Showing papers in "Haemophilia in 2014"

Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project

Abstract: Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0–3 for adult males, 0–5 for adult females and 0–2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.

Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors

Abstract: Factor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti-inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high-titre inhibitors or low-titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1-year period, 17 subjects were treated prophylactically (85 ± 15 U kg(-1) every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on-demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms (P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode-free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on-demand therapy than prophylaxis (P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on-demand treatment, and the safety of prophylaxis is comparable to that of on-demand treatment.

The burden of bleeding in haemophilia: is one bleed too many?

Abstract: Joint bleeding is the hallmark of haemophilia. Increasingly, the pain, restricted movement and anxiety provoked by even a single haemarthrosis are concerns for patients, families and treating physicians. The aims of this study were to determine whether the current paradigm for prophylaxis requires a shift in focus from reducing the frequency of bleeding episodes to a goal of zero bleeding and to review and discuss the published data from in vitro and animal experiments and clinical studies in patients with haemophilia that describe the impact of joint bleeding. More than two to three bleeding into the same joint may cause irreversible and progressive structural damage that compromise health-related quality of life (HRQoL). A goal of zero bleeding episodes - or as close to zero as possible - is key to enhancing joint health and HRQoL in children and adults with haemophilia. Achieving this goal requires individualized, outcome-based, multidisciplinary care to maximize prophylactic efficacy without increasing overall health care costs.

Haemophilia Experiences, Results and Opportunities (HERO) Study: survey methodology and population demographics

Abstract: Psychosocial factors have a significant impact on the quality of life of persons with haemophilia (PWH). The Haemophilia Experiences, Results and Opportunities (HERO) initiative was developed to provide a greater understanding of the psychological components which influence the lives of PWH. This article describes the HERO methodology and the characteristics of respondents. Two online surveys (one for adult PWH ≥18 years and one for parents of children <18 years with haemophilia) were developed by an international advisory board and conducted in 10 countries. The surveys included demographic and treatment characteristics, relationships, sexual intimacy, quality of life, barriers to treatment and sources of information. A total of 675 PWH [age, median (range) 36 (18-86 years)] and 561 parents [39 (23-68 years)] completed the survey. PWH/parents reported haemophilia A (74%/76%), B (13%/16%) or with inhibitors (13%/8%). Spontaneous joint bleeding was reported in 76%/52% of PWH/children with haemophilia A, 67%/47% with haemophilia B and 93%/76% with inhibitors. Median number of bleeds (interquartile range) was 7 (2-20) for PWH and 4 (2-10) for children in the past year. Most PWH and children were treated with factor concentrate. PWH reported arthritis (49%) and HIV/HCV infections (18%/43%) related to haemophilia. Most PWH and parent respondents had received formal education (85%/89%) and were employed full- or part-time (60%/72%). HERO is one of the largest multinational studies focused on psychosocial issues in haemophilia, including historical and treatment information that will allow for multivariate analyses of determinants of health in haemophilia.

Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories.

Abstract: Discrepancies exist for some of the modified coagulation factors when assayed with different one-stage clotting and chromogenic substrate assay reagents. The aim of this study was to evaluate the performance of a recombinant factor VIII Fc fusion protein (rFVIIIFc), currently in clinical development for the treatment of severe haemophilia A, in a variety of one-stage clotting and chromogenic substrate assays in clinical haemostasis laboratories. Haemophilic plasma samples spiked with rFVIIIFc or Advate(®) at 0.05, 0.20 or 0.80 IU mL(-1) were tested by 30 laboratories using their routine procedures and plasma standards. Data were evaluated for intra- and inter-laboratory variation, accuracy and possible rFVIIIFc-specific assay discrepancies. For the one-stage assay, mean recovery was 95% to 100% of expected for both Advate(®) and rFVIIIFc at 0.8 IU mL(-1). Intra-laboratory percent coefficient of variance (CV) ranged from 6.3% to 7.8% for Advate(®), and 6.0% to 10.3% for rFVIIIFc. Inter-laboratory CV ranged from 10% for Advate(®) and 16% for rFVIIIFc at 0.8 IU mL(-1), to over 30% at 0.05 IU mL(-1) for both products. For the chromogenic substrate assay, the average FVIII recovery was 107% ± 5% and 124% ± 8% of label potency across the three concentrations of Advate(®) and rFVIIIFc, respectively. Plasma rFVIIIFc levels can be monitored by either the one-stage or the chromogenic substrate assay routinely performed in clinical laboratories without the need for a product-specific rFVIIIFc laboratory standard. Accuracy by the one-stage assay was comparable to that of Advate(®), while marginally higher results may be observed for rFVIIIFc when using the chromogenic assay.

Severe and moderate haemophilia A and B in US females.

Abstract: Haemophilia A and B are rare X-lined hemorrhagic disorders that typically affect men Women are usually asymptomatic carriers, but may be symptomatic and, rarely, also express severe (factor VIII (FVIII) or factor IX (FIX) <001 U mL(-1)) or moderately severe (FVIII/FIX 001-005 U mL(-1)) phenotypes However, data on clinical manifestations, genotype and the psychosocial ramifications of illness in severely affected females remain anecdotal A national multi-centre retrospective study was conducted to collect a comprehensive data set on affected US girls and women, and to compare clinical observations to previously published information on haemophilic males of comparable severity and mildly affected haemophilic females Twenty-two severe/moderate haemophilia A/B subjects were characterized with respect to clinical manifestations and disease complications; genetic determinants of phenotypic severity; and health-related quality of life (HR-QoL) Clinical data were compared as previously indicated Female patients were older than male patients at diagnosis, but similarly experienced joint haemorrhage, disease- and treatment-related complications and access to treatment Gynaecological and obstetrical bleeding was unexpectedly infrequent F8 or F9 mutations, accompanied by extremely skewed X-chromosome inactivation pattern (XIP), were primary determinants of severity HR-QoL was diminished by arthropathy and viral infection Using systematic case verification of participants in a national surveillance registry, this study elucidated the genetics, clinical phenotype and quality of life issues in female patients with severe/moderate haemophilia An ongoing international case-controlled study will further evaluate these observations Novel mechanistic questions are raised about the relationship between XIP and both age and tissue-specific FVIII and FIX expression

Current status of haemophilia gene therapy.

Abstract: After many reports of successful gene therapy studies in small and large animal models of haemophilia, we have, at last, seen the first signs of success in human patients. These very encouraging results have been achieved with the use of adeno-associated viral (AAV) vectors in patients with severe haemophilia B. Following on from these initial promising studies, there are now three ongoing trials of AAV-mediated gene transfer in haemophilia B all aiming to express the factor IX gene from the liver. Nevertheless, as discussed in the first section of this article, there are still a number of significant hurdles to overcome if haemophilia B gene therapy is to become more widely available. The second section of this article deals with the challenges relating to factor VIII gene transfer. While the recent results in haemophilia B are extremely encouraging, there is, as yet, no similar data for factor VIII gene therapy. It is widely accepted that this therapeutic target will be significantly more problematic for a variety of reasons including accommodating the larger factor VIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of antifactor VIII immunity. In the final section of the article, the alternative approach of lentiviral vector-mediated gene transfer is discussed. While AAV-mediated approaches to transgene delivery have led the way in clinical haemophilia gene therapy, there are still a number of potential advantages of using an alternative delivery vehicle including the fact that ex vivo host cell transduction will avoid the likelihood of immune responses to the vector. Overall, these are exciting times for haemophilia gene therapy with the likelihood of further clinical successes in the near future.

Rare bleeding disorders – bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency

Abstract: Rare bleeding disorders (RBDs) are inherited deficiencies of coagulation factors such as fibrinogen, factor (F) II, FV, FVII, combined FV+FVIII, FX, FXI and FXIII. These disorders usually have a low prevalence in the general population and constitute approximately 3-5% of all coagulation disorders. However, in some countries they may have the same prevalence as haemophilia B due to the practice of consanguineous marriage. The clinical picture of RBDs is highly variable and can vary markedly from mild to severe, making both diagnosis and optimal treatment quite challenging. This review focuses on: (i) the efforts to establish a bleeding assessment tool adequate to RBDs, (ii) the optimal management of patients affected with FXI deficiency and (iii) the correlation between clinical severity and laboratory diagnosis when determining the minimum coagulant activity required to prevent bleeding in each RBD.

Primary haemostasis: newer insights.

Abstract: At the same time as biophysical and omics approaches are drilling deeper into the molecular details of platelets and other blood cells, as well as their receptors and mechanisms of regulation, there is also an increasing awareness of the functional overlap between human vascular systems. Together, these studies are redefining the intricate networks linking haemostasis and thrombosis with inflammation, infectious disease, cancer/metastasis and other vascular pathophysiology. The focus of this state-of-the-art review is some of the newer advances relevant to primary haemostasis. Of particular interest, platelet-specific primary adhesion-signalling receptors and associated activation pathways control platelet function in flowing blood and provide molecular links to other systems. Platelet glycoprotein (GP)Ibα of the GPIb-IX-V complex and GPVI not only initiate platelet aggregation and thrombus formation by primary interactions with von Willebrand factor and collagen, respectively, but are also involved in coagulation, leucocyte engagement, bacterial or viral interactions, and are relevant as potential risk markers in a range of human diseases. Understanding these systems in unprecedented detail promises significant advances in evaluation of individual risk, in new diagnostic or therapeutic possibilities and in monitoring the response to drugs or other treatment.

Evaluation of the activated partial thromboplastin time assay for clinical monitoring of PEGylated recombinant factor VIII (BAY 94-9027) for haemophilia A.

Abstract: Summary Patients with haemophilia (PWH) are usually monitored by the one-stage activated partial thromboplastin time (aPTT) factor VIII (FVIII) assay. Different aPTT activators may affect clotting time (CT) and FVIII:C levels in patients treated with PEGylated FVIII. To evaluate the characteristics of PEGylated FVIII (BAY 94-9027) in various aPTT clotting assays, and to identify suitable aPTT reagents for monitoring BAY 94-9027 during the treatment of PWH, BAY 94-9027 and World Health Organization (WHO) 8th FVIII standards (WHO-8) were spiked into pooled and individual severe haemophilia A plasma at 1.0, 0.25 and 0.05 IU mL−1. Five commercial aPTT reagents widely used in clinical laboratories were compared and evaluated for BAY 94-9027 activity in plasma from PWH. BAY 94-9027 and WHO-8 bestowed similar CT and excellent precision when ellagic acid (SynthAFax, Dade Actin, and Cephascreen) aPTT reagents were used. In contrast, BAY 94-9027 showed significantly prolonged CT and poor precision compared with WHO-8 using silica aPTT reagents (APTT-SP and STA PTT 5). Furthermore, free 60-kDa polyethylene glycol (PEG), used for the conjugation of FVIII, showed a dose-dependent prolongation of CT in the APTT-SP assay. There was no effect on the SynthAFax-APTT, prothrombin time, or FXIa-initiated thrombin generation assay, demonstrating that the PEG moiety on FVIII has no general effect on the coagulation cascade. In summary, ellagic aPTT reagents (SynthAFax, Dade Actin, and Cephascreen) are most suitable for evaluating potency of BAY 94-9027 and should be the preferred aPTT reagents used in clinical laboratories for monitoring FVIII activity after infusion of BAY 94-9027 to PWH.

Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry

Abstract: Haemophilia is a rare disease. To improve knowledge, prospective studies of large numbers of subjects are needed. To establish a large well-documented birth cohort of patients with haemophilia enabling studies on early presentation, side effects and outcome of treatment. Twenty-one haemophilia treatment centres have been collecting data on all children with haemophilia with FVIII/IX levels up to 25% born from 2000 onwards. Another eight centres collected data on severe haemophilia A only. At baseline, details on delivery and diagnosis, gene mutation, family history of haemophilia and inhibitors are collected. For the first 75 exposure days, date, reason, dose and product are recorded for each infusion. Clinically relevant inhibitors are defined as follows: at least two positive inhibitor titres and a FVIII/IX recovery <66% of expected. For inhibitor patients, results of all inhibitor- and recovery tests are collected. For continued treatment, data on bleeding, surgery, prophylaxis and clotting factor consumption are collected annually. Data are downloaded for analysis annually. In May 2013, a total of 1094 patients were included: 701 with severe, 146 with moderate and 247 with mild haemophilia. Gene defect data were available for 87.6% of patients with severe haemophilia A. The first analysis, performed in May 2011, lead to two landmark publications. The outcome of this large collaborative research confirms its value for the improvement of haemophilia care. High-quality prospective observational cohorts form an ideal source to study natural history and treatment in rare diseases such as haemophilia.

Changing paradigm of prophylaxis with longer acting factor concentrates

Abstract: Beginning in the 1960s the care of persons with haemophilia began to improve dramatically through a series of transformative improvements in care: development of lyophilized factor concentrates, home care programmes, prophylaxis and (due to the tragedy of HIV/hepatitis) the development of virally safer plasma-derived and recombinant factor concentrates. Prophylaxis, if commenced early and given in sufficient dose/frequency has been shown to allow persons with haemophilia to maintain excellent joints and lead normal lives. Yet the relatively short half-lives of factor (F) VIII and IX concentrates leads to the need for frequent venous access. This remains a significant burden for patients with haemophilia on prophylaxis causing in many cases reduced patient adherence to prophylaxis and negative longterm outcomes. The last 5 years have witnessed a flourish of new bioengineered longer acting FVIII and IX concentrates manufactured using different technologies (pegylation or fusion to Fc/albumin). These products (especially the longer acting FIX concentrates) are likely to have profound implications on prophylaxis. With these longer acting factor concentrates prophylaxis regimens will almost certainly change. This will involve changes in what trough levels are targeted and how frequently factor is administered. It is hoped that these changes may improve patients' adherence to prophylaxis and their quality of life. These long-acting factor concentrates will undoubtedly have cost repercussions and will raise important questions regarding how decisions about choosing one longer acting concentrate over another, and whether these products are interchangeable, are made. This article will review what changes may ensue with the advent of these new longer acting factor concentrates.

Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders.

Abstract: Bleeding disorders, including haemophilia, von Willebrand disease, and platelet function abnormalities pose a substantial, ongoing management challenge. Patients with these disorders not only require treatment during bleeding events but also need effective management strategies to prepare for events ranging from minor dental procedures to major surgery and childbirth. Moreover, women with bleeding disorders often require ongoing treatment to prevent menorrhagia during childbearing years. Desmopressin (DDAVP), a synthetic derivative of the antidiuretic hormone l-arginine vasopressin, has become a well-established tool for the management of patients with bleeding disorders in a variety of clinical settings. However, despite the widespread use of DDAVP, the available clinical evidence on its efficacy and safety in these settings is limited, and there has not been a recent comprehensive review of its role in the clinical management of patients with bleeding disorders. As such, this article provides a review of the mechanism of action and pharmacokinetic properties of DDAVP, followed by a concise summary of the available evidence for its use in the treatment and prevention of bleeding.

Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects

Abstract: Summary Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on-demand therapy. Male subjects aged 6–65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open-label, four-period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on-demand therapy. In the intent-to-treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on-demand period, the 50 IU kg−1 twice-weekly period, and the 100 IU kg−1 once-weekly period respectively. Differences in ABR between the first on-demand period and both prophylaxis regimens were significant (P < 0.0001); no significant differences were observed between prophylaxis regimens (P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg−1 twice weekly or 100 IU kg−1 once weekly reduced ABR by 89.4% relative to on-demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B.

Considerations in individualizing prophylaxis in patients with haemophilia A.

Abstract: Prophylaxis is considered optimal care for children and adults with severe haemophilia A because of its proven ability to reduce joint and other bleeding episodes. However, a 'one size fits all' approach to prophylaxis is not ideal, potentially leading to over-treatment in some individuals and under-treatment in others. Moreover, a generic plan fails to take into account a patient's lifestyle and personal preferences. This article reviews the factors contributing to bleeding risk and joint damage and uses case studies to illustrate how these contributors can be weighed to individualize the prophylactic regimen, thereby increasing the likelihood of therapeutic success.

Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate.

Abstract: Most studies on immune tolerance induction (ITI) therapy in haemophilia A patients are focused on primary ITI in children. Here we report on the ITI outcome in a large retrospective cohort, including adults and patients with rescue ITI, treated with a pdFVIII/VWF concentrate. Retrospective data from haemophilic patients (FVIII< 2%) with inhibitors from 22 centres in Spain, Italy and Germany, who underwent primary or rescue ITI with pdFVIII/VWF concentrate, were collected. Complete success (CS), partial success (PS) and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. A total of 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults) were evaluated. Success (CS+PS) rate of 87% was achieved in primary ITI and 74% in the higher risk profile of rescue ITI. Eight of nine (85%) patients with poorest prognosis (three or more of the known risk factors of poor response to ITI) achieved success (CS+PS). CS of 100% was observed in eight primary ITI patients with titre at start of ITI ≤2.5 BU and inhibitor peak ≤25 BU. The favourable response rates in primary and rescue ITI in children and in adult patients, even in the presence of poor prognostic factors, should be encouraged for broadening the indication of immune tolerance therapy in haemophilia A patients with inhibitors.

Prevalent inhibitors in haemophilia B subjects enrolled in the Universal Data Collection database

Abstract: Several risk factors for inhibitors have recently been described for haemophilia A. It has been assumed that similar risk factors are also relevant for haemophilia B, but there is limited data to confirm this notion. The aim of this study was to determine the prevalence of and risk factors associated with inhibitors in haemophilia B. 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 haemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Of the 3785 male subjects with haemophilia 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 <11 years (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. Inhibitors in haemophilia B are much less prevalent than haemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in haemophilia A also seem to be present for haemophilia 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.

Comprehensive management of chronic pain in haemophilia.

Abstract: Chronic pain, most often due to haemophilic arthropathy, is a pervasive problem in persons with haemophilia (PWH) that adversely impacts function and quality of life. PWH with inhibitors and older PWH may be especially vulnerable to progressive arthropathy and resulting chronic pain. The development of chronic pain from acute pain involves a complex interplay of biological and psychosocial factors that may all contribute to the perpetuation of chronic pain and the outcome of therapy. In the absence of evidence-based guidelines, an individualized, multimodal approach to chronic pain management is proposed, as it is in individuals without haemophilia who have chronic pain. Pharmacological treatment is central to the management of chronic pain and must be modified based on pain intensity, ongoing response to therapy and the risk for adverse events. Non-pharmacological interventions, including physiotherapy, complementary treatments and surgical (e.g. orthopaedic) or other invasive procedures, may be integral to chronic pain management in this population. Ongoing psychosocial assessment is critical to identify those factors that may be contributing to the perpetuation of chronic pain or acting as barriers to effective management. Additional study is needed to identify optimal pharmacological treatments for chronic pain in PWH based on the unique pathophysiology of haemophilic arthropathy and on risk profile. Systematic determination of the particular psychosocial factors impacting the experience and management of chronic pain in PWH would likewise add value to the treatment of this pervasive problem.

Better adherence to prescribed treatment regimen is related to less chronic pain among adolescents and young adults with moderate or severe haemophilia.

Abstract: Little data exist, especially for adolescent and young adult (AYA) persons with haemophilia (PWH), about the relationship between adherence to prescribed treatment regimen and chronic pain. We examined this relationship among PWH (moderate or severe) aged 13-25 via cross-sectional survey. Adherence was assessed using the Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS)-Pro and VERITAS-PRN for prophylactic and on-demand participants respectively. VERITAS scores range from 24 (most adherent) to 120 (least adherent). Chronic pain was measured using the FPS-R and was dichotomized as high for FPS-R scores ≥4 and low for 4 times as likely as whites to report high chronic pain.

Cardiovascular comorbidities are increased in US patients with haemophilia A: a retrospective database analysis

Abstract: There is conflicting evidence in the literature on whether individuals with haemophilia in the USA have greater, reduced, or similar risks for cardiovascular disease as the general population. This study evaluated the prevalence of cardiovascular comorbidities among USA males with haemophilia A, relative to an unaffected general male population with similar characteristics. Males with haemophilia A and continuous insurance coverage were identified by ICD-9-CM code 286.0 (1 January 2007-31 December 2009) using the MarketScan Commercial and Medicare Research Databases. Individuals with haemophilia A were exact matched 1:3 with males without a diagnosis of haemophilia A. The prevalence of cardiovascular comorbidities identified by ICD-9-CM code was determined for matched cohorts. Of the study population, 2506 were grouped in the haemophilia A cohort and 7518 in the general cohort. Proportions of individuals with haemorrhagic stroke (2.0% vs. 0.5%, P < 0.001), ischemic stroke (4.7% vs. 2.7%, P < 0.001), coronary artery disease (10.7% vs. 5.8%, P < 0.001), myocardial infarction (0.8% vs. 0.3%, P = 0.003), hypertension (22.6% vs. 15.5%, P < 0.001), hyperlipidaemia (15.9% vs. 11.9%, P < 0.001), arterial thrombosis (12.1% vs. 5.9%, P < 0.001), and venous thrombosis (4.4% vs. 1.1%, P < 0.001) were significantly greater for the haemophilia A cohort. Results were consistent across most age groups, and comorbidities appeared at an earlier age in those with haemophilia A than in the general population. Among the USA haemophilia A population cardiovascular comorbidities are more prevalent and they appear earlier in life in comparison to the general male population, suggesting the need for earlier, enhanced screening for age-related comorbidities in the haemophilia community.

Monitoring of modified factor VIII and IX products

Abstract: The dawning era of novel recombinant factor VIII and factor IX concentrates, many of which have been bioengineered to achieve prolonged activity, brings with it the need to consider the most appropriate clinical laboratory approaches for potency assignment, as well as the measurement of postinfusion levels. This session will highlight the known limitations and inconsistencies between existing assay methodologies with respect to currently available products, and discuss some of the early data with respect to the novel agents.

Comparison of ultrasound and magnetic resonance imaging for diagnosis and follow-up of joint lesions in patients with haemophilia.

Abstract: Haematomas and recurrent haemarthroses are a common problem in haemophilia patients from early age. Early diagnosis is critical in preventing haemophilic arthritis, and recent years have seen excellent advances in musculoskeletal ultrasound as a diagnostic tool in soft tissue lesions. In this study, we compared the results of ultrasound imaging for the diagnosis of musculoskeletal injuries in haemophilia patients with scores obtained using magnetic resonance (MRI) scans. A total of 61 haemophilia patients aged 4-82 years were included in this study. Both knees and ankles of each patient were assessed using the Gilbert (clinical assessment) and Pettersson scores (X-ray assessment). Patients with severe haemophilia (n = 30) were examined using ultrasound and MRI (Denver scoring system). Results obtained with ultrasound and MRI in severe patients were correlated using the Pearson test. In patients with severe haemophilia, normal joints were similarly assessed with MRI and ultrasound (κ = 1.000). By component of joint assessment, haemarthrosis was similarly diagnosed with both techniques in all joints (κ = 1.000). A good positive correlation was found between these techniques in detecting and locating synovial hyperplasia (κ = 0.839-1.000, knees and ankles respectively), and erosion of margins (κ = 0.850-1.000). The presence of bone cysts or cartilage loss was better detected with MRI (κ = 0.643-0.552 for knees and ankles, and κ = 0.643-0.462 respectively). Ultrasound is useful in detecting joint bleeds, synovial hyperplasia and joint erosions, with results comparable to those of MRI. A quick and affordable technique, ultrasound imaging may be useful for monitoring joint bleeds and structure normalization and maintenance in routine practice.

Novel products for haemostasis - current status.

Abstract: Summary Currently, new clotting factor concentrates are becoming available or are in advanced clinical studies that will significantly improve the treatment of patients with Haemophilia A or Haemophilia B. Various technologies are applied to extend half-life and/or allow for alternative routes of administration, e.g. subcutaneous route. Today, the advances for recombinant factor IX are significantly with half-life extensions to up to 100 h, allowing substitution intervals of 1–2 weeks. For recombinant factor VIII (FVIII) products the effect so far is only moderate, as the half-life extension is limited to about 15–18 h by the clearance of FVIII through its binding to von Willebrand factor. However, novel products applying new technologies with significantly extended half-life are already at the horizont, as a bispecific antibody that mimics FVIII. The pharmacokinetic improvements of the new products will lead to a revision of our current treatment regimens, with regard to intended trough levels, number of tolerated bleeds and likely will drive a greater individualization of regimens. Clearly, the potential of anti drug antibody response for these modified proteins must not be higher than with our current products. Another challenge are the increasingly diverse biochemical characteristics of the new products, that have to be considered when determining potencies and also when monitoring treatment in patients with the various available assays. Despite these challenges, the new products will significantly improve treatment and quality of life for our patients with haemophilia.

Self-monitoring has potential for home exercise programmes in patients with haemophilia

Abstract: Haemophiliacs who have had to keep a physically inactive lifestyle due to bleeding during childhood are likely to have little motivation for exercise. The purpose of this study is to clarify the effectiveness of the self-monitoring of home exercise for haemophiliacs. A randomized controlled trial was conducted with intervention over 8 weeks at four hospitals in Japan. Subjects included 32 male outpatients aged 26-64 years without an inhibitor who were randomly allocated to a self-monitoring group and a control group. Individual exercise guidance with physical activity for improvement of their knee functions was given to both groups. The self-monitoring materials included an activity monitor and a feedback system so that the self-monitoring group could send feedback via the Internet and cellular phone. The self-monitoring was performed by checking exercise adherence and physical activity levels, bleeding history and injection of a coagulation factor. Both groups showed significant improvements in exercise adherence (P < 0.001) and physical function such as the strength of knee extension (P < 0.001), range of knee extension (P < 0.001), range of ankle dorsiflexion (P < 0.01), a modified Functional Reach (P < 0.05) and 10 metre gait time (P < 0.01). In particular, improvements in exercise adherence (P < 0.05), self-efficacy (P < 0.05), and strength of knee extension (P < 0.05) were significant in the self-monitoring group compared with those in the control group. No increase in bleeding frequency and pain scale was noted. The self-monitoring of home exercise for haemophilic patients is useful for the improvement of exercise adherence, self-efficacy and knee extension strength.

Haemophilia Experiences, Results and Opportunities (HERO) Study: Influence of haemophilia on interpersonal relationships as reported by adults with haemophilia and parents of children with haemophilia

Abstract: Evidence delineating the effects of haemophilia on interpersonal relationships is sparse and largely outdated, failing to reflect the impact of current treatment strategies. HERO (Haemophilia Experiences, Results and Opportunities) was commenced to garner a more comprehensive understanding of psychosocial issues facing persons with haemophilia (PWH). This article describes the findings of the quantitative HERO survey relating to the influence of haemophilia on interpersonal relationships of adult PWH, and parents/caregivers of children with haemophilia. Separate questionnaires were completed by adult PWH and parents of minor children from 10 countries, including satisfaction with support from partners, family, friends and other social contacts; disclosure of haemophilia and carrier status and family dynamics. A total of 675 PWH and 561 parents completed the survey. Over half of PWH (57%) and parents (84%) were married. Most PWH were satisfied with support from partners (94%), family (90%) and friends (85%), with lower percentages reported among those with inhibitors. Most parents were likewise satisfied with support from partners (88%) and family (83%). Whereas PWH were reticent to disclose their diagnosis beyond family and friends, parents were more likely to share their son's diagnosis, and most were satisfied with the support from their son's peers (74%), teachers (83%) and other adults in supervisory roles (85%). PWH and parents surveyed were satisfied overall with the support they received from partners, family, friends and social contacts. Relationships are affected by haemophilia in various ways, and particularly affected in terms of disease burden, age and social life.

Bone density in haemophilia: a single institutional cross-sectional study.

Abstract: Haemophilia has been associated with low bone mineral density (BMD). However, prior clinical studies of this population have neither clearly elucidated risk factors for development of low BMD nor identified who may warrant screening for osteoporosis. The aim of the study was to evaluate the relationship between BMD and haemophilic arthropathy and other demographic and clinical variables. We undertook a cross-sectional study of BMD in adult men with haemophilia. Measures of predictor variables were collected by radiographic studies, physical examination, patient questionnaires and review of medical records. Among 88 enrolled subjects, the median age was 41 years (IQR: 20); median femoral neck BMD (n = 87) was 0.90 g cm(-2) (IQR: 0.24); and median radiographic joint score was 7.5 (IQR: 18). Among subjects <50 years (n = 62), after controlling for BMI, alcohol, HIV and White race, BMD decreased as radiographic joint score increased (est. β = -0.006 mg cm(-2) ; 95% CI -0.009, -0.003; partial R(2) = 0.23). Among subjects ≥50 years (n = 26), 38% had osteoporosis (T score less than or equal to -2.5) and there was no association between BMD and arthropathy. Risk factors for low BMD in men with haemophilia <50 years include haemophilic arthropathy, low or normal BMI and HIV. Men with haemophilia over age 50 years should have routine screening for detection of osteoporosis.

Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B.

Abstract: BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC(0-72) h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg(-1) per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.

Diagnosis and management challenges in patients with mild haemophilia A and discrepant FVIII measurements.

Abstract: Thirty per cent of patients with mild haemophilia A (MHA) present markedly different FVIII: C level when assayed by one-stage clotting and two-stage chromogenic assays. It is, therefore, a real clinical challenge to predict the individual bleeding risk of these patients. The aim of the present work was to study the relationship between the bleeding tendency of these patients with the results of a panel of phenotypic and genotypic tools. Thirty-six patients with MHA were included in this multicentre prospective clinical study. The severity of bleeding symptoms was evaluated using the ISTH/SSC score. FVIII:C levels were measured using an activated partial thromboplastin time-based one-stage FVIII assay (FVIII: C1) and three commercial chromogenic kits (FVIII:CR). FVIII antigen levels, thrombin generation measurement and FVIII gene mutation analysis were also performed. Our results showed that a one-stage FVIII: C assay cannot rule out the diagnosis of MHA, a combined use of FVIII:C1 with a FVIII:CR is suitable for detecting MHA. We observed that FVIII:CR results better reflected the clinical bleeding tendency of patients compared to FVIII:C1. We also observed a relationship between thrombin generation (TG) capacity and FVIII:CR of these patients. FVIII gene mutation analysis showed mutations previously reported in MHA patients with discrepant FVIII:C measurements, but with no predictive value of the individual bleeding phenotype of patients. Overall, we observed a relationship between chromogenic FVIII:C results, TG assay and bleeding tendency of patients with discrepant FVIII:C measurements, while FVIII:C1 was not well correlated with clinical bleeding phenotype in this particular population.

Assessment of the impact of treatment on quality of life of patients with haemophilia A at different ages: insights from two clinical trials on turoctocog alfa.

Abstract: Haemophilia and its treatment interfere with patients' life, so health-related quality of life (HRQoL) should be assessed when evaluating treatments. This study investigated the HRQoL of patients with haemophilia A treated prophylactically with a new recombinant factor VIII. Two phase 3 trials investigated turoctocog alfa in patients with severe haemophilia A: one in children, one in adults and adolescents. HRQoL was a secondary endpoint assessed by the HAEMO-QOL age-specific, self-administered questionnaires. Parent-completed versions were also included for parents of children and adolescents. All HAEMO-QOL questionnaires allow the calculation of domain-specific and total scores ranging from 0 to 100, lower scores indicating better HRQoL. Mean change in all scores was described for 25 children aged 4–7 years, 21 children aged 8–12 years, 18 adolescents aged 13–18 years and 129 adults, overall, and according to the treatment regimen received prior to the study (on-demand; prophylaxis; mixed). Mean changes in HAEMO-QOL total score were 1.4 for children aged 4–7 years, −2.6 for children aged 8–12 years, −5.8 for adolescents and −1.6 for adults. In parent-completed versions, mean changes in total score were −6.0 for children aged 4–7 years, −4.7 for children aged 8–12 years, and −10.0 for adolescents. Patients receiving on-demand treatment before the trial showed greater improvement in HRQoL scores than patients already on prophylaxis. HRQoL of patients remained fairly stable over the course of the trials. However, improvements were observed for adolescents. Switching to prophylaxis was identified as a potential driver of improvement of HRQoL in patients with haemophilia A.

FXI concentrate use and risk of thrombosis

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