Hemophilia A and B: An Overview

TREATMENT OF ACUTE BLEEDS IN PATIENTS WITH FACTOR IX INHIBITORS

rFVIIa and FEIBA are the mainstays of treatment of bleeding episodes in individuals with hemophilia B complicated by an inhibitor to factor IX. Treatment of hemorrhagic episodes in these patients depends on the type of bleeding episode experienced, the inhibitor classification (high- versus low-responding [Table 4]), and the history and severity of infusion reactions. Patients with low-responding inhibitors who have not experienced infusion reactions may be treated with doses of factor IX concentrate calculated to overcome the inhibitor titer and achieve a hemostatic level. In patients with high-responding inhibitors, the use of factor IX concentrates is impractical because of the inhibitor titer or the anamnestic response. Regardless of inhibitor titer, in patients with a history of an anaphylactic event, factor IX usage is contraindicated.

The most commonly used therapy for hemostatic control in patients with high-responding inhibitors with factor IX deficiency and a history of infusion reaction is rFVIIa; the standard dosing regimen is 90 to 120 µg/kg/dose administered every 2 to 3 hours, with a maximum dose of 270 µg/kg/dose. aPCCs, which contain factor IX, can be utilized if the patient has not experienced prior infusion reactions. Repeated exposures to products containing factor IX may stimulate the inhibitor titer and prevent its natural decline over time. This can pose a problem in cases of life- or limb-threatening hemorrhage unresponsive to rFVIIa as these patients will not have factor IX available as an effective mode of therapy. The dosing of FEIBA ranges from 50 to 100 IU/kg every 12 hours, with daily dosing not to exceed 200 IU/kg.

IMMUNE TOLERANCE INDUCTION

Because of the associated inhibitor-related morbidity resulting from limited treatment options, antibody eradication is the ultimate goal in inhibitor management. The only proven strategy for achieving antigen-specific tolerance to factor VIII or factor IX is immune tolerance induction (ITI) therapy. Successful ITI in hemophilia A is currently defined as both an undetectable inhibitor titer (< 0.6 BU), and normalized factor VIII pharmacokinetics, which in turn is defined as plasma factor VIII recovery > 66% of expected and a half-life > 6 hours, determined following a 72-hour factor VIII exposure-free period (Consensus Proceedings from the Second International Conference on Immune Tolerance Therapy, Bonn, Germany, 1997 [unpublished]). Once successful immune tolerance is achieved, long-term prophylaxis is commonly instituted. Using conclusions drawn from international consensus criteria and analysis of the International Immune Tolerance Registry, the I-ITI study has defined ITI failure by the presence of either of 2 criteria:

1. Failure to attain the definition of success within 33 months of uninterrupted ITI;

2. Failure to demonstrate a progressive 20% reduction in inhibitor titer over each 6-month period of uninterrupted ITI, beginning 3 months after initiation to allow for expected anamnesis.^76–78

This definition implies a minimum ITI trial period of 9 months before failure is declared.

The European Hemophilia Standardization Board (EHSB), the International Consensus Panel (ICP), and the United Kingdom Hemophilia Center Doctors’ Organization (UKHCDO) have agreed that it is preferable to initiate ITI at a titer of < 10 BU/mL, unless, per the ICP, the titer does not decline over a period of 1 to 2 years and/or inhibitor development is associated with severe or life-threatening bleeding. The ICP noted that for “poor-risk” ITI patients (defined by a historical titer of > 200 BU/mL and/or a pre-ITI inhibitor titer of > 10 BU/mL and/or an interval of > 5 years since inhibitor diagnosis), published efficacy data are limited to dosing regimens > 200 IU/kg/day. The groups all independently concluded that ITI has been successfully performed using recombinant and plasma-derived factor VIII replacement therapy (usually the product on which they developed the inhibitor), and that there are no data to support the superiority of any single product type.^79–81 However, both EHSB and ICP have suggested that VWF-containing concentrates be considered for patients who fail ITI using high-purity factor VIII.^79,80

The recommendations from US guidelines for ITI in patients with hemophilia A and inhibitors are listed in Table 5.⁸²