thus far, despite extensive treatment with factor VIII, this dog has not developed neutralizing antibodies (‘inhibitors’) to the protein. This novel mutation in a dog gives rise to severe hemophilia A analogous to a mutation seen in humans. This model will be useful for studies of the treatment of hemophilia. PMID:27780008

The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies.

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Shi, Q; Schroeder, J A; Kuether, E L; Montgomery, R R

2015-07-01

Our previous studies have demonstrated that targeting FVIII expression to platelets results in FVIII storage together with von Willebrand factor (VWF) in platelet α-granules and that platelet-derived FVIII (2bF8) corrects the murine hemophilia A phenotype even in the presence of high-titer anti-FVIII inhibitory antibodies (inhibitors). To explore how VWF has an impact on platelet gene therapy for hemophilia A with inhibitors. 2bF8 transgenic mice in the FVIII(-/-) background (2bF8(tg+/-) F8(-/-) ) with varying VWF phenotypes were used in this study. Animals were analyzed by VWF ELISA, FVIII activity assay, Bethesda assay and tail clip survival test. Only 18% of 2bF8(tg+/-) F8(-/-) VWF(-/-) animals, in which VWF was deficient, survived the tail clip challenge with inhibitor titers of 3-8000 BU mL(-1) . In contrast, 82% of 2bF8(tg+/-) F8(-/-) VWF(+/+) mice, which had normal VWF levels, survived tail clipping with inhibitor titers of 10-50,000 BU mL(-1) . All 2bF8(tg+/-) F8(-/-) VWF(-/-) mice without inhibitors survived tail clipping and no VWF(-/-) F8(-/-) mice survived this challenge. Because VWF is synthesized by endothelial cells and megakaryocytes and is distributed in both plasma and platelets in peripheral blood, we further investigated the effect of each compartment of VWF on platelet-FVIII gene therapy for hemophilia A with inhibitors. In the presence of inhibitors, 42% of animals survived tail clipping in the group with plasma-VWF and 50% survived in the platelet-VWF group. VWF is essential for platelet gene therapy for hemophilia A with inhibitors. Both platelet-VWF and plasma-VWF are required for optimal platelet-derived FVIII gene therapy for hemophilia A in the presence of inhibitors. © 2015 International Society on Thrombosis and Haemostasis.

Targeted genome engineering in human induced pluripotent stem cells from patients with hemophilia B using the CRISPR-Cas9 system.

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Lyu, Cuicui; Shen, Jun; Wang, Rui; Gu, Haihui; Zhang, Jianping; Xue, Feng; Liu, Xiaofan; Liu, Wei; Fu, Rongfeng; Zhang, Liyan; Li, Huiyuan; Zhang, Xiaobing; Cheng, Tao; Yang, Renchi; Zhang, Lei

2018-04-06

Replacement therapy for hemophilia remains a lifelong treatment. Only gene therapy can cure hemophilia at a fundamental level. The clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9 (CRISPR-Cas9) system is a versatile and convenient genome editing tool which can be applied to gene therapy for hemophilia. A patient's induced pluripotent stem cells (iPSCs) were generated from their peripheral blood mononuclear cells (PBMNCs) using episomal vectors. The AAVS1-Cas9-sgRNA plasmid which targets the AAVS1 locus and the AAVS1-EF1α-F9 cDNA-puromycin donor plasmid were constructed, and they were electroporated into the iPSCs. When insertion of F9 cDNA into the AAVS1 locus was confirmed, whole genome sequencing (WGS) was carried out to detect the off-target issue. The iPSCs were then differentiated into hepatocytes, and human factor IX (hFIX) antigen and activity were measured in the culture supernatant. Finally, the hepatocytes were transplanted into non-obese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice through splenic injection. The patient's iPSCs were generated from PBMNCs. Human full-length F9 cDNA was inserted into the AAVS1 locus of iPSCs of a hemophilia B patient using the CRISPR-Cas9 system. No off-target mutations were detected by WGS. The hepatocytes differentiated from the inserted iPSCs could secrete hFIX stably and had the ability to be transplanted into the NOD/SCID mice in the short term. PBMNCs are good somatic cell choices for generating iPSCs from hemophilia patients. The iPSC technique is a good tool for genetic therapy for human hereditary diseases. CRISPR-Cas9 is versatile, convenient, and safe to be used in iPSCs with low off-target effects. Our research offers new approaches for clinical gene therapy for hemophilia.

Critical appraisal of the role of recombinant activated factor VII in the treatment of hemophilia patients with inhibitors

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Ampaiwan Chuansumrit

2010-03-01

Full Text Available Ampaiwan Chuansumrit1, Pantep Angchaisuksiri2, Nongnuch Sirachainan11Departments of Pediatrics and 2Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University,  Bangkok, ThailandAbstract: Hemophilia patients with inhibitors faced the constraint of inadequate treatment for several years before the era of recombinant factor VIIa (rFVII. Initially, rFVIIa was used in the compassionate-use programs. After a worldwide license was issued, more than 1.5 million doses were administered. Bleeding of joints and muscles was controlled effectively by means of an early home treatment program, with either a standard dose of 90 μg/kg every 2 to 3 hours for a few doses or a single dose of 270 μg/kg. For more serious bleeding episodes or minor surgery, an initial dose of 90 μg/kg was given every 2 hours for 24 to 48 hours followed by increased intervals of 3 to 6 hours according to the severity of bleeding and efficacy of bleeding control. In cases of major surgery such as orthopedic procedures, the same regimen can be applied except for a higher initial dose of 120 to 180 μg/kg. However, increasing the dose should be considered if there are unexpected bleeding complications since the half-life and clearance of rFVIIa differ between individuals. In addition, prophylaxis is administered to a small number of patients. Finally, the reported thromboembolic events found in hemophilia patients with inhibitors receiving rFVIIa are extremely low, much less than 1%.Keywords: bleeding disorder, hemophilia, inhibitor, NovoSeven, recombinant factor VIIa

A newborn with moderate hemophilia A with severe intracranial and extracranial hemorrhage: A case report

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Şebnem Kader

2017-09-01

Full Text Available Intracranial hemorrhage among term newborns is a rare clinical condition with high morbidity and mortality. Although major bleeding is relatively uncommon, the incidence of intracranial hemorrhage in hemophilic children is higher during the first few days of life than at any other stage in childhood, which relates to the trauma of delive ry. Here, we reported a newborn case diagnosed with moderate hemophilia A, without the presence of a positive family history of hemophilia and presenting with intracranial and extracranial hemorrhage and we aimed to emphasize that the early diagnosis and replacement therapy carries an essential importance.

Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A.

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Collins, P W; Blanchette, V S; Fischer, K; Björkman, S; Oh, M; Fritsch, S; Schroth, P; Spotts, G; Astermark, J; Ewenstein, B

2009-03-01

The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level break-through bleeding in patients with severe hemophilia A on prophylaxis. This study analysed data from 44 patients aged 1-6 and 99 patients aged 10-65 years with severe hemophilia A (FVIII safety and efficacy of a recombinant FVIII (Advate). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL(-1). The data demonstrate that increasing time with a FVIII below 1 IU dL(-1) is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance. These data have important implications for the management of patients with severe hemophilia.

Two-incision laparoscopic appendectomy for a severe hemophilia A child patient with coagulation factor VII deficiency: Case report and review of literature.

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He, Jin Peng; Feng, Jie Xiong

2017-10-01

The main complication of patients with severe hemophilia is recurrent bleeding events that usually affected musculoskeletal contractures. And replacement therapy methods were continuously improved to minimize adverse impacts brought by those complications. However, only several cases reported about the appendectomy for hemophilia A. We report a case of acute appendicitis treated by two-incision laparoscopy in a boy with hemophilia A and coagulation factor VII deficiency for the first time. An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. He received a computed tomography (CT) scan which revealed an enlarged appendix, thickened wall and appendiceal fecalith, and had received a conservative anti-bacterial treatment for his acute appendicitis but failed. He was diagnosed with hemophilia A and coagulation factor VII deficiency. Two-incision laparoscopic appendectomy was made in success with a careful management of perioperative period. We monitored the clotting factor FVIII level and gave him a replacement therapy. The patient had an uneventful recovery. It is important to exclude intraabdominal or retroperitoneal hemorrhage in patients suffering from hemophilia and acute abdominal pain. Pre-operative evaluation of validity of the FVIII replacement therapy is another effective strategy to assess the safety and feasibility of applying an operation procedure. The two-incision laparoscopic appendectomy is an effective treatment for this kind of patients for its minimal trauma and fast recovery characteristics. Our report shows that laparoscopic appendectomy is feasible in a child suffering from hemophilia after adequate blood clotting factor replacement treatment.

Construct validity of patient-reported outcome instruments in US adults with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ study

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Batt K

2017-08-01

Full Text Available Katharine Batt,1 Michael Recht,2 David L Cooper,3 Neeraj N Iyer,3 Christine L Kempton4 1Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 2The Hemophilia Center, Oregon Health & Science University, Portland, OR, 3Novo Nordisk Inc., Plainsboro, NJ, 4Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA Background: People with hemophilia (PWH experience frequent joint bleeding, resulting in pain and functional impairment. Generic and disease-specific patient-reported outcome (PRO instruments have been used in clinical studies, but rarely in the comprehensive hemophilia care setting. Objective: The objective of this study was to assess construct validity of PRO instruments measuring pain, functional impairment, and health-related quality of life in US PWH with a history of joint pain/bleeding. Methods: Adult male PWH completed 4 PRO instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], SF-36v2, Hemophilia Activities List [HAL] and underwent a musculoskeletal examination (Hemophilia Joint Health Score v2.1 [HJHS]. Construct validity between index and domain scores was evaluated by Pearson product-moment correlation coefficient. Results: A total of 381 PWH were enrolled. EQ-5D-5L Mobility correlated with BPI, SF-36v2, and HAL domains related to pain, physical function, and activity of the lower extremities. EQ-5D-5L Self-Care correlated only with HAL Self-Care. EQ-5D-5L Usual Activities correlated with BPI Pain Interference and domains within SF-36v2 and HAL related to pain and physical function/activities (particularly those involving the lower extremities. EQ-5D-5L Pain/Discomfort correlated with Bodily Pain and Physical Summary on SF-36v2, HAL Overall Activity, and all BPI pain domains. EQ-5D-5L Anxiety/Depression correlated with social/emotional/mental aspects of SF-36v2. On BPI, most pain domains correlated with Bodily

Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism.

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O'Brien, Kevin J; Lozier, Jay; Cullinane, Andrew R; Osorio, Brigitte; Nghiem, Khanh; Speransky, Vladislav; Zein, Wadih M; Mullikin, James C; Neff, Anne T; Simon, Karen L; Malicdan, May Christine V; Gahl, William A; Young, Lisa R; Gochuico, Bernadette R

2016-11-01

Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions. This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient

Effectiveness of the Medtep Hemophilia online platform for adherence to prophylactic treatment in haemophilia patients: Results from a 1-year observational study.

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Cuesta-Barriuso, R; López-Pina, J A; Nieto-Munuera, J; Sagarra-Valls, G; Panisello-Royo, J M; Torres-Ortuño, A

2018-03-01

Medtep Hemophilia platform is an online tool that allows patients with congenital coagulopathies to keep track of their daily condition-related events with the objective of ensuring successful adherence to therapy. To assess the effectiveness of Medtep Hemophilia in improving adherence to prophylactic treatment in haemophilia A and B patients in a 1-year prospective observational study, as well as its impact on the patient's disease status. Patients (>13 years old) received support material to familiarize themselves with Medtep Hemophilia. Adherence to treatment, quality of life (QoL) and illness perception were assessed. Values at baseline, 1, 6 and 12 months, and changes from baseline value were analysed. The Hemophilia Joint Health Score (HJHS) test was applied at baseline and study completion. Forty-six patients were enrolled (43 evaluable). After 1 year, 56.4% patients showed continued use of the platform (100% compliance) whereas 25.6% were inactive. Treatment adherence increased both significantly (P 80% of platform use) tended to score better than noncompliant. The HJHS test values remained similar during the study. The Medtep Hemophilia online platform helped the studied patients with haemophilia to improve their adherence to prophylactic treatment, while increasing their QoL and illness perception, as well as joint arthropathies stabilization. © 2018 John Wiley & Sons Ltd.

Risk Factors for Inhibitor Formation in Hemophilia: A Prevalent Case-Control Study

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Ragni, Margaret V.; Ojeifo, Oluseyi; Feng, Jinong; Yan, Jin; Hill, Kathleen A.; Sommer, Steve S.; Trucco, Massimo N.; Brambilla, Donald J.

2009-01-01

Background Inhibitor formation is a major complication of hemophilia treatment. Aim In a prevalent case-control study, we evaluated blood product exposure, genotype, and HLA type on hemophilia A inhibitor formation. Methods Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Results Cases experienced higher intensity factor, 455 vs. 200 U per exposure, p0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titers 0.50. Conclusions Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race, and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. PMID:19563499

Mesenchymal stem cell treatment for hemophilia: a review of current knowledge.

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Sokal, E M; Lombard, C; Mazza, G

2015-06-01

Hemophilia remains a non-curative disease, and patients are constrained to undergo repeated injections of clotting factors. In contrast, the sustained production of endogenous factors VIII (FVIII) or IX (FIX) by the patient's own cells could represent a curative treatment. Gene therapy has thus provided new hope for these patients. However, the issues surrounding the durability of expression and immune responses against gene transfer vectors remain. Cell therapy, involving stem cells expanded in vitro, can provide de novo protein synthesis and, if implanted successfully, could induce a steady-state production of low quantities of factors, which may keep the patient above the level required to prevent spontaneous bleeding. Liver-derived stem cells are already being assessed in clinical trials for inborn errors of metabolism and, in view of their capacity to produce FVIII and FIX in cell culture, they are now also being considered for clinical application in hemophilia patients. © 2015 International Society on Thrombosis and Haemostasis.

Successful medical management of a neonate with spontaneous splenic rupture and severe hemophilia A.

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Badawy, Sherif M; Rossoff, Jenna; Yallapragada, Sushmita; Liem, Robert I; Sharathkumar, Anjali A

2017-03-01

Splenic rupture in neonates is a rare event, usually occurring in the setting of underlying predisposing conditions. Here, we present the case of a term neonate who presented with worsening anemia in the setting of known hemolytic disease during the newborn period and was later found to have a spontaneous splenic rupture. He was subsequently diagnosed with severe hemophilia A, and was managed medically with recombinant factor VIII replacement therapy without any surgical intervention. This is the first reported case of a neonate who had spontaneous splenic rupture and severe hemophilia A, and underwent successful medical treatment without any surgical intervention. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer

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Chirag Sheth

2016-09-01

Full Text Available Acquired factor VIII deficiency (acquired hemophilia A is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII. The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies. We report the case of a 66-year-old male who presented with spontaneous right thigh hematoma with prolonged activated partial prothrombin time and normal prothrombin time. Mixing studies confirmed the presence of an inhibitor. Further investigation for the underlying etiology of acquired hemophilia A leads to diagnosis of prostate cancer. Treatment consisted of bypassing agents including activated factor VII and activated prothrombin plasma concentrate to arrest the bleeding. Steroids and cyclophosphamide were added to suppress the fVIII inhibitors. Concomitant treatment of locally advanced prostate cancer with chemotherapy confirmed the eradication of the inhibitors. To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in favorable patient outcome.

Knee and Ankle Arthroplasty in Hemophilia

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Luigi Piero Solimeno

2017-11-01

Full Text Available Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the “gold standard”, while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described.

Rationale for a randomized controlled trial comparing two prophylaxis regimens in adults with severe hemophilia A: the Hemophilia Adult Prophylaxis Trial

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Ragni, Margaret V

2011-01-01

A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis or regular preventive factor, one or more times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. The purpose of this article is to describe a Phase III randomized controlled trial to evaluate prophylaxis comparing two dose regimens in adults with severe hemophilia A. I hypothesize that adults with mature cartilage and joints are less susceptible to joint bleeds and joint damage, and that once-weekly recombinant factor VIII prophylaxis, with up to two rescue doses per week, is as effective as thrice-weekly prophylaxis in reducing bleeding frequency, but less costly and more acceptable, with higher quality of life. The ultimate goal of this project is to determine whether once-weekly prophylaxis is any worse than thrice-weekly prophylaxis in reducing joint bleeding frequency, while potentially utilizing less factor, at lower cost, leading to a better quality of life. This is an innovative concept, as it challenges the current paradigm of thrice-weekly prophylaxis in adults, which is based on dosing in children. Furthermore, this trial will assess interdose thrombin generation, a novel tissue factor-based assay of hemostasis, to determine if individualized thrombin generation can predict more individualized prophylaxis dosing, which would be practice changing. PMID:21939418

Case report 475: Hemophilic arthropathy of the hip in a woman with hemophilia A

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Farsoe Nielsen, F.; Christensen, S.E.; Carvalho, A. de

1988-04-01

In summary, a case has been presented of a 31-year-old woman with a history of mild trauma at the age of 14 years and recurrent periods of pain in the hip becoming increasingly more severe. The radiological features were those of marked arthropathy of the affected hip with suggested features of ischemic necrosis. The patient was an example of hemophilia A which occurs rarely in females. The nature of the laboratory and clinical features of deficiency in hemophilia was considered and the clinical and radiological manifestations were described. The differential diagnosis was discussed. The radiological features in the background of the clinical information strongly suggest that the diagnosis of hemophilic arthropathy of the hip is justified. (orig./SHA).

Case report 475: Hemophilic arthropathy of the hip in a woman with hemophilia A

International Nuclear Information System (INIS)

Farsoe Nielsen, F.; Christensen, S.E.; Carvalho, A. de

1988-01-01

In summary, a case has been presented of a 31-year-old woman with a history of mild trauma at the age of 14 years and recurrent periods of pain in the hip becoming increasingly more severe. The radiological features were those of marked arthropathy of the affected hip with suggested features of ischemic necrosis. The patient was an example of hemophilia A which occurs rarely in females. The nature of the laboratory and clinical features of deficiency in hemophilia was considered and the clinical and radiological manifestations were described. The differential diagnosis was discussed. The radiological features in the background of the clinical information strongly suggest that the diagnosis of hemophilic arthropathy of the hip is justified. (orig./SHA)

Comparison of radiography, CT and MR imaging in detection of arthropathies in patients with hemophilia

International Nuclear Information System (INIS)

Yu Wei; Lin Qiang; Shang Wei; Zhu Haifeng; Meng Wei; Xu Ruiyi; Zhao Yongqiang; Shi Yongsheng

2007-01-01

Objective: To compare MR, CT, and radiography in the detection of arthropathies in patients with hemophilia. Methods: Forty-one symptomic joint images in the 14 patients with hemophilia, aged from 11 to 24 years, were used in this study. Each joint had the examinations of radiography, CT and MR within one day. The severity of each joint was staged using conventional radiographic classification. Severe HA patients with stage 5 were excluded from the study. Imaging findings of soft tissue swelling, osteoporosis, epiphyseal overgrowth, joint erosion, cyst, joint space narrowing, bone marrow, joint effusion, hemorrhage, synovial hypertrophy, widened intercondylar notch as well as anterior and posterior cruciate ligaments (only for knee joint) were used for the all imaging comparison. Results: The 41 symptomatic joints in 14 patients with hemophilia were classified by radiographic criteria into stage 0 (n=5), stage 1 (n=7), stage 2 (n=6), stage 3 (n=8) and stage 4 (n=15). Soft tissue swelling or joint effusion was observed in 33 joints by radiographs, in 34 joints by both CT and MR. Joint erosions were demonstrated in 34 joints by MR, in 33 joints by CT and 20 joints by radiographs. Joint cysts were shown in 21 joints by MR, in 18 joints by CT and 9 joints by radiographs. Significant differences in detection of erosion and cyst were found between radiography with either CT (P 0.05). MR showed improvement for detecting more foci of both erosion and cyst than CT and radiography, and also CT showed the improvement than radiography. Bone marrow edema 14 joints, hemorrhage in 34 joints and synovial hypertrophy in 27 joints were revealed on MR images. Conclusion: MRI is superior to CT and conventional radiography in detecting the abnormal changes and should be considered as the first choice among the imaging modalities in evaluating hemophilic arthropathies. (authors)

An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

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Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

2017-07-01

Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Comparing the Effects of Therapeutic Exercise and Hydrotherapy on Pain Severity and Knee Range of Motion in Patients with Hemophilia: A Randomized Controlled Trial

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V Mazloum

2013-10-01

. Results: Both experimental groups exhibited significant reduction of pain along with improved knee flexion and extension compared with the control group (P<0.001. Pain reduction in subjects treated in water treatment was significantly higher than exercise group in drought (P0.05. Conclusion: The use of therapeutic exercise in water with regular exercise rehabilitation for patients with hemophilia can be helpful to reduce pain and improve range of motion in hemophilia patients. The effect of exercise therapy on pain reduction is more effective compared to traditional pain therapy. Key words: Hydrotherapy, Exercise Therapy, Hemophilia, Knee Range of Motion

Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

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Gu, Ruo-lan; Liu, Liang; Xie, Liang-zhi; Gai, Wen-lin; Cao, Si-shuo; Meng, Zhi-yun; Gan, Hui; Wu, Zhuo-na; Li, Jian; Zheng, Ying; Zhu, Xiao-xia; Dou, Gui-fang

2016-01-01

Aim: SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. Methods: After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasma FVIII: C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1–200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss. Results: Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. Conclusion: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties. PMID:26806305

Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications.

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Hazendonk, H C A M; Lock, J; Mathôt, R A A; Meijer, K; Peters, M; Laros-van Gorkom, B A P; van der Meer, F J M; Driessens, M H E; Leebeek, F W G; Fijnvandraat, K; Cnossen, M H

2016-03-01

ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory. Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs. This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1)). One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1). Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive

Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM

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Chang Chieh-Ting

2008-06-01

Full Text Available Abstract Background Hemophilia A represents the most common and severe inherited hemorrhagic disorder. It is caused by mutations in the F8 gene, which leads to a deficiency or dysfunctional factor VIII protein, an essential cofactor in the factor X activation complex. Methods We used long-distance polymerase chain reaction and denaturing high performance liquid chromatography for mutation scanning of the F8 gene. We designed the competitive multiplex PCR to identify the carrier with exonal deletions. In order to facilitate throughput and minimize the cost of mutation scanning, we also evaluated a new mutation scanning technique, high resolution melting analysis (HRM, as an alternative screening method. Results We presented the results of detailed screening of 122 Taiwanese families with hemophilia A and reported twenty-nine novel mutations. There was one family identified with whole exons deletion, and the carriers were successfully recognized by multiplex PCR. By HRM, the different melting curve patterns were easily identified in 25 out of 28 cases (89% and 15 out of 15 (100% carriers. The sensitivity was 93 % (40/43. The overall mutation detection rate of hemophilia A was 100% in this study. Conclusion We proposed a diagnostic strategy for hemophilia A genetic diagnosis. We consider HRM as a powerful screening tool that would provide us with a more cost-effective protocol for hemophilia A mutation identification.

Assessment of healthcare measures, healthcare resource use, and cost of care among severe hemophilia A patients in Mumbai region of India.

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Jadhav, U; Mukherjee, K

2017-10-23

In India, the low public health priority given to rare disorders such as hemophilia hinders their management and optimal care, leading to relatively poor health outcomes. This study aims to profile the multidimensional health status of patients with severe hemophilia A, and its association with the use of healthcare resources and the cost of care in Mumbai region of India. A cross-sectional, single-center study was conducted during January-May 2011, among 160 patients diagnosed with severe hemophilia A in Mumbai region of India. Their health status was documented using the Hemophilia Utilization Group Study's validated instrument of Functional Health Status Measure (FHS) and a single item of Self-care Measure. Of 160 patients, 55% (n = 88) scored on the lower side on the FHS, with an average score of 6.65 ± 2.85. The use of healthcare resources and cost of treatment were considerable for patients with a lower mean rank score on the FHS and a higher mean rank score on the self-care measure. The consumption of clotting factor concentrates (CFCs), number of visits to a health facility and incidence of inpatient episodes were significantly associated with a relatively low score on the FHS. Similarly, a higher cost of treatment, in terms of the cost of CFCs, direct cost, emergency room cost, and indirect cost, were significantly associated with a lower score on the FHS. The health status of patients with severe hemophilia A is compromised and has a significant impact on the use of healthcare resources and the cost of treatment.

Hemofilia: aspectos históricos y genéticos Hemophilia: historical and genetic aspects

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Dunia Castillo-González

2012-03-01

Full Text Available La hemofilia es un trastorno hemorrágico con disminución o ausencia de la actividad procoagulante del factor VIII o del IX. Las primeras descripciones de esta enfermedad son tan antiguas como la propia humanidad. A lo largo de los años, la hemofilia ha sido nombrada "enfermedad real" debido a que la padecieron diversos miembros de las familias reales europeas. En la actualidad, mediante estudios moleculares, se encontró el defecto genético causante de la enfermedad en los varones hemofílicos de la familia de la Reina Victoria y se encontró que sus descendientes padecieron una hemofilia B severa. El fenotipo de esta enfermedad es hemorrágico; se observan sangramientos en diversos sitios de la economía condicionados fundamentalmente por los niveles del factor deficiente. Existen otros factores que intervienen en las características fenotípicas variables de estos pacientes, entre ellos: las características intrínsecas de los factores VIII/IX, la presencia de genes modificadores y factores ambientales que influyen sobre la severidad de la enfermedad. Se revisa la correlación genotipo-fenotipo en esta enfermedad mediante las mutaciones más frecuentes en cada tipo de hemofilia. En cuanto a la presencia de los inhibidores, se destacan las evidencias actuales en relación con los factores de riesgo relacionados con su aparición y los aspectos moleculares presentes en la variante de hemofilia B Leyden.Hemophilia is a hemorrhagic disorder characterized by decreasing or absence of the procoagulant activity in factor VIII or IX. First descriptions of this disease are as old as mankind itself. During time, hemophilia has been called "royal disease" since different members of European royal families suffered from it. Currently, by molecular studies, it was found the causing genetic defect of this disease in hemophilic male members of Queen Victoria´s family; and it was found that her descendants suffered a severe hemophilia B. This disease

"Neurologic complications in Hemophilia: A study in 214 cases "

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Ghaffarpoor M

2001-08-01

Full Text Available Intracranial hemorrhage and entrapment neuropathy are the most serious and disabling complications in hemophilia.The occurance of these neurological complications was studied in 214 hemophiliac patients during a 3 month period. Nine patients (4.2% suffered intracranial hemorrhage (One epidural and others intracerebral. All of intracranial hemorrhage patients had the sevee form of disease (<1% factor VIII or IX. 6 out of 9 intracranial hemorrhage cases mentioned a history of head trauma. Entrapment neuropathy was presen in 10 patients (femoral neuropathy 5, ulnar n. 3, radial n. 1 median n. 1 all of entropament neuropathy patients described a history of trauma to the extremities. Eight patients in the latter group had severe disease and two patients had moderate disease (1-5%. The proportion of intracranial hemorrhage following head trauma (20% in this series was greater than other studies. In conclusion, early diagnostic evaluation and replacement therapy may be beneficial in hemophilic patients with trauma.

Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice.

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Verma, Dheeraj; Moghimi, Babak; LoDuca, Paul A; Singh, Harminder D; Hoffman, Brad E; Herzog, Roland W; Daniell, Henry

2010-04-13

To address complications of pathogenic antibody or life-threatening anaphylactic reactions in protein replacement therapy for patients with hemophilia or other inherited protein deficiencies, we have developed a prophylactic protocol using a murine hemophilia B model. Oral delivery of coagulation factor IX fused with cholera toxin beta-subunit (with or without a furin cleavage site; CTB-FFIX or CTB-FIX), expressed in chloroplasts (up to 3.8% soluble protein or 0.4 mg/g leaf tissue), bioencapsulated in plant cells, effectively blocked formation of inhibitory antibodies (undetectable or up to 100-fold less than controls). Moreover, this treatment eliminated fatal anaphylactic reactions that occurred after four to six exposures to intravenous F.IX. Whereas only 20-25% of control animals survived after six to eight F.IX doses, 90-93% of F.IX-fed mice survived 12 injections without signs of allergy or anaphylaxis. Immunostaining confirmed delivery of F.IX to Peyer's patches in the ileum. Within 2-5 h, feeding of CTB-FFIX additionally resulted in systemic delivery of F.IX antigen. This high-responder strain of hemophilia B mice represents a new animal model to study anaphylactic reactions. The protocol was effective over a range of oral antigen doses (equivalent to 5-80 microg recombinant F.IX/kg), and controlled inhibitor formation and anaphylaxis long-term, up to 7 months (approximately 40% life span of this mouse strain). Oral antigen administration caused a deviant immune response that suppressed formation of IgE and inhibitory antibodies. This cost-effective and efficient approach of antigen delivery to the gut should be applicable to several genetic diseases that are prone to pathogenic antibody responses during treatment.

An Analysis of the hemophilia of the royal families of Europe, its startling implication and dentistry's role in treating the hemophiliac patient.

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Maloney, William James; Raymond, George; Hershkowitz, David; Rochlen, Glenn

2015-03-01

Hemophilia is an inherited x-linked recessive disorder. It is known popularly as "The Royal Disease," as it has affected many of the royal families of Europe by virtue of Queen Victoria being a carrier for the gene and, subsequently, passing it on to her offspring. They, in turn, married and had children with other royal families of Europe. Hemophilia is certainly not limited to royalty. There are many hemophiliacs living in our communities, and they must receive both proper dental home-care education and dental treatment in order to prevent possibly life-threatening emergency dental episodes. Individuals with hemophilia pose different management issues to the dental professional. The various precautions and modifications that must be taken in order to ensure the safe delivery of dental care to hemophiliac dental patients are discussed.

A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

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Mehta, Darshan A; Oladapo, Abiola O; Epstein, Joshua D; Novack, Aaron R; Neufeld, Ellis J; Hay, Joel W

2016-02-01

Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to

The CDC Hemophilia B mutation project mutation list: a new online resource.

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Li, Tengguo; Miller, Connie H; Payne, Amanda B; Craig Hooper, W

2013-11-01

Hemophilia B (HB) is caused by mutations in the human gene F9. The mutation type plays a pivotal role in genetic counseling and prediction of inhibitor development. To help the HB community understand the molecular etiology of HB, we have developed a listing of all F9 mutations that are reported to cause HB based on the literature and existing databases. The Centers for Disease Control and Prevention (CDC) Hemophilia B Mutation Project (CHBMP) mutation list is compiled in an easily accessible format of Microsoft Excel and contains 1083 unique mutations that are reported to cause HB. Each mutation is identified using Human Genome Variation Society (HGVS) nomenclature standards. The mutation types and the predicted changes in amino acids, if applicable, are also provided. Related information including the location of mutation, severity of HB, the presence of inhibitor, and original publication reference are listed as well. Therefore, our mutation list provides an easily accessible resource for genetic counselors and HB researchers to predict inhibitors. The CHBMP mutation list is freely accessible at http://www.cdc.gov/hemophiliamutations.

[Effective immunosuppresive therapies including steroid pulse treatment for intramuscular hematoma in iliopsoas in acquired hemophilia].

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Mohri, Hiroshi; Tanabe, Juichi; Takagi, Hiroshi; Murata, Takashi

2007-12-01

Acquired hemophilia is a life-threatening bleeding disorder by the development of autoantibody against factor VIII. The therapeutic approach relies on steroid, cyclophosphamide and/or cyclosporine. A 64-year-old man was referred to our hospital with extensive hematoma in both psoas muscles, severe anemia of 6.8 g/dl, prolonged activated partial thromboplastin time over 200 seconds, and factor VIII coagulation activity (FVIII: C) of 1.9%. A factor VIII inhibitor was detected at 118 Bethesda units (BU). The diagnosis of acquired hemophilia was made in the absence of a detectable cause. The inhibitor was IgG with a subclass of IgG4 and reacted with 72 kDa fragment of factor VIII light chain. Steroid pulse therapy following steroid treatment resulted in the resolution of acquired hemophila with marked and prolonged efficacy.

Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

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Werwitzke, S; Geisen, U; Nowak-Göttl, U; Eichler, H; Stephan, B; Scholz, U; Holstein, K; Klamroth, R; Knöbl, P; Huth-Kühne, A; Bomke, B; Tiede, A

2016-05-01

Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration ( 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference

High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors

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Batsuli, Glaivy; Deng, Wei; Healey, John F.; Parker, Ernest T.; Baldwin, W. Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete

2016-01-01

Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. PMID:27381905

Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

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Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

2017-06-01

Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for  85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice

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Dwaipayan Sen

2016-04-01

Full Text Available The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b in the development of joint disease. To investigate the expression profile of miR-15b during the development of arthropathy, we first isolated and studied small RNA from the acute and chronic hemarthrosis model of hemophilia A mice. We observed that miR-15b was consistently repressed (~1- to 4-fold from the onset of joint bleeding (1, 3, 7 and 24 h until six bleeding episodes (up to 90 days. To test if reconstitution of miR-15b modulates biomarkers of joint damage in a chronic hemarthrosis model, we administered an adeno-associated virus (AAV 5-miR-15b vector intra-articularly alone or in combination with systemic administration of AAV2-factor VIII. miR-15b overexpression downregulated markers of angiogenesis and hypoxia (vascular epithelial growth factor α (VEGF-α and hypoxia inducing factor 2α (HIF-2α, ~70% and ~34%, respectively in the affected joints. In addition, the co-administration of miR-15b and factor VIII vectors reduced the levels of the chondrodegenerative matrix-metalloproteinases (MMPs 1, 3, 9 and 14 (~14% to 60% in the injured joints. These data demonstrate for the first time the role of a miR-15b in the development of hemophilic arthropathy and has implications in development of miR based therapies for joint disease.

Predictors of retention among HIV/hemophilia health care professionals.

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Brown, Larry K; Schultz, Janet R; Forsberg, Ann D; King, Gary; Kocik, Susan M; Butler, Regina B

2002-01-01

Health care professionals working with individuals with chronic medical illness, especially those infected with the Human Immunodeficiency Virus (HIV), may be at risk for burnout and departure due to various job stresses such as the death of patients and social stigma. Factors that prevent burnout and employee attrition are seldom studied. Two hundred thirteen staff (doctors, nurses and mental health workers) at a representative sample of Hemophilia Treatment Centers (HTC) completed instruments to measure Burnout (Maslach Burnout Inventory), and perceived job stresses and satisfaction (job tasks, interactions with colleagues and patient care). The staff were surveyed again after two years and their job status determined after 4 years. After 4 years, 35% of the staff had left the field of Hemophilia/HIV care. Univariate tests found that retention was significantly associated with initial job satisfaction, being married and low levels of stress with colleagues. Burnout, as measured by the Maslach Burnout Inventory, at baseline, was unrelated to job retention over 4 years. An adjusted multiple logistic regression of all significant variables found that colleague support was most related to retention (OR=2.8, CI=1.49,5.1). We conclude that attrition of highly trained staff is a significant issue for patients and HTCs. These data suggest the important role that a well-functioning team can have in buffering the inevitable stresses associated with HIV care. Mental Health professionals have considerable expertise in addressing these issues.

The value of usability testing for Internet-based adolescent self-management interventions: "Managing Hemophilia Online".

Science.gov (United States)

Breakey, Vicky R; Warias, Ashley V; Ignas, Danial M; White, Meghan; Blanchette, Victor S; Stinson, Jennifer N

2013-10-04

As adolescents with hemophilia approach adulthood, they are expected to assume responsibility for their disease management. A bilingual (English and French) Internet-based self-management program, "Teens Taking Charge: Managing Hemophilia Online," was developed to support adolescents with hemophilia in this transition. This study explored the usability of the website and resulted in refinement of the prototype. A purposive sample (n=18; age 13-18; mean age 15.5 years) was recruited from two tertiary care centers to assess the usability of the program in English and French. Qualitative observations using a "think aloud" usability testing method and semi-structured interviews were conducted in four iterative cycles, with changes to the prototype made as necessary following each cycle. This study was approved by research ethics boards at each site. Teens responded positively to the content and appearance of the website and felt that it was easy to navigate and understand. The multimedia components (videos, animations, quizzes) were felt to enrich the experience. Changes to the presentation of content and the website user-interface were made after the first, second and third cycles of testing in English. Cycle four did not result in any further changes. Overall, teens found the website to be easy to use. Usability testing identified end-user concerns that informed improvements to the program. Usability testing is a crucial step in the development of Internet-based self-management programs to ensure information is delivered in a manner that is accessible and understood by users.

Limited protective effect of the CCR5Δ32/CCR5Δ32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus

DEFF Research Database (Denmark)

Iversen, Astrid K. N.; Christiansen, Claus Bohn; Attermann, Jørn

2003-01-01

The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)–infected patients with hemophilia. One patient (0.6%) had the CCR5Δ32/CCR5Δ32 genotype (which occurs in ∼2% of the Scandinavian population...

Hemophilia A Pseudoaneurysm in a Patient with High Responding Inhibitors Complicating Total Knee Arthroplasty: Embolization: A Cost-Reducing Alternative to Medical Therapy

International Nuclear Information System (INIS)

Kickuth, Ralph; Anderson, Suzanne; Peter-Salonen, Kristiina; Laemmle, Bernhard; Eggli, Stefan; Triller, Juergen

2006-01-01

Joint hemorrhages are very common in patients with severe hemophilia. Inhibitors in patients with hemophilia are allo-antibodies that neutralize the activity of the clotting factor. After total knee replacement, rare intra-articular bleeding complications might occur that do not respond to clotting factor replacement. We report a 40-year-old male with severe hemophilia A and high responding inhibitors presenting with recurrent knee joint hemorrhage after bilateral knee prosthetic surgery despite adequate clotting factor treatment. There were two episodes of marked postoperative hemarthrosis requiring extensive use of subsititution therapy. Eleven days postoperatively, there was further hemorrhage into the right knee. Digital subtraction angiography diagnosed a complicating pseudoaneurysm of the inferior lateral geniculate artery and embolization was successfully performed. Because clotting factor replacement therapy has proved to be excessively expensive and prolonged, especially in patients with inhibitors, we recommend the use of cost-effective early angiographic embolization

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia a

NARCIS (Netherlands)

C.L. Eckhardt (Corien); A.S. van Velzen (Alice); M.A.D. Peters (Marjolein); J. Astermark (Jan); P.P. Brons; G. Castaman (Giancarlo); M.H. Cnossen (Marjon); N. Dors (N.); C. Escuriola-Ettingshausen (Carmen); K. Hamulyák (K.); D.P. Hart (Daniel); C.R.M. Hay (Charles R.); S. Haya (Saturnino); W.L. van Heerde; C. Hermans (Cédric); M. Holmström (Margareta); V. Jimenez-Yuste (Victor); R.D. Keenan (Russell); R. Klamroth (Robert); B.A.P. Laros-Van Gorkom (Britta); F.W.G. Leebeek (Frank); R. Liesner (Ri); A. Mäkipernaa (Anne); C. Male (Christoph); E.P. Mauser-Bunschoten (Eveline); M.G. Mazzucconi (Maria); S. McRae (Simon); K. Meijer (K.); M. Mitchell (Michael); M. Morfini (Massimo); M.R. Nijziel (Marten); J. Oldenburg (Jan); K. Peerlinck; P. Petrini (Pia); H. Platokouki (Helena); S.E. Reitter-Pfoertner (Sylvia); E. Santagostino (Elena); P. Schinco (Piercarla); F.J.W. Smiers (Frans); K.D. Siegmund (Kimberly); A. Tagliaferri (Annarita); T.T. Yee (Thynn); P.W. Kamphuisen (Pieter Willem); J.G. van der Bom (Anske); K. Fijnvandraat

2013-01-01

textabstractNeutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into

A systematic review of the effects of hemophilia and von Willebrand disease on arterial trombosis

NARCIS (Netherlands)

Biere-Rafi, Sara; Zwiers, M.; Peters, Marjolein; Van Der Meer, Jan; Rosendaal, Frits R; Buller, Harry R; Kamphuisen, Pieter W

Background: Patients with hemophilia and von Willebrand disease (VWD) may be protected against arterial thrombosis, through a hy-pocoagulable state or atherosclerosis. We performed a systematic review to assess the association between these clotting disorders, arterial thrombosis and the prevalence

The value of HEAD-US system in detecting subclinical abnormalities in joints of patients with hemophilia.

Science.gov (United States)

De la Corte-Rodriguez, Hortensia; Rodriguez-Merchan, E Carlos; Alvarez-Roman, M Teresa; Martin-Salces, Mónica; Martinoli, Carlo; Jimenez-Yuste, Víctor

2018-03-01

Prevention of hemarthrosis is the key factor in the adequate management of people with hemophilia (PWH). If hemarthrosis occurs, early diagnosis of joint damage is essential to make personalized treatments. This study is aimed at gaining an understanding of the ability of point-of-care ultrasound (US) using the `Hemophilia Early Arthropathy Detection with Ultrasound´ (HEAD-US) protocol to detect abnormalities in joints without history of hemarthrosis and clinically asymptomatic joints of PWH. The sample included 976 joints from 167 PWH (mean age 24.86 years). Data were collected from routine practice over a 3-year period and analyzed based on history of hemarthrosis and results of clinical (HJHS 2.1) and HEAD-US examinations. In our series, 14% of patients exhibited HEAD-US signs of incipient arthropathy in joints with no history of bleeding and with a HJHS 2.1 score of 0. The most severely involved joint was the right ankle. Synovitis, articular cartilage and subchondral bone damage scores in joints with subclinical findings were slower than in joints with previous hemarthroses or HJHS 2.1 > 1 Conclusions: Our study demonstrates that HEAD-US is better than hemarthrosis records and the HJHS 2.1 scale in detecting the early signs of joint damage in PWH.

Mutagenesis in sequence encoding of human factor VII for gene therapy of hemophilia

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B Kazemi

2009-12-01

Full Text Available "nBackground: Current treatment of hemophilia which is one of the most common bleeding disorders, involves replacement therapy using concentrates of FVIII and FIX .However, these concentrates have been associated with viral infections and thromboembolic complications and development of antibodies. "nThe use of recombinant human factor VII (rhFVII is effective  for the treatment of patients with  hemophilia A or B, who develop antibodies ( referred as inhibitors against  replacement therapy , because it induces coagulation independent of FVIII and FIX. However, its short half-life and high cost have limited its use. One potential solution to this problem may be the use of FVIIa gene transfer, which would attain continuing therapeutic levels of expression from a single injection. The aim of this study was to engineer a novel hFVII (human FVII gene containing a cleavage site for the intracellular protease and furin, by PCR mutagenesis "nMethods: The sequence encoding light and heavy chains of hFVII, were amplified by using hFVII/pTZ57R and specific primers, separately. The PCR products were cloned in pTZ57R vector. "nResults and discussion: Cloning was confirmed by restriction analysis or PCR amplification using specific primers and plasmid universal primers. Mutagenesis of sequence encoding light and heavy chain was confirmed by restriction enzyme. "nConclusion: In the present study, it was provided recombinant plasmids based on mutant form of DNA encoding light and heavy chains.  Joining mutant form of DNA encoding light chain with mutant heavy chain led to a new variant of hFVII. This variant can be activated by furin and an increase in the proportion of activated form of FVII. This mutant form of hFVII may be used for gene therapy of hemophilia.

Direct detection of common and rare inversion mutations in the genetic diagnosis of severe hemophilia A

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Windsor, A.S.; Lillicrap, D.P.; Taylor, S.A.M. [Queen`s Univ., Ontario (Canada)

1994-09-01

Approximately 50% of the cases of severe hemophilia A (factor VIII:C < 0.01 units/ml) may be due to gross rearrangements of the factor VIII gene. The mutation involves homologous sequences upstream of the factor VIII locus and within intron 22 in an intrachromosomal recombination, inversion, event. The rearrangements can readily be detected on a Southern blot using a probe that is complementary to sequences from within intron 22. We describe here the analysis of this mutation in 71 severe hemophilia A patients. Thirty two of the patients (45%) showed evidence of a rearrangement. Five different patterns of rearrangements were seen, two of which have previously been described and account for the majority of cases (pattern 1, 70% and pattern 2, 16%). Three other abnormal patterns were observed. The inversion mechanism does not usually result in the loss or gain of any genetic material, but in one patient, in whom a unique rearrangement pattern was observed (pattern 3), we have previously documented a gross deletion which removes exons 1-22 of the factor VII gene as well as sequences 5{prime} to the gene. In another individual a fourth pattern in which an extra 19.0 kb band is present was detected. In this case it is unclear as to whether the rearrangement is responsible for the disease or is simply coincident normal variation. A fifth pattern, in which an extra 16.0 kb band was detected, was observed in a family with a new mutation causing hemophilia A. The affected individual and his mother inherited a de novo rearrangement of the factor VIII gene from his unaffected grandfather, implicating it as the cause of the disease. In conclusion, testing for the factor VIII inversion mutation was positive in approximately 45% of severe hemophiliacs, 72% of whom were isolated cases, and as such should constitute the initial stage in the genetic testing protocol for these patients` families.

Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A

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McGinniss, M.J.; Kazazian, H.H. Jr.; Bi, L.; Antonarakis, S.E. (John Hopkins Univ., Baltimore, MD (United States)); Hoyer, L.W. (American Red Cross Blood Services, Rockville, MD (United States)); Inaba, H. (Tokyo Medical College (Japan))

1993-02-01

Hemophilia A is due to the functional deficiency of factor VIII (FVIII, gene locus F8C). Although half the patients have no detectable FVIII protein in their plasma, the more rare patients ([approximately]5%) have normal levels of a dysfunctional FVIII and are termed cross-reacting material (CRM)-positive. More commonly ([approximately]45%), patients have plasma FVIII protein reduced to an extent roughly comparable to the level of FVIII activity and are designated CRM-reduced. We used denaturing gradient gel electrophoresis to screen for mutations within the F8C gene of 11 patients (6CRM-positive, 5 CRM-reduced) and identified 9 different mutations in 9 patients after analyses of all 26 exons, the promoter region, and the polyadenylation site. Six mutations have not been described previously. Five weree missense (Ser289Leu, Ser558Phe, Val634Ala, Val634Met, Asn1441Lys), and the sixth was a 3-bp deletion ([Delta]Phe652). A review of the literature and the assay of FVIII antigen in 5 hemophilia A patients with previously identified missense mutations from this laboratory yielded a total of 20 other unique CRM-reduced and CRM-positive mutations. Almost all CRM-positive/reduced mutations (24/26) were missense, and many (12/26) occurred at CpG dinucleotides. We examined 19 missense mutation for evolutionary conservation using the portions of the porcine and murine F8C sequences that are known, and 18/19 amino acid residue altered by mutation in these patients wer conserved. Almost 50% of mutations (11/26) clustered in the A2 domain, suggesting that this region is critical for the function of FVIII. The results indicate a nonrandom distribution of mutations and suggest that mutations in a limited number of FVIII regions may cause CRM-positive and CRM-reduced heomphilia A. 48 refs., 1 fig., 1 tab.

Detection of hemophilia A carriers by use of frozen plasma samples

International Nuclear Information System (INIS)

Yang, H.C.; Hardin, J.; Vaudreuil, C.

1978-01-01

The efficacy of using promptly frozen plasma samples in the diagnosis of the carrier state for hemophilia A was evaluated by simultaneous measurement of factor VIII activity and antigen in 20 normal women and 20 obligate carriers. Factor VIII antigen was measured by two methods, electroimmunoassay and immunoradiometric assay. When the factor VIII activity and antigen data were evaluated by regression analysis, 94% of the carriers were correctly identified at the 95% confidence level

DESCRIPTIVE EPIDEMIOLOGY OF HEMOPHILIA AND OTHER COAGULATION DISORDERS IN MANSOURA , EGYPT

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Youssef Al Tonbary

2010-08-01

The study included 72 children with hematological disorders registered from 2000 to 2008 in MUCH. The hemophilic patient was defined as a person with physician-diagnosed hemophilia A or B and a measured factor VIII or IX activity level of 30% or less. Persons with acquired inhibitors of FVIII or FIX excluded. Severity level was categorized as mild if the factor activity level was 6–30%, moderate if 1–5% and severe if

Single-tube tetradecaplex panel of highly polymorphic microsatellite markers hemophilia A.

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Zhao, M; Chen, M; Tan, A S C; Cheah, F S H; Mathew, J; Wong, P C; Chong, S S

2017-07-01

Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. Background It is currently not possible to perform single-cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex-PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located ≤ 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ∼70-80% of individuals were heterozygous for ≥ 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic

Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors.

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Chai-Adisaksopha, Chatree; Nevitt, Sarah J; Simpson, Mindy L; Janbain, Maissaa; Konkle, Barbara A

2017-09-25

compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses).The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence).The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study. The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.

Bentall Operation in a Patient With Severe Hemophilia A and Marfan Syndrome by Use of a Biologic Composite Graft.

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Yildirim, Funda; Ozbakkaloglu, Alper; Ozturk, Tulun; Tetik, Omer

2016-03-01

We describe a patient with severe hemophilia A and Marfan syndrome who underwent an elective Bentall operation. Because of the severe hemophilia, anticoagulation could not be given postoperatively; thus, a biologic Valsalva conduit graft was used. During the procedure, factor VIII was given as a bolus dose just before incision, then by continous infusion intraoperatively to maintain the factor VIII activity level between 200% and 300%. Minimal postoperative bleeding occurred. The infusion was continued postoperatively at a lower dose until all chest tubes, pacing wires, and invasive catheters were removed. The patient was discharged on postoperative day 7 without adverse events. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Genética comunitária e hemofilia em uma população brasileira Community genetics and hemophilia in a Brazilian population

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Vânia Maria Caio

2001-06-01

Full Text Available A hemofilia é uma doença hemorrágica importante no Brasil, afetando cerca de um em cada dez mil indivíduos do sexo masculino. A autopercepção do portador a respeito da hemofilia e a sua interação com a comunidade são relevantes na abordagem clínica dessa doença. Nós investigamos vários aspectos sociais, psicológicos e comunitários da hemofilia em uma população brasileira (Campinas, São Paulo. Entrevistamos trinta portadores adultos da hemofilia, uma amostra-controle composta por 73 de seus irmãos normais do sexo masculino e 641 indivíduos da comunidade. A integração comunitária dos portadores da hemofilia mostrou-se afetada apenas nos aspectos sócio-econômicos, sem alteração no que diz respeito ao casamento, à procriação e à aquisição de melhores níveis educacionais. Observaram-se entre os portadores da hemofilia altos níveis de auto-rotulação, acompanhados de depressão, ansiedade e insegurança. A comunidade apresentou uma alta freqüência de completo desconhecimento a respeito da hemofilia (49%, demonstrando contra os hemofílicos os preconceitos normalmente observados contra os portadores de doenças contagiosas, como a AIDS. O trabalho sugere a estruturação de programa comunitário, visando à melhor adequação psicossocial dos portadores da hemofilia.Hemophilia is an important hemorrhagic disease in Brazil, affecting about 1 out of every 10,000 males. Patient's self-perception of hemophilia and interaction with the community are relevant to the clinical management of this disease. We investigated several social, psychological, and community aspects of hemophilia in a Brazilian population (Campinas, São Paulo State, interviewing 30 hemophiliac males, a control sample comprised of 73 non-hemophiliac brothers, and 641 individuals from the community. According to our results, more severe social disability in the hemophiliac patient was related to economic factors, mainly unemployment; however, no

A close insight to factor VIII inhibitor in the congenital hemophilia A.

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Tabriznia-Tabrizi, Shamsoreza; Gholampour, Marzie; Mansouritorghabeh, Hassan

2016-09-01

Hemophilia A (HA) has an X-linked pattern of inheritance and is the most common of the hemorrhagic disorders. HA is caused by a decreased or deficiency of the functional clotting factor VIII (FVIII) and effects 1 in 5000-10,000 male births. The common treatment for hemophilia is replacement therapy by plasma-derived or recombinant FVIII. Approximately 20-30% of people with a severe type of HA develop an inhibitor and this phenomenon is the main challenge in the management of these patients. Genetic factors and environmental determinants contribute to inhibitor development. Here, the roles of various genetic and environmental factors such as the type of FVIII concentrate used, the number of exposure days, and peak treatment time will be discussed in detail. It seems this information is helpful for hematologists. A literature review was done in January 2016 on PubMed and Scopus using the following keywords:' h(a)emophilia A & factor VIII inhibitor', 'h(a)emophilia A & factor VIII alloantibody', 'h(a)emophilia A & inhibitor'. There was no time limitation; however, there was an English language limitation placed on the articles selected. Expert commentary: Influential genetic and environmental factors in developing inhibitors have been discussed. Most of the risk factors are related to previously untreated patients with hemophili.

The value of usability testing for Internet-based adolescent self-management interventions: “Managing Hemophilia Online”

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2013-01-01

Background As adolescents with hemophilia approach adulthood, they are expected to assume responsibility for their disease management. A bilingual (English and French) Internet-based self-management program, “Teens Taking Charge: Managing Hemophilia Online,” was developed to support adolescents with hemophilia in this transition. This study explored the usability of the website and resulted in refinement of the prototype. Methods A purposive sample (n=18; age 13–18; mean age 15.5 years) was recruited from two tertiary care centers to assess the usability of the program in English and French. Qualitative observations using a “think aloud” usability testing method and semi-structured interviews were conducted in four iterative cycles, with changes to the prototype made as necessary following each cycle. This study was approved by research ethics boards at each site. Results Teens responded positively to the content and appearance of the website and felt that it was easy to navigate and understand. The multimedia components (videos, animations, quizzes) were felt to enrich the experience. Changes to the presentation of content and the website user-interface were made after the first, second and third cycles of testing in English. Cycle four did not result in any further changes. Conclusions Overall, teens found the website to be easy to use. Usability testing identified end-user concerns that informed improvements to the program. Usability testing is a crucial step in the development of Internet-based self-management programs to ensure information is delivered in a manner that is accessible and understood by users. PMID:24094082

Considerations in dental treatment of pediatric patients with hemophilia: A case report.

OpenAIRE

Lorena Bravo; Daniela Muñoz

2012-01-01

A male patient, 7 years old, attends the Regional Hospital of Guillermo Grant Benavente derived by a presumptive diagnosis of hemophilia due to bleeding resulting from extraction of a primary tooth and a family history. A hematologic study was realized, where was observed that the factor VIII was decreased, which confirmed the diagnosis. For dental treatment was coordinated with the treating hematologist for inpatient management and control of hematologic parameters during invasive dental pro...

Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B

DEFF Research Database (Denmark)

Miesbach, Wolfgang; Meijer, Karina; Coppens, Michiel

2018-01-01

Hemophilia B gene therapy aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expre...

Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A.

Science.gov (United States)

Nguyen, G N; George, L A; Siner, J I; Davidson, R J; Zander, C B; Zheng, X L; Arruda, V R; Camire, R M; Sabatino, D E

2017-01-01

Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. Background The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2-4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a

International recommendations on the diagnosis and treatment of patients with acquired hemophilia A

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Huth-Kühne, Angela; Baudo, Francesco; Collins, Peter; Ingerslev, Jørgen; Kessler, Craig M.; Lévesque, Hervé; Castellano, Maria Eva Mingot; Shima, Midori; St-Louis, Jean

2009-01-01

Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Typically, patients with no prior history of a bleeding disorder present with spontaneous bleeding and an isolated prolonged aPTT. AHA may, however, present without any bleeding symptoms, therefore an isolated prolonged aPTT should always be investigated further irrespective of the clinical findings. Control of acute bleeding is the first priority, and we recommend first-line therapy with bypassing agents such as recombinant activated FVII or activated prothrombin complex concentrate. Once the diagnosis has been achieved, immediate autoantibody eradication to reduce subsequent bleeding risk should be performed. We recommend initial treatment with corticosteroids or combination therapy with corticosteroids and cyclophosphamide and suggest second-line therapy with rituximab if first-line therapy fails or is contraindicated. In contrast to congenital hemophilia, no comparative studies exist to support treatment recommendations for patients with AHA, therefore treatment guidance must rely on the expertise and clinical experience of specialists in the field. The aim of this document is to provide a set of international practice guidelines based on our collective clinical experience in treating patients with AHA and contribute to improved care for this patient group. PMID:19336751

Labeled factor IX kinetics in patients with hemophilia-B

International Nuclear Information System (INIS)

Smith, K.J.; Thompson, A.R.

1981-01-01

Labeled factor IX was infused five time into four patients with hemophilia-B. Ten-minute plasma recovery average 35% (SD +/- 2) and the mean T 1/2 beta-phase elimination was 23 hr (+/- 5). No alteration in the postinfusion 125I-factor-IX could be detected by radioautography of plasma samples run on polyacrylamide gels or on crossed-immunoelectrophoresis. Label was excreted into the urine as free 125I-iodide. Kinetics were similar when the labeled preparation was infused alone or with a commercial concentrate containing unlabeled factor IX. Infusion of factor IX in man is best described by a two-compartment open pharmacokinetic model where factor IX is distributed in a space larger than the plasma volume

Massive adrenal vein aneurysm mimicking an adrenal tumor in a patient with hemophilia A: a case report and review of the literature

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Richard Sleightholm

2016-12-01

Full Text Available Abstract Background Visceral venous aneurysms are exceedingly rare, and until now, there have been no reports of this phenomenon in the adrenal vasculature. This report details the first adrenal venous aneurysm reported in the literature. The aneurysm presented as an 18-cm mass that was initially suspected to be a hematoma or tumor on the basis of the complex medical history of the patient, which included hemophilia A and testicular cancer. After surgical excision, pathologic examination confirmed this mass to be a 15.9-cm adrenal vein aneurysm, the largest aneurysm of any type or location recorded in the medical literature. Case presentation A 58-year-old caucasian male with hemophilia A presented to the emergency room of another institution with abdominal pain, blood in the stool, and a history of diverticulosis and symptomatic hemorrhoids. A large, left-sided adrenal mass was detected by computed tomography, and because of the patient’s hemophilia A and imaging consistent with a hemorrhagic mass, a hematoma was initially suspected. The patient was transferred to our institution, monitored for further bleeding with a stable hospital course, and discharged from the hospital under close monitoring. After 7–8 weeks with no change in the size of the mass, concerns grew regarding increasing symptoms of both satiety and mass effects from the large anomaly, as well as about the patient’s complicated medical history, which also included cancer. Surgical excision was recommended because of the concerns about increasing symptoms and the possibility of a malignancy. Correction and maintenance of factor VIII levels were incorporated pre-, intra-, and postoperatively, and en bloc surgical resection was performed to minimize bleeding and provide oncologic extirpation of the mass. A bowling ball-sized mass was removed, and careful pathologic examination revealed the mass to be a venous adrenal aneurysm. After a brief hospital stay, the patient made a

Massive adrenal vein aneurysm mimicking an adrenal tumor in a patient with hemophilia A: a case report and review of the literature.

Science.gov (United States)

Sleightholm, Richard; Wahlmeier, Steven; Carson, Jeffrey S; Drincic, Andjela; Lazenby, Audrey; Foster, Jason M

2016-12-01

Visceral venous aneurysms are exceedingly rare, and until now, there have been no reports of this phenomenon in the adrenal vasculature. This report details the first adrenal venous aneurysm reported in the literature. The aneurysm presented as an 18-cm mass that was initially suspected to be a hematoma or tumor on the basis of the complex medical history of the patient, which included hemophilia A and testicular cancer. After surgical excision, pathologic examination confirmed this mass to be a 15.9-cm adrenal vein aneurysm, the largest aneurysm of any type or location recorded in the medical literature. A 58-year-old caucasian male with hemophilia A presented to the emergency room of another institution with abdominal pain, blood in the stool, and a history of diverticulosis and symptomatic hemorrhoids. A large, left-sided adrenal mass was detected by computed tomography, and because of the patient's hemophilia A and imaging consistent with a hemorrhagic mass, a hematoma was initially suspected. The patient was transferred to our institution, monitored for further bleeding with a stable hospital course, and discharged from the hospital under close monitoring. After 7-8 weeks with no change in the size of the mass, concerns grew regarding increasing symptoms of both satiety and mass effects from the large anomaly, as well as about the patient's complicated medical history, which also included cancer. Surgical excision was recommended because of the concerns about increasing symptoms and the possibility of a malignancy. Correction and maintenance of factor VIII levels were incorporated pre-, intra-, and postoperatively, and en bloc surgical resection was performed to minimize bleeding and provide oncologic extirpation of the mass. A bowling ball-sized mass was removed, and careful pathologic examination revealed the mass to be a venous adrenal aneurysm. After a brief hospital stay, the patient made a full recovery. Extensive review of the literature revealed 11

Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A

DEFF Research Database (Denmark)

Hvas, Anne-Mette; Sørensen, Hanne Thykjær; Norengaard, Lisbeth

2007-01-01

examined whether the clot stability in hemophiliacs could be improved by treatment with tranexamic acid (TXA) in combination with recombinant factor VIII (rFVIII). PATIENTS/METHODS: Baseline blood samples were obtained from eight males with severe hemophilia A. Thereafter, a bolus injection of r...

Antibody response to recombinant human coagulation factor VIII in a new rat model of severe hemophilia A

DEFF Research Database (Denmark)

Löfgren, Karin Maria; Sondergaard, H.; Skov, Søren

2016-01-01

Background: Neutralizing antibodies towardFVIII replacement therapy (inhibitors) are the most seri-ous treatment-related complication in hemophilia A(HA). A rat model of severe HA (F8/) has recentlybeen developed, but an immunological characterization isneeded to determine the value of using...

Considerations in dental treatment of pediatric patients with hemophilia: A case report.

Directory of Open Access Journals (Sweden)

Lorena Bravo

2012-12-01

Full Text Available A male patient, 7 years old, attends the Regional Hospital of Guillermo Grant Benavente derived by a presumptive diagnosis of hemophilia due to bleeding resulting from extraction of a primary tooth and a family history. A hematologic study was realized, where was observed that the factor VIII was decreased, which confirmed the diagnosis. For dental treatment was coordinated with the treating hematologist for inpatient management and control of hematologic parameters during invasive dental procedures, by the administration of factor VIII.

Special features of total knee replacement in hemophilia.

Science.gov (United States)

Rodriguez-Merchan, Emerito Carlos

2013-12-01

Total knee replacement is an operation frequently needed by hemophilia patients, which greatly improves their quality of life. This operation, however, carries a higher risk of bleeding and infection for hemophiliacs than it does for osteoarthritis sufferers. It is advisable to implant prosthetic components using antibiotic-loaded cement. It is essential to maintain a level of 100% of the replacement clotting factor for 2 weeks. Hematological treatment must be established, depending on the patient's factor levels and other pharmacokinetic parameters such as recovery and half-life, optimal doses and treatment time. It is preferable to use general anesthesia due to the risk of spinal bleeding. The lifespan of total knee replacement in hemophilic patients is shorter than in patients with osteoarthritis because of the increased risk of infection.

The Effectiveness of a New Hemostatic Agent (Ankaferd Blood Stopper for the Control of Bleeding following Tooth Extraction in Hemophilia: A Controlled Clinical Trial

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Hakkı Oğuz Kazancıoğlu

2013-03-01

Full Text Available Objective: To assess the hemostatic efficacy of a new local hemostatic agent, Ankaferd Blood Stopper (ABS, for the control of bleeding following tooth extraction in hemophiliacs. Materials and Methods: Simple tooth extractions were performed in 27 hemophilia A patients. In the treatment group (n=17 local hemostasis was achieved via application of ABS to the extraction sockets, whereas in the control group (n=10 local hemostasis was achieved via direct packing with gauze. Results: In all, 57 (21 primary and 36 permanent teeth extractions were performed in 27 hemophilia A patients. There were no significant differences in age or factor VIII level distribution between the 2 groups (p>0.05. The most significant clinical difference between the groups was associated with the use of ABS; those in the treatment group had significantly shorter duration of bleeding (p=0.002. Conclusion: This is the first study to evaluate the efficacy of ABS for the control of bleeding following tooth extraction in hemophiliacs. ABS can be considered an alternative local hemostatic agent for reducing clotting factor concentrates in hemophilia patients.

Genetic variation of rs438601 marker in the Iranian Population: An informative marker for molecular diagnosis of hemophilia B

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P Dorri

2014-12-01

Conclusion: The study findings demonstrated that rs438601 marker due to high heterozygosity could be suggested as an appropriate diagnostic marker in linkage analysis and carrier detection of hemophilia B in regard with a sample of Iranian population.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

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Lane, Jérôme; McLaren, Paul J.; Dorrell, Lucy; Shianna, Kevin V.; Stemke, Amanda; Pelak, Kimberly; Moore, Stephen; Oldenburg, Johannes; Alvarez-Roman, Maria Teresa; Angelillo-Scherrer, Anne; Boehlen, Francoise; Bolton-Maggs, Paula H.B.; Brand, Brigit; Brown, Deborah; Chiang, Elaine; Cid-Haro, Ana Rosa; Clotet, Bonaventura; Collins, Peter; Colombo, Sara; Dalmau, Judith; Fogarty, Patrick; Giangrande, Paul; Gringeri, Alessandro; Iyer, Rathi; Katsarou, Olga; Kempton, Christine; Kuriakose, Philip; Lin, Judith; Makris, Mike; Manco-Johnson, Marilyn; Tsakiris, Dimitrios A.; Martinez-Picado, Javier; Mauser-Bunschoten, Evelien; Neff, Anne; Oka, Shinichi; Oyesiku, Lara; Parra, Rafael; Peter-Salonen, Kristiina; Powell, Jerry; Recht, Michael; Shapiro, Amy; Stine, Kimo; Talks, Katherine; Telenti, Amalio; Wilde, Jonathan; Yee, Thynn Thynn; Wolinsky, Steven M.; Martinson, Jeremy; Hussain, Shehnaz K.; Bream, Jay H.; Jacobson, Lisa P.; Carrington, Mary; Goedert, James J.; Haynes, Barton F.; McMichael, Andrew J.; Goldstein, David B.; Fellay, Jacques

2013-01-01

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population. PMID:23372042

In silico evaluation of limited blood sampling strategies for individualized recombinant factor IX prophylaxis in hemophilia B patients

NARCIS (Netherlands)

Preijers, T.; Hazendonk, H. C. A. M.; Fijnvandraat, K.; Leebeek, F. W. G.; Cnossen, M. H.; Mathôt, R. A. A.

2017-01-01

Background Patients with severe hemophilia B regularly administer prophylactic intravenous doses of clotting factor IX concentrate to maintain a trough level of at least 0.01 IU mL(-1) in order to prevent joint bleeds. Assessment of individual pharmacokinetic (PK) parameters allows individualization

Duodenal Tumor Presenting as Acquired Hemophilia in an 88-Year-Old Woman: A Clinical Case and Review of the Literature

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Nigel P. Murray

2012-01-01

Full Text Available Acquired hemophilia is a rare disease, presenting with severe hemorrhage, we present a case caused by a duodenal tumor, the clinical management, ethical implications, treatment recommendations, and a review of the literature.

Effects of therapeutic exercise and hydrotherapy on pain severity and knee range of motion in patients with hemophilia: a randomized controlled trial.

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Mazloum, Vahid; Rahnama, Nader; Khayambashi, Khalil

2014-01-01

Pain and limited range of motion (ROM) are the crucial subsequent results of joint hemorrhages in individuals with bleeding disorders and hemophilia. Exercise interventions are particularly recommended in treatment of such patients. The purpose of this study was to detect the influences of conventional exercise therapy and hydrotherapy on the knee joint complications in patients with hemophilia. A total of 40 patients engaging hemophilia A were randomized into one of three groups: Therapeutic exercise (N = 13), hydrotherapy (N = 14) or control (N = 13). While the first two groups followed their specific programs for 4 weeks, routine life-style was maintained by subjects in the control group in this period. To evaluate the pain level and knee ROM the visual analog scale and standard goniometer were utilized, respectively. The outcome was measured at baseline and after completing the prescribed protocols. Data analysis was performed using one-way analysis of variance and Scheffe statistical tests (P hydrotherapy in comparison to exercise therapy, the difference in ROM improvement was not statistically significant (P > 0.05). Using hydrotherapy in addition to usual rehabilitation training can result in beneficial effect in terms of pain and knee joint ROM. However, it appears that hydrotherapy is more effective in reducing pain.

Patient preferences in the treatment of hemophilia A: impact of storage conditions on product choice.

Science.gov (United States)

Tischer, Bernd; Marino, Renato; Napolitano, Mariasanta

2018-01-01

To gain insights into the usage of factor VIII (FVIII) products by patients diagnosed with moderate/severe hemophilia A, and to assess the impact and perceived importance of product storage. In this study, 200 patients diagnosed with moderate or severe hemophilia A across seven countries participated. Data were collected via a 30-minute, face-to-face interview in six countries and via a web-based survey in the seventh country. The questionnaire evaluated the effect of six features associated with FVIII products on the choice of the product; the structure and flow of data collection was designed to eliminate potential bias. Two-thirds of the respondents were using recombinant FVIII products. Only 17% were generally dissatisfied with current FVIII products, whereas >40% of the respondents were dissatisfied with frequency of administration and storage issues when traveling. The majority noted restrictions in their daily activities, particularly travel and sports. Most of them (85%), stored their product in the refrigerator and of these, 88% believed that it should always be stored there. These patients were also less satisfied with the product overall, more concerned about storage temperature, more restricted in daily activities, and spent more time on preparation and injection compared with patients who stored their product at room temperature. Conjoint analysis revealed that origin of FVIII (plasma-derived vs recombinant) was the strongest driver of product choice among all respondents, followed by storage flexibility (temperature), reconstitution device, and administration frequency. In this study, we did not investigate the efficacy and safety of the product. Not refrigerating FVIII products was associated with greater patient satisfaction and less restriction on daily activities. If efficacy and safety are unaffected, then storing FVIII at room temperature might have a positive impact on product choice. Few patients were aware that FVIII can be stored without

Molecular study in children with hemophilia A in Colombia: analysis of Intron 1 and 22 inversion using long-distance PCR technique

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María Fernanda Garcés

2017-04-01

Conclusions: Inversions of intron 22 and 1 were found in half of this group of patients. These results are reproducible and useful to identify the two most frequent mutations in severe hemophilia A patients.

Hemophilia care in the state of Rio de Janeiro, Brazil El tratamiento de la hemofilia en el estado de Rio de Janeiro, Brasil

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Eva M. A. Fontes

2003-03-01

Full Text Available In the developing countries of the world, few people with hemophilia receive adequate care. Nevertheless, Brazil has made significant advances in the treatment of hemophilia over the last decade. The provision of factor concentrates imported by the Government of Brazil is gradually increasing, and patients receive the concentrates for free. A national register was established as well as a coordinated program for comprehensive care. Of the 6 297 persons with hemophilia in Brazil who were registered as of January 2001, 689 of them (11.1% were registered in the state of Rio de Janeiro. Of those 689, 664 of them were being monitored at the state's coordinating blood transfusion center, which is located in the city of Rio de Janeiro. Among those 664, factor VIII inhibitors were identified in 81 of them (12.2%. Among 653 of the Rio de Janeiro patients who were tested for transfusion-transmitted diseases, the overall prevalence found was 41.5%, with the specific rates being 13.3% for human immunodeficiency virus (HIV, 2.9% for hepatitis B virus (HBV, and 39.4% for hepatitis C virus (HCV. The state of Rio de Janeiro has adopted a comprehensive hemophilia management approach that includes medical, psychological, and social care. As a result, the quality of life of hemophilia patients has improved noticeably. For example, the rate of hospitalization among patients fell by 30% between 1998 and 2001, and there has also been a decline in the school and work activities that they have missed.En los países en desarrollo, pocas personas con hemofilia reciben un tratamiento adecuado. No obstante, el Brasil ha logrado grandes avances en este sentido en el último decenio. La provisión de concentrados de factores de la coagulación importados por el gobierno de Brasil va aumentando gradualmente y los pacientes reciben el concentrado gratis. Un registro nacional se estableció junto con un programa coordinado de atención global. De las 6 297 personas con

Direct detection of hemophilia B F9 gene mutation using multiplex PCR and conformation sensitive gel electrophoresis

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Ki Young Yoo

2010-03-01

Full Text Available Purpose : The F9 gene is known to be the causative gene for hemophilia B, but unfortunately the detection rate for restriction fragment length polymorphism-based linkage analysis is only 55.6%. Direct DNA sequencing can detect 98% of mutations, but this alternative procedure is very costly. Here, we conducted multiplex polymerase chain reactions (PCRs and conformation sensitive gel electrophoresis (CSGE to perform a screened DNA sequencing for the F9 gene, and we compared the results with direct sequencing in terms of accuracy, cost, simplicity, and time consumption. Methods : A total of 27 unrelated hemophilia B patients were enrolled. Direct DNA sequencing was performed for 27 patients by a separate institute, and multiplex PCR-CSGE screened sequencing was done in our laboratory. Results of the direct DNA sequencing were used as a reference, to which the results of the multiplex PCR-CSGE screened sequencing were compared. For the patients whose mutation was not detected by the 2 methods, multiplex ligation-dependent probe amplification (MLPA was conducted. Results : With direct sequencing, the mutations could be identified from 26 patients (96.3%, whereas for multiplex PCR- CSGE screened sequencing, the mutations could be detected in 23 (85.2%. One patient’s mutation was identified by MLPA. A total of 21 different mutations were found among the 27 patients. Conclusion : Multiplex PCR-CSGE screened DNA sequencing detected 88.9% of mutations and reduced costs by 55.7% compared with direct DNA sequencing. However, it was more labor-intensive and time-consuming.

Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B

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Sushrusha eNayak

2011-12-01

Full Text Available Intramuscular (IM administration of an adeno-associated viral (AAV vector represents a simple and safe method of gene transfer for treatment of the X-linked bleeding disorder hemophilia B (factor IX, F.IX, deficiency. However, the approach is hampered by an increased risk of immune responses against F.IX. Previously, we demonstrated that the drug cocktail of immune suppressants rapamycin, IL-10, and a specific peptide (encoding a dominant CD4+ T cell epitope caused an induction of regulatory T cells (Treg with a concomitant apoptosis of antigen-specific effector T cells (J. Thromb. Haemost. 7:1523, 2009. This protocol was effective in preventing inhibitory antibody formation against human F.IX (hF.IX in muscle gene transfer to C3H/HeJ hemophilia B mice (with targeted F9 gene deletion. Here, we show that this protocol can also be used to reverse inhibitor formation. IM injection of AAV1-hF.IX vector resulted in inhibitors of on average 8-10 BU within 1 month. Subsequent treatment with the tolerogenic cocktail accomplished a rapid reduction of hF.IX-specific antibodies to <2 BU, which lasted for >4.5 months. Systemic hF.IX expression increased from undetectable to >200 ng/ml, and coagulation times improved. In addition, we developed an alternative prophylactic protocol against inhibitor formation that did not require knowledge of T cell epitopes, consisting of daily oral administration of rapamycin for 1-month combined with frequent, low-dose intravenous injection of hF.IX protein. Experiments in T cell receptor transgenic mice showed that the route and dosing schedule of drug administration substantially affected Treg induction. When combined with intravenous antigen administration, oral delivery of rapamycin had to be performed daily in order to induce Treg, which were suppressive and phenotypically comparable to natural Treg.

METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

OpenAIRE

N. B. Molchanova

2015-01-01

Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII). The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the mode...

Localised prostate cancer and hemophilia A (AHA: Case report and management of the disease

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Francesco Celestino

2014-09-01

Full Text Available Acquired Hemophilia A (AHA is a rare bleeding diathesis characterized by the development of autoantibodies against factor VIII (FVIII. About half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . AHA is associated with malignancies in 7-15% of cases. We report a case of AHA in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (RP.

Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A

NARCIS (Netherlands)

Collins, P. W.; Blanchette, V. S.; Fischer, K.; Bjorkman, S.; Oh, M.; Fritsch, S.; Schroth, P.; Spotts, G.; Astermark, J.; Ewenstein, B.

Background: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL(-1).

Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment

Science.gov (United States)

The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVII...

Acquired hemophilia A: a review of recent data and new therapeutic options.

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Franchini, Massimo; Vaglio, Stefania; Marano, Giuseppe; Mengoli, Carlo; Gentili, Sara; Pupella, Simonetta; Liumbruno, Giancarlo Maria

2017-10-01

Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

Prevention of the Musculoskeletal Complications of Hemophilia

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E. C. Rodriguez-Merchan

2012-01-01

Full Text Available Hemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including hemarthroses, leading to musculoskeletal complications. The articular problems of hemophiliac patients begin in infancy. These include: recurrent hemarthroses, chronic synovitis, flexion deformities, hypertrophy of the growth epiphyses, damage to the articular cartilage, and hemophilic arthropathy. The most commonly affected joints are the ankle, the knee, and the elbow. Hematologic prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient's deficient factor is prevented from falling below 1% of normal. Hemarthroses can be prevented by the administration of clotting factor concentrates (prophylaxis. However, high costs and the need for venous access devices in younger children continue to complicate recommendations for universal prophylaxis. Prevention of joint arthropathy needs to focus on prevention of hemarthroses through prophylaxis, identifying early joint disease through the optimal use of cost-effective imaging modalities and the validation of serological markers of joint arthropathy. Screening for effects on bone health and optimal management of pain to improve quality of life are, likewise, important issues. Major hemarthrosis and chronic hemophilic synovitis should be treated aggressively to prevent hemophilic arthropathy.

Host genetic factors in susceptibility to HIV-1 infection and ...

Indian Academy of Sciences (India)

AIDS and are also known to regulate the rate of disease progression. This review focuses ... ands for these proteins; (ii) genes within human leukocyte antigens ..... ter AIDS cohort study, Multicenter hemophilia cohort study, San. Francisco city ...

Factor VIII (F8) inversions in severe hemophilia A: Male germ cell origin and diagnosis with RT-PCR

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Antonarakis, S.E. [Geneva Medical School (Switzerland)]|[Johns Hopkins School of Medicine, Baltimore, MD (United States); Rossiter, J.P. [Johns Hopkins School of Medicine, Baltimore, MD (United States); Young, M. [Geneva Medical School (Switzerland)] [and others

1994-09-01

The Factor VIII (F8) gene, which is defective in hemophilia A, is located in the most telomeric megabase of Xq. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of the cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the inversion process, and that therefore the event originates predominantly in male germ cells. In all 21 informative cases in which the inversion originated in a maternal grandparent, DNA polymorphism analysis using markers within or very closely linked to F8, determined that it occurred in the male germline. In addition, all but one of 56 mothers of sporadic cases due to inversions were carriers. The data indicate that the F8 gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells. The mean age of maternal grandfathers at the birth of their carrier daughters was 29.9 years (13 cases), i.e. not different from the mean paternal age in the general population, supporting the hypothesis that the inversions occur in meiosis. The inversions can be diagnosed by Southern blot analysis. For more rapid diagnosis we have used RT-PCR of RNA ectopically expressed in blood. Oligonucleotides were used to PCR amplify, after the initial RT reaction of RNA samples using random hexamers, either the normal transcript (F8 exons 21 to 24;312 bp product) or the novel abnormal transcript that is generated after the inversion. Both type 1 and 2 inversions can be recognized in affecteds and carriers by the presence of the diagnostic PcR product of 248 bp. Correct diagnoses were made in samples from 6 patients and 2 carriers with type 1 inversions, 2 patients and 2 carriers with type 2 inversions and 5 normal controls.

Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice.

Science.gov (United States)

Baumgartner, C K; Mattson, J G; Weiler, H; Shi, Q; Montgomery, R R

2017-01-01

Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive. Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of

Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs

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Dumont, Jennifer A.; Liu, Tongyao; Low, Susan C.; Zhang, Xin; Kamphaus, George; Sakorafas, Paul; Fraley, Cara; Drager, Douglas; Reidy, Thomas; McCue, Justin; Franck, Helen W. G.; Merricks, Elizabeth P.; Nichols, Timothy C.; Bitonti, Alan J.; Pierce, Glenn F.

2012-01-01

Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation. PMID:22246033

Genetic Correction and Hepatic Differentiation of Hemophilia B-specific Human Induced Pluripotent Stem Cells.

Science.gov (United States)

He, Qiong; Wang, Hui-Hui; Cheng, Tao; Yuan, Wei-Ping; Ma, Yu-Po; Jiang, Yong-Ping; Ren, Zhi-Hua

2017-09-27

Objective To genetically correct a disease-causing point mutation in human induced pluripotent stem cells (iPSCs) derived from a hemophilia B patient. Methods First, the disease-causing mutation was detected by sequencing the encoding area of human coagulation factor IX (F IX) gene. Genomic DNA was extracted from the iPSCs, and the primers were designed to amplify the eight exons of F IX. Next, the point mutation in those iPSCs was genetically corrected using CRISPR/Cas9 technology in the presence of a 129-nucleotide homologous repair template that contained two synonymous mutations. Then, top 8 potential off-target sites were subsequently analyzed using Sanger sequencing. Finally, the corrected clones were differentiated into hepatocyte-like cells, and the secretion of F IX was validated by immunocytochemistry and ELISA assay. Results The cell line bore a missense mutation in the 6 th coding exon (c.676 C>T) of F IX gene. Correction of the point mutation was achieved via CRISPR/Cas9 technology in situ with a high efficacy at about 22% (10/45) and no off-target effects detected in the corrected iPSC clones. F IX secretion, which was further visualized by immunocytochemistry and quantified by ELISA in vitro, reached about 6 ng/ml on day 21 of differentiation procedure. Conclusions Mutations in human disease-specific iPSCs could be precisely corrected by CRISPR/Cas9 technology, and corrected cells still maintained hepatic differentiation capability. Our findings might throw a light on iPSC-based personalized therapies in the clinical application, especially for hemophilia B.

Analysis of inversions in the factor VIII gene in Spanish hemophilia A patients and families

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Domenech, M.; Tizzano, E.; Baiget, M. [Hospital de Sant Pau, Barcelona (Spain); Altisent, C. [Hospital Vall d`Hebron, Barcelona (Spain)

1994-09-01

Intron 22 is the largest intron of the factor VIII gene and contains a CpG island from which two additional transcripts originate. One of these transcripts corresponds to the F8A gene which have telomeric extragenic copies in the X chromosome. An inversion involving homologous recombination between the intragenic and the distal or proximal copies of the F8A gene has been recently described as a common cause of severe hemophilia A (HA). We analyzed intron 22 rearrangements in 195 HA patients (123 familial and 72 sporadic cases). According to factor VIII levels, our sample was classified as severe in 114 cases, moderate in 29 cases and mild in 52 cases. An intron 22 (F8A) probe was hybridized to Southern blots of BcII digested DNA obtained from peripheral blood. A clear pattern of altered bands identifies distal or proximal inversions. We detected an abnormal pattern identifying an inversion in 49 (25%) of the analyzed cases. 43% of severe HA patients (49 cases) showed an inversion. As expected, no inversion was found in the moderate and mild group of patients. We found a high proportion (78%) of the distal rearrangement. From 49 identified inversions, 33 were found in familial cases (27%), while the remaining 15 were detected in sporadic patients (22%) in support that this mutational event occurs with a similar frequency in familial or sporadic cases. In addition, we detected a significant tendency of distal inversion to occur more frequently in familial cases than in sporadic cases. Inhibitor development to factor VIII was documented in approximately 1/3 of the patients with inversion. The identification of such a frequent molecular event in severe hemophilia A patients has been applied in our families to carrier and prenatal diagnosis, to determine the origin of the mutation in the sporadic cases and to detect the presence of germinal mosaicism.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

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Mahlangu, Johnny; Kuliczkowski, Kazimierz; Karim, Faraizah Abdul; Stasyshyn, Oleksandra; Kosinova, Marina V.; Lepatan, Lynda Mae; Skotnicki, Aleksander; Boggio, Lisa N.; Klamroth, Robert; Oldenburg, Johannes; Hellmann, Andrzej; Santagostino, Elena; Baker, Ross I.; Fischer, Kathelijn; Gill, Joan C.; P’Ng, Stephanie; Chowdary, Pratima; Escobar, Miguel A.; Khayat, Claudia Djambas; Rusen, Luminita; Bensen-Kennedy, Debra; Blackman, Nicole; Limsakun, Tharin; Veldman, Alex; St. Ledger, Katie

2016-01-01

Recombinant VIII (rVIII)-SingleChain is a novel B-domain–truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927. PMID:27330001

Comparison of Clot-based, Chromogenic, and Fluorescence Assays for Measurement of Factor VIII Inhibitors in the U.S. Hemophilia Inhibitor Research Study

Science.gov (United States)

Miller, Connie H.; Rice, Anne S.; Boylan, Brian; Shapiro, Amy D.; Lentz, Steven R.; Wicklund, Brian M.; Kelly, Fiona M.; Soucie, J. Michael

2015-01-01

Summary Background Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. Methods Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). Results NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0–1.9 NBU specimens and 43.1% and 50.0% of 0.5–0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7–1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5–1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). Conclusions FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5–1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. PMID:23601690

Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency)

International Nuclear Information System (INIS)

Taylor, S.A.M.; Deugau, K.V.; Lillicrap, D.P.

1991-01-01

Studies have shown that hemophilia B (Christmas disease; factor IX deficiency) results from many different mutations in the factor IX gene, of which >95% are single nulceotide substitutions. This study has identified a previously unreported form of hemophilia B in a patient who was a somatic mosaic for a guanine-to-cytosine transversion at nucleotide 31,170 in the factor IX gene. This point mutation changes the codon for residue 350 in the catalytic domain of factor IX from a cysteine to a serine. The authors used differential termination of primer extension to confirm and measure the degree of mosaicism. The study shows that a varying proportion of cells from hepatic, renal, smooth muscle, and hematopoietic populations possessed normal as well as mutant factor IX sequences. These results indicate that the mutation in this patient occurred either as an uncorrected half-chromatid mutation in the female gamete or as a replication or postreplication error in the initial mitotic divisions of the zygote preceding implantation. In addition, this kindred also contains two females in successive generations who have moderately severe factor IX deficiency. The molecular pathogenesis of this latter phenomenon has been studied and seems to relate to the unaccompanied expression of the mutant factor IX gene consequent upon a second, as yet undefined, genetic event that has prevented inactivation of sequences including the mutant factor IX gene on the X chromosome inherited from the affected male

Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

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Young, M.; Antonarakis, S.E. [Univ. of Geneva (Switzerland); Inaba, Hiroshi [Tokyo Medical College (Japan)] [and others

1997-03-01

Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A{sub 8}TA{sub 2} sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient`s plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) {open_quotes}ribosomal frameshifting{close_quotes} resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A{sub 10} instead of A{sub 8}TA{sub 2}, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype. 36 refs., 6 figs.

Direct Puncture Embolization of Scalp Arteriovenous Malformation in a Patient with Severe Hemophilia A: A Case Report

International Nuclear Information System (INIS)

Lee, Kyung Mi; Kim, Eui Jong; Park, Bong Jin; Kim, Keon Ha

2011-01-01

We present a case of scalp arteriovenous malformation (AVM) in a patient with severe hemophilia A. The 22-year-old man presented with a pulsatile right parietal scalp mass. Digital subtraction angiography revealed an AVM in the right parietal scalp, supplied by superficial temporal and occipital arteries that drained into multiple venous structures. We successfully performed direct puncture embolization followed by surgical resection of the scalp AVM in conjunction with supplemental infusion of coagulation factor VIII before, during and after the embolization and the operation.

Direct Puncture Embolization of Scalp Arteriovenous Malformation in a Patient with Severe Hemophilia A: A Case Report

Energy Technology Data Exchange (ETDEWEB)

Lee, Kyung Mi; Kim, Eui Jong [Dept. of Radiology, Kyung Hee University Hospital, Kyung Hee University Graduate School of Medicine, Seoul (Korea, Republic of); Park, Bong Jin [Dept. of Neurosurgery, Kyung Hee University Hospital, Kyung Hee University Graduate School of Medicine, Seoul (Korea, Republic of); Kim, Keon Ha [Dept. of Radiology, Samsug Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2011-09-15

We present a case of scalp arteriovenous malformation (AVM) in a patient with severe hemophilia A. The 22-year-old man presented with a pulsatile right parietal scalp mass. Digital subtraction angiography revealed an AVM in the right parietal scalp, supplied by superficial temporal and occipital arteries that drained into multiple venous structures. We successfully performed direct puncture embolization followed by surgical resection of the scalp AVM in conjunction with supplemental infusion of coagulation factor VIII before, during and after the embolization and the operation.

Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector.

Science.gov (United States)

Herzog, R W; Yang, E Y; Couto, L B; Hagstrom, J N; Elwell, D; Fields, P A; Burton, M; Bellinger, D A; Read, M S; Brinkhous, K M; Podsakoff, G M; Nichols, T C; Kurtzman, G J; High, K A

1999-01-01

Hemophilia B is a severe X-linked bleeding diathesis caused by the absence of functional blood coagulation factor IX, and is an excellent candidate for treatment of a genetic disease by gene therapy. Using an adeno-associated viral vector, we demonstrate sustained expression (>17 months) of factor IX in a large-animal model at levels that would have a therapeutic effect in humans (up to 70 ng/ml, adequate to achieve phenotypic correction, in an animal injected with 8.5x10(12) vector particles/kg). The five hemophilia B dogs treated showed stable, vector dose-dependent partial correction of the whole blood clotting time and, at higher doses, of the activated partial thromboplastin time. In contrast to other viral gene delivery systems, this minimally invasive procedure, consisting of a series of percutaneous intramuscular injections at a single timepoint, was not associated with local or systemic toxicity. Efficient gene transfer to muscle was shown by immunofluorescence staining and DNA analysis of biopsied tissue. Immune responses against factor IX were either absent or transient. These data provide strong support for the feasibility of the approach for therapy of human subjects.

Long-term efficacy and safety of prophylaxis with recombinant factor VIII in Chinese pediatric patients with hemophilia A: a multi-center, retrospective, non-interventional, phase IV (ReCARE) study.

Science.gov (United States)

Li, Changgang; Zhang, Xinsheng; Zhao, Yongqiang; Wu, Runhui; Hu, Qun; Xu, Weiqun; Sun, Jing; Yang, Renchi; Li, Xiaojing; Zhou, Rongfu; Lian, Shinmei; Gu, Jian; Wu, Junde; Hou, Qingsong

2017-07-01

The first recombinant factor VIII (rFVIII) product was launched in China in 2007. However, until now, no study has been conducted to describe the efficacy and safety of prophylaxis with rFVIII in Chinese pediatric patients with hemophilia A (HA). To summarize the efficacy and safety data on prophylaxis with rFVIII in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained regular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers (HTCs) across China. The primary endpoints included reduction in annualized bleeding rate (ABR); the secondary endpoints included evaluation of joint function (number and sites of target joints) using Gilbert score and Hemophilia Joint Health Score (HJHS), quality of life (QoL) and factors affecting treatment choices. Safety assessment of rFVIII was also conducted. We analyzed a total of 183 male pediatric patients (mean age, 7.1 ± 4.23 years) who received prophylaxis between 1 November 2007 and 31 May 2013. Compared with baseline, prophylaxis with rFVIII significantly reduced overall annualized joint bleed rate (AJBR) (p < .001) and ABR (p < .001). Inhibitor formation was reported in 5 (2.7%) patients and hemarthrosis was reported in 1 patient. The mean number of target joints was positively related to age (p < .001) and weight (p = .003) at baseline. Responses from survey questionnaires reported that effective bleeding control, joint protection, improvement in quality of life, favorable medical insurance policies, and economic capability were reasons for choosing prophylaxis. Prophylaxis with rFVIII reduced bleeding and number of target joints, even with a low-dose regimen, in Chinese pediatric patients with HA. Other than the efficacy and safety, factors such as poor disease control, improved economic stability and stable financial support made prophylaxis as an attractive treatment option. ClinicalTrials.gov ID

Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer

OpenAIRE

Buchlis, George; Podsakoff, Gregory M.; Radu, Antonetta; Hawk, Sarah M.; Flake, Alan W.; Mingozzi, Federico; High, Katherine A.

2012-01-01

In previous work we transferred a human factor IX–encoding adeno-associated viral vector (AAV) into skeletal muscle of men with severe hemophilia B. Biopsy of injected muscle up to 1 year after vector injection showed evidence of gene transfer by Southern blot and of protein expression by IHC and immunofluorescent staining. Although the procedure appeared safe, circulating F.IX levels remained subtherapeutic (< 1%). Recently, we obtained muscle tissue from a subject injected 10 years earlier ...

The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A.

Science.gov (United States)

Jiménez-Yuste, V; Lejniece, S; Klamroth, R; Suzuki, T; Santagostino, E; Karim, F A; Saugstrup, T; Møss, J

2015-03-01

Turoctocog alfa (NovoEight(®)) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. Data from previously treated patients with severe hemophilia A (FVIII activity level of ≤ 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg(-1) dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t1(/2) tended to increase with increasing age, with lower AUC and shorter t(1/2) being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products. © 2014 International Society on Thrombosis and Haemostasis.

Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

Science.gov (United States)

Wang, Xiaomei; Su, Jin; Sherman, Alexandra; Rogers, Geoffrey L; Liao, Gongxian; Hoffman, Brad E; Leong, Kam W; Terhorst, Cox; Daniell, Henry; Herzog, Roland W

2015-04-09

Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-β (TGF-β) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses. © 2015 by The American Society of Hematology.

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B

Science.gov (United States)

Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H.; Streatfield, Stephen J.; Herzog, Roland W.; Daniell, Henry

2015-01-01

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (~1mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ~2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP+ regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ~870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft2 per annum yielding 24,000–36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. PMID:26302233

Posterior Reduction and Monosegmental Fusion with Intraoperative Three-dimensional Navigation System in the Treatment of High-grade Developmental Spondylolisthesis

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Wei Tian

2015-01-01

Full Text Available Background: The treatment of high-grade developmental spondylolisthesis (HGDS is still challenging and controversial. In this study, we investigated the efficacy of the posterior reduction and monosegmental fusion assisted by intraoperative three-dimensional (3D navigation system in managing the HGDS. Methods: Thirteen consecutive HGDS patients were treated with posterior decompression, reduction and monosegmental fusion of L5/S1, assisted by intraoperative 3D navigation system. The clinical and radiographic outcomes were evaluated, with a minimum follow-up of 2 years. The differences between the pre- and post-operative measures were statistically analyzed using a two-tailed, paired t-test. Results: At most recent follow-up, 12 patients were pain-free. Only 1 patient had moderate pain. There were no permanent neurological complications or pseudarthrosis. The magnetic resonance imaging showed that there was no obvious disc degeneration in the adjacent segment. All radiographic parameters were improved. Mean slippage improved from 63.2% before surgery to 12.2% after surgery and 11.0% at latest follow-up. Lumbar lordosis changed from preoperative 34.9 ± 13.3° to postoperative 50.4 ± 9.9°, and 49.3 ± 7.8° at last follow-up. L5 incidence improved from 71.0 ± 11.3° to 54.0 ± 11.9° and did not change significantly at the last follow-up 53.1 ± 15.4°. While pelvic incidence remained unchanged, sacral slip significantly decreased from preoperative 32.7 ± 12.5° to postoperative 42.6 ± 9.8°and remained constant to the last follow-up 44.4 ± 6.9°. Pelvic tilt significantly decreased from 38.4 ± 12.5° to 30.9 ± 8.1° and remained unchanged at the last follow-up 28.1 ± 11.2°. Conclusions: Posterior reduction and monosegmental fusion of L5/S1 assisted by intraoperative 3D navigation are an effective technique for managing high-grade dysplastic spondylolisthesis. A complete reduction of local deformity and excellent correction of overall

Minimizing the Risk of Perioperative Bleeding in a Child with Hemophilia A during Dental Rehabilitation under General Anesthesia: A Case Report

OpenAIRE

Yehia El Batawi, Hisham

2013-01-01

ABSTRACT Hemophilia, among other bleeding disorders, raises concerns for dental service providers who routinely use sharp hand and rotary instruments, address highly vascular soft tissue and provide dental extractions. In pediatric dentistry, dealing with fearful or irritable children increases the possibility of trauma and subsequent bleeding risks in hemophilic pediatric dental patients. In the current report, we discuss how anesthetic, pediatric and dental management may contribute to the ...

Real-World Analysis of Dispensed IUs of Coagulation Factor IX and Resultant Expenditures in Hemophilia B Patients Receiving Standard Half-life Versus Extended Half-life Products and Those Switching from Standard Half-life to Extended Half-life Products.

Science.gov (United States)

Tortella, Bartholomew J; Alvir, José; McDonald, Margaret; Spurden, Dean; Fogarty, Patrick F; Chhabra, Amit; Pleil, Andreas M

2018-01-24

Hemophilia B requires replacement therapy with factor IX (FIX) coagulation products to treat and prevent bleeding episodes. A recently introduced extended half-life (EHL) recombinant FIX replacement product provided the opportunity to compare the amount of dispensed factor and expenditures for EHL treatment compared with a standard half-life (SHL) product. To determine factor international units (IUs) dispensed and expenditures associated with switching from nonacog alfa, the most commonly used SHL replacement product, to eftrenonacog alfa, an EHL FIX replacement product. Two U.S. claims databases were analyzed. A large national specialty pharmacy dispensation claims database was used to identify the number of IUs dispensed and monthly charges for all patients with hemophilia B from April 2015 to June 2016. Truven Health MarketScan Research Databases (January 2010-July 2016) were used to identify IUs and expenditures for patients with claims data for at least 3 months before and after switching from the SHL to the EHL product. Medians for IUs and expenditures are presented to accommodate for skewness of data distribution. The national specialty pharmacy database analysis included 296 patients with moderate or severe hemophilia B (233 on SHL; 94 on EHL). Median monthly factor dispensed was 11% lower (2,142 IU) in the EHL versus SHL cohort over the study period, while individual monthly reductions ranged from 32% to 47% (9,838 IU to 16,514 IU). Using the wholesale acquisition cost, the median per-patient monthly factor expenditures over the 15-month study period were 94% higher ($23,005) for the EHL than for the SHL product. Individual median monthly expenditure differences ranged from 15% ($6,562) to 49% ($19,624). In the Truven database, 14 patients switched from the SHL to the EHL product. The amount of factor dispensed was variable; in the 1-year period before and after the switch from the SHL to the EHL product, mean IUs dispensed decreased by 3,005 IU, while

Severe hemophilia A in a female by cryptic translocation: Order and orientation of factor VIII within Xq28

Energy Technology Data Exchange (ETDEWEB)

Migeon, B.R.; McGinniss, M.J.; Antonarakis, S.E.; Axelman, J.; Stasiowski, B.A.; Youssoufian, H.; Kearns, W.G.; Chung, A.; Pearson, P.L.; Kazazian, H.H. Jr. (Johns Hopkins Univ., Baltimore, MD (United States)); Muneer, R.S. (Univ. of Oklahoma, Norman (United States))

1993-04-01

The authors report studies of a female with severe hemophilia A resulting from a complex de novo translocation of chromosomes X and 17 (46,X,t(X; 17)). Somatic cell hybrids containing the normal X, the der(X), or the der(17) were analyzed for coagulation factor VIII (F8C) sequences using Southern blots and polymerase chain reaction. The normal X, always late replicating, contains a normal F8C gene, whereas the der(X) has no F8C sequences. The der(17) chromosome containing Xq24-Xq28 carries a functional G6PD locus and a deleted F8C allele that lacks exons 1--15. Also, it lacks the DXYS64-X locus, situated between the F8C locus and the Xq telomere. These results indicate that a cryptic breakpoint within Xq28 deleted the 5[prime] end of F8C, but left the more proximal G6PD locus intact on the der(17)chromosome. As the deleted segment includes the 5[prime] half of F8C as well as the subtelomeric DXYS64 locus, F8C must be oriented on the chromosome with its 5[prime] region closest to the telomere. Therefore, the order of these loci is Xcen-G6PD-3[prime]F8C-5[prime]F8C-DXYS64-Xqtel. The analysis of somatic cell hybrids has elucidated the true nature of the F8C mutation in the pro-band, revealing a more complex rearrangement (three chromosomes involved) than that expected from cytogenetic analysis, chromosome painting, and Southern blots. A 900-kb segment within Xq28 has been translocated to another autosome. Hemophilia A in this heterozygous female is due to the decapitation of the F8C gene on the der(17) and inactivation of the intact allele on the normal X. 27 refs., 5 figs., 1 tab.

The upward spiral of drug costs: a time series analysis of drugs used in the treatment of hemophilia.

Science.gov (United States)

Rogoff, Edward G; Guirguis, Hany S; Lipton, Richard A; Seremetis, Stephanie V; DiMichele, Donna M; Agnew, George M; Karpatkin, Margaret; Barish, Robert J; Jones, Robert L; Bianco, Celso; Knothe, Barbara D; Lee, Myung-Soo

2002-10-01

Hemophilia is an expensive disease because its treatment is heavily dependent on costly clotting factor drugs. Over the last nine years,a consortium of three Comprehensive Hemophilia Treatment Centers and other hospitals, which purchased clotting factors for their patients, has seen treatment costs escalate on average 17% annually. Currently, new, even more expensive drugs are entering the market. This study analyzes 3,244 purchases that were made over a nine-year period totaling nearly 500 million units of clotting factor, representing every product on the market. Purchases were made both apart from and under the Federal Public Health Service (PHS)discount pricing rules. The main cause of the increases was the move to newer, more expensive products. The average price of existing products increased less than 2%per year, but new products were priced, on average, 47% higher than existing products. Overall consumption increased by an average of 5% per year, likely reflecting prophylactic treatment modalities that require greater amounts of clotting factor. Government pricing programs, such as the PHS program, were ineffective or counterproductive at reducing costs. There is a notable absence of competition in this market, with a few dominant companies having a functional monopoly in the largest segments of the market. Prices of older products are not lowered, even when new products are brought to market. A few products that serve small patient groups have had their prices increased substantially. This escalation is likely to continue as new, more expensive clotting factor drugs are developed. Since these new products are not proven to be any safer or more effective than the current products, this situation creates a risk of intervention by government and insurers to address both treatment costs and exhaustion of patients' insurance caps. Drug companies are not serving the patients by pricing new, but often very similar, products so aggressively. The trends seen in

A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report

Directory of Open Access Journals (Sweden)

Nagao Yoshiro

2012-02-01

Full Text Available Abstract Introduction Hypereosinophilic syndrome is defined as a prolonged state (more than six months of eosinophilia (greater than 1500 cells/μL, without an apparent etiology and with end-organ damage. Hypereosinophilic syndrome can cause coagulation abnormalities. Among hypereosinophilic syndrome types, the lymphocytic variant (lymphocytic hypereosinophilic syndrome is derived from a monoclonal proliferation of T lymphocytes. Here, we describe the case of a patient with lymphocytic hypereosinophilic syndrome who presented with a coagulation abnormality. To the best of our knowledge, this is the first such report including a detailed clinical picture and temporal cytokine profile. Case presentation A 77-year-old Japanese man presented to our facility with massive hematuria and hypereosinophilia (greater than 2600 cells/μl. His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL. Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor α, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality. Conclusions To the best of our knowledge, this is the first case in which lymphocytic hypereosinophilic syndrome and IgG4-related disease have overlapped. In addition, our patient is only the second case of hypereosinophilic disease that manifested with acquired hemophilia. Our patient relapsed with the

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B.

Science.gov (United States)

Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H; Streatfield, Stephen J; Herzog, Roland W; Daniell, Henry

2015-11-01

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP(+) regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft(2) per annum yielding 24,000-36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

AI mass spectrometers for space shuttle health monitoring

Science.gov (United States)

Adams, F. W.

1991-01-01

The facility Hazardous Gas Detection System (HGDS) at Kennedy Space Center (KSC) is a mass spectrometer based gas analyzer. Two instruments make up the HGDS, which is installed in a prime/backup arrangement, with the option of using both analyzers on the same sample line, or on two different lines simultaneously. It is used for monitoring the Shuttle during fuel loading, countdown, and drainback, if necessary. The use of complex instruments, operated over many shifts, has caused problems in tracking the status of the ground support equipment (GSE) and the vehicle. A requirement for overall system reliability has been a major force in the development of Shuttle GSE, and is the ultimate driver in the choice to pursue artificial intelligence (AI) techniques for Shuttle and Advanced Launch System (ALS) mass spectrometer systems. Shuttle applications of AI are detailed.

Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry.

Science.gov (United States)

Baudo, Francesco; Collins, Peter; Huth-Kühne, Angela; Lévesque, Hervé; Marco, Pascual; Nemes, László; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul

2012-07-05

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

Status and trend analysis of prophylactic usage of recombinant factor VIII in Chinese pediatric patients with hemophilia A: ReCare - a retrospective, phase IV, non-interventional study.

Science.gov (United States)

Li, Changgang; Zhang, Xinsheng; Zhao, Yongqiang; Wu, Runhui; Hu, Qun; Xu, Vicky; Sun, Jing; Yang, Renchi; Li, Xiaojing; Zhou, Rongfu; Lian, Shinmei; Gu, Jian; Wu, Junde; Hou, Qingsong

2017-09-01

No study has reported the status and chronological trend of prophylactic recombinant factor VIII (rFVIII) use in Chinese pediatric patients with hemophilia A (HA). We aimed to analyze the status and trend of rFVIII-containing prophylaxis in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained REgular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers across China. The trend of prophylaxis was evaluated by determining the mean duration of prophylaxis, mean injection frequency (per week), mean dose of each injection (IU/kg), mean total dose injected/week (IU) and proportion of rFVIII consumption relative to factor VIII (FVIII) consumption over the study period. We analyzed 183 male pediatric patients with HA (mean age, 7.1 ± 4.23 years), who received intermittent prophylaxis between 1 November 2007 and 31 May 2013. The mean duration of prophylaxis with rFVIII increased from 16.72 weeks in 2008 to 32.77 in 2012. Per injection dose of rFVIII increased significantly from 2008 to 2013 (25.89 to 28.31 IU/kg, p < .001). An increase was also reported in the mean total FVIII consumed (699.97 ± 173.25 IU in 2008 and 891.30 ± 730.341 in 2013) and mean proportion of rFVIII used (33.33 ± 57.73% in 2008 to 85.50 ± 29.077% in 2013). Our data revealed an overall improvement in treatment dosage and duration with an increase in the number of patients receiving prophylaxis. The total proportion of rFVIII also increased gradually indicating the development of economy and safety awareness. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02263066).

Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage.

Science.gov (United States)

Saito, Tatsuya; Mukae, Jyunichi; Nakamura, Yosuke; Inaba, Hiroshi; Nogami, Keiji; Koyama, Takatoshi; Fukutake, Katsuyuki; Yamamoto, Koh

2017-01-01

A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA.

Validation of the Brazilian version of the VERITAS-Pro scale to assess adherence to prophylactic regimens in hemophilia

Directory of Open Access Journals (Sweden)

Adriana Aparecida Ferreira

2018-01-01

Full Text Available Introduction: Prophylaxis is the treatment of choice for patients with severe hemophilia. Low adherence may limit the effectiveness of the prophylactic regimen, thereby compromising outcomes. Objective: The objective of this study was to validate the Brazilian version of the VERITAS-Pro prophylaxis adherence scale, originally an American questionnaire that can be answered by the individual responsible for prophylaxis as well as by an observer. Methods: The scale has 24 questions divided into six subscales: Routine, Dosage, Plan, Remember, Skip and Communicate. Participants were recruited at a blood center in southeastern Brazil for validation and reliability analyses. Validation measures included the results obtained using analog visual scales of adherence, interval between medication dispensed by the treatment center pharmacy and the percentage of recommended doses administered and infusions registered in the patients’ logs. Results: The study included 32 individuals responsible for prophylaxis and five observers. The internal consistency was very good for the VERITAS-Pro total score, excellent for the Remember, Skip and Communicate subscales, good for the Dosage subscale, and acceptable for the Routine and Plan subscales. Twelve participants answered the questionnaire on more than one occasion to evaluate reproducibility. The intraclass correlation coefficient was excellent. Regarding convergent validity, the VERITAS-Pro scores were moderately correlated with the global adherence scale and with infusion log records, but showed a weak correlation with pharmacy dispensation records. Conclusion: The Brazilian version of VERITAS-Pro is a valid and reliable instrument, enabling the understanding of specific factors related to non-adherence and allowing targeted interventions for proper treatment. Keywords: Hemophilia, Medication adherence, Questionnaire, Validation study

A DNA fragment from Xq21 replaces a deleted region containing the entire FVIII gene in a severe hemophilia A patient

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Murru, S.; Casula, L.; Moi, P. [Insituto di Clinica e Biologia dell` Eta Evolutiva, Cagliari (Italy)] [and others

1994-09-15

In this paper the authors report the molecular characterization of a large deletion that removes the entire Factor VIII gene in a severe hemophilia A patient. Accurate DNA analysis of the breakpoint region revealed that a large DNA fragment replaced the 300-kb one, which was removed by the deletion. Pulsed-field gel electrophoresis analysis revealed that the size of the inserted fragment is about 550 kb. In situ hybridization demonstrated that part of the inserted region normally maps to Xq21 and to the tip of the short arm of the Y chromosome (Yp). In this patient this locus is present both in Xq21 and in Xq28, in addition to the Yp, being thus duplicated in the X chromosome. Sequence analysis of the 3` breakpoint suggested that an illegitimate recombination is probably the cause of this complex rearrangement. 52 refs., 7 figs.

Cost-utility analysis of immune tolerance induction therapy versus on-demand treatment with recombinant factor VII for hemophilia A with high titer inhibitors in Iran

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Rasekh HR

2011-11-01

Full Text Available Hamid Reza Rasekh1, Ali Imani1, Mehran Karimi2, Mina Golestani11Shahid Beheshti University of Medical Sciences, Department of Pharmaceutical Management and Pharmacoeconomics, School of Pharmacy, Tehran, 2University of Shiraz Medical Sciences, Hematology Research Center, Shiraz, IranBackground: In developing countries, the treatment of hemophilia patients with inhibitors is presently the most challenging and serious issue in hemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the health care of patients in this setting. In the setting of chronic diseases, cost-utility analysis, which takes into account the beneficial effects of a given treatment/health care intervention in terms of health-related quality of life, is likely to be the most appropriate approach.Objective: The aim of this study was to assess the incremental cost-effectiveness ratios of immune tolerance induction (ITI therapy with plasma-derived factor VIII concentrates versus on-demand treatment with recombinant-activated FVIIa (rFVIIa in hemophilia A with high titer inhibitors from an Iranian Ministry of Health perspective.Methods: This study was based on the study of Knight et al, which evaluated the cost-effectiveness ratios of different treatments for hemophilia A with high-responding inhibitors. To adapt Knight et al's results to the Iranian context, a few clinical parameters were varied, and cost data were replaced with the corresponding Iranian estimates of resource use. The time horizon of the analysis was 10 years. One-way sensitivity analyses were performed, varying the cost of the clotting factor, the drug dose, and the administration frequency, to test the robustness of the analysis.Results: Comparison of the incremental cost-effectiveness ratios between the three ITI protocols and the on-demand regimen with rFVIIa shows that all three ITI protocols dominate the on-demand regimen with r

Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: Family studies indicate a mutation type-dependent sex ratio of mutation frequencies

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Becker, J.; Schmidt, W.; Olek, K. [Univ. of Bonn (Germany)] [and others

1996-04-01

The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients-all exclusively from sporadic families-were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7%). Fifty-five patients (37.4%) showed a F8A-gene inversion, 47 (32.0%) a point mutation, 14 (9.5%) a small deletion, 8 (5.4%) a large deletion, and 2 (1.4%) a small insertion. Further, four (2.7%) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6%). Sixteen (10.9%) of the P identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9%) of 76 patients` mothers, comprising 3 of 16 de novo mutations in the patients` mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patient`s mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold- higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its proportion of the different mutation types. 68 refs., 1 fig., 5 tabs.

Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

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Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

2012-07-05

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

Acquired hemophilia as the cause of life-threatening hemorrhage in a 94-year-old man: a case report

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Blanchard Elizabeth

2010-07-01

Full Text Available Abstract Introduction Acquired factor VIII deficiency is a rare entity that can lead to severe and life-threatening bleeding. We describe a case of severe bleeding from the tongue secondary to acquired hemophilia and discuss treatment options, including aminocaproic acid and recombinant factor VIII, which have not been widely reported in the literature for the management of such patients. Case presentation A 94-year-old Caucasian man presented to our institution with diffuse bruising and extensive bleeding from the tongue secondary to mechanical trauma. He had no prior history of bleeding and his medical history was unremarkable except for dementia and hypertension. Coagulation studies revealed a prolonged activated partial thromboplastin time and a mixing study was consistent with the presence of an inhibitor. Quantitative assays revealed a reduced level of factor VIII activity (1% and the presence of a factor VIII inhibitor, measured at seven Bethesda units, in the serum. Oral prednisone therapy (60mg/day was given. He also received intravenous aminocaproic acid and human concentrate of factor VIII (Humate-P and topical anti-thrombolytic agents (100 units of topical thrombin cream. His hospital course was prolonged because of persistent bleeding and the development of profuse melena. He required eight units of packed red blood cells for transfusion. Hospitalization was also complicated by bradycardia of unclear etiology, which started after infusion of aminocaproic acid. His activated partial thromboplastin time gradually normalized. He was discharged to a rehabilitation facility three weeks later with improving symptoms, stable hematocrit and resolving bruises. Conclusions Clinicians should suspect a diagnosis of acquired hemophilia in older patients with unexplained persistent and profound bleeding from uncommon soft tissues, including the tongue. Use of factor VIII (Humate-P and aminocaproic acid can be useful in this coagulopathy but

Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells.

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Sherman, Alexandra; Su, Jin; Lin, Shina; Wang, Xiaomei; Herzog, Roland W; Daniell, Henry

2014-09-04

Hemophilia A is the X-linked bleeding disorder caused by deficiency of coagulation factor VIII (FVIII). To address serious complications of inhibitory antibody formation in current replacement therapy, we created tobacco transplastomic lines expressing FVIII antigens, heavy chain (HC) and C2, fused with the transmucosal carrier, cholera toxin B subunit. Cholera toxin B-HC and cholera toxin B-C2 fusion proteins expressed up to 80 or 370 µg/g in fresh leaves, assembled into pentameric forms, and bound to GM1 receptors. Protection of FVIII antigen through bioencapsulation in plant cells and oral delivery to the gut immune system was confirmed by immunostaining. Feeding of HC/C2 mixture substantially suppressed T helper cell responses and inhibitor formation against FVIII in mice of 2 different strain backgrounds with hemophilia A. Prolonged oral delivery was required to control inhibitor formation long-term. Substantial reduction of inhibitor titers in preimmune mice demonstrated that the protocol could also reverse inhibitor formation. Gene expression and flow cytometry analyses showed upregulation of immune suppressive cytokines (transforming growth factor β and interleukin 10). Adoptive transfer experiments confirmed an active suppression mechanism and revealed induction of CD4(+)CD25(+) and CD4(+)CD25(-) T cells that potently suppressed anti-FVIII formation. In sum, these data support plant cell-based oral tolerance for suppression of inhibitor formation against FVIII. © 2014 by The American Society of Hematology.

Magnetic resonance imaging of myocardial infarction during prothrombin complex concentrate therapy of hemophilia A

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Gruen, D.R.; Winchester, P.H.; Brill, P.W.; Ramirez, E.

1997-01-01

In patients with hemophilia, prothrombin complex concentrates (PCCs) have been successfully used to bypass inhibitors to fctor VIII during bleeding episodes. The use of PCCS, including FEIBA (factor eight inhibitor bypassing activity), has been associated with thromboembolic complications. Myocardial infarction (MI) is a rare but serious complication, reported in 13 previous cases, six in the pediatric age group. In all four patients who died during the acute MI, autopsy revealed extensive myocardial hemorrhage. The hearts of three other patients examined at least 5 months after the acute MI showed no evidence of prior hemorrhage. Magnetic resonance (MR) imaging has been shown to be able to evaluate the sequelae of myocardial infarction in adults with coronary artery disease and in children with Kawasaki syndrome. We report the first case of the used of MR imaging in the evaluation of myocardial damage during the acute stage of a FEIBA-associated MI in a 10-year-old boy. (orig.)

Magnetic resonance imaging of myocardial infarction during prothrombin complex concentrate therapy of hemophilia A

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Gruen, D.R. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Winchester, P.H. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Brill, P.W. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Ramirez, E. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States)

1997-03-01

In patients with hemophilia, prothrombin complex concentrates (PCCs) have been successfully used to bypass inhibitors to fctor VIII during bleeding episodes. The use of PCCS, including FEIBA (factor eight inhibitor bypassing activity), has been associated with thromboembolic complications. Myocardial infarction (MI) is a rare but serious complication, reported in 13 previous cases, six in the pediatric age group. In all four patients who died during the acute MI, autopsy revealed extensive myocardial hemorrhage. The hearts of three other patients examined at least 5 months after the acute MI showed no evidence of prior hemorrhage. Magnetic resonance (MR) imaging has been shown to be able to evaluate the sequelae of myocardial infarction in adults with coronary artery disease and in children with Kawasaki syndrome. We report the first case of the used of MR imaging in the evaluation of myocardial damage during the acute stage of a FEIBA-associated MI in a 10-year-old boy. (orig.)

Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts.

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Anna L Mitchell

Full Text Available Gene variants known to contribute to Autoimmune Addison's disease (AAD susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls. In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls. In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007. In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively.Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.

Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers.

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Kearney, S; Sharathkumar, A; Rodriguez, V; Chitlur, M; Valentino, L; Boggio, L; Gill, J

2015-01-01

Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty-eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia. © 2014 John Wiley & Sons Ltd.

Acquired hemophilia in the patient suffering from rheumatoid arthritis: case report.

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Drobiecki, Arkadiusz; Pasiarski, Marcin; Hus, Iwona; Sokołowska, Bożena; Wątek, Marzena

2013-12-01

Acquired hemophilia is a severe bleeding diathesis caused by autoantibodies against a coagulation factor VIII (FVIII inhibitor). Massive bleeding diathesis, often life threatening are observed in almost 90% of patients. In 50-60% of cases, inhibitor emerges spontaneously. However, there are some conditions like pregnancy, puerperium, autoimmune disorders or cancers that seem to induce acquired hemophilia. We report a case of a 49-year-old woman suffering from rheumatoid arthritis (RA) for several years, who was diagnosed with acquired hemophilia in September 2011. The patient had been treated by steroids and leflunomide during the last few months. At the time of diagnosis, diffuse bruising of the forearms and the trunk was observed. The patient was treated with recombinant activated factor VII, and the first-line immunosuppressive therapy was introduced (cyclophosphamide and prednisone). We observed the elimination of symptoms and the disappearance of diathesis. Significant reduction of the titer of inhibitor was achieved, but only partial remission was obtained. It lasted until the beginning of December 2011, when the titer of the inhibitor increased again and massive bleeding to the left lower limb occurred. It was necessary to administer recombinant factor VIIa together with the second-line immunosuppressive therapy based on the Budapest protocol. The rapid reduction of the diathesis and improvement of the patient's general condition was achieved as previously. However, still there was no complete remission. After 2 weeks of treatment, the titer of inhibitor diminished, and factor VIII activity increased slightly. Because of RA, the patient was treated with methylprednisolone in maintenance doses during the next few weeks. Unfortunately, after over a month, the increase of inhibitor titer and the decrease of FVIII level were observed again. Some bruises appeared. It was necessary to increase doses of corticosteroids to therapeutic levels and add cyclophosphamide

Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts.

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Saber, Hamidreza; Yakoob, Mohammad Yawar; Shi, Peilin; Longstreth, W T; Lemaitre, Rozenn N; Siscovick, David; Rexrode, Kathryn M; Willett, Walter C; Mozaffarian, Dariush

2017-10-01

The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke. We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses' Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis. A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results. In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid. © 2017

Genetic diagnosis in Hemophilia A from southern China: five novel mutations and one preimplantation genetic analysis.

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Chen, J; Wang, J; Lin, X Y; Xu, Y W; He, Z H; Li, H Y; Chen, S Q; Jiang, W Y

2017-04-01

As there is currently no complete cure for hemophilia A (HA), the identification of pathogenic mutations in factor VIII (FVIII) gene from HA patients and carriers, which can contribute to genetic counseling prenatal diagnosis, and preimplantation genetic diagnosis (PGD), is an important step to prevent HA. A total of 14 unrelated Chinese HA subjects (FVIII activity C, c.304_305insA, c.1594T>A, c.6045G>A, and c.2645_2646insG) were found. The real-time PCR showed that the expression of FVIII mRNAs was lower in HA patients than in normal subjects. Prenatal diagnosis and PGD were successfully performed: Two of three fetuses and four of eight blastomeres were confirmed to be normal. In conclusion, genetic diagnosis of 14 unrelated HA subjects, 20 carrier subjects, three fetuses, and one PGD was successfully performed in our study. © 2016 John Wiley & Sons Ltd.

Analysis of risk factors for infant mortality in the 1992-3 and 2002-3 birth cohorts in rural Guinea-Bissau

DEFF Research Database (Denmark)

Byberg, Stine; Østergaard, Marie Louise Drivsholm; Rodrigues, Amabelia

2017-01-01

INTRODUCTION: Though still high, the infant mortality rate in Guinea-Bissau has declined. We aimed to identify risk factors including vaccination coverage, for infant mortality in the rural population of Guinea-Bissau and assess whether these risk factors changed from 1992-3 to 2002-3. METHODS......, age groups (defined by current vaccination schedule) and cohort to assess whether the risk factors were the same for boys and girls, in different age groups in 1992-3 and in 2002-3. RESULTS: The infant mortality rate declined from 148/1000 person years (PYRS) in 1992-3 to 124/1000 PYRS in 2002-3 (HR...... = 0.88;95%CI:0.77-0.99); this decline was significant for girls (0.77;0.64-0.94) but not for boys (0.97;0.82-1.15) (p = 0.10 for interaction). Risk factors did not differ significantly by cohort in either distribution or effect. Mortality decline was most marked among girls aged 9-11 months (0...

First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Hemophilia Assessment and Resource Management System.

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Traore, A N; Chan, A K C; Webert, K E; Heddle, N; Ritchie, B; St-Louis, J; Teitel, J; Lillicrap, D; Iorio, A; Walker, I

2014-07-01

The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1,009,097,765 IU) and FIX (272,406,859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs. © 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

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Alanna McEneny-King

2017-10-01

Full Text Available The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.

The new albumin-free recombinant factor VIII concentrates for treatment of hemophilia: do they represent an actual incremental improvement?

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Josephson, Cassandra D; Abshire, Thomas

2004-07-01

The goal of eliminating the low levels of infectious disease risk from hemophilia treatment has resulted in the development of multiple generations of recombinant factor VIII (rFVIII) products. The ideal product should be devoid of human and animal proteins, which may transmit infectious agents. These products should also maintain molecular integrity, hemostatic efficacy, similar immunogenicity, and acceptable side effect profiles as compared to plasma-derived factor VIII. Currently available first-, second-, and third-generation rFVIII products include Recombinate; Kogenate FS/Helixate FS and ReFacto; and Advate, respectively. During the evolution of rFVIII products, either full-length or B-domain-deleted factor VIII were transfected into immortalized cell lines. The B-domain-deleted product, ReFacto, has resulted in an additional method to monitor factor VIII levels. The third-generation products offer the theoretical advantage of being produced without human and/or animal proteins. Upon initial introduction into the marketplace, the newer products have a higher cost. However, when analyzing historical trends, the prices of these products are almost equivalent to first-generation products within 3 years of licensure. Thus, the initial cost of the product may be a minimal issue in the medical decision process when selecting rFVIII replacement therapy.

Single nucleotide primer extension to detect genetic diseases: Experimental application to hemophilia B (factor IX) and cystic fibrosis genes

International Nuclear Information System (INIS)

Kuppuswamy, M.N.; Hoffmann, J.W.; Spitzer, S.G.; Groce, S.L.; Bajaj, S.P.; Kasper, C.K.

1991-01-01

In this report, the authors describe an approach to detect the presence of abnormal alleles in those genetic diseases in which frequency of occurrence of the same mutation is high (e.g., hemophilia B). Initially, from each subject, the DNA fragment containing the putative mutation site is amplified by the polymerase chain reaction. For each fragment two reaction mixtures are then prepared. Each contains the amplified fragment, a primer (18-mer or longer) whose sequence is identical to the coding sequence of the normal gene immediately flanking the 5' end of the mutation site, and either an α- 32 P-labeled nucleotide corresponding to the normal coding sequence at the mutation site or an α- 32 P-labeled nucleotide corresponding to the mutant sequence. An essential feature of the present methodology is that the base immediately 3' to the template-bound primer is one of those altered in the mutant, since in this way an extension of the primer by a single base will give an extended molecule characteristic of either the mutant or the wild type. The method is rapid and should be useful in carrier detection and prenatal diagnosis of every genetic disease with a known sequence variation

Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias.

Science.gov (United States)

Mancuso, Maria Elisa; Mannucci, Pier Mannuccio

2014-01-01

Prophylaxis with regular infusions of factor VIII (FVIII)- or factor IX (FIX)- containing products is the mainstay of modern hemophilia care. However, this therapeutic regimen is inconvenient, requiring repeated intravenous injections from childhood. Approaches meant to prolong the half-life of FVIII and FIX in plasma have been developed in order to improve the feasibility and acceptability of replacement therapy, extending protection from bleeding, reducing infusion frequency and hence the need for venous access devices in young children. Several strategies have been implemented to enhance the pharmacokinetics of clotting factors, including conjugation with polyethylene glycol and the production by genetic engineering of fusion proteins containing the coagulation factors linked to a long-lived plasma protein such as albumin or the Fc fragment of immunoglobulin (Ig)G. The latter technology is one of the most promising, since the prolongation of FVIII and FIX half-life is obtained by exploiting the physiological binding of the Fc domain to the neonatal Fc receptor. Fc fusion monomers have been obtained with both recombinant FVIII (rFVIIIFc) and FIX (rFIXFc), and data from preclinical and clinical studies showed improved pharmacokinetics for both factors, which are produced in human embryonic kidney (HEK) 293 cells, thus ensuring full human post-translational modifications. In Phase I/IIa studies, rFVIIIFc and rFIXFc showed 1.5-1.7 fold and 3.0-4.0 fold longer elimination half-life, respectively. Similar data have been obtained in the Phase III clinical studies with rFVIIIFc and rFIX-Fc published recently. Both drugs were satisfactorily safe, particularly with respect to immunogenicity, and no serious adverse event was observed.

Hemofilia A adquirida Acquired hemophilia A

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Delfina Almagro Vázquez

2010-12-01

Full Text Available La hemofilia A adquirida (HAA es un trastorno hemorrágico poco frecuente caracterizado por la presencia de autoanticuerpos contra el factor VIII (FVIII circulante. Aproximadamente en la mitad de los casos se ha observado un grupo heterogéneo de procesos patológicos que incluyen, entre otros, enfermedades autoinmunes y malignas y durante el embarazo, parto y puerperio. Las manifestaciones hemorrágicas son variables y fundamentalmente de tipo cutáneo mucoso. El diagnóstico se basa en el hallazgo en un paciente con manifestaciones hemorrágicas, prolongación del tiempo parcial de tromboplastina activado (TPTA, disminución de la actividad del FVIII y presencia de inhibidores del FVIII. El tratamiento de HAA incluye el control de las manifestaciones hemorrágicas y la supresión de la producción del anticuerpo. El concentrado de factor VIIa recombinante (FVIIar y el concentrado de complejo protrombínico (CCPA se consideran el tratamiento antihemorrágico de primera línea. Como terapéutica alternativa, en algunos casos puede utilizarse el concentrado de FVIII, la plasmaféresis y la inmunoadsorción extracorpórea. La prednisona sola o asociada con la ciclofosfamida, constituye el tratamiento inmunosupresor de primera línea. En pacientes refractarios puede administrarse como terapéutica de segunda línea, el rituximab (anti-CD20. Con la azatiopina, la ciclosporina, la vincristina y el micofenolato de mofetil, se han obtenido resultados variables.Acquired hemophilia A (AHA is an uncommon hemorrhagic disorder characterized by presence of autoantibodies to circulating factor VIII. Approximately in half of cases it is noted a heterogeneous group of pathological processes including among others, autoimmune and malignant diseases and during pregnancy, labor and puerperium. Hemorrhagic manifestations are variable and mainly of mucous cutaneous type. Diagnosis is based on the finding of a patient presenting with hemorrhagic manifestations

Mutation, detection, prenatal testing, and delineation of the germline origin in a family with sporadic hemophilia B and no living hemophiliacs

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Vielhaber, E.; Sommer, S.S. [Mayo Clinic/Foundation, Rochester, MN (United States); Freedenberg, D. [Scott and White Clinic, Temple, TX (United States)

1994-01-15

Hemophilia B is an X-linked recessive disorder affecting 1 in 30,000 males. Determination of carrier status for at risk females can be done by utilizing indirect methods such as DNA sequencing. However, in most cases, reliable carrier testing is not possible without first analyzing the DNA from an affected male in the family to determine his haplotype/causative sequence change. In the case presented here, the only affected male in the family has been deceased for 25 years; no DNA was available from him. The sister (III-2) of the affected individual was a suspected carrier based on her factor IX coagulant (36%); she was pregnant with a male fetus, and requested prenatal testing. 6 refs., 2 figs.

Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory anti-factor VIII antibodies during the treatment of hemophilia a: a computational assessment.

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Gouri Shankar Pandey

Full Text Available The development of neutralizing anti-drug-antibodies to the Factor VIII protein-therapeutic is currently the most significant impediment to the effective management of hemophilia A. Common non-synonymous single nucleotide polymorphisms (ns-SNPs in the F8 gene occur as six haplotypes in the human population (denoted H1 to H6 of which H3 and H4 have been associated with an increased risk of developing anti-drug antibodies. There is evidence that CD4+ T-cell response is essential for the development of anti-drug antibodies and such a response requires the presentation of the peptides by the MHC-class-II (MHC-II molecules of the patient. We measured the binding and half-life of peptide-MHC-II complexes using synthetic peptides from regions of the Factor VIII protein where ns-SNPs occur and showed that these wild type peptides form stable complexes with six common MHC-II alleles, representing 46.5% of the North American population. Next, we compared the affinities computed by NetMHCIIpan, a neural network-based algorithm for MHC-II peptide binding prediction, to the experimentally measured values and concluded that these are in good agreement (area under the ROC-curve of 0.778 to 0.972 for the six MHC-II variants. Using a computational binding predictor, we were able to expand our analysis to (a include all wild type peptides spanning each polymorphic position; and (b consider more MHC-II variants, thus allowing for a better estimation of the risk for clinical manifestation of anti-drug antibodies in the entire population (or a specific sub-population. Analysis of these computational data confirmed that peptides which have the wild type sequence at positions where the polymorphisms associated with haplotypes H3, H4 and H5 occur bind MHC-II proteins significantly more than a negative control. Taken together, the experimental and computational results suggest that wild type peptides from polymorphic regions of FVIII constitute potential T-cell epitopes

The Omega-3 Index and relative risk for coronary heart disease mortality: Estimation from 10 cohort studies.

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Harris, William S; Del Gobbo, Liana; Tintle, Nathan L

2017-07-01

A recent 19-cohort meta-analysis examined the relationships between biomarkers of omega-3 fatty acids and risk for coronary heart disease (CHD). That study did not, however, report hazard ratios (HRs) specifically as a function of erythrocyte eicosapentaenoic (EPA) plus docosahexaenoic (DHA) levels, a metric called the Omega-3 Index in which EPA + DHA content is expressed as a percent of total fatty acids. The Omega-3 Index has been used in several recent studies and is a validated biomarker of omega-3 fatty acid tissue levels, but additional data are needed to confirm (or refute) the originally-proposed clinical cut-points of Omega-3 Index and median quintile values for this metric across 10 of the cohorts for which the needed data were available. The overall mean (SD) for the Omega-3 Index in these 10 cohort studies was 6.1% (2.1%), and the HR for a 1-SD increase was 0.85 (95% confidence interval, 0.80-0.91). Median quintile 1 and 5 levels were 4.2% vs. 8.3%, respectively. Based on these values, we estimate that risk for fatal CHD would have been reduced by about 30% moving from an Omega-3 Index of 4%-8%. These findings support the use of 8% as reasonable therapeutic targets for the Omega-3 Index. Copyright © 2017 Elsevier B.V. All rights reserved.

Estudio familiar de las hemofilias A y B: 5 años de experiencia en la detección de portadoras Family study of hemophilia A and B: 5 years of experience in carrier detection

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Yaixa Piloto Roque

2010-08-01

Full Text Available La hemofilia se caracteriza por ser una enfermedad congénita del trastorno de la coagulación y constituye un desorden recesivo ligado al cromosoma X. El estudio molecular se realiza por estudios indirectos por ser causada por mutaciones heterogéneas en los genes del FVIII y FIX. Se realizó el estudio de 40 familias afectadas con hemofilia A (HA y 10 hemofilia B (HB. La extracción de ADN se realizó por el método de precipitación salina a 293 muestras de sangre y 19 de líquido amniótico, y se hizo el análisis de los polimorfismos St14, Bcl I y Hind III para la HA y Taq I, Xmn I y Dde I para la HB. Se usó la técnica de PCR. En el caso de la HA se obtuvo el 35 % de informatividad para St14 y Hind III y 32,5 para Bcl 1. El polimorfismo Dde I fue el más informativo para la HB con el 33 %; mientras que Taq I representó el 10 % de informatividad y XmnI el 0 %. Se comprobó que de las 40 familias analizadas con HA, 23 fueron informativas. Por otra parte, fueron informativas 4 familias de las afectadas con HB. Se realizaron 19 diagnósticos prenatales con previa determinación del sexo fetal, incluidos 3 varones enfermos.Hemophilia is a congenital disease of coagulation disorder and it is a recessive disorder linked to X-chromosome. The molecular study is conducted by indirect studies due to it is caused by heterogeneous mutations in gen of FVIII and FIX in 40 families with hemophilia A (HA and 10 with hemophilia B (HB. DNA extraction was carried out by saline precipitation method in 293 blood samples and 19 samples of amniotic fluid, as well as the analysis of St14, Bcl I and Hind III polymorphism for the AH and Taq I, Xmn I and Dde I for BH. The PCR technique was used. In the caser of AH it was possible to achieve a 35 % of information for St14 and Hind III and a 32.5 % for Bcl. Dde polymorphism supplied more information for BH for a 33 %; whereas the Taq I represented the 10 % of information and Xmn I the 0 %. We verified that from the

Cesarean section and risk of obesity in childhood, adolescence, and early adulthood: evidence from 3 Brazilian birth cohorts.

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Barros, Fernando C; Matijasevich, Alicia; Hallal, Pedro C; Horta, Bernardo L; Barros, Aluísio J; Menezes, Ana B; Santos, Iná S; Gigante, Denise P; Victora, Cesar G

2012-02-01

The number of cesarean sections (CSs) is increasing in many countries, and there are concerns about their short- and long-term effects. A recent Brazilian study showed a 58% higher prevalence of obesity in young adults born by CS than in young adults born vaginally. Because CS-born individuals do not make contact at birth with maternal vaginal and intestinal bacteria, the authors proposed that this could lead to long-term changes in the gut microbiota that could contribute to obesity. We assessed whether CS births lead to increased obesity during childhood, adolescence, and early adulthood in 3 birth cohorts. We analyzed data from 3 birth-cohort studies started in 1982, 1993, and 2004 in Southern Brazil. Subjects were assessed at different ages until 23 y of age. Poisson regression was used to estimate prevalence ratios with adjustment for ≤15 socioeconomic, demographic, maternal, anthropometric, and behavioral covariates. In the crude analyses, subjects born by CS had ∼50% higher prevalence of obesity at 4, 11, and 15 y of age but not at 23 y of age. After adjustment for covariates, prevalence ratios were markedly reduced and no longer significant for men or women. The only exception was an association for 4-y-old boys in the 1993 cohort, which was not observed in the other 2 cohorts or for girls. In these 3 birth cohorts, CSs do not seem to lead to an important increased risk of obesity during childhood, adolescence, or early adulthood.

The Development of FVIII Inhibitors in Relation to IL10 Gene Polymorphism in Hemophilia A Egyptian Pediatric Patients.

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Sadek, Hoda; Youssry, Ilham; Ibrahim, Nihal Salah Eldeen; Abou-Elalla, Amany Ahmed; Atef, Gehad; Mousa, Somaia Mohammed

2017-06-01

Development of inhibitors against Factor VIII (FVIII) in hemophilia A patients is a serious complication of therapy. Many cytokines, including interleukin-10 (IL10), may affect inhibitor development; however, literature data are not sufficient to prove this association. The aim of this study was to investigate the relation between FVIII inhibitor formation and IL10-1082A/G polymorphism among Egyptian hemophiliacs. Patients were screened for FVIII inhibitors using the Bethesda method. IL10-1082A/G polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism. Six patients (12%) developed inhibitors. No statistically significant difference was found between inhibitor positive and negative patients regarding IL10-1082A/G genotypes, disease severity, or treatment-related variables (type of FVIII received, treatment regimen, age at first exposure to FVIII, and frequency of replacement therapy). FVIII inhibitor formation in this group of Egyptian hemophiliacs was not correlated to IL10-1082A/G polymorphism, disease severity, or any of the treatment variables.

Plasma YKL-40 and CHI3L1 in systemic inflammation and sepsis—Experience from two prospective cohorts

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Kornblit, Brian; Hellemann, Dorthe; Munthe-Fog, Lea

2013-01-01

YKL-40, derived from the CHI3L1 gene, has been associated with outcome of infectious and inflammatory diseases. We hypothesized that plasma YKL-40 concentrations and CHI3L1 genotype could be used as prognostic biomarkers in the assessment of systemic inflammatory response syndrome (SIRS) and sepsis....... The objective of the study was to assess the prognostic value of plasma YKL-40 and CHI3L1 genotype in patients with SIRS and sepsis. Plasma YKL-40 and CHI3L1 genotype (rs4950928) were analyzed at time of admission to intensive care units (ICU), in two prospective cohorts of consecutive SIRS patients (cohort 1...

Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer.

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Buchlis, George; Podsakoff, Gregory M; Radu, Antonetta; Hawk, Sarah M; Flake, Alan W; Mingozzi, Federico; High, Katherine A

2012-03-29

In previous work we transferred a human factor IX-encoding adeno-associated viral vector (AAV) into skeletal muscle of men with severe hemophilia B. Biopsy of injected muscle up to 1 year after vector injection showed evidence of gene transfer by Southern blot and of protein expression by IHC and immunofluorescent staining. Although the procedure appeared safe, circulating F.IX levels remained subtherapeutic (< 1%). Recently, we obtained muscle tissue from a subject injected 10 years earlier who died of causes unrelated to gene transfer. Using Western blot, IHC, and immunofluorescent staining, we show persistent factor IX expression in injected muscle tissue. F.IX transcripts were detected in injected skeletal muscle using RT-PCR, and isolated whole genomic DNA tested positive for the presence of the transferred AAV vector sequence. This is the longest reported transgene expression to date from a parenterally administered AAV vector, with broad implications for the future of muscle-directed gene transfer.

Clinical characteristics and outcomes of acquired hemophilia A: experience at a single center in Japan.

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Ogawa, Yoshiyuki; Yanagisawa, Kunio; Uchiumi, Hideki; Ishizaki, Takuma; Mitsui, Takeki; Gouda, Fumito; Ieko, Masahiro; Ichinose, Akitada; Nojima, Yoshihisa; Handa, Hiroshi

2017-07-01

Acquired hemophilia A (AHA), which is caused by autoantibodies against coagulation factor VIII (FVIII) is a rare, life-threatening bleeding disorder, the incidence of which appears to be increasing in Japan as the population ages. However, the clinical characteristics, treatment, and outcomes of AHA remain difficult to establish due to the rarity of this disease. We retrospectively analyzed data from 25 patients (median age 73 years; range 24-92 years; male n = 15) diagnosed with AHA between 1999 and 2015 at Gunma University Hospital. We identified autoimmune diseases and malignancy as underlying conditions in four and three patients, respectively. Factor VIII activity was significantly decreased in all patients (median 2.0%; range <1.0-8.0) by FVIII inhibitor (median 47.0 BU/mL; range 2.0-1010). Among 71 bleeding events, subcutaneous or intramuscular hemorrhage was the most prevalent. Seventeen patients required bypassing agents. Twenty-two (91.7%) of 24 patients treated with immunosuppressive agents achieved complete response (CR) during a median of 57.5 days (range 19-714 days). Although three patients (12%) relapsed and seven (28%) died of infection, none of the deaths were related to bleeding. Although most of our patients achieved CR after immunosuppressive therapy, the rate of infection-related mortality was unsatisfactorily high.

Tratamiento de la displasia fibrosa asociada a hemofilia C: a propósito de un caso Treatment for fibrous dysplasia when associated with hemophilia C: A case report

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T. Creo Martínez

2007-12-01

Full Text Available La displasia fibrosa es una enfermedad ósea benigna que cambia el tejido óseo normal por una proliferación de tejido conectivo. Se piensa que la alteración del gen Gsalfa es la principal razón de la enfermedad. La hemofilia C es una enfermedad sanguínea, hereditaria rara, que provoca hemorragias en pacientes afectos. Es autonómica recesiva, por lo que hombres y mujeres pueden estar afectos. Paciente de 13 años que desarrolla una displasia fibrosa en maxilar superior derecho que empieza con dolor durante la masticación de alimentos duros. Presenta abombamiento de vestíbulo y enrojecimiento de paladar derecho. Presenta un déficit discreto de factor XI (heterocigoto. Por ello, necesita una preparación especial antes de extirpar la lesión debido a su déficit. Se ha descubierto que la razón de la displasia fibrosa es la mutación del gen Gsalfa (GNAS1 que está en el cromosoma 20q. La causa de la hemofilia C es el déficit del factor XI debido a una mutación del gen FXI en el cromosoma 4. Quizás estas dos raras enfermedades tengan una relación, porque ambas se presentan en el mismo paciente.Fibrous Dysplasia is a benign bone disease that changes normal bone tissue for a proliferation of connective fibrous tissue. It is thought that an alteration of the Gsalpha gene is the main cause of the disease. Hemophilia C is a rare inherited blood disease leading to abnormal hemorrhages in affected patients. They have a factor XI deficiency. It is the least frequent of all hemophilias. It is a recessive autosomal disease, affecting both men and women. A 13 year-old patient developed fibrous dysplasia in right upper maxilla. The patient started with pain on chewing hard food. She had vestibular swelling and reddening of the right side of the palate. She had a discrete factor XI deficiency (heterozygotic. She needed special preparation before the lesion could be removed because of her deficiency. It has been discovered that the mutation of gene

32 CFR 57.3 - Definitions.

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2010-07-01

..., rheumatic fever, nephritis, asthma, sickle cell anemia, hemophilia, seizure disorder, lead poisoning, leukemia, or diabetes. (bbb) Parent. The biological father or mother of a child; a person who, by order of a court of competent jurisdiction, has been declared the father or mother of a child by adoption...

Assessment of Relative Bioavailability of Moroctocog Alfa and Moroctocog Alfa (AF-CC) in Subjects With Severe Hemophilia A.

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Korth-Bradley, Joan; Rupon, Jeremy; Plotka, Anna; Charnigo, Robert; Rendo, Pablo

2018-05-01

An open-label, single-dose, randomized, two-period, crossover study comparing the pharmacokinetics of factor VIII activity in plasma (FVIII:C) after administration of an albumin-free presentation of moroctocog alfa (test) and moroctocog alfa manufactured using the previous technique (reference) was conducted in 30 (25 evaluable) male subjects who had severe hemophilia A (FVIII:C < 1 IU/dL). Blood samples were collected for 48 h after administration of each dose. C was assayed using a chromogenic substrate assay. The FVIII:C pharmacokinetic parameters were calculated using noncompartmental analysis. The presentations would be bioequivalent if the 90% confidence limits of the ratio of the geometric mean values of AUC inf and recovery fell within the interval of 80-125%. The bioequivalence criteria were met. A total of 10 treatment-related adverse events were observed in a total of nine subjects. All were mild and none was determined to be related to administration of study medication. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Seroprevalence of hepatitis C, hepatitis B and HIV viruses in hemophiliacs born 1985-2010 in west Azarbaijan of Iran

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Nasim Valizadeh

2013-01-01

Full Text Available Background: Although, in the past the risk of transfusion transmitted viral infections were high in hemophilia patients, but introduction of viral inactivation methods in1985,decreased the risk of human immunodeficiency and hepatitis C and B viruses transmission significantly. The aim of study was seroprevalence of hepatitis B surface antigen (HBs Ag, hepatitis C virus antibody (HCV Ab and human immunodeficiency virus antibody (HIVAb in hemophiliacs in west Azarbaijan of Iran, born in 1985-2010. Materials and Methods: In a cross-sectional study, fifty patients with hereditary bleeding disorders born in 1985-2010, from total 250 patients who had been registered in Urmia Hemophilia Society were enrolled through the year 2010 to assess their seroprevalence for HCV Ab, HIV Ab and HBs Ag. Thirty five of 50 patients had hemophilia. Also; we performed a subset analysis for hemophilia patients. Results: All 50 patients with hereditary bleeding disorders including 35 patients with hemophilia were seronegative for HIV Ab and HBs Ag. HCV-Ab was detected in serum of 3 of 50 (6% patients with bleeding disorders. After subset analysis for hemophilia (A and B patients, we found HCV infection in 8.57% (3 of 35 of hemophiliacs. Conclusion: In this study prevalence of HCV infection was very smaller than similar studies in Iran and other countries. This study shows the safety of using viral inactivated factor concentrates and recombinant factors after year 1985.None of Hemophiliacs were seropositive for HIV Ab and HBs Ag.

Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011

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Palmer, Benedict P.; Chalmers, Elizabeth A.; Hart, Daniel P.; Liesner, Ri; Rangarajan, Savita; Talks, Katherine; Williams, Michael; Hay, Charles R. M.

2014-01-01

The effect of recombinant factor VIII (rFVIII) brand on inhibitor development was investigated in all 407 severe hemophilia A previously untreated patients born in the United Kingdom (UK) between 1 January 2000 and 31 December 2011. Eighty-eight (22%) had been in the RODIN study. Information was extracted from the National Haemophilia Database. Because exposure days (EDs) were not known for some patients, time from first treatment was used as a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titer, after a median (interquartile range) of 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate NexGen, 45 (35.2%, 95% confidence interval [CI] 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95% CI 18.6% to 31.4%) with Advate (P = .04). The adjusted hazard ratio (HR) (95% CI) for Kogenate Bayer/Helixate NexGen compared with Advate was 2.14 (1.12-4.10) (P = .02) for high titer and 1.75 (1.11-2.76) (P = .02) for all inhibitors. When excluding UK-RODIN patients, the adjusted HR (95% CI) for high-titer inhibitors was 2.00 (0.93-4.34) (P = .08). ReFacto AF was associated with a higher incidence of all, but not high-titer, inhibitors than Advate. These results will help inform debate around the relative immunogenicity and use of rFVIII brands. PMID:25339360

User-centered requirements engineering in health information systems: a study in the hemophilia field.

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Teixeira, Leonor; Ferreira, Carlos; Santos, Beatriz Sousa

2012-06-01

The use of sophisticated information and communication technologies (ICTs) in the health care domain is a way to improve the quality of services. However, there are also hazards associated with the introduction of ICTs in this domain and a great number of projects have failed due to the lack of systematic consideration of human and other non-technology issues throughout the design or implementation process, particularly in the requirements engineering process. This paper presents the methodological approach followed in the design process of a web-based information system (WbIS) for managing the clinical information in hemophilia care, which integrates the values and practices of user-centered design (UCD) activities into the principles of software engineering, particularly in the phase of requirements engineering (RE). This process followed a paradigm that combines a grounded theory for data collection with an evolutionary design based on constant development and refinement of the generic domain model using three well-known methodological approaches: (a) object-oriented system analysis; (b) task analysis; and, (c) prototyping, in a triangulation work. This approach seems to be a good solution for the requirements engineering process in this particular case of the health care domain, since the inherent weaknesses of individual methods are reduced, and emergent requirements are easier to elicit. Moreover, the requirements triangulation matrix gives the opportunity to look across the results of all used methods and decide what requirements are critical for the system success. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models

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Siner, Joshua I.; Samelson-Jones, Benjamin J.; Crudele, Julie M.; French, Robert A.; Lee, Benjamin J.; Zhou, Shanzhen; Merricks, Elizabeth; Raymer, Robin; Camire, Rodney M.; Arruda, Valder R.

2016-01-01

Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645–1648) in the design of B-domain–deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity. Inhibition of furin increases the secretion and decreases the intracellular retention of FVIII-BDD protein in mammalian cells. Our new variant (FVIII-ΔF), in which this recognition motif is removed, efficiently circumvents furin. FVIII-ΔF demonstrates increased recombinant protein yields, enhanced clotting activity, and higher circulating FVIII levels after adeno-associated viral vector–based liver gene therapy in a murine model of severe hemophilia A (HA) compared with FVIII-BDD. Moreover, we observed an amelioration of the bleeding phenotype in severe HA dogs with sustained therapeutic FVIII levels after FVIII-ΔF gene therapy at a lower vector dose than previously employed in this model. The immunogenicity of FVIII-ΔF did not differ from that of FVIII-BDD as a protein or a gene therapeutic. Thus, contrary to previous suppositions, FVIII variants that can avoid furin processing are likely to have enhanced translational potential for HA therapy. PMID:27734034

Analysis of risk factors for infant mortality in the 1992-3 and 2002-3 birth cohorts in rural Guinea-Bissau.

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Stine Byberg

Full Text Available Though still high, the infant mortality rate in Guinea-Bissau has declined. We aimed to identify risk factors including vaccination coverage, for infant mortality in the rural population of Guinea-Bissau and assess whether these risk factors changed from 1992-3 to 2002-3.The Bandim Health Project (BHP continuously surveys children in rural Guinea-Bissau. We investigated the association between maternal and infant factors (especially DTP and measles coverage and infant mortality. Hazard ratios (HR were calculated using Cox regression. We tested for interactions with sex, age groups (defined by current vaccination schedule and cohort to assess whether the risk factors were the same for boys and girls, in different age groups in 1992-3 and in 2002-3.The infant mortality rate declined from 148/1000 person years (PYRS in 1992-3 to 124/1000 PYRS in 2002-3 (HR = 0.88;95%CI:0.77-0.99; this decline was significant for girls (0.77;0.64-0.94 but not for boys (0.97;0.82-1.15 (p = 0.10 for interaction. Risk factors did not differ significantly by cohort in either distribution or effect. Mortality decline was most marked among girls aged 9-11 months (0.56;0.37-0.83. There was no significant mortality decline for girls 1.5-8 months of age (0.93;0.68-1.28 (p = 0.05 for interaction. DTP and measles coverage increased from 1992-3 to 2002-3.Risk factors did not change with the decline in mortality. Due to beneficial non-specific effects for girls, the increased coverage of measles vaccination may have contributed to the disproportional decline in mortality by sex and age group.

Consumption of fruit and vegetables and risk of frailty: a dose-response analysis of 3 prospective cohorts of community-dwelling older adults.

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García-Esquinas, Esther; Rahi, Berna; Peres, Karine; Colpo, Marco; Dartigues, Jean-François; Bandinelli, Stefania; Feart, Catherine; Rodríguez-Artalejo, Fernando

2016-07-01

Consuming fruit and vegetables (FVs) may protect against frailty, but to our knowledge no study has yet assessed their prospective dose-response relation. We sought to examine the dose-response association between FV consumption and the risk of frailty in older adults. Data were taken from 3 independent cohorts of community-dwelling older adults: the Seniors-ENRICA (Study on Nutrition and Cardiovascular Risk Factors in Spain) cohort (n = 1872), Three-City (3C) Bordeaux cohort (n = 581), and integrated multidisciplinary approach cohort (n = 473). Baseline food consumption was assessed with a validated computerized diet history (Seniors-ENRICA) or with a food-frequency questionnaire (3C Bordeaux and AMI). In all cohorts, incident frailty was assessed with the use of the Fried criteria. Results across cohorts were pooled with the use of a random-effects model. During a mean 2.5-y follow-up, 300 incident frailty cases occurred. Fully adjusted models showed that the pooled ORs (95% CIs) of incident frailty comparing participants who consumed 1, 2, or ≥3 portions of fruit/d to those with no consumption were, respectively, 0.59 (0.27, 0.90), 0.58 (0.29, 0.86), and 0.48 (0.20, 0.75), with a P-trend of 0.04. The corresponding values for vegetables were 0.69 (0.42, 0.97), 0.56 (0.35, 0.77), and 0.52 (0.13, 0.92), with a P-trend consumption of fruit and risk of exhaustion, low physical activity, and slow walking speed, whereas the consumption of vegetables was associated with a decreased risk of exhaustion and unintentional weight loss. Among community-dwelling older adults, FV consumption was associated with a lower short-term risk of frailty in a dose-response manner, and the strongest association was obtained with 3 portions of fruit/d and 2 portions of vegetables/d. © 2016 American Society for Nutrition.

METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

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N. B. Molchanova

2015-01-01

Full Text Available Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII. The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the modeling of market volume we have used the data about the number of hamophilia A patients on the basis of the federal registry, Russian and international morbidity indices, and the data of a real practice about average consumption of drugs of bloodcoagulation factors and data about the drugs prescription according to the standards and protocols of assistance rendering. According to the standards of care delivery, average annual volume of FVIII drugs consumption amounted to 406 325 244 IU for children and 964 578 678 IU for adults, i.e. an average volume of a “perfect” market is equal to 1 370 903 922 IU for all patients. The market volume is 1.8 times bigger than a real volume of FVIII drugs which, according to the data of IMS marketing agency, amounted to 765 000 000 IU in 2013. The modeling conducted has shown that despite a relatively high patients’ coverage there is a potential for almost double growth.

Methodology Series Module 1: Cohort Studies.

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Setia, Maninder Singh

2016-01-01

Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1) Framingham Cohort study, (2) Swiss HIV Cohort study, and (3) The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models) are useful in analysis of these studies.

Methodology series module 1: Cohort studies

Directory of Open Access Journals (Sweden)

Maninder Singh Setia

2016-01-01

Full Text Available Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1 Framingham Cohort study, (2 Swiss HIV Cohort study, and (3 The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models are useful in analysis of these studies.

Cohort Coefficients

DEFF Research Database (Denmark)

Kristensen, Gustav

2013-01-01

Cohorts are the aggregate of individuals who experience the same event within the same time interval. Cohorts can be based on people born in a given year, for example in 1940 or within a span of years, e.g. born in 1940-1944. The year of birth is here the defining event for cohorts. The health di...... differs between cohorts. This article focuses on the protective and detrimental cohort effect in relation to the risk of death from apoplexy. A dummy variable method is recommended to describe the changing cohort effect over a century....

Hemophilia as a defect of the tissue factor pathway of blood coagulation: Effect of factors VIII and IX on factor X activation in a continuous-flow reactor

International Nuclear Information System (INIS)

Repke, D.; Gemmell, C.H.; Guha, A.; Turitto, V.T.; Nemerson, Y.; Broze, G.J. Jr.

1990-01-01

The effect of factors VIII and IX on the ability of the tissue factor-factor VIIa complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIIa, VIII, IX, and X flowing at a wall shear rate of 57, 300, or 1130 sec -1 . The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2 endash-to 3 endash fold increase. The direct activation of factor X by tissue factor-factor VIIa could be virtually eliminated by the lipoprotein-associated coagulation inhibitor. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia

Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

Science.gov (United States)

Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

2013-11-01

Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study.

Science.gov (United States)

Lin, Swu-Jane; Hatoum, Hind T; Buchner, Deborah; Cox, David; Balu, Sanjeev

2012-07-23

1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; pRAs. Further studies on impact of step therapy policy are

PNPLA3 Association with Alcoholic Liver Disease in a Cohort of Heavy Drinkers.

Science.gov (United States)

Kolla, Bhanu Prakash; Schneekloth, Terry D; Biernacka, Joanna; Shah, Vijay; Lazaridis, Konstantinos N; Geske, Jennifer; Karpyak, Victor

2018-02-21

Prior studies have established variation at the PNPLA3gene to be associated with a risk of developing alcoholic liver disease (ALD). We attempt to replicate this finding and other potential genetic variations previously associated with ALD utilizing a case-control design in a cohort of subjects with alcohol use disorders. This case-control study performed in a US clinical sample of heavy drinkers, replicates the previously reported association between ALD and rs738409 polymorphism in the PNPLA3gene in heavy drinkers. This association persisted after accounting for the subject's diabetes status. Patients of European ancestry with a history of ALD were identified (n = 169). Controls consisted of patients without ALD who were from the same cohorts and were ≥ 30 years of age, had lifetime total years drinking ≥20 and lifetime maximum drinks per day ≥12 (n = 259). Patients were genotyped for 40 candidate single nucleotide polymorphisms (SNPs) selected for the purpose of testing their association with ALD. The association of each SNP with ALD was tested using a logistic regression model, assuming log-additive allele effects. Bonferroni correction was applied and multivariable logistic regression models were used to account for relevant covariates. Age, sex, and body mass index (BMI) distributions were similar between cases and controls. Diabetes was more prevalent in the ALD cases. Three SNPs were associated with ALD at the nominal significance level (rs738409 in PNPLA3, P = 0.00029; rs3741559 in AQP2, P = 0.0185; rs4290029 in NVL, P = 0.0192); only PNPLA3rs738409 SNP was significant at the Bonferroni-corrected P-value threshold of 0.00125. Association results remained significant after adjustment for diabetes status. Our case-control study confirmed that PNPLA3 rs738409 SNP is associated with ALD. This is an important replication in a US clinical sample with control subjects who had long histories of alcohol consumption.

Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study

Directory of Open Access Journals (Sweden)

Lin Swu-Jane

2012-07-01

Full Text Available Abstract Background 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs, and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT-induced nausea and vomiting (CINV associated with moderately (MEC and highly emetogenic CT agents (HEC. This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED admissions. Methods Patients who received cyclophosphamide post breast cancer (BC surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin or cisplatin (LC-cisplatin were selected from PharMetrics’ (IMS LifeLink claims dataset (2005-2008. Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Results Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin. Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%. Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin, and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p 3 RA group (p�

Germ-line origins of mutation in families with hemophilia B: The sex ratio varies with the type of mutation

Energy Technology Data Exchange (ETDEWEB)

Ketterling, R.P.; Vielhaber, E.; Bottema, C.D.K.; Schaid, D.J.; Sommer, S.S. (Mayo Clinic/Foundation, Rochester, MN (United States)); Cohen, M.P. (Vanderbilt Univ., Nashville, TN (United States)); Sexauer, C.L. (Children' s Hospital, Oklahoma City, OK (United States))

1993-01-01

Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, the authors report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by them, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males. 62 refs., 1 fig., 5 tabs.

Cohort profile

DEFF Research Database (Denmark)

Tollånes, Mette C; Strandberg-Larsen, Katrine; Forthun, Ingeborg

2016-01-01

PURPOSE: The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design. PARTICIPANTS: MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts-the Norweg......PURPOSE: The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design. PARTICIPANTS: MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts......-the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries. FINDINGS TO DATE: Initial harmonisation of data from the 2 cohorts...... has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies...

Derivation of HVR1, HVR2 and HVR3 human embryonic stem cell lines from IVF embryos after preimplantation genetic diagnosis (PGD) for monogenic disorder

OpenAIRE

Abdelkrim Hmadcha; Yolanda Aguilera; Maria Dolores Lozano-Arana; Nuria Mellado; Javier Sánchez; Cristina Moya; Luis Sánchez-Palazón; Jose Palacios; Guillermo Antiñolo; Bernat Soria

2016-01-01

From 106 human blastocyts donate for research after in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) for monogenetic disorder, 3 human embryonic stem cells (hESCs) HVR1, HVR2 and HVR3 were successfully derived. HVR1 was assumed to be genetically normal, HVR2 carrying Becker muscular dystrophy and HVR3 Hemophilia B. Despite the translocation t(9;15)(q34.3;q14) detected in HVR2, all the 3 cell lines were characterised in vitro and in vivo as normal hESCs lines and were r...

Mortality, stroke, and heart failure in atrial fibrillation cohorts after ablation versus propensity-matched cohorts.

Science.gov (United States)

Jarman, Julian We; Hunter, Tina D; Hussain, Wajid; March, Jamie L; Wong, Tom; Markides, Vias

2017-01-01

We sought to determine from key clinical outcomes whether catheter ablation of atrial fibrillation (AF) is associated with increased survival. Using routinely collected hospital data, ablation patients were matched to two control cohorts using direct and propensity score methodology. Four thousand nine hundred ninety-one ablation patients were matched 1:1 with general AF controls without ablation. Five thousand four hundred seven ablation patients were similarly matched to controls who underwent cardioversion. We examined the rates of ischemic stroke or transient ischemic attack (stroke/TIA), heart failure hospitalization, and death. Matched populations had very similar comorbidity profiles, including nearly identical CHA 2 DS 2 -VASc risk distribution ( p =0.6948 and p =0.8152 vs general AF and cardioversion cohorts). Kaplan-Meier models showed increased survival after ablation for all outcomes compared with both control cohorts ( p vs general AF, p =0.0087 for stroke/TIA, p vs cardioversion). Cox regression models also showed improved survival after ablation for all outcomes compared with the general AF cohort (hazard ratio [HR]=0.4, 95% confidence interval [95% CI]: 0.3-0.6, p stroke/TIA; HR=0.4, 95% CI: 0.2-0.6, p stroke/TIA; HR=0.4, 95% CI: 0.3-0.6, p stroke/TIA, and heart failure compared with a matched general AF population and a matched population who underwent cardioversion. Potential confounding of outcomes was minimized by very tight cohort matching.

E3N, a French cohort study on cancer risk factors. E3N Group. Etude Epidémiologique auprès de femmes de l'Education Nationale.

Science.gov (United States)

Clavel-Chapelon, F; van Liere, M J; Giubout, C; Niravong, M Y; Goulard, H; Le Corre, C; Hoang, L A; Amoyel, J; Auquier, A; Duquesnel, E

1997-10-01

This paper describes the design of E3N, a prospective cohort study conducted in France on risk factors for female cancers. The cohort comprises 100,000 women, aged 40-65 years at baseline in 1990. Participants were asked to complete questionnaires every 18 months. The main hypotheses studied concern the relationship between diet and cancer and between hormonal treatments and cancer. All cancers diagnosed are registered, together with other diseases (cardiovascular diseases, diabetes, osteoporosis). The study population and the follow-up procedure are described.

Cohort profile: the lidA Cohort Study-a German Cohort Study on Work, Age, Health and Work Participation.

Science.gov (United States)

Hasselhorn, Hans Martin; Peter, Richard; Rauch, Angela; Schröder, Helmut; Swart, Enno; Bender, Stefan; du Prel, Jean-Baptist; Ebener, Melanie; March, Stefanie; Trappmann, Mark; Steinwede, Jacob; Müller, Bernd Hans

2014-12-01

The lidA Cohort Study (German Cohort Study on Work, Age, Health and Work Participation) was set up to investigate and follow the effects of work and work context on the physical and psychological health of the ageing workforce in Germany and subsequently on work participation. Cohort participants are initially employed people subject to social security contributions and born in either 1959 (n = 2909) or 1965 (n = 3676). They were personally interviewed in their homes in 2011 and will be visited every 3 years. Data collection comprises socio-demographic data, work and private exposures, work ability, work and work participation attitudes, health, health-related behaviour, personality and attitudinal indicators. Employment biographies are assessed using register data. Subjective health reports and physical strength measures are complemented by health insurance claims data, where permission was given. A conceptual framework has been developed for the lidA Cohort Study within which three confirmatory sub-models assess the interdependencies of work and health considering age, gender and socioeconomic status. The first set of the data will be available to the scientific community by 2015. Access will be given by the Research Data Centre of the German Federal Employment Agency at the Institute for Employment Research (http://fdz.iab.de/en.aspx). © The Author 2014. Published by Oxford University Press on behalf of the International Epidemiological Association.

Cohort Differences in Cognitive Aging in the Longitudinal Aging Study Amsterdam.

Science.gov (United States)

Brailean, Anamaria; Huisman, Martijn; Prince, Martin; Prina, A Matthew; Deeg, Dorly J H; Comijs, Hannie

2016-09-30

This study aims to examine cohort differences in cognitive performance and rates of change in episodic memory, processing speed, inductive reasoning, and general cognitive performance and to investigate whether these cohort effects may be accounted for by education attainment. The first cohort (N = 705) was born between 1920 and 1930, whereas the second cohort (N = 646) was born between 1931 and 1941. Both birth cohorts were aged 65 to 75 years at baseline and were followed up 3 and 6 years later. Data were analyzed using linear mixed models. The later born cohort had better general cognitive performance, inductive reasoning, and processing speed at baseline, but cohort differences in inductive reasoning and general cognitive performance disappeared after adjusting for education. The later born cohort showed steeper decline in processing speed. Memory decline was steeper in the earlier born cohort but only from Time 1 to Time 3 when the same memory test was administered. Education did not account for cohort differences in cognitive decline. The later born cohort showed better initial performance in certain cognitive abilities, but no better preservation of cognitive abilities overtime compared with the earlier born cohort. These findings carry implications for healthy cognitive aging. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.

Japanese Legacy Cohorts: The Life Span Study Atomic Bomb Survivor Cohort and Survivors’ Offspring

Directory of Open Access Journals (Sweden)

Kotaro Ozasa

2018-04-01

Full Text Available Cohorts of atomic bomb survivors—including those exposed in utero—and children conceived after parental exposure were established to investigate late health effects of atomic bomb radiation and its transgenerational effects by the Atomic Bomb Casualty Commission (ABCC in the 1950s. ABCC was reorganized to the Radiation Effects Research Foundation (RERF in 1975, and all work has been continued at RERF. The Life Span Study, the cohort of survivors, consists of about 120,000 subjects and has been followed since 1950. Cohorts of in utero survivors and the survivors’ children include about 3,600 and 77,000 subjects, respectively, and have been followed since 1945. Atomic bomb radiation dose was estimated for each subject based on location at the time of the bombing and shielding conditions from exposure, which were obtained through enormous efforts of investigators and cooperation of subjects. Outcomes include vital status, cause of death, and cancer incidence. In addition, sub-cohorts of these three cohorts were constructed to examine clinical features of late health effects, and the subjects have been invited to periodic health examinations at clinics of ABCC and RERF. They were also asked to donate biosamples for biomedical investigations. Epidemiological studies have observed increased radiation risks for malignant diseases among survivors, including those exposed in utero, and possible risks for some non-cancer diseases. In children of survivors, no increased risks due to parental exposure to radiation have been observed for malignancies or other diseases, but investigations are continuing, as these cohorts are still relatively young.

Japanese Legacy Cohorts: The Life Span Study Atomic Bomb Survivor Cohort and Survivors' Offspring.

Science.gov (United States)

Ozasa, Kotaro; Grant, Eric J; Kodama, Kazunori

2018-04-05

Cohorts of atomic bomb survivors-including those exposed in utero-and children conceived after parental exposure were established to investigate late health effects of atomic bomb radiation and its transgenerational effects by the Atomic Bomb Casualty Commission (ABCC) in the 1950s. ABCC was reorganized to the Radiation Effects Research Foundation (RERF) in 1975, and all work has been continued at RERF. The Life Span Study, the cohort of survivors, consists of about 120,000 subjects and has been followed since 1950. Cohorts of in utero survivors and the survivors' children include about 3,600 and 77,000 subjects, respectively, and have been followed since 1945. Atomic bomb radiation dose was estimated for each subject based on location at the time of the bombing and shielding conditions from exposure, which were obtained through enormous efforts of investigators and cooperation of subjects. Outcomes include vital status, cause of death, and cancer incidence. In addition, sub-cohorts of these three cohorts were constructed to examine clinical features of late health effects, and the subjects have been invited to periodic health examinations at clinics of ABCC and RERF. They were also asked to donate biosamples for biomedical investigations. Epidemiological studies have observed increased radiation risks for malignant diseases among survivors, including those exposed in utero, and possible risks for some non-cancer diseases. In children of survivors, no increased risks due to parental exposure to radiation have been observed for malignancies or other diseases, but investigations are continuing, as these cohorts are still relatively young.

Japanese Legacy Cohorts: The Life Span Study Atomic Bomb Survivor Cohort and Survivors’ Offspring

Science.gov (United States)

Grant, Eric J; Kodama, Kazunori

2018-01-01

Cohorts of atomic bomb survivors—including those exposed in utero—and children conceived after parental exposure were established to investigate late health effects of atomic bomb radiation and its transgenerational effects by the Atomic Bomb Casualty Commission (ABCC) in the 1950s. ABCC was reorganized to the Radiation Effects Research Foundation (RERF) in 1975, and all work has been continued at RERF. The Life Span Study, the cohort of survivors, consists of about 120,000 subjects and has been followed since 1950. Cohorts of in utero survivors and the survivors’ children include about 3,600 and 77,000 subjects, respectively, and have been followed since 1945. Atomic bomb radiation dose was estimated for each subject based on location at the time of the bombing and shielding conditions from exposure, which were obtained through enormous efforts of investigators and cooperation of subjects. Outcomes include vital status, cause of death, and cancer incidence. In addition, sub-cohorts of these three cohorts were constructed to examine clinical features of late health effects, and the subjects have been invited to periodic health examinations at clinics of ABCC and RERF. They were also asked to donate biosamples for biomedical investigations. Epidemiological studies have observed increased radiation risks for malignant diseases among survivors, including those exposed in utero, and possible risks for some non-cancer diseases. In children of survivors, no increased risks due to parental exposure to radiation have been observed for malignancies or other diseases, but investigations are continuing, as these cohorts are still relatively young. PMID:29553058

Derivation of HVR1, HVR2 and HVR3 human embryonic stem cell lines from IVF embryos after preimplantation genetic diagnosis (PGD for monogenic disorder

Directory of Open Access Journals (Sweden)

Abdelkrim Hmadcha

2016-05-01

Full Text Available From 106 human blastocyts donate for research after in vitro fertilization (IVF and preimplantation genetic diagnosis (PGD for monogenetic disorder, 3 human embryonic stem cells (hESCs HVR1, HVR2 and HVR3 were successfully derived. HVR1 was assumed to be genetically normal, HVR2 carrying Becker muscular dystrophy and HVR3 Hemophilia B. Despite the translocation t(9;15(q34.3;q14 detected in HVR2, all the 3 cell lines were characterised in vitro and in vivo as normal hESCs lines and were registered in the Spanish Stem Cell Bank.

Cohort Profile: Antiretroviral Therapy Cohort Collaboration (ART-CC)

Science.gov (United States)

May, Margaret T; Ingle, Suzanne M; Costagliola, Dominique; Justice, Amy C; de Wolf, Frank; Cavassini, Matthias; D’Arminio Monforte, Antonella; Casabona, Jordi; Hogg, Robert S; Mocroft, Amanda; Lampe, Fiona C; Dabis, François; Fätkenheuer, Gerd; Sterling, Timothy R; del Amo, Julia; Gill, M John; Crane, Heidi M; Saag, Michael S; Guest, Jodie; Brodt, Hans-Reinhard; Sterne, Jonathan AC

2014-01-01

The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events, so that some prognostic analyses of individual cohort studies of human immunodeficiency virus-infected individuals had low statistical power. Because of this, the Antiretroviral Therapy Cohort Collaboration (ART-CC) of HIV cohort studies in Europe and North America was established in 2000, with the aim of studying the prognosis for clinical events in acquired immune deficiency syndrome (AIDS) and the mortality of adult patients treated for HIV-1 infection. In 2002, the ART-CC collected data on more than 12,000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004, 2006, 2008, and 2010. The ART-CC data base now includes data on more than 70 000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex, age, assumed transmission group, race/ethnicity, geographical origin), HIV biomarkers (e.g. CD4 cell count, plasma viral load of HIV-1), ART regimen, dates and types of AIDS events, and dates and causes of death. In recent years, additional data on co-infections such as hepatitis C; risk factors such as smoking, alcohol and drug use; non-HIV biomarkers such as haemoglobin and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts, whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org). PMID:23599235

Physical activity during pregnancy and infant's birth weight: results from the 3D Birth Cohort.

Science.gov (United States)

Bisson, Michèle; Croteau, Jordie; Guinhouya, Benjamin C; Bujold, Emmanuel; Audibert, François; Fraser, William D; Marc, Isabelle

2017-01-01

To evaluate the association between maternal physical activity and infant's birth weight or risk of inappropriate weight for gestational age (GA), and whether this association differs by infant's sex, maternal body mass index (BMI) or pregnancy complications in a prospective cohort study. 1913 pregnant women from the 3D Birth Cohort (Québec, Canada) completed the Pregnancy Physical Activity Questionnaire at each trimester. Energy expenditure (metabolic equivalent of task (MET)*hours/week) for total activity, sports and exercise and vigorous intensity activities was calculated. The associations with birth weight and risk of inappropriate weight for GA were evaluated by regression modelling. Interactions were tested with infant's sex, maternal prepregnancy BMI, gestational diabetes, hypertensive disorders and prematurity. Each 1 MET/hours/week increase in sports and exercise in the first trimester was associated with a 2.5 g reduction in infant's birth weight (95% CI -4.8 to -0.3) but was not associated with the risk of small weight for GA. In contrast, although not significant, a 17% reduction in the risk of large weight for GA was observed with increasing sports and exercise. Furthermore, in women with subsequent pre-eclampsia (but not normotensive or hypertensive women), each 1 MET/hours/week increment spent in any vigorous exercise in the first trimester reduced the infant's birth weight by 19.8 g (95% CI -35.2 to -4.3). Pregnant women with higher sports and exercise levels in the first trimester delivered infants with a lower birth weight. The risk of reducing infant's birth weight with vigorous exercise in women who develop pre-eclampsia later in pregnancy requires evaluation.

Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea.

Science.gov (United States)

Seong, Sang Cheol; Kim, Yeon-Yong; Park, Sue K; Khang, Young Ho; Kim, Hyeon Chang; Park, Jong Heon; Kang, Hee-Jin; Do, Cheol-Ho; Song, Jong-Sun; Lee, Eun-Joo; Ha, Seongjun; Shin, Soon Ae; Jeong, Seung-Lyeal

2017-09-24

The National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) is a cohort of participants who participated in health screening programmes provided by the NHIS in the Republic of Korea. The NHIS constructed the NHIS-HEALS cohort database in 2015. The purpose of this cohort is to offer relevant and useful data for health researchers, especially in the field of non-communicable diseases and health risk factors, and policy-maker. To construct the NHIS-HEALS database, a sample cohort was first selected from the 2002 and 2003 health screening participants, who were aged between 40 and 79 in 2002 and followed up through 2013. This cohort included 514 866 health screening participants who comprised a random selection of 10% of all health screening participants in 2002 and 2003. The age-standardised prevalence of anaemia, diabetes mellitus, hypertension, obesity, hypercholesterolaemia and abnormal urine protein were 9.8%, 8.2%, 35.6%, 2.7%, 14.2% and 2.0%, respectively. The age-standardised mortality rate for the first 2 years (through 2004) was 442.0 per 100 000 person-years, while the rate for 10 years (through 2012) was 865.9 per 100 000 person-years. The most common cause of death was malignant neoplasm in both sexes (364.1 per 100 000 person-years for men, 128.3 per 100 000 person-years for women). This database can be used to study the risk factors of non-communicable diseases and dental health problems, which are important health issues that have not yet been fully investigated. The cohort will be maintained and continuously updated by the NHIS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The Netherlands Cohort Study−Meat Investigation Cohort; a population-based cohort over-represented with vegetarians, pescetarians and low meat consumers.

Science.gov (United States)

Gilsing, Anne M J; Weijenberg, Matty P; Goldbohm, R Alexandra; Dagnelie, Pieter C; van den Brandt, Piet A; Schouten, Leo J

2013-11-29

Vegetarian diets have been associated with lower risk of chronic disease, but little is known about the health effects of low meat diets and the reliability of self-reported vegetarian status. We aimed to establish an analytical cohort over-represented with vegetarians, pescetarians and 1 day/week meat consumers, and to describe their lifestyle and dietary characteristics. In addition, we were able to compare self-reported vegetarians with vegetarians whose status has been confirmed by their response on the extensive food frequency questionnaire (FFQ). Embedded within the Netherlands Cohort Study (n = 120,852; including 1150 self-reported vegetarians), the NLCS-Meat Investigation Cohort (NLCS-MIC) was defined by combining all FFQ-confirmed-vegetarians (n = 702), pescetarians (n = 394), and 1 day/week meat consumers (n = 1,396) from the total cohort with a random sample of 2-5 days/week- and 6-7 days/week meat consumers (n = 2,965 and 5,648, respectively). Vegetarians, pescetarians, and 1 day/week meat consumers had more favorable dietary intakes (e.g., higher fiber/vegetables) and lifestyle characteristics (e.g. lower smoking rates) compared to regular meat consumers in both sexes. Vegetarians adhered to their diet longer than pescetarians and 1 day/week meat consumers. 75% of vegetarians with a prevalent cancer at baseline had changed to this diet after diagnosis. 50% of self-reported vegetarians reported meat or fish consumption on the FFQ. Although the misclassification that occurred in terms of diet and lifestyle when merely relying on self-reporting was relatively small, the impact on associations with disease risk remains to be studied. We established an analytical cohort over-represented with persons at the lower end of the meat consumption spectrum which should facilitate prospective studies of major cancers and causes of death using ≥20.3 years of follow-up.

The International Childhood Cardiovascular Cohort (i3C) consortium outcomes study of childhood cardiovascular risk factors and adult cardiovascular morbidity and mortality: Design and recruitment.

Science.gov (United States)

Sinaiko, Alan R; Jacobs, David R; Woo, Jessica G; Bazzano, Lydia; Burns, Trudy; Hu, Tian; Juonala, Markus; Prineas, Ronald; Raitakari, Olli; Steinberger, Julia; Urbina, Elaine; Venn, Alison; Jaquish, Cashell; Dwyer, Terry

2018-04-22

Although it is widely thought that childhood levels of cardiovascular (CV) risk factors are related to adult CV disease, longitudinal data directly linking the two are lacking. This paper describes the design and organization of the International Childhood Cardiovascular Cohort Consortium Outcomes Study (i3C Outcomes), the first longitudinal cohort study designed to locate adults with detailed, repeated, childhood biological, physical, and socioeconomic measurements and a harmonized database. I3C Outcomes uses a Heart Health Survey (HHS) to obtain information on adult CV endpoints, using mail, email, telephone, and clinic visits in the United States (U.S.) and Australia and a national health database in Finland. Microsoft Access, REsearch Data Capture (REDCap) (U.S.), LimeSurvey (Australia), and Medidata™ Rave data systems are used to collect, transfer and organize data. Self-reported CV events are adjudicated via hospital and doctor-released medical records. After the first two study years, participants (N = 10,968) were more likely to be female (56% vs. 48%), non-Hispanic white (90% vs. 80%), and older (10.4 ± 3.8 years vs. 9.4 ± 3.3 years) at their initial childhood study visit than the currently non-recruited cohort members. Over 48% of cohort members seen during both adulthood and childhood have been found and recruited, to date, vs. 5% of those not seen since childhood. Self-reported prevalences were 0.7% Type 1 Diabetes, 7.5% Type 2 Diabetes, 33% hypertension, and 12.8% CV event. 32% of CV events were judged to be true. I3C Outcomes is uniquely able to establish evidence-based guidelines for child health care and to clarify relations to adult CV disease. Copyright © 2018 Elsevier Inc. All rights reserved.

A prospective randomized cohort study evaluating 3 weeks vs 6 weeks of oral antibiotic treatment in the setting of "maximal medical therapy" for chronic rhinosinusitis.

Science.gov (United States)

Sreenath, Satyan B; Taylor, Robert J; Miller, Justin D; Ambrose, Emily C; Rawal, Rounak B; Ebert, Charles S; Senior, Brent A; Zanation, Adam M

2015-09-01

Surprisingly, little literature exists evaluating the optimal duration of antibiotic treatment in "maximal medical therapy" for chronic rhinosinusitis (CRS). As such, we investigated whether 3 weeks vs 6 weeks of antibiotic therapy resulted in significant differences in clinical response. A prospective, randomized cohort study was performed with patients assigned to 3-week or 6-week cohorts. Our primary outcome was failure of "maximal medical therapy" and surgical recommendation. Secondary outcomes included changes in pretherapy and posttherapy scores for the Rhinosinusitis Disability Index (RSDI), Chronic Sinusitis Survey (CSS), and computed tomography (CT)-based Lund-Mackay (LM) evaluation. Analyses were substratified based on presence of nasal polyps. Forty patients were randomized to the 3-week or 6-week treatment cohorts, with near-complete clinical follow-up achieved. No significant difference was found between the proportion of patients who failed medical therapy and were deemed surgical candidates between the 2 cohorts (71% vs 68%, p = 1.000). No significant difference was found in the change of RSDI or CSS scores in the 3 vs 6 weeks of treatment groups (mean ± standard error of the mean [SEM]; RSDI: 9.62 ± 4.14 vs 1.53 ± 4.01, p = 0.868; CSS: 5.75 ± 4.36 vs 9.65 ± 5.34, p = 0.573). Last, no significant difference was found in the change of LM scores (3.35 ± 1.11 vs 1.53 ± 0.81, p = 0.829). Based on this data, there is little difference in clinical outcomes between 3 weeks vs 6 weeks of antibiotic treatment as part of "maximal medical therapy" for CRS. Increased duration of antibiotic treatment theoretically may increase risk from side effects and creates higher healthcare costs. © 2015 ARS-AAOA, LLC.

Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in the factor VIII gene of two unrelated patients with cross-reacting material-positive hemophilia A.

Science.gov (United States)

Arai, M; Higuchi, M; Antonarakis, S E; Kazazian, H H; Phillips, J A; Janco, R L; Hoyer, L W

1990-01-15

The molecular defect responsible for moderate and severe hemophilia A has been identified for two unrelated patients with the CRM-positive form of this disorder (factor VIII activity of 0.02 and 0.05 U/mL with factor VIII antigen of 0.87 and 2.20 U/mL). In both cases, the immunopurified dysfunctional factor VIII protein is abnormal, in that the 80 Kd light chain is not cleaved by thrombin at arginine-1689. The basis for this failure was identified by polymerase chain reaction amplification of exon 14 of the variant factor VIII genes and direct sequencing of the amplified products. In both cases, a single base substitution (C to T) was identified that produces an arginine to cysteine substitution at amino acid residue 1689. These data identify the molecular defects of the two identical factor VIII variant proteins. The dysfunctional factor VIII has been designated "Factor VIII-East Hartford," the residence of the patient in whom the defect was first identified.

Cohort Fertility Patterns in the Nordic Countries

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Gunnar Andersson

2009-04-01

Full Text Available Previous analyses of period fertility suggest that the trends of the Nordic countries are sufficiently similar to speak of a common "Nordic fertility regime". We investigate whether this assumption can be corroborated by comparing cohort fertility patterns in the Nordic countries. We study cumulated and completed fertility of Nordic birth cohorts based on the childbearing histories of women born in 1935 and later derived from the population registers of Denmark, Finland, Norway, and Sweden. We further explore childbearing behaviour by women's educational attainment. The results show remarkable similarities in postponement and recuperation between the countries and very small differences in completed fertility across educational groups. Median childbearing age is about 2-3 years higher in the 1960-64 cohort than in the 1950-54 cohort, but the younger cohort recuperates the fertility level of the older cohort at ages 30 and above. A similar pattern of recuperation can be observed for highly educated women as compared to women with less education. An interesting finding is that of a positive relationship between educational level and the final number of children when women who become mothers at similar ages are compared. Country differences in fertility outcome are generally rather low. Childlessness is highest in Finland and lowest in Norway, and the educational differentials are largest in Norway. Despite such differences, the cohort analyses in many ways support the notion of a common Nordic fertility regime.

Birth cohorts in Asia: The importance, advantages, and disadvantages of different-sized cohorts.

Science.gov (United States)

Kishi, Reiko; Araki, Atsuko; Minatoya, Machiko; Itoh, Sachiko; Goudarzi, Houman; Miyashita, Chihiro

2018-02-15

Asia contains half of the world's children, and the countries of Asia are the most rapidly industrializing nations on the globe. Environmental threats to the health of children in Asia are myriad. Several birth cohorts were started in Asia in early 2000, and currently more than 30 cohorts in 13 countries have been established for study. Cohorts can contain from approximately 100-200 to 20,000-30,000 participants. Furthermore, national cohorts targeting over 100,000 participants have been launched in Japan and Korea. The aim of this manuscript is to discuss the importance of Asian cohorts, and the advantages and disadvantages of different-sized cohorts. As for case, one small-sized (n=514) cohort indicate that even relatively low level exposure to dioxin in utero could alter birth size, neurodevelopment, and immune and hormonal functions. Several Asian cohorts focus prenatal exposure to perfluoroalkyo substances and reported associations with birth size, thyroid hormone levels, allergies and neurodevelopment. Inconsistent findings may possibly be explained by the differences in exposure levels and target chemicals, and by possible statistical errors. In a smaller cohort, novel hypotheses or preliminary examinations are more easily verifiable. In larger cohorts, the etiology of rare diseases, such as birth defects, can be analyzed; however, they require a large cost and significant human resources. Therefore, conducting studies in only one large cohort may not always be the best strategy. International collaborations, such as the Birth Cohort Consortium of Asia, would cover the inherent limitation of sample size in addition to heterogeneity of exposure, ethnicity, and socioeconomic conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

Body Esteem in a Western Australian Cleft Lip and/or Palate Cohort Across 3 Age Groups.

Science.gov (United States)

Nicholls, Wendy; Harper, Craig; Selvey, Linda A; Robinson, Suzanne; Hartig, Gerald; Persson, Martin

2018-04-01

To determine if patients with cleft lip and/or palate (CL/P) from a Western Australian (WA) cohort were more dissatisfied with their body esteem than a normative non-cleft cohort, and identify demographic variables that may have significant associations with body esteem. Questionnaire study using the Body-Esteem Scale (BES) and Cleft Research Questionnaire (CRQ). Self-selected participants from a Western Australian CL/P population across 3 age groups (n=359). The BES is comprised of 3 factors: BE-Appearance, BE-Weight and BE-Attribution. Study mean BES factor scores were compared to normative non-cleft scores. Regression analysis was used to determine significant associations within each age group between BES factor scores and CRQ variables of: gender, self-reported body weight category, cleft type and importance of facial appearance rating. Study mean BE-Attribution scores were significantly lower than the normative scores and significantly lower than the mean BE-Appearance and BE-Weight factor scores within the same age groups of this study. Having a cleft type of lip and palate, being overweight, and placing a high importance on facial appearance had significant negative associations with BES scores. Maintaining a normal body weight and placing a lower level of importance on facial appearance had significant positive associations. Gender had no significant associations. In this study, the attribution aspect of body esteem had a greater negative impact on patients than their appearance and body weight. This has important implications for clinical treatment and support of patients.

The dataset from administration of single or combined immunomodulation agents to modulate anti-FVIII antibody responses in FVIII plasmid or protein primed hemophilia A mice

Directory of Open Access Journals (Sweden)

Chao Lien Liu

2016-06-01

Full Text Available Hemophilia A mice with pre-existing inhibitory antibodies against factor VIII (FVIII were treated with single agents, AMD3100 and GCS-F, respectively. Inhibitor titers in treated mice and control HemA inhibitors mice were followed over time. Total B cells and plasma cells (PCs were characterized by flow cytometry. HemA inhibitor mice were then treated with a combination regimen of IL-2/IL-2mAb complexes plus rapamycin and AMD3100. Finally, HemA inhibitor mice were treated with a new combination therapy using include IL-2/IL-2mAb complexes + Anti-CD20+AMD3100+G-CSF. The timeline of combination therapy was illustrated. Inhibitor titers following treatment in FVIII plasmid or protein induced inhibitor mice were evaluated overtime. A representative figure and gating strategies to characterize the subsets of Treg cells and B cells are presented. Please see http://dx.doi.org/10.1016/j.cellimm.2016.01.005 [1] for interpretation and discussion of these data and results.

Copenhagen Airport Cohort

DEFF Research Database (Denmark)

Møller, Karina Lauenborg; Brauer, Charlotte; Mikkelsen, Sigurd

2017-01-01

PURPOSE: Copenhagen Airport Cohort 1990-2012 presents a unique data source for studies of health effects of occupational exposure to air pollution (ultrafine particles) and manual baggage handling among airport employees. We describe the extent of information in the cohort and in the follow...... covers 69 175 men in unskilled positions. The exposed cohort includes men in unskilled jobs employed at Copenhagen Airport in the period 1990-2012 either as baggage handlers or in other outdoor work. The reference cohort includes men in unskilled jobs working in the greater Copenhagen area. FINDINGS...... TO DATE: The cohort includes environmental Global Positioning System (GPS) measurements in Copenhagen Airport, information on job function/task for each calendar year of employment between 1990 and 2012, exposure to air pollution at residence, average weight of baggage lifted per day and lifestyle...

Fish, Long-Chain n-3 PUFA and Incidence of Elevated Blood Pressure: A Meta-Analysis of Prospective Cohort Studies

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Bo Yang

2016-01-01

Full Text Available Results from prospective cohort studies on fish or long-chain (LC n-3 polyunsaturated fatty acid (PUFA intake and elevated blood pressure (EBP are inconsistent. We aimed to investigate the summary effects. Pertinent studies were identified from PubMed and EMBASE database through October 2015. Multivariate-adjusted risk ratios (RRs for incidence of EBP in the highest verses the bottom category of baseline intake of fish or LC n-3 PUFA were pooled using a random-effects meta-analysis. Over the follow-up ranging from 3 to 20 years, 20,497 EBP events occurred among 56,204 adults from eight prospective cohort studies. The summary RR (SRR was 0.96 (95% CI: 0.81, 1.14; I2 = 44.70% for fish in four studies, and 0.73 (95% CI: 0.60, 0.89; I2 = 75.00% for LC n-3 PUFA in six studies (three studies for biomarker vs. three studies for diet. Circulating LC n-3 PUFA as biomarker was inversely associated with incidence of EBP (SRR: 0.67; 95% CI: 0.55, 0.83, especially docosahexaenoic acid (SRR: 0.64; 95% CI: 0.45, 0.88, whereas no significant association was found for dietary intake (SRR: 0.80; 95% CI: 0.58, 1.10. The present finding suggests that increased intake of docosahexaenoic acid to improve its circulating levels may benefit primary prevention of EBP.

Comparing the burden of illness of haemophilia between resource-constrained and unconstrained countries: the São Paulo-Toronto Hemophilia Study.

Science.gov (United States)

Carneiro, J D A; Blanchette, V; Ozelo, M C; Antunes, S V; Villaca, P R; Young, N L; Castro, D; Brandão, L R; Carcao, M; Abad, A; Feldman, B M

2017-09-01

Although the regular replacement of clotting factor concentrates (prophylaxis) has been well established as the standard of care for severe haemophilia, the high cost of factor concentrates has limited access to prophylaxis in countries with under-developed or developing economies. We studied the health gap that could be addressed by providing unlimited access to clotting factor concentrates with implementation of long-term prophylaxis initiated from an early age in life. We performed a cross-sectional study of a random, representative sample of boys with moderate and severe haemophilia at three haemophilia treatment centres in Sao Paulo, Brazil, and one centre in Toronto, Canada. Canadian subjects were more often treated with prophylaxis, and began treatment at an earlier age. Fewer Canadian subjects had bleeds within the preceding 6 months (19 vs. 34, P = 0.003). Canadian subjects had lower (better) Pettersson radiographic scores (1.5 vs. 6.0, P = 0.0016), lower (better) Hemophilia Joint Health Scores (5.5 vs. 10.5, P = 0.0038), higher (better) Activity Scale for Kids scores (96.6 vs. 92.0, P = 0.033), more time spent in vigorous activity, and higher (better) social participation scores. Our findings suggest that increasing access to clotting factor concentrates for young boys with severe haemophilia is a global imperative. © 2017 John Wiley & Sons Ltd.

Somatic mosaicism in families with hemophilia B: 11% of germline mutations originate within a few cell divisions post-fertilization

Energy Technology Data Exchange (ETDEWEB)

Knoell, A.; Ketterling, R.P.; Vielhaber, E. [Mayo Clinic/Foundation, Rochester, MN (United States)] [and others

1994-09-01

Previous molecular estimates of mosaicism in the dystrophin and other genes generally have focused on the transmission of the mutated allele to two or more children by an individual without the mutation in leukocyte DNA. We have analyzed 414 families with hemophilia B by direct genomic sequencing and haplotype analysis, and have deduced the origin of mutation in 56 families. There was no origin individual who transmitted a mutant allele to more than one child. However, somatic mosaicism was detected by sequence analysis of four origin individuals (3{female} and 1{male}). The sensitivity of this analysis is typically one part in ten. In one additional female who had close to a 50:50 ratio of mutant to normal alleles, three of four noncarrier daughters inherited the haplotype associated with the mutant allele. This highlights a caveat in molecular analysis: a presumptive carrier in a family with sporadic disease does not necessarily have a 50% probability of transmitting the mutant allele to her offspring. After eliminating those families in which mosaicism could not be detected because of a total gene deletion or absence of DNA from a deduced origin individual, 5 of 43 origin individuals exhibited somatic mosaicism at a level that reflects a mutation within the first few cell divisions after fertilization. In one patient, analysis of cervical scrapings and buccal mucosa confirm the generalized distribution of somatic mutation. Are the first few cell divisions post-fertilization highly mutagenic, or do mutations at later divisions also give rise to somatic mosaicism? To address this question, DNA from origin individuals are being analyzed to detect somatic mosaicism at a sensitivity of 1:1000. Single nucleotide primer extension (SNuPE) has been utilized in eight families to date and no mosaicism has been detected. When the remaining 30 samples are analyzed, it will be possible to compare the frequency of somatic mosaicism at 0.1-10% with that of {ge}10%.

Baseline characteristics of patients with chronic kidney disease stage 3 and stage 4 in spain: the MERENA observational cohort study

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Montes Rafael

2011-10-01

Full Text Available Abstract Background To obtain information on cardiovascular morbidity, hypertension control, anemia and mineral metabolism based on the analysis of the baseline characteristics of a large cohort of Spanish patients enrolled in an ongoing prospective, observational, multicenter study of patients with stages 3 and 4 chronic kidney diseases (CKD. Methods Multicenter study from Spanish government hospital-based Nephrology outpatient clinics involving 1129 patients with CKD stages 3 (n = 434 and 4 (n = 695 defined by GFR calculated by the MDRD formula. Additional analysis was performed with GFR calculated using the CKD-EPI and Cockcroft-Gault formula. Results In the cohort as a whole, median age 70.9 years, morbidity from all cardiovascular disease (CVD was very high (39.1%. In CKD stage 4, CVD prevalence was higher than in stage 3 (42.2 vs 35.6% p 300 mg/day was present in more than 60% of patients and there was no significant differences between stages 3 and 4 CKD (1.2 ± 1.8 and 1.3 ± 1.8 g/day, respectively. A majority of the patients had hemoglobin levels greater than 11 g/dL (91.1 and 85.5% in stages 3 and 4 CKD respectively p Conclusion This study provides an overview of key clinical parameters in patients with CKD Stages 3 and 4 where delivery or care was largely by nephrologists working in a network of hospital-based clinics of the Spanish National Healthcare System.

Intake of total omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid and risk of coronary heart disease in the Spanish EPIC cohort study.

Science.gov (United States)

Amiano, P; Machón, M; Dorronsoro, M; Chirlaque, M Dolores; Barricarte, A; Sánchez, M-J; Navarro, C; Huerta, J M; Molina-Montes, E; Sánchez-Cantalejo, E; Urtizberea, M; Arriola, L; Larrañaga, N; Ardanaz, E; Quirós, J R; Moreno-Iribas, C; González, C A

2014-03-01

The evidence about the benefits of omega-3 fatty acid intake on coronary heart disease (CHD) is not consistent. We thus aimed to assess the relation between dietary intake of total omega-3 fatty acids (from plant and marine foods) and marine polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the risk of CHD in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 41,091 men and women aged 20-69 years, recruited from 1992 to 1996 and followed-up until December 2004. Omega-3 fatty acid intake was estimated from a validated dietary questionnaire. Only participants with definite incident CHD event were considered as cases. Cox regression models were used to assess the association between the intake of total omega-3 fatty acids, EPA or DHA and CHD. A total of 609 participants (79% men) had a definite CHD event. Mean intakes of total omega-3 fatty acids, EPA and DHA were very similar in the cases and in the cohort, both in men and women. In the multivariate adjusted model, omega-3 fatty acids, EPA and DHA were not related to incident CHD in either men or women. The hazard ratios (HR) for omega-3 were 1.23 in men (95% CI 0.94-15.9, p = 0.20); and 0.77 in women (95% CI 0.46-1.30, p = 0.76). In the Spanish EPIC cohort, with a relatively high intake of fish, no association was found between EPA, DHA and total omega-3 fatty acid intake and risk of CHD. Copyright © 2013 Elsevier B.V. All rights reserved.

Lung cancer risk comparison among male smokers between the "six-prefecture cohort" in Japan and the British physicians' cohort.

Science.gov (United States)

Mizuno, S; Akiba, S; Hirayama, T

1989-12-01

We estimated the effective duration of cigarette smoking using the data of lung cancer mortality among male smokers of a large-scale cohort study in Japan and evaluated its role in the lung cancer risk difference between male smokers of the Japanese cohort and the British physicians' cohort. By selecting male cohort members who answered that they had started smoking at ages 18-22 (average = 20.3), the subjects of our analysis, which numbered 49,013, were made relatively homogeneous in terms of age at which smoking was started. Assuming lung cancer mortality to be proportional to the 4.5th power of the effective duration of cigarette smoking, i.e., (age-theta)4.5, as was proposed on the basis of the British cohort study by Doll and Peto, the parameter theta was estimated to be 29.4 for male smokers aged 40-64 in 1966; therefore, the estimated duration of cigarette smoking was, on average, 9.1 years (95% confidence interval = 5.8-11.6) shorter than that calculated from the reported age at which smoking was started. Our findings suggested that the low lung cancer mortality relative to daily cigarette consumption in Japan resulted from the shorter duration of cigarette smoking in the Japanese cohort, possibly due to the severe shortage of cigarettes during and shortly after World War II. Once the effective duration of cigarette smoking was adjusted, lung cancer mortality in the range of 5-34 cigarettes per day was fairly comparable to that observed among the cohort of male British physicians.

Cohort profile: the Spanish WORKing life Social Security (WORKss) cohort study.

Science.gov (United States)

López Gómez, María Andrée; Durán, Xavier; Zaballa, Elena; Sanchez-Niubo, Albert; Delclos, George L; Benavides, Fernando G

2016-03-07

The global economy is changing the labour market and social protection systems in Europe. The effect of both changes on health needs to be monitored in view of an ageing population and the resulting increase in prevalence of chronic health conditions. The Spanish WORKing life Social Security (WORKss) cohort study provides unique longitudinal data to study the impact of labour trajectories and employment conditions on health, in terms of sickness absence, permanent disability and death. The WORKss cohort originated from the Continuous Working Life Sample (CWLS) generated by the General Directorate for the Organization of the Social Security in Spain. The CWLS contains a 4% representative sample of all individuals in contact with the Social Security system. The WORKss cohort exclusively includes individuals with a labour trajectory from 1981 or later. In 2004, the cohort was initiated with 1,022 ,79 Social Security members: 840,770 (82.2%) contributors and 182,009 (17.8%) beneficiaries aged 16 and older. The WORKss cohort includes demographic characteristics, chronological data about employment history, retirement, permanent disability and death. These data make possible the measurement of incidence of permanent disability, the number of potential years of working life lost, and the number of contracts and inactive periods with the Social Security system. The WORKss cohort was linked to temporary sickness absence registries to study medical diagnoses that lead to permanent disability and consequently to an earlier exit from the labour market in unhealthy conditions. Thanks to its administrative source, the WORKss cohort study will continue follow-up in the coming years, keeping the representativeness of the Spanish population affiliated to the Social Security system. The linkage between the WORKss cohort and temporary sickness absence registries is envisioned to continue. Future plans include the linkage of the cohort with mortality registries. Published by the BMJ

The Netherlands Cohort Study – Meat Investigation Cohort; a population-based cohort over-represented with vegetarians, pescetarians and low meat consumers

Science.gov (United States)

2013-01-01

Background Vegetarian diets have been associated with lower risk of chronic disease, but little is known about the health effects of low meat diets and the reliability of self-reported vegetarian status. We aimed to establish an analytical cohort over-represented with vegetarians, pescetarians and 1 day/week meat consumers, and to describe their lifestyle and dietary characteristics. In addition, we were able to compare self-reported vegetarians with vegetarians whose status has been confirmed by their response on the extensive food frequency questionnaire (FFQ). Study methods Embedded within the Netherlands Cohort Study (n = 120,852; including 1150 self-reported vegetarians), the NLCS-Meat Investigation Cohort (NLCS-MIC) was defined by combining all FFQ-confirmed-vegetarians (n = 702), pescetarians (n = 394), and 1 day/week meat consumers (n = 1,396) from the total cohort with a random sample of 2–5 days/week- and 6–7 days/week meat consumers (n = 2,965 and 5,648, respectively). Results Vegetarians, pescetarians, and 1 day/week meat consumers had more favorable dietary intakes (e.g. higher fiber/vegetables) and lifestyle characteristics (e.g. lower smoking rates) compared to regular meat consumers in both sexes. Vegetarians adhered to their diet longer than pescetarians and 1 day/week meat consumers. 75% of vegetarians with a prevalent cancer at baseline had changed to this diet after diagnosis. 50% of self-reported vegetarians reported meat or fish consumption on the FFQ. Although the misclassification that occurred in terms of diet and lifestyle when merely relying on self-reporting was relatively small, the impact on associations with disease risk remains to be studied. Conclusion We established an analytical cohort over-represented with persons at the lower end of the meat consumption spectrum which should facilitate prospective studies of major cancers and causes of death using ≥20.3 years of follow-up. PMID:24289207

FIBRIN GLUE DAN APLIKASINYA

Directory of Open Access Journals (Sweden)

Agi Harliani S

2015-08-01

Full Text Available Fibrin Tissue Adhesive (FTA, Fibrin Sealant (FS or Fibrin Glue (FG are names given to a group of product that lead to the formation of fibrin clot at the site of application. Fibrin Glue represents a new revolution for local haemostatic, which produced by based on the understanding about blood coagulation process. The mechanism of FG mimics the last stage of blood coagulation process. Haemophilia, is a congenital inherited bleeding disorder, characterized by repeated bleeding episodes. The basic pathology is deficiency of factor VIII (hemophilia A or factor IX (hemophilia B. At bleeding episodes, hemophilia patients need replacement therapy. Hemophilia patients need transfusion of cryoprecipitate, Fresh Frozen Plasma (FFP or factor concentrate as replacement therapy. Oral surgery, dental extraction, circumcision, and orthopedic operations are the most important indications for fibrin glue in hemophilia care. As haemostatic local, FG minimizes bleeding, reducing the need of transfusion or factor concentrate, reducing the complication of transfusion, hospitalization and cost.

Estimated dietary dioxin exposure and breast cancer risk among women from the French E3N prospective cohort.

Science.gov (United States)

Danjou, Aurélie M N; Fervers, Béatrice; Boutron-Ruault, Marie-Christine; Philip, Thierry; Clavel-Chapelon, Françoise; Dossus, Laure

2015-03-17

Dioxins are environmental and persistent pollutants mostly emitted from combustion facilities (e.g. waste incinerators, metal and cement industries). Known to be endocrine disrupting chemicals, dioxins are suspected to increase breast cancer (BC) risk. Although diet is considered the primary source of dioxin exposure, no previous study has been published on dietary dioxin exposure in relation to BC risk. We aimed to assess dietary dioxin exposure among women from the E3N cohort and estimate BC risk associated with this exposure. The study included 63,830 women from the E3N cohort who completed a diet history questionnaire (DHQ) in 1993 and were followed until 2008. Dietary dioxin exposure was estimated by combining consumption data from the E3N DHQ and food dioxin contamination data from a French national monitoring program. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox models adjusted for BC risk factors. Mean dietary dioxin exposure was estimated at 1.3 ± 0.4 pg/kg body weight (BW)/day. A 0.4 pg/kg BW/d increase in dioxin intake was not associated with overall BC risk (HR = 1.00; 95% CI: 0.96, 1.05). A significant decrease in risk of estrogen receptor negative (ER-)/progesterone receptor negative (PR-) tumors was observed among post-menopausal women in the upper quartile of estimated dioxin intake (HR for Q4 vs. Q1: 0.65; 95% CI: 0.45, 0.96; P for trend across quartiles = 0.0463). Overall, no association between estimated dietary dioxin exposure and BC risk was found among E3N women. Further studies should include both dietary and environmental exposures to determine whether low-dose dioxin exposure is associated with BC risk.

Clinical audit of inherited bleeding disorders in a developing country

Directory of Open Access Journals (Sweden)

Sajid Raihan

2010-01-01

Full Text Available Objective: We did a clinical audit to determine the status of coagulation disorders in a hemophilia care center in Pakistan. Setting: Fatimid foundation blood bank and hematological diseases center, Lahore. Study Design: This is a retrospective descriptive study. Materials and Methods: All patients registered at Lahore center were included. Data was collected using a questionnaire including age, gender, diagnosis, hepatitis and human immune deficiency virus (HIV status, number of episodes of bleeding, most common site of bleeding, severity of disorder and number of transfusions required to treat the episode. Results: During the study period, a total of 923 registered patients were reviewed at Lahore center and of these, 408 patients (44.2% were on regular follow-up. Inherited bleeding disorders identified in these patients included hemophilia A, hemophilia B, vWD, factor VII deficiency, factor V deficiency, factor X deficiency, dysfibrinogenemia, afibrinogenemia, factor XIII deficiency; and platelet function defects. Median age was 17 years with a range of three to 57 years. Median age at diagnosis was one year. There were 329 (80.6% males and 79 (19.3% females. The products used in these patients included factor VIII concentrate, fresh frozen plasma, cryoprecipitate, cryosupernatant and platelets. Testing for transmission of viral infections was also done in these patients and one patient (0.2% was found hepatitis B positive, six patients (1.4% were hepatitis C positive and two patients (0.49% were HIV positive. Conclusion: Hemophilia A, hemophilia B and vWD are the commonly encountered inherited bleeding disorders in our patients followed by other recessively transmitted disorders with a median age of 17 years and male to female ratio of 4: 1. Most of the patients utilized services available at Fatimid foundation with good clinical results. In Pakistan, non-governmental organizations (NGOs are trying their best for providing optimal treatment

Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study

Science.gov (United States)

Klamroth, Robert; Scharf, Rüdiger E.; Trappe, Ralf U.; Holstein, Katharina; Huth-Kühne, Angela; Gottstein, Saskia; Geisen, Ulrich; Schenk, Joachim; Scholz, Ute; Schilling, Kristina; Neumeister, Peter; Miesbach, Wolfgang; Manner, Daniela; Greil, Richard; von Auer, Charis; Krause, Manuela; Leimkühler, Klaus; Kalus, Ulrich; Blumtritt, Jan-Malte; Werwitzke, Sonja; Budde, Eva; Koch, Armin; Knöbl, Paul

2015-01-01

Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA. PMID:25525118

34 CFR 668.207 - Preventing evasion of the consequences of cohort default rates.

Science.gov (United States)

2010-07-01

... 34 Education 3 2010-07-01 2010-07-01 false Preventing evasion of the consequences of cohort default rates. 668.207 Section 668.207 Education Regulations of the Offices of the Department of Education... Cohort Default Rates § 668.207 Preventing evasion of the consequences of cohort default rates. (a...

34 CFR 668.188 - Preventing evasion of the consequences of cohort default rates.

Science.gov (United States)

2010-07-01

... 34 Education 3 2010-07-01 2010-07-01 false Preventing evasion of the consequences of cohort default rates. 668.188 Section 668.188 Education Regulations of the Offices of the Department of Education... Two Year Cohort Default Rates § 668.188 Preventing evasion of the consequences of cohort default rates...

The Danish National Birth Cohort

DEFF Research Database (Denmark)

Andersen, Anne-Marie Nybo; Olsen, Jørn

2011-01-01

, physical exercise, working conditions, medication and infections during pregnancy, and environmental possible toxins. The study designs cover straightforward cohort analyses, case-control studies and sub-cohort analyses with enriched data collection. CONCLUSION: So far, the Danish National Birth Cohort has......INTRODUCTION: In this review a selection of studies published during the period 2002-2010, based on data from the Danish National Birth Cohort linked with other health registers, is described. Illustrative examples of studies addressing perinatal health outcomes (pregnancy complications and fetal...... that this investment in epidemiologic infrastructure was well spent. The existence of the Danish National Birth Cohort together with other cohorts and national registers has given Denmark a leading position in reproductive epidemiology....

Copenhagen Airport Cohort

DEFF Research Database (Denmark)

Møller, Karina Lauenborg; Brauer, Charlotte; Mikkelsen, Sigurd

2017-01-01

TO DATE: The cohort includes environmental Global Positioning System (GPS) measurements in Copenhagen Airport, information on job function/task for each calendar year of employment between 1990 and 2012, exposure to air pollution at residence, average weight of baggage lifted per day and lifestyle...... covers 69 175 men in unskilled positions. The exposed cohort includes men in unskilled jobs employed at Copenhagen Airport in the period 1990-2012 either as baggage handlers or in other outdoor work. The reference cohort includes men in unskilled jobs working in the greater Copenhagen area. FINDINGS...

Riyadh Mother and Baby Multicenter Cohort Study: The Cohort Profile.

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Hayfaa Wahabi

Full Text Available To assess the effects of non-communicable diseases, such as diabetes, hypertension and obesity, on the mother and the infant.A multicentre cohort study was conducted in three hospitals in the city of Riyadh in Saudi Arabia. All Saudi women and their babies who delivered in participating hospitals were eligible for recruitment. Data on socio-demographic characteristics in addition to the maternal and neonatal outcomes of pregnancy were collected. The cohort demographic profile was recorded and the prevalence of maternal conditions including gestational diabetes, pre-gestational diabetes, hypertensive disorders in pregnancy and obesity were estimated.The total number of women who delivered in participating hospitals during the study period was 16,012 of which 14,568 women participated in the study. The mean age of the participants was 29 ± 5.9 years and over 40% were university graduates. Most of the participants were housewives, 70% were high or middle income and 22% were exposed to secondhand smoke. Of the total cohort, 24% were married to a first cousin. More than 68% of the participants were either overweight or obese. The preterm delivery rate was 9%, while 1.5% of the deliveries were postdate. The stillbirth rate was 13/1000 live birth. The prevalence of gestational diabetes was 24% and that of pre-gestational diabetes was 4.3%. The preeclampsia prevalence was 1.1%. The labour induction rate was 15.5% and the cesarean section rate was 25%.Pregnant women in Saudi Arabia have a unique demographic profile. The prevalence of obesity and diabetes in pregnancy are among the highest in the world.

Cohort profile: cerebral palsy in the Norwegian and Danish birth cohorts (MOBAND-CP)

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Tollånes, Mette C; Strandberg-Larsen, Katrine; Forthun, Ingeborg; Petersen, Tanja Gram; Moster, Dag; Andersen, Anne-Marie Nybo; Stoltenberg, Camilla; Olsen, Jørn; Wilcox, Allen J

2016-01-01

Purpose The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design. Participants MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts—the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries. Findings to date Initial harmonisation of data from the 2 cohorts has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies investigating various hypotheses regarding CP aetiology are currently on-going. Future plans Additional data can be harmonised as necessary to meet requirements of new projects. Biological specimens collected during pregnancy and at delivery are potentially available for assay, as are results from assays conducted on these specimens for other projects. The study size allows consideration of CP subtypes, which is rare in aetiological studies of CP. In addition, MOBAND-CP provides a platform within the context of a merged birth cohort of exceptional size that could, after appropriate permissions have been sought, be used for cohort and case-cohort studies of other relatively rare health conditions of infants and children. PMID:27591025

Recent pharmacological management of oral bleeding in hemophilic patient

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Monica Widyawati Setiawan

2011-09-01

Full Text Available Background: Hemophilia is a hereditary bleeding disorder that can increase the risk of disease in oral cavity. Sometimes hemophilia is not always established already in a patient. The lack of awareness of hemophilia presence can cause serious problem. Purpose: The purpose of this review is to explain about dental bleeding manifestation and management in hemophilic patient. Reviews: Hemophilia can be manifested as dental bleeding that cannot stop spontaneously. It should be treated with factor VIIII either by giving whole blood, fresh plasma, fresh frozen plasma, cryoprecipitate, and factor VIII concentrate. Factor VIII dose for hemophilia treatment can be calculated based on factor VIII present in hemophilia patient’s body. Factor VIII can also be given as prophylaxis to prevent bleeding. Complications that can be caused by factor VIII replacement therapy are the presence of factor VIII inhibitor and transfusion related diseases. Treatment of dental bleeding due to hemophilia consists of factor replacement therapy and supportive therapy. Conclusion: Treatment of dental bleeding due to hemophilia consists of factor replacement therapy and supportive therapy. There are complications that can happen due to factor VIII replacement therapy that should be considered and anticipated.Latar belakang: Hemofilia adalah kelainan pembekuan darah yang diturunkan. Hemophilia dapat meningkatkan resiko penyakit rongga mulut. Hemofilia tidak selalu sudah terdiagnosa saat penderita melakukan kunjungan ke dokter gigi. Kurangnya kewaspadaan akan adanya hemofilia dapat menyebabkan masalah serius. Tujuan: Tujuan dari kajian pustaka ini adalah memaparkan tentang manifestasi dan penanganan perdarahan gigi pada penderita hemofilia. Tinjauan pustaka: hemofilia dapat bermanifestasi sebagai perdarahan gigi yang tidak dapat berhenti secara spontan. Pada keadaan perdarahan tersebut, pemberian faktor VIII yang diberikan sebagai whole blood, fresh plasma, fresh frozen plasma

Cohort profile

DEFF Research Database (Denmark)

Maret-Ouda, John; Wahlin, Karl; Artama, Miia

2017-01-01

Purpose: To describe a newly created all-Nordic cohort of patients with gastro-oesophageal reflux disease (GORD), entitled the Nordic Antireflux Surgery Cohort (NordASCo), which will be used to compare participants having undergone antireflux surgery with those who have not regarding risk...... age at primary antireflux surgery ranged from 47 to 52 years in the different countries. The coding practices of GORD seem to have differed between the Nordic countries. Future plans: The NordASCo will initially be used to analyse the risk of developing known or potential GORD-related cancers, that is......, tumours of the oesophagus, stomach, larynx, pharynx and lung, and to evaluate the mortality in the short-term and long-term perspectives. Additionally, the cohort will be used to evaluate the risk of non-malignant respiratory conditions that might be caused by aspiration of gastric contents....

Comparing Three South African Student Cohorts on Their Attitudes to the Rights of Working Women

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Patel, Cynthia Joan

2016-01-01

This study compares three cohorts (1998-1999, 2005-2006 and 2010) of undergraduate psychology students at a South African university on the level of support for working women (women in paid employment) on various issues considered to be feminist. Cohort 1 (n?=?244), cohort 2 (n?=?311) and cohort 3 (n?=?266) completed an adapted version of a…

Hypospadias in a cohort of 1072 Danish newborn boys

DEFF Research Database (Denmark)

Boisen, K A; Chellakooty, M; Schmidt, I M

2005-01-01

and reproductive hormone levels at 3 months of age. DESIGN: A prospective cohort study was conducted with 3-yr follow-up (1997-2004). SETTING: The population-based study was conducted at the University Hospital of Copenhagen. PARTICIPANTS: A total of 1072 Danish boys were consecutively recruited antenatally...... = 0.023) were significantly lower, and FSH was significantly higher (1.48 vs. 1.15 IU/liter; P = 0.007) in boys with hypospadias, compared with healthy boys. CONCLUSIONS: We found a surprisingly high total rate of hypospadias of 4.6% in this large prospective cohort study. Seventy-two percent...

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

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Wells, J. Michael; Farris, Roopan F.; Gosdin, Taylor A.; Dransfield, Mark T.; Wood, Michelle E.; Bell, Scott C.; Rowe, Steven M.

2017-01-01

Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations. Methods We analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort. Findings We found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:Apulmonary exacerbation risk in two well-characterized cohorts. PA:A may be a predictive marker in CF. PMID:27298019

Irritable bowel syndrome and chronic fatigue 3 years after acute giardiasis: historic cohort study.

Science.gov (United States)

Wensaas, Knut-Arne; Langeland, Nina; Hanevik, Kurt; Mørch, Kristine; Eide, Geir Egil; Rortveit, Guri

2012-02-01

Giardia lamblia is a common cause of gastroenteritis worldwide, but there is limited knowledge about the long-term complications. To estimate the relative risk of irritable bowel syndrome (IBS) and chronic fatigue 3 years after acute giardiasis. Controlled historic cohort study with 3 years' follow-up. Data collected by mailed questionnaire. Waterborne outbreak of giardiasis in the city of Bergen, Norway. 817 patients exposed to Giardia lamblia infection verified by detection of cysts in stool samples and 1128 matched controls. IBS and chronic fatigue. The prevalence of IBS in the exposed group was 46.1%, compared with 14.0% in the control group, and the adjusted RR=3.4 (95% CI 2.9 to 3.8). Chronic fatigue was reported by 46.1% of the exposed group and 12.0% of the controls, the adjusted RR was 4.0 (95% CI 3.5 to 4.5). IBS and chronic fatigue were associated and the RR for the exposed group of having a combination of the two outcomes was 6.8 (95% CI 5.3 to 8.5). The RR was also increased for having just one of the two syndromes, 1.8 for IBS (95% CI 1.4 to 2.3) and 2.2 for chronic fatigue (95% CI 1.7 to 2.8). Infection with Giardia lamblia in a non-endemic area was associated with a high prevalence of IBS and chronic fatigue 3 years after acute illness, and the risk was significantly higher than in the control group. This shows that the potential consequences of giardiasis are more serious than previously known. Further studies are needed, especially in areas where giardiasis is endemic.

Cohort Profile : LifeLines, a three-generation cohort study and biobank

NARCIS (Netherlands)

Scholtens, Salome; Smidt, Nynke; Swertz, Morris A.; Bakker, Stephan J. L.; Dotinga, Aafje; Vonk, Judith M.; van Dijk, Freerk; van Zon, Sander K. R.; Wijmenga, Cisca; Wolffenbuttel, Bruce H. R.; Stolk, Ronald P.

The LifeLines Cohort Study is a large population-based cohort study and biobank that was established as a resource for research on complex interactions between environmental, phenotypic and genomic factors in the development of chronic diseases and healthy ageing. Between 2006 and 2013, inhabitants

Anti-pentraxin 3 auto-antibodies might be protective in lupus nephritis: a large cohort study.

Science.gov (United States)

Yuan, Mo; Tan, Ying; Pang, Yun; Li, Yong-Zhe; Song, Yan; Yu, Feng; Zhao, Ming-Hui

2017-11-01

Anti-pentraxin 3 (PTX3) auto-antibodies were found to be associated with the absence of renal involvement in systemic lupus erythematosus (SLE). This study is to investigate the prevalence of anti-PTX3 auto-antibodies and their clinical significance based on a large Chinese lupus nephritis cohort. One hundred and ninety-six active lupus nephritis patients, 150 SLE patients without clinical renal involvement, and 100 healthy controls were enrolled. Serum anti-PTX3 auto-antibodies and PTX3 levels were screened by enzyme-linked immunosorbent assay (ELISA). The associations between anti-PTX3 auto-antibodies and clinicopathological parameters in lupus nephritis were further analyzed. Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement (19.4% (38/196) versus 40.7% (61/150), p auto-antibodies were negatively correlated with proteinuria in lupus nephritis (r = -.143, p = .047). The levels of proteinuria, serum creatinine, and the prevalence of thrombotic microangiopathy were significantly higher in patients with higher PTX3 levels (≥3.207 ng/ml) and without anti-PTX3 auto-antibodies compared with patients with lower PTX3 levels (auto-antibodies (4.79 (3.39-8.28) versus 3.95 (1.78-7.0), p = .03; 168.84 ± 153.63 versus 101.44 ± 47.36, p = .01; 34.1% (14/41) versus 0% (0/9), p = .04; respectively). Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement and associated with less severe renal damage, especially with the combined evaluation of serum PTX3 levels.

Birth weight and stuttering: Evidence from three birth cohorts.

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McAllister, Jan; Collier, Jacqueline

2014-03-01

Previous studies have produced conflicting results with regard to the association between birth weight and developmental stuttering. This study sought to determine whether birth weight was associated with childhood and/or adolescent stuttering in three British birth cohort samples. Logistic regression analyses were carried out on data from the Millenium Cohort Study (MCS), British Cohort Study (BCS70) and National Child Development Study (NCDS), whose initial cohorts comprised over 56,000 individuals. The outcome variables were parent-reported stuttering in childhood or in adolescence; the predictors, based on prior research, were birth weight, sex, multiple birth status, vocabulary score and mother's level of education. Birth weight was analysed both as a categorical variable (low birth weight, stuttering during childhood (age 3, 5 and 7 and MCS, BCS70 and NCDS, respectively) or at age 16, when developmental stuttering is likely to be persistent. None of the multivariate analyses revealed an association between birth weight and parent-reported stuttering. Sex was a significant predictor of stuttering in all the analyses, with males 1.6-3.6 times more likely than females to stutter. Our results suggest that birth weight is not a clinically useful predictor of childhood or persistent stuttering. Copyright © 2013 Elsevier Inc. All rights reserved.

Medical symptoms among pilots associated with work and home environments: a 3-year cohort study.

Science.gov (United States)

Fu, Xi; Lindgren, Torsten; Norbäck, Dan

2015-05-01

To study associations between the cockpit environment, psychosocial work environment, home environment, and medical symptoms in a cohort of commercial pilots followed over 3 yr. A standardized questionnaire was mailed in February-March 1997 to all Stockholm-based pilots on duty in a Scandinavian flight company (N = 622); 577 (93%) participated. During this time smoking was allowed on long haul flights, but not on shorter flights. Smoking was prohibited on all flights after September 1997. The same questionnaire was sent to the cohort of 577 pilots in February-March 2000; 436 participated (76%). The questionnaire contained questions on symptoms, the psychosocial work environment, and the home environment. Associations were investigated using multiple logistic and ordinal regression. Symptoms were common, especially eye symptoms (38.5%), nose symptoms (39.9%), and tiredness (29.9%). Pilots exposed to environmental tobacco smoke (ETS) on long haul flights had more eye symptoms (odds ratio = 1.91) and tiredness (odds ratio = 2.73). These symptoms were reduced when no longer exposed to ETS. Those who started working on long haul flights developed more nose symptoms. Pilots reporting increased work demands developed more nose and dermal symptoms and tiredness and those with decreased work control developed more eye symptoms. Pilots living in new houses, multifamily houses, and in recently painted homes reported more symptoms. Eliminating ETS exposure on board reduced medical symptoms. Further work to reduce ETS exposure globally is needed. Psychosocial aspects of the work environment for commercial pilots should be considered, as well as the home environment.

Hemophilia B with mutations at glycine-48 of factor IX exhibited delayed activation by the factor VIIa-tissue factor complex.

Science.gov (United States)

Wu, P C; Hamaguchi, N; Yu, Y S; Shen, M C; Lin, S W

2000-10-01

Gly-48 is in the conserved DGDQC sequence (residues 47-51 of human factor IX) of the first EGF (EGF-1)-like domain of factor IX. The importance of the Gly-48 is manifested by two hemophilia B patients; factor IXTainan and factor IXMalmo27, with Gly-48 replaced by arginine (designated IXG48R) and valine (IXG48V), respectively. Both patients were CRM+ exhibiting mild hemophilic episodes with 25% (former) and 19% (latter) normal clotting activities. We characterize both factor IX variants to show the roles of Gly-48 and the conservation of the DGDQC sequence in factor IX. Purified plasma and recombinant factor IX variants exhibited approximately 26%-27% normal factor IX's clotting activities with G48R or G48V mutation. Both variants depicted normal quenching of the intrinsic fluorescence by increasing concentrations of calcium ions and Tb3+, indicating that arginine and valine substitution for Gly-48 did not perturb the calcium site in the EGF-1 domain. Activation of both mutants by factor XIa appeared normal. The reduced clotting activity of factors IXG48R and IXG48V was attributed to the failure of both mutants to cleavage factor X: in the presence of only phospholipids and calcium ions, both mutants showed a 4 to approximately 7-fold elevation in Km, and by adding factor VIIIa to the system, although factor VIIIa potentiated the activation of factor X by the mutants factor IXaG48R and factor IXaG48V, a 2 to approximately 3-fold decrease in the catalytic function was observed with the mutant factor IXa's, despite that they bound factor VIIIa on the phospholipid vesicles with only slightly reduced affinity when compared to wild-type factor IXa. The apparent Kd for factor VIIIa binding was 0.83 nM for normal factor IXa, 1.74 nM for IXaG48R and 1.4 nM for IXaG48V. Strikingly, when interaction with the factor VIIa-TF complex was examined, both mutations were barely activated by the VIIa-TF complex and they also showed abnormal interaction with VIIa-TF in bovine

1970 British Cohort Study

Directory of Open Access Journals (Sweden)

Matt Brown

2014-10-01

Full Text Available The 1970 British Cohort Study (BCS70 is one of Britain’s world famous national longitudinal birth cohort studies, three of which are run by the Centre for Longitudinal Studies at the Institute of Education, University of London.  BCS70 follows the lives of more than 17,000 people born in England, Scotland and Wales in a single week of 1970. Over the course of cohort members lives, the BCS70 has collected information on health, physical, educational and social development, and economic circumstances among other factors. Since the birth survey in 1970, there have been nine ‘sweeps’ of all cohort members at ages 5, 10, 16, 26, 30, 34, 38 and most recently at 42. Data has been collected from a number of different sources (the midwife present at birth, parents of the cohort members, head and class teachers, school health service personnel and the cohort members themselves. The data has been collected in a variety of ways including via paper and electronic questionnaires, clinical records, medical examinations, physical measurements, tests of ability, educational assessments and diaries. The majority of BCS70 survey data can be accessed by bona fide researchers through the UK Data Service at the University of Essex.

Opportunistic Infections (OIs) in Patients with Hematologic Malignancies (HM) Treated with Bruton’s Tyrosine Kinase (BTK) and Phosphoinositide 3 Kinase (PI3K) Inhibitors: An 8-Year Retrospective Cohort Study

OpenAIRE

Issa, Nicolas; Arbona-Haddad, Esther; Nevett-Fernandez, Alexandra; Prestes, Daniel; Liakos, Alexis; Woolley, Ann; Hammond, Sarah; Brown, Jennifer; Baden, Lindsey; Marty, Francisco

2017-01-01

Abstract Background: BTK and PI3K inhibitors are increasingly used for treatment in patients with HM. OIs when these agents were used as first line therapy signaled an increased level of immunosuppression beyond what was expected from the mechanism of action of these drugs. The epidemiology of OIs in the setting of BTK and PI3K inhibitor use has not been characterized. Methods: We retrospectively studied a cohort of patients with HM who received BTK (ibrutinib, acalabrutinib, spebrutinib) or ...

IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3.

Directory of Open Access Journals (Sweden)

Alpa V Patel

2008-07-01

Full Text Available IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3. This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

ACTN3 R577X and ACE I/D gene variants influence performance in elite sprinters: a multi-cohort study.

Science.gov (United States)

Papadimitriou, Ioannis D; Lucia, Alejandro; Pitsiladis, Yannis P; Pushkarev, Vladimir P; Dyatlov, Dmitry A; Orekhov, Evgeniy F; Artioli, Guilherme G; Guilherme, João Paulo L F; Lancha, Antonio H; Ginevičienė, Valentina; Cieszczyk, Pawel; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Muniesa, Carlos A; Kouvatsi, Anastasia; Massidda, Myosotis; Calò, Carla Maria; Garton, Fleur; Houweling, Peter J; Wang, Guan; Austin, Krista; Druzhevskaya, Anastasiya M; Astratenkova, Irina V; Ahmetov, Ildus I; Bishop, David J; North, Kathryn N; Eynon, Nir

2016-04-13

To date, studies investigating the association between ACTN3 R577X and ACE I/D gene variants and elite sprint/power performance have been limited by small cohorts from mixed sport disciplines, without quantitative measures of performance. To examine the association between these variants and sprint time in elite athletes. We collected a total of 555 best personal 100-, 200-, and 400-m times of 346 elite sprinters in a large cohort of elite Caucasian or African origin sprinters from 10 different countries. Sprinters were genotyped for ACTN3 R577X and ACE ID variants. On average, male Caucasian sprinters with the ACTN3 577RR or the ACE DD genotype had faster best 200-m sprint time than their 577XX (21.19 ± 0.53 s vs. 21.86 ± 0.54 s, p = 0.016) and ACE II (21.33 ± 0.56 vs. 21.93 ± 0.67 sec, p = 0.004) counterparts and only one case of ACE II, and no cases of ACTN3 577XX, had a faster 200-m time than the 2012 London Olympics qualifying (vs. 12 qualified sprinters with 577RR or 577RX genotype). Caucasian sprinters with the ACE DD genotype had faster best 400-m sprint time than their ACE II counterparts (46.94 ± 1.19 s vs. 48.50 ± 1.07 s, p = 0.003). Using genetic models we found that the ACTN3 577R allele and ACE D allele dominant model account for 0.92 % and 1.48 % of sprint time variance, respectively. Despite sprint performance relying on many gene variants and environment, the % sprint time variance explained by ACE and ACTN3 is substantial at the elite level and might be the difference between a world record and only making the final.

The role of birth cohorts in studies of adult health: the New York women's birth cohort.

Science.gov (United States)

Terry, Mary Beth; Flom, Julie; Tehranifar, Parisa; Susser, Ezra

2009-09-01

Epidemiological studies investigating associations between early life factors and adult health are often limited to studying exposures that can be reliably recalled in adulthood or obtained from existing medical records. There are few US studies with detailed data on the pre- and postnatal environment whose study populations are now in adulthood; one exception is the Collaborative Perinatal Project (CPP). We contacted former female participants of the New York site of the CPP who were born from 1959 to 1963 and were prospectively followed for 7 years to examine whether the pre- and postnatal environment is associated with adult health in women 40 years after birth. The New York CPP cohort is particularly diverse; at enrolment, the race/ethnicity distribution of mothers was approximately 30% White, 40% Black and 30% Puerto Rican. Of the 841 eligible women, we successfully traced 375 women (45%) and enrolled 262 women (70% of those traced). Baseline data were available for all eligible women, and we compared those who participated with the remaining cohort (n = 579). Higher family socio-economic status at age 7, availability of maternal social security number, and White race/ethnicity were statistically significantly associated with a higher probability of tracing. Of those traced, race/ethnicity was associated with participation, with Blacks and Puerto Ricans less likely to participate than Whites (OR = 0.5, 95% CI 0.3, 0.8, and OR = 0.5, 95% CI 0.3, 1.0, respectively). In addition, higher weight at 7 years was associated with lower participation (OR = 0.95, 95% CI 0.92, 0.99), but this association was observed only among the non-White participants. None of the other maternal characteristics, infant or early childhood growth measures was associated with participation or with tracing, either overall or within each racial/ethnic subgroup. Daughters' recall of early life factors such as pre-eclampsia (sensitivity = 24%) and birthweight were generally poor, with the

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... heavy menstrual periods. Individuals with a gene for hemophilia, including symptomatic female carriers who have heavy menstrual ... Heart-Healthy Lifestyle Changes Heart Failure Hemolytic Anemia Hemophilia Pernicious Anemia Restless Legs Syndrome Von Willebrand Disease ...

Cohort profile: LIFEWORK, a prospective cohort study on occupational and environmental risk factors and health in the Netherlands.

Science.gov (United States)

Reedijk, Marije; Lenters, Virissa; Slottje, Pauline; Pijpe, Anouk; Peeters, Petra H; Korevaar, Joke C; Bueno-de-Mesquita, Bas; Verschuren, W M Monique; Verheij, Robert A; Pieterson, Inka; van Leeuwen, Flora E; Rookus, Matti A; Kromhout, Hans; Vermeulen, Roel C H

2018-02-03

LIFEWORK is a large federated prospective cohort established in the Netherlands to quantify the health effects of occupational and environmental exposures. This cohort is also the Dutch contribution to the international Cohort Study of Mobile Phone Use and Health (COSMOS). In this paper, we describe the study design, ongoing data collection, baseline characteristics of participants and the repeatability of key questionnaire items. 88 466 participants were enrolled in three cohort studies in 2011-2012. Exposure information was collected by a harmonised core questionnaire, or modelled based on occupational and residential histories; domains include air pollution (eg, nitrogen dioxide (NO 2 ), particulate matter with diameter ≤2.5 µm (PM 2.5 )), noise, electromagnetic fields (EMF), mobile phone use, shift work and occupational chemical exposures. Chronic and subacute health outcomes are assessed by self-report and through linkage with health registries. Participants had a median age of 51 years at baseline (range 19-87), and the majority are female (90%), with nurses being over-represented. Median exposure levels of NO 2 , PM 2.5 , EMF from base stations and noise at the participants' home addresses at baseline were 22.9 µg/m 3 , 16.6 µg/m 3 , 0.003 mWm 2 and 53.1 dB, respectively. Twenty-two per cent of participants reported to have started using a mobile phone more than 10 years prior to baseline. Repeatability for self-reported exposures was moderate to high (weighted kappa range: 0.69-1) for a subset of participants (n=237) who completed the questionnaire twice. We are actively and passively observing participants; we plan to administer a follow-up questionnaire every 4-5 years-the first follow-up will be completed in 2018-and linkage to cause-of-death and cancer registries occurs on a (bi)annual basis. This prospective cohort offers a unique, large and rich resource for research on contemporary occupational and environmental health risks and will

Strabismus Incidence in a Danish Population-Based Cohort of Children

DEFF Research Database (Denmark)

Torp-Pedersen, Tobias; Boyd, Heather A; Skotte, Line

2017-01-01

, overall and by subtype, among children 7 years or younger. Design, Setting, and Participants: This population-based cohort study was conducted with data from 96 842 children enrolled in the Danish National Birth Cohort. Main Outcomes and Measures: Age-specific incidence and cumulative incidence and median...... identified in the cohort. We found an overall cumulative strabismus incidence of 2.56% (95% CI, 2.42-2.69) at 7 years. The overall incidence was similar among boys and girls. Two hundred sixteen participants (16.5%) (95% CI, 14.5-18.6) had congenital esotropia, 177 (13.5%) (95% CI, 11.7-15.5) had fully...... accommodative esotropia, 252 (19.3%) (95% CI, 17.1-21.5) had partially accommodative esotropia, and 181 (13.8%) (95% CI, 12.0-15.8) had exotropia. The esotropia:exotropia ratio was 5.4:1 (95% CI, 3.4:1 to 7.5:1). Age-specific incidence curves for congenital esotropia, fully accommodative esotropia, partially...

Satisfaction with social networks: an examination of socioemotional selectivity theory across cohorts.

Science.gov (United States)

Lansford, J E; Sherman, A M; Antonucci, T C

1998-12-01

This study examines L. L. Carstensen's (1993, 1995) socioemotional selectivity theory within and across three cohorts spanning 4 decades. Socioemotional selectivity theory predicts that as individuals age, they narrow their social networks to devote more emotional resources to fewer relationships with close friends and family. Data from 3 cohorts of nationally representative samples were analyzed to determine whether respondents' satisfaction with the size of their social networks differed by age, cohort, or both. Results support socioemotional selectivity theory: More older adults than younger adults were satisfied with the current size of their social networks rather than wanting larger networks. These findings are consistent across all cohorts. Results are discussed with respect to social relationships across the life course.

Hemophilie A et B: a propos de dix cas colliges a Lome (Togo ...

African Journals Online (AJOL)

E Padaro, I.M.D. Kueviakoe, K.J. Guedenon, H Magnang, K Mawussi, Y Layibo, ... and paraclinical (partial thromboplastin time Activator and assay of factors VIII and IX). ... Six patients (60%) had hemophilia A and 4 (40%) hemophilia B. Seven ...

Particulate air pollution and mortality in a cohort of Chinese men

International Nuclear Information System (INIS)

Zhou, Maigeng; Liu, Yunning; Wang, Lijun; Kuang, Xingya; Xu, Xiaohui; Kan, Haidong

2014-01-01

Few prior cohort studies exist in developing countries examining the association of ambient particulate matter (PM) with mortality. We examined the association of particulate air pollution with mortality in a prospective cohort study of 71,431 middle-aged Chinese men. Baseline data were obtained during 1990–1991. The follow-up evaluation was completed in January, 2006. Annual average PM exposure between 1990 and 2005, including TSP and PM 10 , were estimated by linking fixed-site monitoring data with residential communities. We found significant associations between PM 10 and mortality from cardiopulmonary diseases; each 10 μg/m 3 PM 10 was associated with a 1.6% (95%CI: 0.7%, 2.6%), 1.8% (95%CI: 0.8%, 2.9%) and 1.7% (95%CI: 0.3%, 3.2%) increased risk of total, cardiovascular and respiratory mortality, respectively. For TSP, we observed significant associations only for cardiovascular morality. These data contribute to the scientific literature on long-term effects of particulate air pollution for high exposure settings typical in developing countries. -- Highlights: • There have been few air pollution cohort studies in developing countries. • PM 10 was associated with increased cardiorespiratory mortality in 71,431 Chinese men. • PM was not significantly associated with lung cancer mortality. -- PM 10 was associated with increased cardiorespiratory mortality in a cohort of 71,431 Chinese men

Association of Neovascular Glaucoma with Risk of Stroke: A Population-Based Cohort Study

Directory of Open Access Journals (Sweden)

Cheng-Wen Su

2017-01-01

Full Text Available Neovascular glaucoma (NVG, caused by ocular ischemia, is a serious ocular disease complicated by intractably increased intraocular pressure. Cerebrovascular accidents are classified into ischemic and hemorrhagic stroke. Based on the similar pathogenic mechanisms of NVG and ischemic stroke, we investigated the relationship between NVG and stroke by using a nationally representative sample. This study included 416 NVG patients and 4160 controls. Medical comorbidities were also evaluated. The cumulative incidence of ischemic stroke was 15.6% higher in the NVG cohort than in the control cohort (p<0.001; the incidence density rates of stroke were 3.80 and 1.19 per 10,000 person-years in the NVG and control cohorts, respectively. According to the multivariable Cox regression results, the estimated adjusted hazard ratio (aHR of stroke was 2.07 (95% confidence interval (CI = 1.41–3.02 for the NVG cohort. Furthermore, the NVG cohort was 2.24-fold more likely to develop ischemic stroke (95% CI = 1.51–3.32. The risk of ischemic stroke was higher in patients with hypertension (aHR = 2.09, 95% CI = 1.55–2.82 and in patients with diabetic retinopathy (aHR = 1.69, 95% CI = 1.05–2.72. Notably, patients with NVG have a higher risk of ischemic stroke, but not hemorrhagic stroke.

75 FR 22137 - Agency Forms Undergoing Paperwork Reduction Act Review

Science.gov (United States)

2010-04-27

... conducting research. The type of information requested reflects a diversity of needs. Topics include homecare, orthopedics, physical therapy, rare factor deficiencies, psychosocial issues, blood safety, women's health..., advocacy and research for people and families with hemophilia and other bleeding disorders. The Hemophilia...

Effect of resistance and aerobic exercises on bone mineral density ...

African Journals Online (AJOL)

Conclusion: Based on obtained data, it can be concluded that, resistance and aerobic exercise training program is effective in increasing BMD, muscle strength and functional ability in children with hemophilia. Keywords: Hemophilia; Resistance; Aerobic exercise; Bone mineral density; Strength; Functional ability ...

Evolutionary pattern of mutation in the factor IX genes of great apes: How does it compare to the pattern of recent germline mutation in patients with hemophilia B?

Energy Technology Data Exchange (ETDEWEB)

Grouse, L.H.; Ketterling, R.P.; Sommer, S.S. [Mayo Clinic/Foundation, Rochester, MN (United States)

1994-09-01

Most mutations causing hemophilia B have arisen within the past 150 years. By correcting for multiple biases, the underlying rates of spontaneous germline mutation have been estimated in the factor IX gene. From these rates, an underlying pattern of mutation has emerged. To determine if this pattern compares to a underlying pattern found in the great apes, sequence changes were determined in intronic regions of the factor IX gene. The following species were studied: Gorilla gorilla, Pan troglodytes (chimpanzee), Pongo pygmacus (orangutan) and Homo sapiens. Intronic sequences at least 200 bp from a splice junction were randomly chosen, amplified by cross-species PCR, and sequenced. These regions are expected to be subject to little if any selective pressure. Early diverged species of Old World monkeys were also studied to help determine the direction of mutational changes. A total of 62 sequence changes were observed. Initial data suggest that the average pattern since evolution of the great apes has a paucity of transitions at CpG dinucleotides and an excess of microinsertions to microdeletions when compared to the pattern observed in humans during the past 150 years (p<.05). A larger study is in progress to confirm these results.

Purification and characterization of factor VIII 1,689-Cys: a nonfunctional cofactor occurring in a patient with severe hemophilia A.

Science.gov (United States)

O'Brien, D P; Tuddenham, E G

1989-06-01

We have purified the factor VIII from a CRM+ Hemophilia A plasma (90 U/dL VIII:Ag but 0 U/dL VIII:C) and analyzed the protein before and after thrombin activation by Western blotting with monoclonal antibodies (MoAbs). Normal or patient citrated plasma was ultracentrifuged, cryo-ethanol-precipitated and chromatographed on Sepharose 6B. The void volume fractions were reduced and subjected to ion exchange chromatography yielding material of specific activity approximately 1,000 U/mg protein (VIII:C or VIII:Ag). Factor VIII purified in this way from normal plasma is fully activatable by thrombin with proteolytic fragmentation as previously described by F. Rotblat et al (Biochemistry 24: 4294, 1985). Factor VIII 1,689-Cys has the normal distribution of factor VIII light and heavy chains prior to thrombin activation. After exposure to thrombin the heavy chain polypeptides were fully proteolysed but the light chain was totally resistant to cleavage. This is consistent with the demonstration in the patient's leucocyte DNA of a C to T transition in codon 1,689 converting Arg to Cys at the light chain thrombin cleavage site as previously described by J. Gitschier et al (Blood 72:1022, 1988). Uncleaved light chain of Factor VIII 1,689-Cys is not released from von Willebrand factor (vWF) by thrombin, but this is not the sole cause of the functional defect since the protein purified free of vWF has no coagulant activity. We conclude that the functional defect in factor VIII 1,689-Cys is a consequence of failure to release the acidic peptide from the light chain upon thrombin activation.

Associations between social networks and life satisfaction among older Japanese: Does birth cohort make a difference?

Science.gov (United States)

Kobayashi, Erika; Liang, Jersey; Sugawara, Ikuko; Fukaya, Taro; Shinkai, Shoji; Akiyama, Hiroko

2015-12-01

Japanese older people experienced drastic changes in family structure and values after World War II at different life stages by birth cohorts. We examined how linkages between different types of social ties and life satisfaction (LS) vary across cohorts, in conjunction with age and survey year differences. Data from face-to-face interviews conducted in 1987, 1999, and 2012 with a nationally representative sample of older Japanese (N = 4,917) were analyzed. The participants were members of 4 birth cohorts (C1: 1901-1912, C2: 1913-1924, C3: 1925-1936, C4: 1937-1949), categorized into 6 groups based on cohort and age at time of measurement (young-old [YO]: 63-74; old-old [OO]: 75-86): C1OO, C2YO, C2OO, C3YO, C3OO, and C4YO. Effects of social networks on LS among the 6 groups were compared simultaneously and separately by gender using the Amos software. There were significant cohort variations in the linkages between family network and LS. The positive association between being married and LS was stronger for later cohorts (C3, C4) among men, whereas that of co-residence with a child and LS was stronger for the earlier cohorts (C1, C2) among women. Moreover, the positive association between meeting with nonfamily members and LS increased from 1987 to 2012 among women, indicating a period effect over a cohort effect. The effects of being married and participation in community groups on LS also changed with age. Our results suggest that linkages between social relations and LS should be interpreted within the context of individual and social changes over time. (c) 2015 APA, all rights reserved).

Cohort Profile

DEFF Research Database (Denmark)

Jespersen, Sanne; Hønge, Bo Langhoff; Oliveira, Inés

2014-01-01

The West African country Guinea-Bissau is home to the world’s highest prevalence of HIV-2, and its HIV-1 prevalence is rising. Other chronic viral infections like human T-lymphotropic virus type 1 (HTLV-1) and hepatitis B virus are common as well. The Bissau HIV Cohort was started in 2007 to gain...... new insights into the overall effect of introducing antiretroviral treatment in a treatment-naı ̈ve population with concomitant infection with three retroviruses (HIV-1, HIV-2 and HTLV-1) and tuberculosis. The cohort includes patients from the HIV clinic at Hospital Nacional Sima ̃ o Mendes, the main...

Age-period-cohort analysis of suicides among Japanese 1950-2003: a Bayesian cohort model analysis.

Science.gov (United States)

Ooe, Yosuke; Ohno, Yuko; Nakamura, Takashi

2009-07-01

The suicide rate in Japan is one of the highest in the world and presents us with a considerable challenge. Demographic statistics show that the number of suicides is on the rise, and at roughly 30,000 people per year have committed suicide since 1998. Suicide trends are not only related to economic boom and bust but also to certain generations and age groups. During the 1950s, there was a remarkably high suicide rate among people in their 20s, and this cohort was identical to that of the middle-age generation in the 1980s. It is important to separately understand both the trend of suicide rates and the numbers analyzed to determine the different factors that influence suicide. These include age, time period, cohort, interaction between age and time period, and changes in population composition. We performed an age-period-cohort analysis of annual trends of suicide rates by age group in Japan using a Bayesian cohort model. With the help of the Nakamura method, we have been able to break down the effects of age, time period, cohort, and the age-by-period interaction. The cohort comprised of people born in the 1930s demonstrated a relatively high suicide rate. Men currently in their 50s also belong to a high suicide rate cohort. Regarding the period effect, business cycles and by-period interaction effect, it became apparent that the high suicide rate among young adults in their early 20s around 1960 was slowing, especially among men. Instead, there was an obvious recent trend for men in their late 50s to have the highest suicide rate. This study confirmed that age-period-cohort analysis can describe these trends of suicide mortality of the Japanese.

Factor VIII and von Willebrand factor co-delivery by endothelial cells

NARCIS (Netherlands)

Bouwens, E.A.M.|info:eu-repo/dai/nl/314061894

2011-01-01

A defect in coagulation factor VIII (FVIII) results in the inherited bleeding disorder hemophilia A. Current treatment of hemophilia A is hampered by the need of frequent administration of costly FVIII products. Therefore gene therapy is an attractive alternative for protein replacement to treat

Application of Molecular Genetics to the Investigation of Inherited Bleeding Disorders

DEFF Research Database (Denmark)

Lethagen, Stefan Rune; Dunø, Morten; Nielsen, Lars Bo

2013-01-01

Hemophilia is an inherited bleeding disorder primarily caused by deficiency of coagulation factor (F)VIII (hemophilia A) or FIX (hemophilia B). Both conditions are X-linked. More than 2100 different F8 mutations have been described, the most common being a 500 kb inversion involving exon 1 to exo...... quality control systems in place, and participate in established external quality assessment programs....... the causative mutation is unknown. More rare bleeding disorders are generally recessively inherited, and are often caused by mutations that are specific for individual families, and mutations are scattered throughout the genes. Laboratories performing molecular genetic analyses must have validated internal...

O USO DE CÉLULAS-TRONCO MESENQUIMAIS COMO NOVA PERSPECTIVA DE TRATAMENTO PARA HEMOFILIA B

Directory of Open Access Journals (Sweden)

Andrielle de Castilho FERNANDES

2011-01-01

Full Text Available Hemophilia B is an X-linked bleeding disorder that results from a deficiency in functional coagulation factor IX (hFIX. Clinically, this disease is characterized by bleeding episodes mainly in the soft tissues, joints and muscles. The treatment is given by replacement therapy the plasmaderived FIX (pdFIX or recombinant human FIX (rhFIX. Annoying intravenous infusions, along with thehigh cost of pdFIX and / or rhFIX, encouraged the development of new therapeutic approaches that allow more stable and lasting results. It is postulated that the gene therapy, insertion of functional genes into cells and / or tissues of the patient, could meet the physiological need of active FIX in a patient with hemophilia B, but the patient's immunological barriers posed a major obstacle to this therapy. Thus, the unsatisfactory results obtained with gene therapy plus the possibility of therapeutic use of mesenchymal stem cells (MSCs, considered immunoprivileged cells, directed to therapeutic approaches for the combination of gene and cell therapies, in other words, or genetic manipulation of MSCs ex vivo in orderto transplant them in hosts, and thus correct efficiently and effectively the phenotype of hemophilia B. Therefore, this article reviews the characteristics of hemophilia, treatments available and the prospects for the use of MSCs in the treatment of hemophilia B.

Age, time period, and birth cohort differences in self-esteem: Reexamining a cohort-sequential longitudinal study.

Science.gov (United States)

Twenge, Jean M; Carter, Nathan T; Campbell, W Keith

2017-05-01

Orth, Trzesniewski, and Robins (2010) concluded that the nationally representative Americans' Changing Lives (ACL) cohort-sequential study demonstrated moderate to large age differences in self-esteem, and no birth cohort (generational) differences in the age trajectory. In a reanalysis of these data using 2 different statistical techniques, we find significant increases in self-esteem that could be attributed to birth cohort or time period. First, hierarchical linear modeling analyses with birth cohort as a continuous variable (vs. the multiple group formulation used by Orth et al.) find that birth cohort has a measurable influence on self-esteem through its interaction with age. Participants born in later years (e.g., 1960) were higher in self-esteem and were more likely to increase in self-esteem as they aged than participants born in earlier years (e.g., 1920). However, the estimated age trajectory up to age 60 is similar in Orth et al.'s results and in the results from our analyses including cohort. Second, comparing ACL respondents of the same age in 1986 versus 2002 (a time-lag design) yields significant birth cohort differences in self-esteem, with 2002 participants of the same age higher in self-esteem than those in 1986. Combined with some previous studies finding significant increases in self-esteem and positive self-views over time, these results suggest that cultural change in the form of cohort and time period cannot be ignored as influences in cross-sectional and longitudinal studies. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Cancer in ANCA-Associated Glomerulonephritis: A Registry-Based Cohort Study

Directory of Open Access Journals (Sweden)

Sanjeevan Sriskandarajah

2017-01-01

Full Text Available Background. Immunosuppressive therapy for antineutrophil cytoplasmic antibody-associated vasculitis has been associated with increased malignancy risk. Objectives. To quantify the cancer risk associated with contemporary cyclophosphamide-sparing protocols. Methods. Patients from the Norwegian Kidney Biopsy Registry between 1988 and 2012 who had biopsy-verified pauci-immune glomerulonephritis and positive antineutrophil cytoplasmic antibody (ANCA serology were included. Standardised incidence ratios (SIRs were calculated to compare the study cohort with the general population. Results. The study cohort included 419 patients. During 3010 person-years, cancer developed in 41 patients (9.79%; the expected number of cancer cases was 37.5 (8.95%. The cohort had SIRs as follows: 1.09, all cancer types (95% CI, 0.81 to 1.49; 0.96, all types except nonmelanoma skin cancer (95% CI, 0.69 to 1.34; 3.40, nonmelanoma skin cancer (95% CI, 1.62 to 7.14; 3.52, hematologic cancer (95% CI, 1.32 to 9.37; 2.12, posttransplant cancer (95% CI, 1.01 to 4.44; and 1.53, during the 1–5-year follow-up after diagnosis (95% CI, 1.01 to 2.32. Conclusions. Cancer risk did not increase significantly in this cohort with ANCA-associated glomerulonephritis. However, increased risk of nonmelanoma skin cancer, posttransplant cancer, and hematologic cancer indicates an association between immunosuppression and malignancy.

Nonkin in older adults' personal networks: more important among later cohorts?

Science.gov (United States)

Suanet, Bianca; van Tilburg, Theo G; Broese van Groenou, Marjolein I

2013-07-01

Research on age-related changes in personal networks has found compelling evidence for socioemotional selectivity theory and exchange theory holding that older adults experience a decline in less emotionally close nonkin relations as they age. However, recent societal developments are likely to have increased the salience of nonkin relations. We hypothesize that age-related decline in the proportion of nonkin in personal networks has been delayed or is slower in late birth cohorts of older adults compared with earlier cohorts. Seven observations by the Longitudinal Aging Study Amsterdam covering a time span of 17 years since 1992 were analyzed using multilevel regression analysis. The sample had 12,949 person-year observations from 3,516 respondents born between 1908 and 1937. Age-related decline in the proportion of nonkin is absent for cohorts born after 1922 and large for cohorts born in 1922 and before. Mediating variables for health and other resources did not explain cohort differences in age-related change. The salience of nonkin relationships is likely to have increased due to societal changes, resulting in absence or delay of decline in later cohorts. The findings raise the need for a reevaluation of old age and the creation of new theoretical perspectives.

Efficacy of a high-purity factor IX concentrate in hemophilia B patients undergoing surgery Eficácia do concentrado de alta pureza do fator IX em pacientes cirúrgicos portadores de hemofilia B

Directory of Open Access Journals (Sweden)

Vesa Rasi

2002-04-01

Full Text Available A plasma derived, high purity, solvent-detergent treated and subsequently nanofiltered factor IX concentrate (BEMOFIL was evaluated in 19 hemophilia B patients, including four with severe, thirteen with mild or moderate type of disease and two hemophilia B carriers undergoing 31 surgical procedures. The mean in vivo recovery was 52 %, range 36 - 76 %. The mean preoperative plasma factor IX activity after the initial loading dose was 0.86 IU mL-1, range 0.59 - 1.32 IU mL-1. In eight major orthopedic procedures, the mean usage of factor IX was 44600 IU or 574 IU kg-1 during the hospital stay, mean 11.6 days. Thromboprophylaxis was not used. The hemostatic efficacy was evaluated good in all cases and there were no thromboembolic complications. In conclusion, BEMOFIL used as bolus dosing was found to be safe and effective in achieving hemostasis in subjects with hereditary F IX deficiency undergoing surgery.O concentrado de fator IX ( Bemofil , um derivado plasmático de alta pureza tratado com solventes- detergente e nano-filtrado , foi avaliado em 19 pacientes portadores de Hemofilia B .Quatro pacientes apresentavam a forma grave da moléstia, 13 a forma leve e moderada e dois portadores em um total de 31 atos cirúrgicos.A recuperação média "in vivo" foi de 52% (36-76%. A atividade plasmática média pré-operatória do fator IX após a dose inicial foi de 0,86 UI ml -1 , média de 0,59 - 1,32 UI ml-1. Em oito procedimentos ortopédicos extensos , a média de utilização do fator IX foi de 44.600 UI ou 574 UI kg -1 durante a hospitalização que teve a média de 11,6 dias. A tromboprofilaxia não foi utilizada. A eficácia hemostática avaliada em todos os casos foi boa ,e não ocorreu nenhum tipo de complicação tromboembólica. Concluímos que o Bemofil em bolus foi considerado seguro e eficaz para a hemostasia em pacientes portadores de hemofilia B que necessitam de um procedimento cirúrgico.

International Childhood Cancer Cohort Consortium

Science.gov (United States)

An alliance of several large-scale prospective cohort studies of children to pool data and biospecimens from individual cohorts to study various modifiable and genetic factors in relation to cancer risk

Idiopathic factor VIII inhibitor autoantibody in a man presented after accident.

NARCIS (Netherlands)

Mansouritorghabeh, H.; Lak, M.; Heerde, W.L. van

2009-01-01

Acquired hemophilia A is a rare but severe autoimmune bleeding disorder caused by autoantibodies against factor VIII activity and is a potentially life-threatening hemorrhagic disorder. The incidence of acquired hemophilia A has been estimated as 1.48 cases per million per year. The overall rate of

Normal Coagulation

Science.gov (United States)

2014-09-04

factor VIII, or hemophilia A, is a well- characterized bleeding disorder linked to the X chromosome . Severe hemophilia A therefore occurs almost... disappears from the fluid phase of the reaction. Thus, the “initial clot” is a mixture composed of fibrin and fibrinogen. with the somatomedin B

Association between omega-3 fatty acids consumption and the risk of type 2 diabetes: A meta-analysis of cohort studies.

Science.gov (United States)

Chen, Cai; Yang, Yan; Yu, Xuefeng; Hu, Shuhong; Shao, Shiying

2017-07-01

Epidemiological evidence for the effect of omega-3 fatty acids on the risk of type 2 diabetes is controversial. A meta-analysis based on prospective cohorts was carried out to evaluate this issue. Pooled diabetic risk was calculated using a fixed or random effects model. The dose-response relationship was assessed by meta-regression analysis. The study showed that consumption of single omega-3 was associated with an increased risk of type 2 diabetes (relative risk [RR] = 1.45, P omega-3 was statistically insignificant. The dose-response curve presented an inverted U-shape of diabetes risk corresponding to the dose of omega-3 consumption. Subanalysis showed that omega-3 was inversely associated with type 2 diabetes risk in Asians (RR = 0.82, P omega-3 intake. The present findings suggest that dosage and composition of omega-3, ethnicity, trial duration, and age could influence the effect of omega-3 on type 2 diabetes progression. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Development and characterization of recombinant ovine coagulation factor VIII.

Directory of Open Access Journals (Sweden)

Philip M Zakas

Full Text Available Animal models of the bleeding disorder, hemophilia A, have been an integral component of the biopharmaceutical development process and have facilitated the development of recombinant coagulation factor VIII (fVIII products capable of restoring median survival of persons with hemophilia A to that of the general population. However, there remain several limitations to recombinant fVIII as a biotherapeutic, including invasiveness of intravenous infusion, short half-life, immunogenicity, and lack of availability to the majority of the world's population. The recently described ovine model of hemophilia A is the largest and most accurate phenocopy. Affected sheep die prematurely due to bleeding-related pathogenesis and display robust adaptive humoral immunity to non-ovine fVIII. Herein, we describe the development and characterization of recombinant ovine fVIII (ofVIII to support further the utility of the ovine hemophilia A model. Full-length and B-domain deleted (BDD ofVIII cDNAs were generated and demonstrated to facilitate greater biosynthetic rates than their human fVIII counterparts while both BDD constructs showed greater expression rates than the same-species full-length versions. A top recombinant BDD ofVIII producing baby hamster kidney clone was identified and used to biosynthesize raw material for purification and biochemical characterization. Highly purified recombinant BDD ofVIII preparations possess a specific activity nearly 2-fold higher than recombinant BDD human fVIII and display a differential glycosylation pattern. However, binding to the carrier protein, von Willebrand factor, which is critical for stability of fVIII in circulation, is indistinguishable. Decay of thrombin-activated ofVIIIa is 2-fold slower than human fVIII indicating greater intrinsic stability. Furthermore, intravenous administration of ofVIII effectively reverses the bleeding phenotype in the murine model of hemophilia A. Recombinant ofVIII should facilitate

Comparison of 3- and 20-Gradient Direction Diffusion-Weighted Imaging in a Clinical Subacute Cohort of Patients with Transient Ischemic Attack

DEFF Research Database (Denmark)

Havsteen, Inger; Ovesen, Christian; Willer, Lasse

2017-01-01

Objective: Diffusion tensor imaging may aid brain ischemia assessment but is more time consuming than conventional diffusion-weighted imaging (DWI). We compared 3-gradient direction DWI (3DWI) and 20-gradient direction DWI (20DWI) standard vendor protocols in a hospital-based prospective cohort...... of patients with transient ischemic attack (TIA) for lesion detection, lesion brightness, predictability of persisting infarction, and final infarct size. Methods: We performed 3T-magnetic resonance imaging including diffusion and T2-fluid attenuated inversion recovery (FLAIR) within 72 h and 8 weeks after...... uniquely 20DWI positive. 3DWI was visually brightest for 34 lesions. 12 lesions were brightest on 20DWI. The median 3DWI lesion area was larger for lesions equally bright, or brightest on 20DWI [median (IQR) 39 (18-95) versus 18 (10-34) mm2, P = 0.007]. 3DWI showed highest measured relative lesion signal...

Assessment of individual dose utilization vs. physician prescribing recommendations for recombinant activated factor VII (rFVIIa) in paediatric and adult patients with congenital haemophilia and alloantibody inhibitors (CHwI): the Dosing Observational Study in Hemophilia (DOSE).

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Gruppo, R A; Kessler, C M; Neufeld, E J; Cooper, D L

2013-07-01

Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII (rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver-reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥ 4 bleeding episodes within a 3-month period prescribed rFVIIa as first-line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥ 90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician-prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1-400.0) mcg kg(-1) vs. 200.0 (61.0-270.0) mcg kg(-1) for children, and 231.3 (59.3-379.7) mcg kg(-1) vs. 123.0 (81.0-289.0) mcg kg(-1) for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg(-1) ), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed. © 2013 John Wiley & Sons Ltd.

Time trends in cigarette smoking in two German cohorts--results from EPIC Germany.

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Rohrmann, S; Kroke, A; Boeing, H; Becker, N

2003-08-01

Smoking prevention is less advanced in Germany compared with other European and North American countries, and fewer data exist, especially on the consumption habits at the individual level over time. EPIC Germany, which is part of a European multicentre study on diet and cancer, collected data on individual smoking behaviour and allows for consideration of the changing consumption pattern for both centres and different age groups. Within EPIC 25 546 and 27 548 participants, respectively, were recruited in Heidelberg and Potsdam. Data on smoking habits were collected by means of a computer-guided interview during the baseline examination between 1994 and 1998. For each birth cohort smoking prevalence and mean number of cigarettes smoked per day at different ages were calculated. Additionally, the prevalence of non-filter cigarette smoking was computed. Smoking prevalence in the 1990s was still higher among men (Heidelberg 16.3-32.3%; Potsdam 18.2-29.3%) than among women (Heidelberg 12.8-32.0%; Potsdam 10.4-27.8%). However, the percentage of women smokers was still increasing. Filter cigarettes comprised a growing percentage of the cigarettes smoked, but especially among men differences between both German cohorts can still be seen: depending on age, 10.0-12.7% of men in the Heidelberg cohort smoked non-filter cigarettes, but only 1.1-2.3% in the Potsdam cohort. The quantity smoked was higher in the Heidelberg than in the Potsdam cohort with respect to the mean number of cigarettes smoked per day as well as the pack-years of smoking. In conclusion, smoking habits in the Potsdam and the Heidelberg cohorts did not strongly differ by smoking prevalence. However, they did differ according to the quantity and quality of smoking. These differences, as well as the changes over the last 40 years may contribute to a changing pattern of diseases in different groups of the German population.

DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts.

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Huang, Tao; Zheng, Yan; Qi, Qibin; Xu, Min; Ley, Sylvia H; Li, Yanping; Kang, Jae H; Wiggs, Janey; Pasquale, Louis R; Chan, Andrew T; Rimm, Eric B; Hunter, David J; Manson, JoAnn E; Willett, Walter C; Hu, Frank B; Qi, Lu

2015-09-01

The first epigenome-wide association study of BMI identified DNA methylation at an HIF3A locus associated with BMI. We tested the hypothesis that DNA methylation variants are associated with BMI according to intake of B vitamins. In two large cohorts, we found significant interactions between the DNA methylation-associated HIF3A single nucleotide polymorphism (SNP) rs3826795 and intake of B vitamins on 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B2 and B12 intake (all P for interaction vitamin B2 intake and -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.10 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B12 intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B2, vitamin B12, and folate. These findings suggest a potential causal relation between DNA methylation and adiposity. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Nested Cohort - R software package

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NestedCohort is an R software package for fitting Kaplan-Meier and Cox Models to estimate standardized survival and attributable risks for studies where covariates of interest are observed on only a sample of the cohort.

A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design.

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Staley, James R; Jones, Edmund; Kaptoge, Stephen; Butterworth, Adam S; Sweeting, Michael J; Wood, Angela M; Howson, Joanna M M

2017-06-01

Logistic regression is often used instead of Cox regression to analyse genome-wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP-disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease.

Cohort profile: LIFEWORK, a prospective cohort study on occupational and environmental risk factors and health in the Netherlands.

NARCIS (Netherlands)

Reedijk, M.; Lenters, V.; Slottje, P.; Pijpe, A.; Peeters, P.H.; Korevaar, J.C.; Bueno-de-Mesquita, B.; Verschuren, W.M.M.; Verheij, R.A.; Pieterson, I.; Leeuwen, F.E. van; Rookus, M.A.; Kromhout, H.; Vermeulen, R.C.H.

2017-01-01

Purpose LIFEWORK is a large federated prospective cohort established in the Netherlands to quantify the health effects of occupational and environmental exposures. This cohort is also the Dutch contribution to the international Cohort Study of Mobile Phone Use and Health (COSMOS). In this paper, we

Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A by use of a fluorescence-based immunoassay

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Boylan, Brian; Rice, Anne S.; Dunn, Amy L.; Tarantino, Michael D.; Brettler, Doreen B.; Barrett, John C.; Miller, Connie H.

2015-01-01

Summary Background The development of neutralizing antibodies, referred to as inhibitors, against factor VIII (FVIII) is a major complication associated with FVIII infusion therapy for the treatment of hemophilia A (HA). Previous studies have shown that a subset of HA patients and a low percentage of healthy individuals harbor non-neutralizing anti-FVIII antibodies that do not elicit the clinical manifestations associated with inhibitor development. Objective Assess HA patients' anti-FVIII antibody profiles as potential predictors of clinical outcomes. Methods A fluorescence immunoassay (FLI) was used to detect anti-FVIII antibodies in 491 samples from 371 HA patients. Results Assessments of antibody profiles showed that the presence of anti-FVIII IgG1, IgG2, or IgG4 correlated qualitatively and quantitatively with the presence of a FVIII inhibitor as reported by the Nijmegen-Bethesda assay (NBA). Forty-eight patients with a negative inhibitor history contributed serial samples to the study, including seven patients who had negative NBA titers initially and later converted to NBA-positive. The FLI detected anti-FVIII IgG1 in five of those seven patients prior to their conversion to NBA-positive. Five of 15 serial-sample patients who had a negative inhibitor history and a positive anti-FVIII IgG1 later developed an inhibitor, compared to 2 of 33 patients with a negative inhibitor history without anti-FVIII IgG1. Conclusions These data provide a rationale for future studies designed both to monitor the dynamics of anti-FVIII antibody profiles in HA patients as a potential predictor of future inhibitor development and to assess the value of the anti-FVIII FLI as a supplement to traditional inhibitor testing. PMID:25354263

Analysis of Clinical Cohort Data Using Nested Case-control and Case-cohort Sampling Designs. A Powerful and Economical Tool.

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Ohneberg, K; Wolkewitz, M; Beyersmann, J; Palomar-Martinez, M; Olaechea-Astigarraga, P; Alvarez-Lerma, F; Schumacher, M

2015-01-01

Sampling from a large cohort in order to derive a subsample that would be sufficient for statistical analysis is a frequently used method for handling large data sets in epidemiological studies with limited resources for exposure measurement. For clinical studies however, when interest is in the influence of a potential risk factor, cohort studies are often the first choice with all individuals entering the analysis. Our aim is to close the gap between epidemiological and clinical studies with respect to design and power considerations. Schoenfeld's formula for the number of events required for a Cox' proportional hazards model is fundamental. Our objective is to compare the power of analyzing the full cohort and the power of a nested case-control and a case-cohort design. We compare formulas for power for sampling designs and cohort studies. In our data example we simultaneously apply a nested case-control design with a varying number of controls matched to each case, a case cohort design with varying subcohort size, a random subsample and a full cohort analysis. For each design we calculate the standard error for estimated regression coefficients and the mean number of distinct persons, for whom covariate information is required. The formula for the power of a nested case-control design and the power of a case-cohort design is directly connected to the power of a cohort study using the well known Schoenfeld formula. The loss in precision of parameter estimates is relatively small compared to the saving in resources. Nested case-control and case-cohort studies, but not random subsamples yield an attractive alternative for analyzing clinical studies in the situation of a low event rate. Power calculations can be conducted straightforwardly to quantify the loss of power compared to the savings in the num-ber of patients using a sampling design instead of analyzing the full cohort.

International Network of Chronic Kidney Disease cohort studies (iNET-CKD): a global network of chronic kidney disease cohorts.

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Dienemann, Thomas; Fujii, Naohiko; Orlandi, Paula; Nessel, Lisa; Furth, Susan L; Hoy, Wendy E; Matsuo, Seiichi; Mayer, Gert; Methven, Shona; Schaefer, Franz; Schaeffner, Elke S; Solá, Laura; Stengel, Bénédicte; Wanner, Christoph; Zhang, Luxia; Levin, Adeera; Eckardt, Kai-Uwe; Feldman, Harold I

2016-09-02

Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study. Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and 3) minimum follow-up of three years. Participating studies were surveyed regarding design, data, and biosample resources. Twelve prospective cohort studies and two registries covering 21 countries were included. Participants age ranges from >2 to >70 years at inclusion, CKD severity ranges from stage 2 to stage 5. Patient data and biosamples (not available in the registry studies) are measured yearly or biennially. Many studies included multiple ethnicities; cohort size ranges from 400 to more than 13,000 participants. Studies' areas of emphasis all include but are not limited to renal outcomes, such as progression to ESRD and death. iNET-CKD (International Network of CKD cohort studies) was established, to promote collaborative research, foster exchange of expertise, and create opportunities for research training. Participating studies have many commonalities that will facilitate comparative research; however, we also observed substantial differences. The diversity we observed across

Impact of Mild versus Moderate Intensity Aerobic Walking Exercise ...

African Journals Online (AJOL)

Background: Patients with hemophilia A have low bone density than healthy controls. It is now widely recognized that physical activity and sports are beneficial for patients with hemophilia. Objective: The aim of this study was to compare the effects of mild and moderate intensity treadmill walking exercises on markers of ...

Efficient detection of factor IX mutations by denaturing high-performance liquid chromatography in Taiwanese hemophilia B patients, and the identification of two novel mutations

Directory of Open Access Journals (Sweden)

Pei-Chin Lin

2014-04-01

Full Text Available Hemophilia B (HB is an X-linked recessive disorder characterized by mutations in the clotting factor IX (FIX gene that result in FIX deficiency. Previous studies have shown a wide variation of FIX gene mutations in HB. Although the quality of life in HB has greatly improved mainly because of prophylactic replacement therapy with FIX concentrates, there exists a significant burden on affected families and the medical care system. Accurate detection of FIX gene mutations is critical for genetic counseling and disease prevention in HB. In this study, we used denaturing high-performance liquid chromatography (DHPLC, which has proved to be a highly informative and practical means of detecting mutations, for the molecular diagnosis of our patients with HB. Ten Taiwanese families affected by HB were enrolled. We used the DHPLC technique followed by direct sequencing of suspected segments to detect FIX gene mutations. In all, 11 FIX gene mutations (8 point mutations, 2 small deletions/insertions, and 1 large deletion, including two novel mutations (exon6 c.687–695, del 9 mer and c.460–461, ins T were found. According to the HB pedigrees, 25% and 75% of our patients were defined as familial and sporadic HB cases, respectively. We show that DHPLC is a highly sensitive and cost-effective method for FIX gene analysis and can be used as a convenient system for disease prevention.

[Connecting biobanks of large European cohorts (EU Project BBMRI-LPC)].

Science.gov (United States)

Kuhn, Klaus A; Bild, Raffael; Anton, Gabriele; Schuffenhauer, Simone; Wichmann, H-Erich

2016-03-01

In addition to the Biobanking and BioMolecular resources Research Initiative (BBMRI), which is establishing a European research infrastructure for biobanks, a network for large European prospective cohorts (LPC) is being built to facilitate transnational research into important groups of diseases and health care. One instrument for this is the database "LPC Catalogue," which supports access to the biomaterials of the participating cohorts. To present the LPC Catalogue as a relevant tool for connecting European biobanks. In addition, the LPC Catalogue has been extended to establish compatibility with existing Minimum Information About Biobank data Sharing (MIABIS) and to allow for more detailed search requests. This article describes the LPC Catalogue, its organizational and technical structure, and the aforementioned extensions. The LPC Catalogue provides a structured overview of the participating LPCs. It offers various retrieval possibilities and a search function. To support more detailed search requests, a new module has been developed, called a "data cube". The provision of data by the cohorts is being supported by a "connector" component. The LPC Catalogue contains data on 22 cohorts and more than 3.8 million biosamples. At present, data on the biosamples of three cohorts have been acquired for the "cube," which is continuously being expanded. In the BBMRI-LPC, tendering for scientific projects using the data and samples of the participating cohorts is currently being carried out. In this context, several proposals have already been approved. The LPC Catalogue is supporting transnational access to biosamples. A comparison with existing solutions illustrates the relevance of its functionality.

Haemophilia Laboratory diagnosis training and care in Rural communities in Sudan

Directory of Open Access Journals (Sweden)

Fathelrahman M. Hassan

2012-06-01

Full Text Available Sixty nine per cent of people with hemophilia symptoms in rural areas were accessed to laboratory diagnosis and care support in Sudan, where technical expertise and health care facilities was less than optimal. There were many reasons for the inadequate care of hemophilic patients: the perception of rarity of the disease; lacked of laboratory facilities to diagnose the disorder; lacked of understanding of the disorder by patients, their relatives, and even healthcare providers; poorly developed blood bank facilities; and lacked of adequate factor supply were just some examples. The Sudanese Hemophilia Care Association (SHCA was attempted to address many of these issues by establishing hemophilia care programs and by educating and training healthcare practitioners so that a healthcare team could be organized that attempts to ameliorate these problems and provides treatment options. However, it was possible to manage hemophiliac’s patients with limited resources. Strategies for conserving factor concentrates were included education of doctors and patients, prenatal diagnosis, increasing the use of anti fibrinolytic agents, physiotherapy, the use of fibrin glue, and simple orthotics and prosthetic measures. An outreach program would be initiated to ensure that hemophilia care and diagnosis was available outside the capital city. Official recognition of hemophilia laboratory diagnosis and treatment centers and designated centers by the government could also be very beneficial in ensuring adequate care in rural areas in Sudan.

A Cohort Study on Meniscal Lesions among Airport Baggage Handlers

DEFF Research Database (Denmark)

Mikkelsen, Sigurd; Brauer, Charlotte; Pedersen, Ellen Bøtker

2016-01-01

socioeconomic background and less knee-straining work. Baggage handlers lifted suitcases with an average weight of approximately 15 kg, in total approximately five tonnes during a 9-hour workday. The cohort was followed in the National Patient Register and Civil Registration System. The outcome was a first time......Meniscal lesions are common and may contribute to the development of knee arthrosis. A few case-control and cross-sectional studies have identified knee-straining work as risk factors for meniscal lesions, but exposure-response relations and the role of specific exposures are uncertain...... of unskilled men employed at Copenhagen Airport or in other companies in the metropolitan Copenhagen area from 1990 to 2012 (the Copenhagen Airport Cohort). The cohort at risk included 3,307 airport baggage handlers with heavy lifting and kneeling or squatting work tasks and 63,934 referents with a similar...

Mortality of first world war military personnel: comparison of two military cohorts.

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Wilson, Nick; Clement, Christine; Summers, Jennifer A; Bannister, John; Harper, Glyn

2014-12-16

To identify the impact of the first world war on the lifespan of participating military personnel (including in veterans who survived the war). Comparison of two cohorts of military personnel, followed to death. Military personnel leaving New Zealand to participate in the first world war. From a dataset of the New Zealand Expeditionary Forces, we randomly selected participants who embarked on troopships in 1914 and a comparison non-combat cohort who departed on troopships in late 1918 (350 in each group). Lifespan based on dates of birth and death from a range of sources (such as individual military files and an official database of birth and death records). A quarter of the 1914 cohort died during the war, with deaths from injury predominating (94%) over deaths from disease (6%). This cohort had a significantly shorter lifespan than the late 1918 "non-combat" cohort, with median ages of death being 65.9 versus 74.2, respectively (a difference of 8.3 years shown also in Kaplan-Meier survival curves, log rank Pworld war in 1914 from New Zealand lost around eight years of life (relative to a comparable military cohort). In the postwar period they continued to have an increased risk of premature death. © Wilson et al 2014.

Risk factors for soil-transmitted helminth infections during the first 3 years of life in the tropics; findings from a birth cohort.

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Menzies, Stefanie K; Rodriguez, Alejandro; Chico, Martha; Sandoval, Carlos; Broncano, Nely; Guadalupe, Irene; Cooper, Philip J

2014-02-01

Soil-transmitted helminths (STH) infect more than 2 billion humans worldwide, causing significant morbidity in children. There are few data on the epidemiology and risk factors for infection in pre-school children. To investigate risk factors for infection in early childhood, we analysed data prospectively collected in the ECUAVIDA birth cohort in Ecuador. Children were recruited at birth and followed up to 3 years of age with periodic collection of stool samples that were examined microscopically for STH parasites. Data on social, demographic, and environmental risk factors were collected from the mother at time of enrollment. Associations between exposures and detection of STH infections were analysed by multivariable logistic regression. Data were analysed from 1,697 children for whom a stool sample was obtained at 3 years. 42.3% had at least one STH infection in the first 3 years of life and the most common infections were caused by A. lumbricoides (33.2% of children) and T. trichiura (21.2%). Hookworm infection was detected in 0.9% of children. Risk of STH infection was associated with factors indicative of poverty in our study population such as Afro-Ecuadorian ethnicity and low maternal educational level. Maternal STH infections during pregnancy were strong risk factors for any childhood STH infection, infections with either A. lumbricoides or T. trichiura, and early age of first STH infection. Children of mothers with moderate to high infections intensities with A. lumbricoides were most at risk. Our data show high rates of infection with STH parasites during the first 3 years of life in an Ecuadorian birth cohort, an observation that was strongly associated with maternal STH infections during pregnancy. The targeted treatment of women of childbearing age, in particular before pregnancy, with anthelmintic drugs could offer a novel approach to the prevention of STH infections in pre-school children.

Risk factors for soil-transmitted helminth infections during the first 3 years of life in the tropics; findings from a birth cohort.

Directory of Open Access Journals (Sweden)

Stefanie K Menzies

2014-02-01

Full Text Available Soil-transmitted helminths (STH infect more than 2 billion humans worldwide, causing significant morbidity in children. There are few data on the epidemiology and risk factors for infection in pre-school children. To investigate risk factors for infection in early childhood, we analysed data prospectively collected in the ECUAVIDA birth cohort in Ecuador.Children were recruited at birth and followed up to 3 years of age with periodic collection of stool samples that were examined microscopically for STH parasites. Data on social, demographic, and environmental risk factors were collected from the mother at time of enrollment. Associations between exposures and detection of STH infections were analysed by multivariable logistic regression. Data were analysed from 1,697 children for whom a stool sample was obtained at 3 years. 42.3% had at least one STH infection in the first 3 years of life and the most common infections were caused by A. lumbricoides (33.2% of children and T. trichiura (21.2%. Hookworm infection was detected in 0.9% of children. Risk of STH infection was associated with factors indicative of poverty in our study population such as Afro-Ecuadorian ethnicity and low maternal educational level. Maternal STH infections during pregnancy were strong risk factors for any childhood STH infection, infections with either A. lumbricoides or T. trichiura, and early age of first STH infection. Children of mothers with moderate to high infections intensities with A. lumbricoides were most at risk.Our data show high rates of infection with STH parasites during the first 3 years of life in an Ecuadorian birth cohort, an observation that was strongly associated with maternal STH infections during pregnancy. The targeted treatment of women of childbearing age, in particular before pregnancy, with anthelmintic drugs could offer a novel approach to the prevention of STH infections in pre-school children.

Trends in Visual Health Inequalities in Childhood Through Associations of Visual Function With Sex and Social Position Across 3 UK Birth Cohorts.

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Bountziouka, Vasiliki; Cumberland, Phillippa M; Rahi, Jugnoo S

2017-09-01

Despite the existing country-specific strategies tackling social inequalities in visual health in adults, little is known about trends in visual function in childhood and its association with social position. To investigate the distribution of childhood visual function in the United Kingdom and associations with early-life social position between 1961 and 1986, a period of significant social change. Longitudinal cohort study using harmonized data sets from the British 1946, 1958, and 1970 national birth cohorts. In total, 14 283 cohort members with complete data on visual acuity at age 15 or 16 years, measured in 1961, 1974, and 1986, respectively, for each cohort, and social position were assessed. Using habitual distance visual acuity (with correction if prescribed), participants were assigned to a visual function category ranging from bilateral normal to visual impairment/severe visual impairment/blindness (International Statistical Classification of Diseases, Tenth Revision, Clinical Modification). Distribution of visual function over time and associations with social position (risk ratios [RRs] and 95% confidence intervals) were analyzed. Complete data were available for 3152 participants (aged 15 years; 53% boys [n = 1660]) in the 1946 Medical Research Council National Survey of Health and Development, 6683 participants (aged 16 years; 51% boys [n = 3420]) in the 1958 National Child Development Study, and 4448 participants (aged 16 years; 48% boys [n = 2156]) in the 1970 British Birth Cohort Study. The proportion of children with bilateral normal vision decreased by 1.3% (95% CI, -5.1% to 2.7%) in 1974 and 1.7% (95% CI, -5.9% to 2.7%) in 1986. The risk of overall impaired vision increased by 1.20 times (95% CI, 1.01-1.43) and the risk of visual impairment/severe visual impairment/blindness by 1.75 times (95% CI, 1.03-2.98) during this period. Girls were consistently at increased risk of all vision impairment categories. Higher social position at

Cohort profile: seek, test, treat and retain United States criminal justice cohort.

Science.gov (United States)

Chandler, Redonna; Gordon, Michael S; Kruszka, Bridget; Strand, Lauren N; Altice, Frederick L; Beckwith, Curt G; Biggs, Mary L; Cunningham, William; Chris Delaney, J A; Flynn, Patrick M; Golin, Carol E; Knight, Kevin; Kral, Alex H; Kuo, Irene; Lorvick, Jennifer; Nance, Robin M; Ouellet, Lawrence J; Rich, Josiah D; Sacks, Stanley; Seal, David; Spaulding, Anne; Springer, Sandra A; Taxman, Faye; Wohl, David; Young, Jeremy D; Young, Rebekah; Crane, Heidi M

2017-05-16

The STTR treatment cascade provides a framework for research aimed at improving the delivery of services, care and outcomes of PLWH. The development of effective approaches to increase HIV diagnoses and engage PLWH in subsequent steps of the treatment cascade could lead to earlier and sustained ART treatment resulting in viral suppression. There is an unmet need for research applying the treatment cascade to improve outcomes for those with criminal justice involvement. The Seek, Test, Treat, and Retain (STTR) criminal justice (CJ) cohort combines data from 11 studies across the HIV treatment cascade that focused on persons involved in the criminal justice system, often but not exclusively for reasons related to substance use. The studies were conducted in a variety of CJ settings and collected information across 11 pre-selected domains: demographic characteristics, CJ involvement, HIV risk behaviors, HIV and/or Hepatitis C infections, laboratory measures of CD4 T-cell count (CD4) and HIV RNA viral load (VL), mental illness, health related quality of life (QoL), socioeconomic status, health care access, substance use, and social support. The STTR CJ cohort includes data on 11,070 individuals with and without HIV infection who range in age from 18 to 77 years, with a median age at baseline of 37 years. The cohort reflects racial, ethnic and gender distributions in the U.S. CJ system, and 64% of participants are African-American, 12% are Hispanic and 83% are men. Cohort members reported a wide range of HIV risk behaviors including history of injection drug use and, among those who reported on pre-incarceration sexual behaviors, the prevalence of unprotected sexual intercourse ranged across studies from 4% to 79%. Across all studies, 53% percent of the STTR CJ cohort reported recent polysubstance use. The STTR CJ cohort is comprised of participants from a wide range of CJ settings including jail, prison, and community supervision who report considerable diversity in

Meat consumption and K-ras mutations in sporadic colon and rectal cancer in The Netherlands Cohort Study

NARCIS (Netherlands)

Brink, M.; Weijenberg, M.P.; Goeij, A.F.P.M. de; Roemen, G.M.J.M.; Lentjes, M.H.F.M.; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den

2005-01-01

Case-cohort analyses were performed on meat and fish consumption in relation to K-ras mutations in 448 colon and 160 rectal cancers that occurred during 7.3 years of follow-up, excluding the first 2.3 years, and 2948 subcohort members of The Netherlands Cohort Study on diet and cancer. Adjusted

Possibilities and considerations when merging dietary data from the world's two largest pregnancy cohorts: the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study.

Science.gov (United States)

Olsen, Sjurdur F; Birgisdottir, Bryndis Eva; Halldorsson, Thorhallur I; Brantsaeter, Anne Lise; Haugen, Margaretha; Torjusen, Hanne; Petersen, Sesilje B; Strøm, Marin; Meltzer, Helle Margrete

2014-11-01

To elucidate the research possibilities when merging data on maternal diet from the Danish National Birth Cohort (DNBC) and the Norwegian Mother and Child Cohort Study (MoBa), through comparison of (i) the methodology used for dietary assessment and (ii) the estimated intake of selected food groups in the two cohorts. Qualitative and quantitative comparison of the two dietary databases. Two national prospective pregnancy cohorts. Denmark, Norway. Comparison of food intake using food frequency questionnaires (FFQs). The FFQs had overlapping time windows and a majority of the questions in the two FFQs were comparable. Calculation principles shared similar features, including the software used and use of global questions to calibrate intakes of different food groups. A total of 63 food groups were defined that could be compared across the two cohorts; these were further aggregated down to 31 broader groups. A comparison of food intakes (grams/d) showed 39, 74 and 141% lower daily intakes of fish, potatoes and rice, respectively, in DNBC vs. MoBa and 39, 54 and 65% higher daily intakes of milk, butter and potatoes in DNBC vs. MoBa. For most other food groups, differences in consumption data were below 20%. The two FFQs are to a large extent compatible and substantial differences in dietary habits were observed between the two cohorts. This may strengthen studies using pooled analysis to examine diet-disease relations. This is a conclusion of great importance given the colossal and costly task involved to establish each of these two cohorts. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

The prevalence of SDQ-measured mental health problems at age 5-7 years and identification of predictors from birth to preschool age in a Danish birth cohort: the Copenhagen Child Cohort 2000

DEFF Research Database (Denmark)

Elberling, Hanne; Linneberg, Allan; Olsen, Else Marie

2010-01-01

version of the Strengths and Difficulties Questionnaire (SDQ) was answered by parents and pre-school teachers. Data from Danish national registers included perinatal data, socioeconomic data and data on child mental illness diagnosed at hospital in preschool age. Register data from the first year of life......The objective of the study is to investigate the prevalence, distribution and predictors of mental health problems in 5-7-year-old Danish children in the general population. This study is a 5-7-year follow-up study of a birth cohort of 6,090 children, the Copenhagen Child Cohort 2000. The extended...... was obtained from 99.7% of the children in the cohort. Of 5,898 eligible children, 3,501 participated in the SDQ assessment (59%). The overall estimated 6-month prevalence of mental health problems was 4.8% (95% CI 4.1-5.6). Conduct problems were found in 3.0% (95% CI 2.4-3.6), problems of hyperactivity...

Fish intake during pregnancy, fetal growth, and gestational length in 19 European birth cohort studies.

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Leventakou, Vasiliki; Roumeliotaki, Theano; Martinez, David; Barros, Henrique; Brantsaeter, Anne-Lise; Casas, Maribel; Charles, Marie-Aline; Cordier, Sylvaine; Eggesbø, Merete; van Eijsden, Manon; Forastiere, Francesco; Gehring, Ulrike; Govarts, Eva; Halldórsson, Thorhallur I; Hanke, Wojciech; Haugen, Margaretha; Heppe, Denise H M; Heude, Barbara; Inskip, Hazel M; Jaddoe, Vincent W V; Jansen, Maria; Kelleher, Cecily; Meltzer, Helle Margrete; Merletti, Franco; Moltó-Puigmartí, Carolina; Mommers, Monique; Murcia, Mario; Oliveira, Andreia; Olsen, Sjúrður F; Pele, Fabienne; Polanska, Kinga; Porta, Daniela; Richiardi, Lorenzo; Robinson, Siân M; Stigum, Hein; Strøm, Marin; Sunyer, Jordi; Thijs, Carel; Viljoen, Karien; Vrijkotte, Tanja G M; Wijga, Alet H; Kogevinas, Manolis; Vrijheid, Martine; Chatzi, Leda

2014-03-01

Fish is a rich source of essential nutrients for fetal development, but in contrast, it is also a well-known route of exposure to environmental pollutants. We assessed whether fish intake during pregnancy is associated with fetal growth and the length of gestation in a panel of European birth cohort studies. The study sample of 151,880 mother-child pairs was derived from 19 population-based European birth cohort studies. Individual data from cohorts were pooled and harmonized. Adjusted cohort-specific effect estimates were combined by using a random- and fixed-effects meta-analysis. Women who ate fish >1 time/wk during pregnancy had lower risk of preterm birth than did women who rarely ate fish (≤ 1 time/wk); the adjusted RR of fish intake >1 but 1 but <3 times/wk and 15.2 g (95% CI: 8.9, 21.5 g) for ≥ 3 times/wk independent of gestational age. The association was greater in smokers and in overweight or obese women. Findings were consistent across cohorts. This large, international study indicates that moderate fish intake during pregnancy is associated with lower risk of preterm birth and a small but significant increase in birth weight.

Complementary Cohort Strategy for Multimodal Face Pair Matching

DEFF Research Database (Denmark)

Sun, Yunlian; Nasrollahi, Kamal; Sun, Zhenan

2016-01-01

Face pair matching is the task of determining whether two face images represent the same person. Due to the limited expressive information embedded in the two face images as well as various sources of facial variations, it becomes a quite difficult problem. Towards the issue of few available images...... provided to represent each face, we propose to exploit an extra cohort set (identities in the cohort set are different from those being compared) by a series of cohort list comparisons. Useful cohort coefficients are then extracted from both sorted cohort identities and sorted cohort images...... for complementary information. To augment its robustness to complicated facial variations, we further employ multiple face modalities owing to their complementary value to each other for the face pair matching task. The final decision is made by fusing the extracted cohort coefficients with the direct matching...

Psychosocial work conditions and registered sickness absence : a 3-year prospective cohort study among office employees

NARCIS (Netherlands)

Roelen, C. A. M.; Koopmans, P. C.; Bultmann, U.; Groothoff, J. W.; van der Klink, J. J. L.

2009-01-01

Purpose To investigate associations between a wide variety of psychosocial work conditions and sickness absence in a medium-sized company. Methods Prospective cohort study of 395 employees working in an insurance office. Self-reported psychosocial work conditions were measured by questionnaire in

C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.

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Bomback, Andrew S; Santoriello, Dominick; Avasare, Rupali S; Regunathan-Shenk, Renu; Canetta, Pietro A; Ahn, Wooin; Radhakrishnan, Jai; Marasa, Maddalena; Rosenstiel, Paul E; Herlitz, Leal C; Markowitz, Glen S; D'Agati, Vivette D; Appel, Gerald B

2018-04-01

C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Trends in Dementia Incidence in a Birth Cohort Analysis of the Einstein Aging Study.

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Derby, Carol A; Katz, Mindy J; Lipton, Richard B; Hall, Charles B

2017-11-01

Trends in dementia incidence rates have important implications for planning and prevention. To better understand incidence trends over time requires separation of age and cohort effects, and few prior studies have used this approach. To examine trends in dementia incidence and concomitant trends in cardiovascular comorbidities among individuals aged 70 years or older who were enrolled in the Einstein Aging Study between 1993 and 2015. In this birth cohort analysis of all-cause dementia incidence in persons enrolled in the Einstein Aging Study from October 20, 1993, through November 17, 2015, a systematically recruited, population-based sample of 1348 participants from Bronx County, New York, who were 70 years or older without dementia at enrollment and at least one annual follow-up was studied. Poisson regression was used to model dementia incidence as a function of age, sex, educational level, race, and birth cohort, with profile likelihood used to identify the timing of significant increases or decreases in incidence. Birth year and age. Incident dementia defined by consensus case conference based on annual, standardized neuropsychological and neurologic examination findings, using criteria from the DSM-IV. Among 1348 individuals (mean [SD] baseline age, 78.5 [5.4] years; 830 [61.6%] female; 915 [67.9%] non-Hispanic white), 150 incident dementia cases developed during 5932 person-years (mean [SD] follow-up, 4.4 [3.4] years). Dementia incidence decreased in successive birth cohorts. Incidence per 100 person-years was 5.09 in birth cohorts before 1920, 3.11 in the 1920 through 1924 birth cohorts, 1.73 in the 1925 through 1929 birth cohorts, and 0.23 in cohorts born after 1929. Change point analyses identified a significant decrease in dementia incidence among those born after July 1929 (95% CI, June 1929 to January 1930). The relative rate for birth cohorts before July 1929 vs after was 0.13 (95% CI, 0.04-0.41). Prevalence of stroke and myocardial infarction

Hemofilia B sob um olhar panorâmico

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Andrielle de CASTILHO-FERNANDES

2012-01-01

Full Text Available Hemophilia B is a hereditary disease linked to chromosome X and consists in the deficiency of factor IXblood clotting. This hemorrhagic disease affects one in 30,000 men worldwide. The level of biologically active FactorIX in the patients’ plasma is directly related to the severity and frequency of bleeding episodes. Since the advent ofrecombinant DNA technology, it was feasible to clone the gene for factor IX, which made possible its molecularcharacterization. Knowledge of the molecular basis of hemophilia B has allowed a better understanding of therelationships between factor IX gene structure and active Factor IX protein function. The existing treatment is given bybiological replacement therapy, through intravenous infusions of Factor IX derived from human plasma or recombinantFactor IX. This article aims to summarize the knowledge about the molecular basis of hemophilia B (gene, RNA, andprotein, the cascade of blood clotting, the process of development of recombinant Factor IX and the situation inworldwide and Brazil in face of the current treatment and the future prospects of hemophilia B.

Optimal management of hemophilic arthropathy and hematomas

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Lobet S

2014-10-01

Full Text Available Sébastien Lobet,1,2 Cedric Hermans,1 Catherine Lambert1 1Hemostasis-Thrombosis Unit, Division of Hematology, 2Division of Physical Medicine and Rehabilitation, Cliniques Universitaires Saint-Luc, Brussels, Belgium Abstract: Hemophilia is a hematological disorder characterized by a partial or complete deficiency of clotting factor VIII or IX. Its bleeding complications primarily affect the musculoskeletal system. Hemarthrosis is a major hemophilia-related complication, responsible for a particularly debilitating chronic arthropathy, in the long term. In addition to clotting factor concentrates, usually prescribed by the hematologist, managing acute hemarthrosis and chronic arthropathy requires a close collaboration between the orthopedic surgeon and physiotherapist. This collaboration, comprising a coagulation and musculoskeletal specialist, is key to effectively preventing hemarthrosis, managing acute joint bleeding episodes, assessing joint function, and actively treating chronic arthropathy. This paper reviews, from a practical point of view, the pathophysiology, clinical manifestations, and treatment of hemarthrosis and chronic hemophilia-induced arthropathy for hematologists, orthopedic surgeons, and physiotherapists. Keywords: hemophilia, arthropathy, hemarthrosis, hematoma, physiotherapy, target joint

Incidence of obesity during childhood and adolescence in a large contemporary cohort.

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Hughes, Adrienne R; Sherriff, Andrea; Lawlor, Debbie A; Ness, Andrew R; Reilly, John J

2011-05-01

Timing of obesity development during childhood and adolescence is unclear, hindering preventive strategies. The primary aim of the present study was to quantify the incidence of overweight and obesity throughout childhood and adolescence in a large contemporary cohort of English children (the Avon Longitudinal Study of Parents and Children, ALSPAC; children born 1991-1992). A secondary aim was to examine the persistence of overweight and obesity. Longitudinal data on weight and height were collected annually from age 7-15 years in the entire ALSPAC cohort (n=4283), and from 3 to 15 years in a randomly selected subsample of the cohort (n=549; 'Children in Focus' CiF). Incidence of overweight and obesity (BMI (Body mass index) at or above the 85th and 95th centiles relative to U.K. reference data) was calculated. Risk ratios (RR) for overweight and obesity at 15 years based on weight status at 3, 7, and 11 years were also calculated. In the entire cohort, four-year incidence of obesity was higher between ages 7 and 11 years than between 11 and 15 years (5.0% vs. 1.4% respectively). In the CiF sub-sample, four-year incidence of obesity was also highest during mid-childhood (age 7-11years, 6.7%), slightly lower during early childhood (3-7 years, 5.1%) and lowest during adolescence (11-15 years 1.6%). Overweight and obesity at all ages had a strong tendency to persist to age 15 years as indicated by risk ratios (95% CI (Confidence interval)) for overweight and obesity at 15 years from overweight and obesity (relative to healthy weight status) at 3 years (2.4, 1.8-3.1), 7 years (4.6, 3.6-5.8), and 11 years (9.3, 6.5-13.2). Mid-late childhood (around age 7-11 years) may merit greater attention in future obesity prevention interventions. Copyright © 2011 Elsevier Inc. All rights reserved.

Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts

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Pagnoux, Christian; Carette, Simon; Khalidi, Nader A.; Walsh, Michael; Hiemstra, Thomas F.; Cuthbertson, David; Langford, Carol; Hoffman, Gary S.; Koening, Curry L.; Monach, Paul A.; Moreland, Larry; Mouthon, Luc; Seo, Phil; Specks, Ulrich; Ytterberg, Steven; Westman, Kerstin; Hoglund, Peter; Harper, Lorraine; Flossmann, Oliver; Luqmani, Raashid; Savage, Caroline; Rasmussen, Niels; de Groot, Kirstin; Tesar, Vladimir; Jayne, David; Merkel, Pater A.; Guillevin, Loic

2015-01-01

Objective To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. Methods The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). Results 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6±13.9 vs. 46.8±17.3 years), had higher Birmingham vasculitis activity score (19.5±9.1 vs. 16.9±7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). Conclusion Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations. PMID:26016754

Cataract surgery in a population-based cohort of patients with type 1 diabetes

DEFF Research Database (Denmark)

Grauslund, Jakob; Green, Anders; Sjølie, Anne K

2011-01-01

.05-3.40) were the only statistically significant predictors of cataract surgery. Duration of diabetes, gender, glycaemic regulation, proteinuria, smoking, blood pressure and level of retinopathy were not associated with cataract surgery. Conclusion: Type 1 diabetes is associated with a high long-term incidence......ABSTRACT. Purpose: To estimate the long-term cumulative incidence of cataract surgery and associated risk factors in a 25-year follow-up of a population-based cohort of patients with type 1 diabetes. Methods: Based on insulin prescriptions, a population-based cohort of 727 patients with type 1...... of surgery were 59.3 and 42 years, respectively. Cataract surgery in the cohort took place approximately 20 years earlier compared to non-diabetic persons. In a multivariate regression analysis, baseline age [hazard ratio (HR) 1.89 per 10 years, 95% CI 1.46-2.27] and maculopathy (HR 1.89, 95% CI 1...

Missed epidemics and missing links: international birth cohort trends in multiple sclerosis.

Science.gov (United States)

Ajdacic-Gross, V; Tschopp, A; Schmid, M; Bopp, M; Gutzwiller, F

2013-03-01

Many hypotheses on the etiopathogenesis of multiple sclerosis (MS) focus on risk factors occurring early in life. This study examined the variability of birth cohort trends in international MS data by means of age-period-cohort (APC) analysis. The data from 25 countries were taken from the WHO mortality database. Data were encoded according to the International Classification of Diseases and covered slightly varying periods between 1951 and 2009. The APC analyses were based on logit models applied to cohort tables with 5-year age- and period intervals. In most countries, the birth cohort estimates peaked in those born in the first half of the 20th century. In countries from Central and Western Europe, the peak concerned those born before and around 1920. A second group of countries (Denmark, Sweden, Italy, Ireland, Scotland) shared a later peak amongst cohorts born in the 1920s and 1930s. Group 3 included Commonwealth countries, the USA and Norway, with a double or extended peak starting in the 1910s or 1920s, and ending by the 1950s. The fourth group, consisting of Mediterranean countries and Finland, was characterized by a steady increase in the birth cohort estimates until the 1950s. The fifth group with countries from Eastern Europe and Japan showed no particular pattern. Birth cohort trends have influenced the change in MS risk across the 20th century in many Western countries. This silent epidemic points to a most important but unknown latent risk factor in MS. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Dietary folate intake and K-ras mutations in sporadic colon and rectal cancer in the Netherlands Cohort Study

NARCIS (Netherlands)

Brink, M.; Weijenberg, M.P.; Goeij, A.F.P.M. de; Roemen, G.M.J.M.; Lentjes, M.H.F.M.; Bruïne, A.P. de; Engeland, M. van; Goldbohm, R.A.; Brandt, P.A. van den

2005-01-01

We studied the association between dietary folate and specific K-ras mutations in colon and rectal cancer in The Netherlands Cohort Study on diet and cancer. After 7.3 years of follow-up, 448 colon and 160 rectal cancer patients and 3,048 sub-cohort members (55-69 years at baseline) were available

Comparison of neurological health outcomes between two adolescent cohorts exposed to pesticides in Egypt.

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Ahmed A Ismail

Full Text Available Pesticide-exposed adolescents may have a higher risk of neurotoxic effects because of their developing brains and bodies. However, only a limited number of studies have addressed this risk among adolescents. The aim of this study was to compare neurological outcomes from two cohorts of Egyptian adolescents working as pesticide applicators. In 2005 and 2009, two cohorts of male adolescents working as pesticide applicators for the cotton crop were recruited from Menoufia Governorate, Egypt. The same application schedule and pesticides were used at both times, including both organophosphorus, and pyrethroid compounds. Participants in both cohorts completed three neurobehavioral tests, health and exposure questionnaires, and medical and neurological screening examinations. In addition, blood samples were collected to measure butyryl cholinesterase (BChE activity. Pesticide applicators in both cohorts reported more neurological symptoms and signs than non-applicators, particularly among participants in the 2005 cohort (OR ranged from 1.18 to 15.3. Except for one test (Trail Making B, there were no significant differences between either applicators or non-applicators of both cohorts on the neurobehavioral outcome measures (p > 0.05. The 2005 cohort showed greater inhibition of serum BChE activity than the 2009 cohort (p < 0.05. In addition, participants with depressed BChE activity showed more symptoms and signs than others without BChE depression (p < 0.05. Our study is the first to examine the consistency of health outcomes associated with pesticide exposure across two cohorts tested at different times from the same geographical region in rural Egypt. This similar pattern of findings across the two cohorts provides strong evidence of the health impact of exposure of adolescents to pesticides.

Global patterns and trends in stomach cancer incidence: Age, period and birth cohort analysis.

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Luo, Ganfeng; Zhang, Yanting; Guo, Pi; Wang, Li; Huang, Yuanwei; Li, Ke

2017-10-01

The cases of stomach cancer (SC) incidence are increasing per year and the SC burden has remained very high in some countries. We aimed to evaluate the global geographical variation in SC incidence and temporal trends from 1978 to 2007, with an emphasis on the effect of birth cohort. Joinpoint regression and age-period-cohort model were applied. From 2003 to 2007, male rate were 1.5- to 3-fold higher than female in all countries. Rates were highest in Eastern Asian and South American countries. Except for Uganda, all countries showed favorable trends. Pronounced cohort-specific increases in risk for recent birth cohorts were seen in Brazil, Colombia, Iceland, New Zealand, Norway, Uganda and US white people for males and in Australia, Brazil, Colombia, Costa Rica, Czech Republic, Ecuador, Iceland, India, Malta, New Zealand, Norway, Switzerland, United Kingdom, Uganda, US black and white people for females. The cohort-specific ratio for male significantly decreased in Japan, Malta and Spain for cohorts born since 1950 and in Austria, China, Croatia, Ecuador, Russia, Switzerland and Thailand for cohorts born since 1960 and for female in Japan for cohorts born since 1950 and in Canada, China, Croatia, Latvia, Russia and Thailand for cohorts born since 1960. Disparities in incidence and carcinogenic risk persist worldwide. The favorable trends may be due to changes in environmental exposure and lifestyle, including decreased Helicobacter pylori prevalence, increased intake of fresh fruits and vegetables, the availability of refrigeration and decreased intake of salted and preserved food and smoking prevalence. © 2017 UICC.

Sleep disorders increase the risk of burning mouth syndrome: a retrospective population-based cohort study.

Science.gov (United States)

Lee, Chun-Feng; Lin, Kuan-Yu; Lin, Ming-Chia; Lin, Cheng-Li; Chang, Shih-Ni; Kao, Chia-Hung

2014-11-01

Sleep disorders (SD), including apnea and nonapnea, and burning mouth syndrome (BMS) have been mutually associated with systemic diseases. Based on our research, the association between BMS and SD has not been elucidated. We determined whether SD patients have an increased risk of BMS. We used information from health insurance claims obtained from the Taiwanese National Health Insurance (NHI) program. We identified patients newly diagnosed with sleep apnea syndrome between 1998 and 2001 as the apnea SD cohort, and newly diagnosed patients with nonapnea SD as the nonapnea SD cohort. The non-SD cohort was 1:2 frequency matched the case group according to sex, age, and index year. We analyzed the risks of BMS by using Cox proportional hazards regression models. Compared with the non-SD cohort, both of the apnea SD (adjusted HR = 2.56, 95% CI = 1.30-5.05) and nonapnea SD (adjusted HR = 2.89, 95% CI = 2.51-3.34) were associated with a significantly higher risk of BMS. The hazard ratio (HR) increased with increased age in the apnea SD cohort and in the nonapnea SD cohort compared with patients younger than 40 years of age. Female apnea SD patients (IRR = 4.63, 95% CI = 3.82-5.61) had a higher risk of developing BMS than did male patients (IRR = 1.76, 95% CI = 1.39-2.24). Based on our research, SD might increase the risk of BMS. Copyright © 2014 Elsevier B.V. All rights reserved.

Generational cohorts and their attitudes toward advertising

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Ernest Cyril de Run

2013-12-01

Full Text Available This research is aimed at determining the attitudes with regard to advertising from the perspective of generational cohorts in Sarawak. A two-phase of study was conducted to firstly identify generational cohorts in the state and, secondly, to investigate the attitude of each cohort to advertising. Utilizing theories of generations, a qualitative approach by means of personal interviews was used at the outset to identify external events which bring about the formation of cohorts. Accordingly, 48 interviews were conducted and data were content-analyzed. The findings were then incorporated into the second phase of study to investigate cohorts’ views about advertising, using theory of reasoned action. A quantitative approach via questionnaire-based survey was administered, and 1,410 copies were collected for analysis. Five distinct cohorts are proposed in the initial findings. They are labeled as Neoteric Inheritors, Prospective Pursuers, Social Strivers, Idealistic Strugglers and Battling Lifers on the basis of their respective engagement with events during the coming-of-age years. The subsequent findings show that beliefs about advertising are significant predictors of the attitudes to advertising, and so are the attitudes with regard to the intention of every cohort. However, their beliefs and attitudes to advertising are found to differ significantly, especially in the older cohort. The study thus highlights the implication of generational differences on the attitudes to advertising.

[Application of cohort study in cancer prevention and control].

Science.gov (United States)

Dai, Min; Bai, Yana; Pu, Hongquan; Cheng, Ning; Li, Haiyan; He, Jie

2016-03-01

Cancer control is a long-term work. Cancer research and intervention really need the support of cohort study. In the recent years, more and more cohort studies on cancer control were conducted in China along with the increased ability of scientific research in China. Since 2010, Cancer Hospital, Chinese Academy of Medical Sciences, collaborated with Lanzhou University and the Worker' s Hospital of Jinchuan Group Company Limited, have carried out a large-scale cohort study on cancer, which covered a population of more than 50 000 called " Jinchang cohort". Since 2012, a National Key Public Health Project, "cancer screening in urban China" , has been conducted in Jinchang, which strengthened the Jinchang cohort study. Based on the Jinchang cohort study, historical cohort study, cross-sectional study and prospective cohort study have been conducted, which would provide a lot of evidence for the cancer control in China.

Intracranial hemorrhage in congenital bleeding disorders.

Science.gov (United States)

Tabibian, Shadi; Motlagh, Hoda; Naderi, Majid; Dorgalaleh, Akbar

2018-01-01

: Intracranial hemorrhage (ICH), as a life-threatening bleeding among all kinds of congenital bleeding disorders (CBDs), is a rare manifestation except in factor XIII (FXIII) deficiency, which is accompanied by ICH, early in life, in about one-third of patients. Most inherited platelet function disorders (IPFDs) are mild to moderate bleeding disorders that can never experience a severe bleeding as in ICH; however, Glanzmann's thrombasthenia, a common and severe inherited platelet function disorder, can lead to ICH and occasional death. This bleeding feature can also be observed in grey platelet syndrome, though less frequently than in Glanzmann's thrombasthenia. In hemophilia, intracerebral hemorrhage is affected by various risk factors one of which is the severity of the disease. The precise prevalence of ICH in these patients is not clear but an estimated incidence of 3.5-4% among newborns with hemophilia is largely ascertained. Although ICH is a rare phenomenon in CBDs, it can be experienced by every patient with severe hemophilia A and B, FXIII deficiency (FXIIID), FVIID, FXD, FVD, FIID, and afibrinogenemia. Upon observing the general signs and symptoms of ICH such as vomiting, seizure, unconsciousness, and headache, appropriate replacement therapies and cranial ultrasound scans must be done to decrease ICH-related morbidity and mortality.

As bases moleculares da hemofilia A

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Simone Ferreira Pio

2009-01-01

Full Text Available As hemofilias são doenças hemorrágicas resultantes da deficiência de fator VIII (hemofilia A ou de fator IX (hemofilia B da coagulação, decorrentes de mutações nos genes que codificam os fatores VIII ou IX, respectivamente. A hemofilia A é mais frequente que a hemofilia B e acomete aproximadamente 1:10.000 nascimentos masculinos. A gravidade e frequência dos episódios hemorrágicos está relacionado ao nível residual de atividade de fator VIII presente no plasma e este relaciona-se ao tipo de mutação associada à doença. A clonagem do gene do fator VIII tornou possível o conhecimento das bases moleculares da hemofilia A, sendo hoje conhecidas mais de 1.000 mutações associadas à doença. O conhecimento das bases moleculares da hemofilia A permite uma melhor compreensão da relação genótipo-fenótipo da doença, tomada de condutas clínicas diferenciadas em casos de mutações associadas a um maior risco de desenvolvimento de inibidor, determinação da condição de portadora de hemofilia em mulheres relacionadas aos pacientes, implementação de programa de aconselhamento genético/orientação familiar e melhor compreensão das relações estruturais-funcionais do gene-proteína. Este artigo propõe revisar as bases moleculares da hemofilia A, os métodos laboratoriais utilizados para a caracterização das mutações e as implicações clínicas envolvidas no diagnóstico molecular da hemofilia A.Hemophilias are bleeding disorders due to deficiency of the blood coagulation factor VIII (hemophilia A or factor IX (hemophilia B, resulting from mutation on the gene coding for factor VIII or factor IX. Hemophilia A is more frequent than hemophilia B and affects 1:10,000 male newborns. The severity and frequency of hemorrhagic episodes is related to residual activity of factor VIII present in the plasma and relates to the type of mutation associated with the disorder. Cloning of the factor VIII gene has enabled researchers to

Adult outcomes of teen mothers across birth cohorts

Directory of Open Access Journals (Sweden)

Anne Driscoll

2014-04-01

Full Text Available Background: Teen and young adult mothers have lower socioeconomic status than older mothers. Objective: This study analyzes the socioeconomic status (SES of teen, young adult, and older adult mothers across four five-year birth cohorts from 1956 to 1975 who were teens from 1971 to 1994. Methods: Data were pooled from the 1995, 2002, and 2006-2010 National Survey of Family Growth (NSFG. Mothers were categorized by age at first birth and by their birth cohorts. The SES (education, single motherhood, poverty, employment of teen, young adult, and older mothers was compared across cohorts and within cohorts. Results: Among teen mothers, the odds of fulltime employment improved across birth cohorts and the odds of educational attainment beyond high school did not vary. Their odds of single motherhood and living in poverty increased across cohorts. The odds of higher education and single motherhood increased across birth cohorts for young adult mothers as did the odds of living in poverty, even if working fulltime. Among older adult mothers, educational attainment and the odds of single motherhood rose for recent cohorts. Conclusions: Comparisons between teen mothers and both young adult and all adult mothers within cohorts suggest that gaps in single motherhood and poverty between teen and adult mothers have widened over time, to the detriment of teen mothers. Teen mothers have become more likely to be single and poor than in the past and compared to older mothers.

Rationale, design, and preliminary results of the Quebec Warfarin Cohort Study.

Science.gov (United States)

Perreault, Sylvie; Shahabi, Payman; Côté, Robert; Dumas, Stéphanie; Rouleau-Mailloux, Étienne; Feroz Zada, Yassamin; Provost, Sylvie; Mongrain, Ian; Dorais, Marc; Huynh, Thao; Kouz, Simon; Diaz, Ariel; Blostein, Mark; de Denus, Simon; Turgeon, Jacques; Ginsberg, Jeffrey; Lelorier, Jacques; Lalonde, Lyne; Busque, Lambert; Kassis, Jeannine; Talajic, Mario; Tardif, Jean-Claude; Dubé, Marie-Pierre

2018-05-01

Over- and undercoagulation with warfarin are associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control. The Quebec Warfarin Cohort (QWC) comprises 1059 new warfarin users, with prospective follow-up using telephone questionnaires every 3 months for 1 year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5 years prior to cohort entry and up to 10 years following active patient participation. Genetic material was collected, and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within therapeutic range, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report baseline characteristics and outcomes after 1 year of follow-up. Poor anticoagulation control was defined as time in therapeutic range <60% in the 3- to 12-month interval. Participants had a mean age of 71 years, and 62% were men. The most common indication for warfarin was atrial fibrillation (87%). Mean time in therapeutic range was 56% (±25%) in the 3 months following warfarin initiation, and 70% (±21%) in the 3- to 12-month interval. During follow-up, the rate of stroke or systemic embolism was 1.8 events per 100 person-years; for major bleeding events, 3.3 events per 100 person-years. Independent predictors of poor anticoagulation control were chronic kidney disease, heart failure, dyslipidemia, and age. The QWC represents a good research cohort to investigate clinical and genetic factors in a warfarin-anticoagulated population. © 2018 Wiley Periodicals, Inc.

Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort

DEFF Research Database (Denmark)

Westh, Lena; Mogensen, Trine Hyrup; Dalgaard, Lars Skov

2017-01-01

infections were seen in 92.7% of the patients. The prevalence of non-infectious complications was similar to that of previously reported cohorts: bronchiectasis (35.8%), splenomegaly (22.4%), lymphadenopathy (26.3%), granulomatous inflammation (3.9%) and idiopathic thrombocytopenic purpura (14.5%). Non...

Decreases in Smoking-Related Cancer Mortality Rates Are Associated with Birth Cohort Effects in Korean Men.

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Jee, Yon Ho; Shin, Aesun; Lee, Jong-Keun; Oh, Chang-Mo

2016-12-05

Background: This study aimed to examine trends in smoking-related cancer mortality rates and to investigate the effect birth cohort on smoking-related cancer mortality in Korean men. Methods: The number of smoking-related cancer deaths and corresponding population numbers were obtained from Statistics Korea for the period 1984-2013. Joinpoint regression analysis was used to detect changes in trends in age-standardized mortality rates. Birth-cohort specific mortality rates were illustrated by 5 year age groups. Results: The age-standardized mortality rates for oropharyngeal decreased from 2003 to 2013 (annual percent change (APC): -3.1 (95% CI, -4.6 to -1.6)) and lung cancers decreased from 2002 to 2013 (APC -2.4 (95% CI -2.7 to -2.2)). The mortality rates for esophageal declined from 1994 to 2002 (APC -2.5 (95% CI -4.1 to -0.8)) and from 2002 to 2013 (APC -5.2 (95% CI -5.7 to -4.7)) and laryngeal cancer declined from 1995 to 2013 (average annual percent change (AAPC): -3.3 (95% CI -4.7 to -1.8)). By the age group, the trends for the smoking-related cancer mortality except for oropharyngeal cancer have changed earlier to decrease in the younger age group. The birth-cohort specific mortality rates and age-period-cohort analysis consistently showed that all birth cohorts born after 1930 showed reduced mortality of smoking-related cancers. Conclusions: In Korean men, smoking-related cancer mortality rates have decreased. Our findings also indicate that current decreases in smoking-related cancer mortality rates have mainly been due to a decrease in the birth cohort effect, which suggest that decrease in smoking rates.

Cohort profile: the Nordic Antireflux Surgery Cohort (NordASCo).

Science.gov (United States)

Maret-Ouda, John; Wahlin, Karl; Artama, Miia; Brusselaers, Nele; Färkkilä, Martti; Lynge, Elsebeth; Mattsson, Fredrik; Pukkala, Eero; Romundstad, Pål; Tryggvadóttir, Laufey; Euler-Chelpin, My von; Lagergren, Jesper

2017-06-08

To describe a newly created all-Nordic cohort of patients with gastro-oesophageal reflux disease (GORD), entitled the Nordic Antireflux Surgery Cohort (NordASCo), which will be used to compare participants having undergone antireflux surgery with those who have not regarding risk of cancers, other diseases and mortality. Included were individuals with a GORD diagnosis recorded in any of the nationwide patient registries in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) in 1964-2014 (with various start and end years in different countries). Data regarding cancer, other diseases and mortality were retrieved from the nationwide registries for cancer, patients and causes of death, respectively. The NordASCo includes 945 153 individuals with a diagnosis of GORD. Of these, 48 433 (5.1%) have undergone primary antireflux surgery. Median age at primary antireflux surgery ranged from 47 to 52 years in the different countries. The coding practices of GORD seem to have differed between the Nordic countries. The NordASCo will initially be used to analyse the risk of developing known or potential GORD-related cancers, that is, tumours of the oesophagus, stomach, larynx, pharynx and lung, and to evaluate the mortality in the short-term and long-term perspectives. Additionally, the cohort will be used to evaluate the risk of non-malignant respiratory conditions that might be caused by aspiration of gastric contents. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Design, methods and demographics from phase I of Alberta's Tomorrow Project cohort: a prospective cohort profile.

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Robson, Paula J; Solbak, Nathan M; Haig, Tiffany R; Whelan, Heather K; Vena, Jennifer E; Akawung, Alianu K; Rosner, William K; Brenner, Darren R; Cook, Linda S; Csizmadi, Ilona; Kopciuk, Karen A; McGregor, S Elizabeth; Friedenreich, Christine M

2016-01-01

Prospective cohorts have the potential to support multifactorial, health-related research, particularly if they are drawn from the general population, incorporate active and passive follow-up and permission is obtained to allow access by researchers to data repositories. This paper describes Phase I of the Alberta's Tomorrow Project cohort, a broad-based research platform designed to support investigations into factors that influence cancer and chronic disease risk. Adults aged 35-69 years living in Alberta, Canada, with no previous cancer diagnosis other than nonmelanoma skin cancer were recruited to the project by telephone-based random digit dialling. Participants were enrolled if they returned a Health and Lifestyle Questionnaire. Past year diet and physical activity questionnaires were mailed 3 months after enrolment. Consent was sought for active follow-up and linkage with administrative databases. Depending on enrolment date, participants were invited to complete up to 2 follow-up questionnaires (2004 and 2008). Between 2001 and 2009, 31 072 (39% men) participants (mean age 50.2 [± 9.2] yr) were enrolled and 99% consented to linkage with administrative databases. Participants reported a wide range of educational attainment and household income. Compared with provincial surveillance data from the Canadian Community Health Survey, Alberta's Tomorrow Project participants had higher body mass index, lower prevalence of smoking and similar distribution of chronic health conditions. Follow-up questionnaires were completed by 83% and 72% of participants in 2004 and 2008, respectively. Robust quality control measures resulted in low frequencies of missing data. Alberta's Tomorrow Project provides a robust platform, based on a prospective cohort design, to support research into risk factors for cancer and chronic disease.

Cohort changes in cognitive function among Danish centenarians. A comparative study of 2 birth cohorts born in 1895 and 1905

DEFF Research Database (Denmark)

Engberg, Henriette; Christensen, Kaare; Andersen-Ranberg, Karen

2008-01-01

of 276 persons participated (75%). The Danish 1905 Cohort Survey includes all individuals born in 1905. In total, 225 out of 364 persons who reached the age of 100 in the cohort participated in the most recent 2005 follow-up (62%). In both cohorts, cognitive function was assessed using the Mini-Mental...

Mammography Among Women With Severe Mental Illness: Exploring Disparities Through a Large Retrospective Cohort Study.

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Thomas, Melanie; James, Monique; Vittinghoff, Eric; Creasman, Jennifer M; Schillinger, Dean; Mangurian, Christina

2018-01-01

This study examined mammogram screening rates among women with severe mental illness by using a socioecological framework. Because it has been shown that people with severe mental illness receive less preventive health care overall, the analysis included psychosocial predictors of mammogram screening rates in a cohort of women with severe mental illness. This retrospective cohort study (N=14,651) used existing statewide data for women ages 48-67 in California with Medicaid insurance who received treatment in the specialty mental health care system. The primary outcome of interest was evidence of breast cancer screening via mammogram. The associations of each predictor of interest with mammogram screening were evaluated by using Poisson models with robust standard errors. Across all demographic and diagnostic categories, rates of breast cancer screening in this cohort of women with severe mental illness fell below the national average. Only 26.3% (3,859/14,651) of women in the cohort received breast cancer screening in the past year. This study replicated previous findings that women with schizophrenia spectrum disorder and those with a comorbid substance use disorder are less likely to receive screening than those with other types of mental illness. In this cohort of women with severe mental illness, evidence of nonpsychiatric health care utilization was strongly associated with breast cancer screening (adjusted risk ratio=3.30, 95% confidence interval=2.61-4.16, pmental illness, such as targeted outreach to population subsets and colocation of primary care services in mental health treatment settings.

Epilepsy in adults with mitochondrial disease: A cohort study.

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Whittaker, Roger G; Devine, Helen E; Gorman, Grainne S; Schaefer, Andrew M; Horvath, Rita; Ng, Yi; Nesbitt, Victoria; Lax, Nichola Z; McFarland, Robert; Cunningham, Mark O; Taylor, Robert W; Turnbull, Douglass M

2015-12-01

The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7-year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke-like episode, and death. Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke-like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83). Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke-like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. © 2015 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Environmental Variation and Cohort Effects in an Antarctic Predator

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Garrott, Robert A.; Rotella, Jay J.; Siniff, Donald B.; Parkinson, Claire L.; Stauffer, Glenn E.

2011-01-01

Understanding the potential influence of environmental variation experienced by animals during early stages of development on their subsequent demographic performance can contribute to our understanding of population processes and aid in predicting impacts of global climate change on ecosystem functioning. Using data from 4,178 tagged female Weddell seal pups born into 20 different cohorts, and 30 years of observations of the tagged seals, we evaluated the hypothesis that environmental conditions experienced by young seals, either indirectly through maternal effects and/or directly during the initial period of juvenile nutritional independence, have long-term effects on individual demographic performance. We documented an approximately 3-fold difference in the proportion of each cohort that returned to the pupping colonies and produced a pup within the first 10 years after birth. We found only weak evidence for a correlation between annual environmental conditions during the juvenile-independence period and cohort recruitment probability. Instead, the data strongly supported an association between cohort recruitment probability and the regional extent of sea ice experienced by the mother during the winter the pup was in utero. We suggest that inter-annual variation in winter sea-ice extent influences the foraging success of pregnant seals by moderating the regional abundance of competing predators that cannot occupy areas of consolidated sea ice, and by directly influencing the abundance of mid-trophic prey species that are sea-ice obligates. We hypothesize that this environmentally-induced variation in maternal nutrition dictates the extent of maternal energetic investment in offspring, resulting in cohort variation in mean size of pups at weaning which, in turn, contributes to an individual?s phenotype and its ultimate fitness. These linkages between sea ice and trophic dynamics, combined with demonstrated and predicted changes in the duration and extent of sea

Cancer Epidemiology Cohorts

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Cohort studies are fundamental for epidemiological research by helping researchers better understand the etiology of cancer and provide insights into the key determinants of this disease and its outcomes.

Mother's education and offspring asthma risk in 10 European cohort studies.

Science.gov (United States)

Lewis, Kate Marie; Ruiz, Milagros; Goldblatt, Peter; Morrison, Joana; Porta, Daniela; Forastiere, Francesco; Hryhorczuk, Daniel; Zvinchuk, Oleksandr; Saurel-Cubizolles, Marie-Josephe; Lioret, Sandrine; Annesi-Maesano, Isabella; Vrijheid, Martine; Torrent, Maties; Iniguez, Carmen; Larranaga, Isabel; Harskamp-van Ginkel, Margreet W; Vrijkotte, Tanja G M; Klanova, Jana; Svancara, Jan; Barross, Henrique; Correia, Sofia; Jarvelin, Marjo-Riitta; Taanila, Anja; Ludvigsson, Johnny; Faresjo, Tomas; Marmot, Michael; Pikhart, Hynek

2017-09-01

Highly prevalent and typically beginning in childhood, asthma is a burdensome disease, yet the risk factors for this condition are not clarified. To enhance understanding, this study assessed the cohort-specific and pooled risk of maternal education on asthma in children aged 3-8 across 10 European countries. Data on 47,099 children were obtained from prospective birth cohort studies across 10 European countries. We calculated cohort-specific prevalence difference in asthma outcomes using the relative index of inequality (RII) and slope index of inequality (SII). Results from all countries were pooled using random-effects meta-analysis procedures to obtain mean RII and SII scores at the European level. Final models were adjusted for child sex, smoking during pregnancy, parity, mother's age and ethnicity. The higher the score the greater the magnitude of relative (RII, reference 1) and absolute (SII, reference 0) inequity. The pooled RII estimate for asthma risk across all cohorts was 1.46 (95% CI 1.26, 1.71) and the pooled SII estimate was 1.90 (95% CI 0.26, 3.54). Of the countries examined, France, the United Kingdom and the Netherlands had the highest prevalence's of childhood asthma and the largest inequity in asthma risk. Smaller inverse associations were noted for all other countries except Italy, which presented contradictory scores, but with small effect sizes. Tests for heterogeneity yielded significant results for SII scores. Overall, offspring of mothers with a low level of education had an increased relative and absolute risk of asthma compared to offspring of high-educated mothers.

Cohorts based on decade of death: no evidence for secular trends favoring later cohorts in cognitive aging and terminal decline in the AHEAD study.

Science.gov (United States)

Hülür, Gizem; Infurna, Frank J; Ram, Nilam; Gerstorf, Denis

2013-03-01

Studies of birth-year cohorts examined over the same age range often report secular trends favoring later-born cohorts, who are cognitively fitter and show less steep cognitive declines than earlier-born cohorts. However, there is initial evidence that those advantages of later-born cohorts do not carry into the last years of life, suggesting that pervasive mortality-related processes minimize differences that were apparent earlier in life. Elaborating this work from an alternative perspective on cohort differences, we compared rates of cognitive aging and terminal decline in episodic memory between cohorts based on the year participants had died, earlier (between 1993 and 1999) or later in historical time (between 2000 and 2010). Specifically, we compared trajectories of cognitive decline in 2 death-year cohorts of participants in the Asset and Health Dynamics Among the Oldest Old study that were matched on age at death and education and controlled for a variety of additional covariates. Results revealed little evidence of secular trends favoring later cohorts. To the contrary, the cohort that died in the 2000s showed a less favorable trajectory of age-related memory decline than the cohort that died in the 1990s. In examinations of change in relation to time to death, the cohort dying in the 2000s experienced even steeper terminal declines than the cohort dying in the 1990s. We suggest that secular increases in "manufacturing" survival may exacerbate age- and mortality-related cognitive declines among the oldest old.

Homelessness as an independent risk factor for mortality: results from a retrospective cohort study.

Science.gov (United States)

Morrison, David S

2009-06-01

Homelessness is associated with increased risks of mortality but it has not previously been possible to distinguish whether this is typical of other socio-economically deprived populations, the result of a higher prevalence of morbidity or an independent risk of homelessness itself. The aim of this study was to describe mortality among a cohort of homeless adults and adjust for the effects of morbidity and socio-economic deprivation. Retrospective 5-year study of two fixed cohorts, homeless adults and an age- and sex-matched random sample of the local non-homeless population in Greater Glasgow National Health Service Board area for comparison. Over 5 years of observation, 1.7% (209/12 451) of the general population and 7.2% (457/6323) of the homeless cohort died. The hazard ratio of all-cause mortality in homeless compared with non-homeless cohorts was 4.4 (95% CI: 3.8-5.2). After adjustment for age, sex and previous hospitalization, homelessness was associated with an all-cause mortality hazard ratio of 1.6 (95% CI: 1.3-1.9). Homelessness had differential effects on cause-specific mortality. Among patients who had been hospitalized for drug-related conditions, the homeless cohort experienced a 7-fold increase in risk of death from drugs compared with the general population. Homelessness is an independent risk factor for deaths from specific causes. Preventive programmes might be most effectively targeted at the homeless with these conditions.

Regulation of Viable and Optimal Cohorts

Energy Technology Data Exchange (ETDEWEB)

Aubin, Jean-Pierre, E-mail: aubin.jp@gmail.com [VIMADES (Viabilité, Marchés, Automatique, Décisions) (France)

2015-10-15

This study deals with the evolution of (scalar) attributes (resources or income in evolutionary demography or economics, position in traffic management, etc.) of a population of “mobiles” (economic agents, vehicles, etc.). The set of mobiles sharing the same attributes is regarded as an instantaneous cohort described by the number of its elements. The union of instantaneous cohorts during a mobile window between two attributes is a cohort. Given a measure defining the number of instantaneous cohorts, the accumulation of the mobile attributes on a evolving mobile window is the measure of the cohort on this temporal mobile window. Imposing accumulation constraints and departure conditions, this study is devoted to the regulation of the evolutions of the attributes which are1.viable in the sense that the accumulations constraints are satisfied at each instant;2.and, among them, optimal, in the sense that both the duration of the temporal mobile window is maximum and that the accumulation on this temporal mobile window is the largest viable one. This value is the “accumulation valuation” function. Viable and optimal evolutions under accumulation constraints are regulated by an “implicit Volterra integro-differential inclusion” built from the accumulation valuation function, solution to an Hamilton–Jacobi–Bellman partial differential equation under constraints which is constructed for this purpose.

Cohort profile

DEFF Research Database (Denmark)

Kreiberg, Michael; Bandak, Mikkel; Lauritsen, Jakob

2018-01-01

The cohort was set up in order to analyze late effects in long-term testicular cancer survivors (TCS) and to contribute to the design of future follow-up programs addressing and potentially preventing late effects. Data for this cross-sectional study were collected between January 1, 2014, and De...

A new approach to age-period-cohort analysis using partial least squares regression: the trend in blood pressure in the Glasgow Alumni cohort.

Directory of Open Access Journals (Sweden)

Yu-Kang Tu

2011-04-01

Full Text Available Due to a problem of identification, how to estimate the distinct effects of age, time period and cohort has been a controversial issue in the analysis of trends in health outcomes in epidemiology. In this study, we propose a novel approach, partial least squares (PLS analysis, to separate the effects of age, period, and cohort. Our example for illustration is taken from the Glasgow Alumni cohort. A total of 15,322 students (11,755 men and 3,567 women received medical screening at the Glasgow University between 1948 and 1968. The aim is to investigate the secular trends in blood pressure over 1925 and 1950 while taking into account the year of examination and age at examination. We excluded students born before 1925 or aged over 25 years at examination and those with missing values in confounders from the analyses, resulting in 12,546 and 12,516 students for analysis of systolic and diastolic blood pressure, respectively. PLS analysis shows that both systolic and diastolic blood pressure increased with students' age, and students born later had on average lower blood pressure (SBP: -0.17 mmHg/per year [95% confidence intervals: -0.19 to -0.15] for men and -0.25 [-0.28 to -0.22] for women; DBP: -0.14 [-0.15 to -0.13] for men; -0.09 [-0.11 to -0.07] for women. PLS also shows a decreasing trend in blood pressure over the examination period. As identification is not a problem for PLS, it provides a flexible modelling strategy for age-period-cohort analysis. More emphasis is then required to clarify the substantive and conceptual issues surrounding the definitions and interpretations of age, period and cohort effects.

Side effects and potential risk factors of botulinum toxin type A intramuscular injections in knee flexion contractures of hemophiliacs.

Science.gov (United States)

Rodriguez-Merchan, E Carlos; De la Corte-Rodriguez, Hortensia

2017-07-01

Knee flexion contracture (KFC) is a common complication of recurrent hemarthrosis in children and young adults with hemophilia. If the KFC is not prevented (by means of primary prophylaxis) and treated properly and early (be means of physical medicine and rehabilitation), it will become fixed. Areas covered: The aim of this article is to review the potential role of botulinum toxin type A (BTX-A) intramuscular injections for the treatment of KFC in people with hemophilia (PWH). Expert commentary: Although two recent reports have mentioned the benefits of intramuscular injections of BTX-A in PWH with KFC, the data are still scant and too preliminary. The use of intramuscular injections of BTX-A in PWH today should not be recommended until more case studies/small series (ideally well-designed clinical trials) fully demonstrate that this is safe and effective. The risks of intramuscular injections to a hemophilia patient cannot be underestimated (iatrogenic muscle hematomas and pseudotumors). This paper calls the attention of hemophilia treaters on the potential risks of this apparently interesting technique. The current use of BTX-A intramuscular injections in KFC of PWH could make no sense. Raising false expectations in these patients should be avoided.

Influence of exposure assessment and parameterization on exposure response. Aspects of epidemiologic cohort analysis using the Libby Amphibole asbestos worker cohort.