Factor VIII (FVIII) replacement therapy remains the mainstay in hemophilia A care. The major complication of replacement therapy is formation of antibodies, which inhibit FVIII activity, thus dramatically reducing treatment efficiency. The present review summarizes the accumulated knowledge on epitopes of FVIII inhibitors and mechanisms of their inhibitory effects. FVIII inhibitors most frequently target the A2, C2 and A3 domains of FVIII and interfere with important interactions of FVIII at various stages of its functional pathway; a class of FVIII inhibitors inactivates FVIII by proteolysis. We discuss therapeutic approaches currently used for treatment of hemophilia A patients with inhibitors and analyze the factors that influence the outcome. The choice between options should depend on the level of inhibitors and consideration of efficacy, safety, and availability of particular regimens. Advances of basic science open avenues for alternative targeted, specific and long-lasting treatments, such as the use of peptide decoys for blocking FVIII inhibitors, bypassing them with human/porcine FVIII hybrids, neutralizing FVIII-reactive CD4+ T cells with anti-clonotypic antibodies, or inducing immune tolerance to FVIII with the use of universal CD4+ epitopes or by genetic approaches.
aDepartment of Biochemistry, J. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, Maryland, USA, bINSERM U430, Institut des Cordeliers, Paris, France, cDepartment of Obstetrics and Gynecology, Medical University of Lubeck, Germany and dDepartment of Pediatrics, Nara Medical University, Nara, Japan.
Correspondence and requests for reprints to Natalya M. Ananyeva, Ph.D., Department of Biochemistry, J. Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, USA. Tel: +1 301 738 0743; fax: +1 301 738 0499; e-mail: email@example.com
Received 16 May 2003 Revised 23 September 2003 Accepted 25 September 2003