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.

Another role for the VW molecule.

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

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.

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.

Optimizing the treatment of haemophilia B: laboratory and clinical perspectives.

Hemophilia A and B are traditionally thought of as a single bleeding disorder, viewed as opposite sides of the same coin. Yet the differences between the 2 forms of congenital hemophilia extend far beyond the type of deficient clotting factor--factor VIII for hemophilia A and factor IX (FIX) for hemophilia B. This supplement focuses on the unique laboratory and clinical issues associated with FIX replacement therapy for children and adults with hemophilia B.

Emerging clinical concerns in the ageing haemophilia patient.

The availability of safe replacement clotting factor concentrates together with effective antiviral drugs to treat human immunodeficiency and hepatitis C viruses and the provision of care at designated haemophilia treatment centres have resulted in a new phenomenon in haemophilia management - the ageing patient. Today, increasing numbers of persons with haemophilia (PWH) are middle-aged and older, and they face the same age-related health issues as the general population. The impact of these risks on PWH is unclear, however, and there is a paucity of information about how to manage comorbidities in this patient population. This review focuses on five comorbidities that uniquely affect older PWH: cardiovascular disease, liver disease, cancer, renal disease and joint disease. Available research is summarized and potential management approaches are suggested.

Factor VIII inhibitor bypassing activity (FEIBA) - addressing safety issues.

Bypassing therapy is usually necessary to control or prevent bleeding episodes in patients with haemophilia A or B and high-titre inhibitors. Factor VIII inhibitor bypassing activity (FEIBA) has a long history of successful use in the acute, surgical and prophylactic treatment settings, but safety concerns have made some reluctant to administer this bypassing agent. A review of the literature and clinical trial data show that FEIBA has a low prevalence of thrombosis, a low prevalence of anamnesis that does not impact haemostatic efficacy and an excellent record of pathogen safety and clinical tolerability.

Efficacy of factor VIII/von Willebrand factor concentrate Alphanate in preventing excessive bleeding during surgery in subjects with von Willebrand disease.

The adequacy of perioperative haemostasis with a high-purity, plasma-derived factor VIII product containing von Willebrand factor was retrospectively evaluated in 39 patients with type 1, 2 or 3 von Willebrand disease who underwent 61 major or minor surgical or invasive procedures. Overall, 93.5% of the responses to treatment were rated as excellent or good by the physician investigators. These ratings were confirmed by an independent panel of physician referees.

The effect of salicylates on the hemostatic properties of platelets in man.

Ingestion of 1.5 g of aspirin, but not of sodium salicylate, produced a significant prolongation of the bleeding time in six normal male subjects when compared with the effects of a placebo. Similar differences in the effect of the two drugs on platelets was also observed. Aspirin ingestion resulted in impaired platelet aggregation by connective tissue and was associated with a decreased release of platelet adenosine diphosphate (ADP); sodium salicylate had no effect on these values. In vitro, incubation of platelet-rich plasma with an optimum aspirin concentration of 0.50 mmole/liter (0.045 mg/ml) inhibited both the adhesion of platelets to connective tissue and the release of ADP as well as the secondary wave of platelet aggregation produced with ADP or epinephrine; sodium salicylate had no effect on these reactions, which were also normal in patients with von Willebrand's disease. The inhibitory effect produced by ingesting a single 1.8 g dose of aspirin was detectable for 4-7 days at which time salicylate was no longer detectable in the blood, which suggested an irreversible effect on the platelet. Aspirin also inhibited the release of platelet adenosine triphosphate (ATP), but had no effect on the platelet surface charge, available platelet ATP or ADP, or the destruction of ADP by plasma ADPase. These studies lend further support to the hypothesis that ingestion of aspirin, in contrast to sodium salicylate, prolongs the bleeding time by inhibiting the release of platelet ADP, perhaps reflecting the findings in other cell systems which suggest that aspirin alters membrane permeability.

Amino acid metabolism of platelets in leukemia.

Platelets from patients with acute myelogenous leukemia, both before and after remission induction, were evaluated for their ability to incorporate D-[U-14C]glucose into the four amino acids, glutamine, asparagine, glutamic acid, and aspartic acid. Normal platelets incorporated about 80% of the activity into the amides, glutamine and asparagine, and only 20% into their respective amino acids, glutamic acid and aspartic acid. Platelets from patients with acute myelogenous leukemia in the acute stage showed a reversal of this pattern, which then returned to normal during remission. However, the concentration of amino acids was higher than normal, suggesting that remission platelets behaved like a young cell population. The abnormal pattern of labeling could be interpreted as a defect in the platelet citric acid cycle thereby compromising its energy source.