The need for speed in the management of haemophilia patients with inhibitors.

Rapid control of bleeding is the key to reducing bleeding complications and thereby preserving joint and musculoskeletal function in haemophilia patients with inhibitors. However, this requires early diagnosis following the onset of bleeding and strategies for rapid treatment in an outpatient setting. Overarching themes on the need for speed in managing bleeds in haemophilia patients were examined by a panel of clinicians experienced in managing inhibitor patients and joint disease during the Third Zürich Haemophilia Forum on 8 May 2009. This report summarizes the opinions of the panel on how to achieve rapid bleeding control in inhibitor patients and areas that were identified by the panel for future research or as needing new consensus guidelines. The consensus was that home treatment should be established for haemophilia patients with inhibitors, as it is associated with a faster time to treatment, as well as improvements in the quality of life of patients and their carers. In addition, as improved haemostatic control now allows inhibitor patients to participate in a wider range of physical activities, specific guidelines are required on which types of sport and work are appropriate. It was agreed that clear, systematic approaches are needed for early diagnosis of joint and muscle bleeds in inhibitor patients, which could facilitate rapid treatment. There may be opportunities for exploiting new diagnostic techniques from osteoarthritis to enable earlier diagnosis of haemophilic arthropathy. Overall, it was concluded that greater emphasis should be placed on education and patients' psychological needs, to enable inhibitor patients to cope up more effectively with their disease.

The role of prophylaxis in bleeding disorders.

SUMMARY: The rationale for long-term prophylaxis in more severe forms of von Willebrand's disease (VWD) is obvious, as mucosal bleeding and haemophilia-like joint bleeds resulting in chronic morbidity may occur. However, the experience with prophylactic treatment in this group is scanty. An international VWD Prophylaxis Network (VWD PN) was established in 2006. The VWD PN will investigate prophylaxis with retrospective and prospective studies. Eighteen centres in Europe and North America are recruiting patients and an additional 40 centres are preparing for or evaluating participation. In the absence of randomized prospective studies for most rare bleeding disorders, guidelines for prophylaxis are a subject of controversy. In situations where there is a strong family history of bleeding, long-term prophylaxis is administered in selected cases. Short intervals of prophylaxis can also be given before some surgeries or during pregnancy. The benefits of prophylaxis must be balanced by the risk of side effects. Therefore, it is essential to delineate its management in a specialized comprehensive care environment. In haemophilia, decades of clinical experience and numerous retrospective and, recently, prospective studies clearly demonstrate that prophylactic treatment is superior to on-demand treatment, regardless of whether the outcome is the number of joint- or life-threatening bleeds, arthropathy evaluated by X-ray or MRI, or quality of life measured by generic or haemophilia-specific instruments. Optimal prophylactic treatment should be started early in life (primary prophylaxis) but various options exist for the dose and dose interval. These depend on the objective of treatment in the individual patient, which, in turn, is dependent on resources in the health care system.

Paediatric haemophilia with inhibitors: existing management options, treatment gaps and unmet needs.

Development of inhibitors is a severe complication of haemophilia posing many management challenges. While a long-term goal in inhibitor patients is eradication of inhibitors through immune tolerance induction, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are essential for control of bleeding episodes. Paediatric patients with haemophilia and inhibitors are at particular risk of recurrent haemarthroses, and management of these patients should seek to avoid joint damage and support the child's full social and physical development. Current options for management of bleeding complications include on-demand treatment of acute bleeding episodes, secondary prophylaxis to avoid recurrent bleeds and surgery to treat affected joints. There is also a rationale for adopting prophylactic approaches to prevent bleeding in inhibitor patients, allowing this group similar opportunities for protection against arthropathy development as are given to non-inhibitor patients. This paper, based on a roundtable meeting of haematology experts at the first Zürich Haemophilia Forum in May 2008, reviews the current evidence supporting more intense and prophylactic approaches to manage bleeding risk in paediatric haemophilia patients with inhibitors, and highlights the need for investigations of primary prophylaxis in this vulnerable patient group, to support best long-term outcome.

Why does the mutation G17736A/Val107Val (silent) in the F9 gene cause mild haemophilia B in five Swedish families?

The mutation G17736A/Val107Val (silent) was found in five of a total of 86 families with haemophilia B in Sweden. It is unlikely that five families with analogous clinical expression will have the same polymorphism, which is not found in other patients or normal subjects, or that they will be the only families in the population without any other causative mutation. All affected individuals in the five families were found to have factor IX (F9) coagulation activity 15-20 U dL(-1), corresponding F9 protein levels and the same clinical history of mild haemophilia. Lymphocyte mRNA was extracted from one of the haemophiliacs and from a healthy male. RT-PCR of the mRNA and subsequent PCR amplification produced cDNA fragments of the same length from the patient and the normal subject, indicating no exon skipping or retention of introns. Sequencing of cDNA from codon 68 in exon D to codon 180 in exon F revealed that the patient had the G17736A mutation but no other abnormalities. We conclude that G17736A/Val107Val causes mild haemophilia B. Although, exon skipping and retention of introns can be excluded as pathophysiological mechanisms, it is plausible that the studied mutation has more subtle effects on a splicing site or interferes with a splicing enhancer site. Also, changes to synonymous codons may reduce the translation rate and thereby alter F9 protein folding in vivo, which would explain the phenotype. Confirmation of these assumptions requires methods that are more sensitive than those available today, and our discussion illustrates the existing obstacles.

Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors.

Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 microg kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.

Functional analysis of the EGF-like domain mutations Pro55Ser and Pro55Leu, which cause mild hemophilia B.

We studied the functional role of two mutations, Pro55Ser and Pro55Leu, located in the N-terminal Epidermal Growth Factor-like domain (EGF1) of coagulation factor (F) IX. Both mutations cause mild hemophilia B with habitual FIX coagulant activities of 10-12% and FIX antigen levels of 50%. We found that activation by FVIIa/TF and FXIa was normal for FIXPro55Ser, but resulted in proteolysis of FIXPro55Leu at Arg318-Ser319 with a concomitant loss of amidolytic activity, suggesting intramolecular communication between EGF1 and the serine protease domain in FIX. This was further supported by experiments using an anti-EGF1 monoclonal antibody. Activation of FX by FIXaPro55Ser was impaired in both the presence and the absence of phospholipid or FVIIIa, indicating that Pro55 is not directly involved in binding to FVIIIa. We also studied the effect of the two Pro55 mutations on Ca2+ affinity and found only small changes. Thus, the Pro55Ser mutation causes hemophilia primarily through to an impaired ability to activate FX whereas at least in vitro the Pro55Leu defect interferes with the activation of FIX.

Inhibitors in the Swedish population with severe haemophilia A and B: a 20-year survey.

AIM: To survey the entire population (n = 116) afflicted with severe haemophilia A or B born in Sweden over a 20-y period (1980-1999), and to examine the epidemiological, genetic and clinical aspects of development of inhibitors to factors VIII and IX (FVIII/FIX). METHODS: One hundred of the subjects had haemophilia A and 16 had haemophilia B. All of these subjects had received prophylactic treatment and had a check-up of inhibitor status at least twice a year. Sixty-one were born between 1980 and 1989 and 55 between 1990 and 1999. RESULTS: Nineteen percent (19/100) of those with haemophilia A and 37% (6/16) with haemophilia B developed inhibitors at 12-18 mo of age, after exposure to FVIII/FIX concentrates for an average of 14 d in the case of haemophilia A and 16 d in haemophilia B. All patients with inhibitors carried mutations that impaired protein synthesis. The high incidence of FIX inhibitors may have been due to the large number of complete deletions (13%) in the Swedish haemophilia B population. Patients with haemophilia A showed no significant increase (p = 0.65) in incidence of inhibitors (n = 10/48, total incidence 21%) in the 1990s, when they were treated mainly with recombinant products, as compared to the 1980s (n = 9/52, 17%), when they received intermediate/high-purity plasma-derived concentrates. CONCLUSION: Our population-based study verifies that genotype has a general impact on the incidence of FVIII/FIX inhibitors, and that recombinant FIII/FIX concentrates are not a predisposing factor for inhibitor development.

Breastfeeding does not influence the development of inhibitors in haemophilia.

Our aim was to test the hypothesis that breastfeeding may reduce development of inhibitors in male infants with haemophilia by inducing an oral immune tolerance to factor VIII. To achieve that goal, we performed a structured epidemiological survey comprising all males born with severe haemophilia A (in all 100 patients, 19 with inhibitors) or haemophilia B (in all 16 patients, six with inhibitors) in Sweden in 1980-99. Our results show no protective effect of breastfeeding.

Aspects of haemophilia prophylaxis in Sweden.

Prophylactic treatment of haemophilia has been gaining acceptance as the optimal therapeutic option in an increasing number of haemophilia centres in the developed world in recent years. This paper focus on three aspects of prophylactic therapy: when to start treatment, venous access and the dose/dose interval. Evidence is in favour of prophylactic treatment to be started at an early age using either a peripheral vein with 1-2 injections per week and a successive increase in the frequency depending on the child and the veins, or, using a Port-A-Cath which allows a better prophylactic coverage by infusions preferably every second day in haemophilia A and every third day in haemophilia B.