Hemophilia A and B: An Overview
In the Italian ESPRIT study, it was shown that children randomly assigned to prophylaxis had significantly fewer total bleeding episodes and joint bleeding episodes compared with those assigned to episodic therapy. Eleven of 21 patients (52%) in the prophylaxis group had on average less than 1 hemarthrosis per year, whereas only 4 of 19 patients in the episodic therapy group (21%) had the same low frequency of bleeding (P < 0.05).40 In a study of long-term prophylaxis versus on-demand treatment comparing age-matched Danish and Russian patients, the median annual number of joint bleeds in patients on prophylaxis was 1, while patients managed with on-demand treatment experienced a median of 37 joint bleeds. Patients taking prophylaxis also had a statistically significantly better quality of life estimate (P < 0.001) and better functional independence.41 In another trial, prophylaxis was initiated between the ages of 6 and 30 months based on a history of joint hemorrhage rather than age. Radiologic evidence of preserved joint architecture was found in 93% of participants in the prophylaxis group at 6 years of age. In this group, 18 of 32 (56%) children had 1 or 2 bleeds into one or more index joints before prophylaxis, and 17 (53%) had 1 to 5 hemorrhages into 1 or more index joints during prophylaxis. Prophylaxis was efficacious in decreasing bleeding and joint damage after up to 5 hemarthroses.42
Optimal Prophylactic Regimen
Although the benefits of prophylactic replacement therapy are firmly established, the optimal dose and frequency remain unclear. The half-life of clotting factor concentrates is short: about 8 hours for factor VIII in children, and about 12 hours for factor IX. As a result, prophylactic therapy is most effective when given frequently. The most common factor VIII concentrate dosing regimen for prophylaxis in hemophilia A is 25 to 40 IU/kg 3 times per week; for hemophilia B, a dose of 80 to 100 IU/kg is given twice weekly. This is aimed at a pre-infusion level > 1% to mimic the clinical phenotype of moderate hemophilia.
,Recently, the US Food and Drug Administration (FDA) approved the first long-lasting antihemophilic factor (recombinant) Fc fusion protein for use in adults and children with hemophilia A. This medication contains the Fc region of human immunoglobulin G1 (IgG1), which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation and prolonging their plasma half-life. Dosing for routine prophylaxis is 50 IU/kg every 4 days; it may be adjusted based on patient response, with dosing in the range of 25 to 65 IU/kg at 3- to 5-day intervals. More frequent or higher doses up to 80 IU/kg may be required in children younger than 6 years.43
DEVELOPMENT OF INHIBITORS
FACTOR VIII INHIBITORS
Despite the success in the clinical management of hemophilia A, treated patients remain at risk for developing neutralizing antibodies that inhibit factor VIII activity. An inhibitor is a polyclonal high-affinity IgG that is directed against the factor VIII protein and renders exogenous factor ineffective. IgG4 antibodies are predominant and do not fix complement.
Risk Factors
The pathophysiology underlying the development of factor VIII inhibitors is a T-helper (Th)–cell dependent event that involves antigen-presenting cells and B lymphocytes; why only a fraction of patients experience this adverse effect of factor therapy is not known. Patients with mild/moderate hemophilia have a lower risk for inhibitor development than those with severe hemophilia A. The estimated prevalence of inhibitors ranges from 3% to 13% in mild to moderate disease,44–46 and up to 36% in severe hemophilia A.47,48 Usually the presence of an inhibitor in patients with mild/moderate hemophilia is suggested by a change in bleeding pattern: patients who previously used to bleed only after trauma or surgery suddenly start to experience severe spontaneous bleeding. This change in bleeding pattern is explained by cross-reactivity of the inhibitor with the mutated factor VIII of the patient, resulting in a residual factor level of < 0.01 IU/dL.49–51 Occasionally, there is no change in the residual factor VIII level but an inhibitor is detected in the Bethesda assay and/or there is lack of efficacy of factor VIII trans-fusions.51–53
Genetic factors. Data indicate that the risk of developing neutralizing antibodies is to a large extent determined by patient-related genetic factors.54,55 The immune response to factor VIII is similar in up to 80% of family members, significantly higher than expected compared with data from unrelated subjects. In a meta-analysis of patients with severe hemophilia A, the inhibitor incidence was twice as high in African American patients as compared with white patients.56 One study showed that patients of Hispanic ancestry with severe hemophilia A have a higher prevalence of neutralizing inhibitors than non-Hispanic white patients.57
Type of causative mutation. In severe hemophilia A, the risk of inhibitor formation is associated with the type of mutation. More disruptive mutations in the factor VIII gene, such as the intron 22 inversion, large gene deletions, and stop codons are associated with an approximately 35% risk of inhibitor formation, compared with only about 5% in those with missense mutation and small deletions.58 Persons with mutations involving large gene deletions, nonsense mutations, and intrachromosomal aberrations are usually at higher risk for the development of inhibitors than persons with missense mutations, small deletions/insertions, and splice site mutations.59,60 A relatively high risk is also encountered in patients with splicing errors and frame-shift mutations.61
Major histocompatibility complex. The HLA class I alleles A3, B7, and C7, as well as the class II alleles DQA0102, DQB0602, and DR15 have all been associated with a slightly higher risk for inhibitor development in unrelated patients, whereas the HLA C2, DQA0103, DQB0603, and DR13 alleles might be protective.62,63
Immune-regulatory molecules. In the Malmö International Brother Study, polymorphic sites in the genes coding for interleukin 10 (IL-10), tumor necrosis factor-α, and cytotoxic T lymphocyte–associated protein 4 were all associated with the risk of developing inhibitors.64–66 In this study, a 134 bp–long variant of a CAA microsatellite in the promoter region (IL-10.G) was identified in 26.8% of patients with hemophilia A. Thirty-two of these patients (72.7%) developed inhibitors as compared with 37.5% of those without the allele.65
Intensive exposure to factor VIII. Inhibitors in mild/moderate hemophilia seem to occur more commonly later in life, and an episode of intensive treatment with factor VIII concentrate has been reported to precede detection in most reported cases. In the series reported by Hay et al,67 16 out of 26 inhibitors were detected after such intensive replacement therapy, and no particular concentrate was implicated.
