Fifth Åland Island conference on von Willebrand disease.

The fifth Åland Island meeting on von Willebrand disease (VWD) was held on the Åland Islands, Finland, from 22 to 24 September 2016-90 years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926. This meeting brought together experts in the field of VWD to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of von Willebrand factor (VWF), epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis and VWF inhibitors.

The evolution of comprehensive haemophilia care in the United States: perspectives from the frontline.

The establishment of dedicated comprehensive treatment centres more than a half century ago transformed the management of haemophilia in the United States. Formerly, a disease associated with crippling disability and premature death, today, persons with haemophilia who are treated appropriately from infancy and do not develop inhibitors can expect a normal life expectancy and relatively few bleeding episodes. The evolution of the comprehensive haemophilia care, while chastened by the viral epidemics of the 1980s, has been marked by ongoing advances, including prophylaxis, immune tolerance induction, new drugs and gene therapy research. Current challenges include sustaining the comprehensive care model despite decreased funding and expanding the delivery and affordability of comprehensive haemophilia care.

The EPIC study: a lesson to learn.

INTRODUCTION: Inhibitory antibodies to factor VIII occur in about 30% of previously untreated patients (PUPs) and are the most serious complication of haemophilia A. It is unclear why some patients develop inhibitors and others do not. AIMS: The Early Prophylaxis Immunologic Challenge (EPIC) study was designed to test the hypothesis that inhibitor incidence in PUPs with severe or moderately severe haemophilia A could be reduced when a once-weekly FVIII prophylaxis starts with 25 IU kg(-1) rAHF-PFM before 1 year of age and immunological danger signals are minimized. METHODS: These signals were minimized by avoiding: surgery; the first FVIII infusion during severe bleeding or an infection; central venous access devices and administering vaccinations intramuscularly 3-4 days before or after FVIII. RESULTS: Eight of the 19 treated subjects (42.1%) developed confirmed inhibitors. Eleven of the 19 treated subjects were PUPs without any prior exposure to FVIII. Three of them (27.3%) developed a confirmed inhibitor together with FVIII-binding antibodies. The study was stopped because the likelihood to reach the primary objective was minimal, a decision endorsed by the data safety monitoring board. CONCLUSION: Because of early termination, the EPIC study hypothesis could not be corroborated. Nonetheless, our data analyses indicate that the current definition of an inhibitor only based on plasma inhibitor activity ≥0.6 BU mL(-1) may not always reflect the presence of FVIII-neutralizing antibodies. The findings of this study teach us that low-level inhibitor activity results need in addition a confirmatory test and/or the assessment of the therapeutic response.

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

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.

Tertiary prophylaxis in adults: is there a rationale?

There is lack of evidence-based recommendations or clear-cut consensus regarding the clinical and economic utility of regular prophylaxis started in adulthood, with the aim of keeping the clinical situation from getting worse by prevention of further bleeds contributing to increasing musculo-skeletal or other morbidity in haemophilia. Such a prophylaxis program has been shown in relatively small cohorts to be effective in reducing bleeding occurrence, with a variable effect on the joint status, but with significantly higher factor consumption and consequently higher costs than on-demand therapy. There has been no attempt to identify subsets of patients who may benefit from "tertiary" prophylaxis more than others, for example, due to their bleeding phenotype and/or requirements for product issued on-demand or to identify the dosage that provides the optimal balance of clinical benefit and cost effectiveness. This article reviews the published literature on prophylaxis started beyond the age of 18 years, the barriers to the uptake of prophylaxis programs particularly in adults and highlights areas in need of further research.

Why should we care about quality of life in persons with haemophilia?

The very high cost of haemophilia care, including the increase in use of factor prophylaxis in both children and adults requires that funders of clotting factor concentrates require objective measures of health, such as joint status and quality of life (QOL). Many clinical trials, especially those for licensing of new products, are including QOL instruments in their protocols to evaluate the patients' perspective of wellbeing before and during therapy. This article gives a perspective on QOL the importance of QOL measurement in the field of haemophilia and its impact on patient outcome.

Another role for the VW molecule.

My comments on the implication of the vW molecule in down-regulating the immunogenicity of factor VIII.

The use of a single von Willebrand factor-containing, plasma-derived FVIII product in hemophilia A immune tolerance induction: the US experience.

BACKGROUND: Inhibitors are a serious complication for patients with severe hemophilia A. Immune tolerance induction (ITI) is the primary method for eradicating these inhibitors. The role of type of concentrate and in particular the use of von Willebrand factor-containing, plasma-derived factor VIII (VWF/pd-FVIII) concentrate in primary or rescue ITI remains unclear. OBJECTIVES: To report retrospective collection of data on the use of a single VWF/pd-FVIII concentrate in primary and rescue ITI. METHODS: Retrospective chart review of hemophilia A inhibitor patients at 11 US institutions who received VWF/pd-FVIII concentrate in primary or rescue ITI. RESULTS: Primary ITI was carried out in eight inhibitor patients with a 75% complete and partial success. Secondary ITI was carried out in 25 inhibitor patients, with 52% attaining complete or partial success. CONCLUSIONS: This report represents the largest group of primarily pediatric, high-titer inhibitor patients treated with a single VWF/pd-FVIII concentrate. It adds retrospective data to the use of VWF-containing plasma-derived factor VIII concentrate in primary and rescue ITI, particularly in those patients with characteristics of poor response to ITI.

Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies.

BACKGROUND: As a result of the infrequency of inhibitors in previously treated patients (PTPs) with hemophilia A and the small size of available clinical studies, the immunogenicity of factor (F)VIII products has been difficult to assess. OBJECTIVES: A meta-analysis of prospective clinical studies was conducted to test the hypothesis that de novo inhibitor incidence differs between PTPs receiving full-length recombinant FVIII (FL-rFVIII) and B-domain deleted recombinant FVIII (BDD-rFVIII). METHODS: Prospective studies with data on inhibitors in PTPs receiving FL-rFVIII or BDD-rFVIII were sought using systematic methods including bibliographic database searches. Data were secured from published study reports and inquiries to investigators. Between-group differences in inhibitor incidence rates were evaluated using mixed effects Cox regression. RESULTS: Twenty-nine studies with 3012 total PTPs were included. Patients were at risk of de novo inhibitor development for a median of 79 exposure days. A total of 35 de novo inhibitors were observed. The cumulative hazard for all de novo inhibitors was 1.25% with a 95% confidence interval (CI) of 0.63-1.88%. The corresponding rate for high-titer de novo inhibitors [> 5 Bethesda units (BU)] was 0.29% (CI, 0.01-0.57%). Exposure to BDD-rFVIII was associated with an increased risk of all de novo inhibitors (hazard ratio, 7.26; CI, 2.12-24.9; P = 0.0016) and of high-titer de novo inhibitors (hazard ratio, 10.8; CI, 2.17-53.7; P = 0.0037), compared with FL-rFVIII. CONCLUSIONS: This meta-analysis of prospective clinical studies suggests that recombinant FVIII products may differ in immunogenicity.

Sexual evaluation and treatment of ageing males with haemophilia.

Sexual dysfunction is common in ageing men and may be exacerbated by the special medical issues and psychological problems associated with haemophilia. Sexual healthcare for men with haemophilia (MWH) requires a background understanding of common patterns of sexual function and dysfunction in the ageing male, expectable sexual complications of haemophilia and related comorbidities, and of sexually related psychological issues. Healthcare providers who treat MWH must be able to elicit a sexual history sufficient to differentiate problems involving a loss of sexual desire from ejaculatory difficulties and erectile dysfunction (ED). Other necessary skills include evaluating patients with ED for treatable causes, distinguishing organic from psychogenic ED, using phosphodieterase-5 inhibitors as first-line treatment for ED, and referring to specialized sexual urology and mental health professionals when appropriate.

Harmonization of clinical trial guidelines for assessing the risk of inhibitor development in hemophilia A treatment.

At the present time, the most significant complication of hemophilia therapy is the development of neutralizing antibodies (inhibitors) to factor (F) VIII, which adds greatly to the difficulty and expense of preventing and treating bleeding episodes. Both patient-related and therapy-related variables contribute to the development of inhibitors. The multifactorial nature of inhibitor development and the relatively small numbers of patients that participate in clinical trials make it difficult to accurately assess the risk of inhibitor development. Adding to that challenge is the lack of a uniform standard of design for conducting clinical trials to evaluate the safety of FVIII products. This hinders the comparison of products and is an obstacle to the meta-analysis necessary to make statistically valid assessments of inhibitor risk. This article reviews similarities and differences in clinical trial guidelines of European and US regulatory agencies and discusses the need for their harmonization to facilitate the assessment of FVIII products.