Factor VIII inhibitors: a 50-year perspective.

Inhibitors of factor VIII (FVIII) have been studied for more than 50 years, but diagnostic and therapeutic challenges remain. To describe the features that distinguish alloantibodies from autoantibodies, list predisposing factors, and review methods for tolerance induction and autoantibody suppression. Review of key articles published during the past half-century that have advanced knowledge in this field. Alloantibodies generally bind to the A2 or C2 domains of FVIII and disrupt the formation of the FVIII-FIX complex. They exhibit type 1 reaction kinetics, are saturable by FVIII, and display anamnesis. In contrast, autoantibodies usually bind to the C2 domain of FVIII, interfering with phospholipid and von Willebrand factor binding. They have type-2 kinetics and are poorly neutralized by FVIII. Repeated exposures to FVIII induce tolerance in 70-80% of haemophiliacs with inhibitors, whereas drugs that deplete B-lymphocytes restore self-tolerance to FVIII in a similar percentage of non-haemophiliacs. Future work should focus on improving assays that detect and quantify inhibitors, examining the pathophysiology of inhibitor formation using contemporary immunologic tools, and investigating new treatment modalities. These should include agents to control bleeding with less thrombotic risk, more specific immunomodulating drugs to curtail antibody formation, and, for haemophilia patients, genetic therapies to provide FVIII resistant to or protected from inactivation by inhibitors.