The Impact of Factor VIII/von Willebrand Factor Concentrate in Inhibitor Development and Management of Patients with Hemophilia A with Inhibitors

Abstract

The development of inhibitor antibodies that bind to active sites on the factor VIII (FVIII) molecule and neutralize its function and/or accelerate its clearance is the most serious adverse event and safety issue associated with the treatment of hemophilia A. Inhibitor development complicates hemostasis management and increases morbidity and the cost of treatment because bleeding episodes do not respond to standard replacement therapy. Risk factors for inhibitor development include genetic and non-genetic factors. Immunogenicity of the type of product used for replacement therapy may also play a role. Within the category of human-derived products, the presence of von Willebrand factor (vWF) bound to FVIII (vWF/FVIII products) may reduce its immunogenicity. The challenge for inhibitors is to reduce their incidence and, when present, to facilitate their eradication. Factor-bypassing agents have been used to treat acute bleeds in patients who have inhibitors. Immune tolerance induction (ITI) therapy is an alternative approach whose goal is to create tolerance to inhibitors and return patients to their native state. The use of ITI therapy has raised many questions, including the optimal regimen and cost. The basic science data on reduced immunogenicity of vWF/FVIII-containing products and their success in achieving ITI have given us an incentive to continue to explore this approach to both primary and secondary ITI.