title: Inhibitors in hemophilia A: mechanisms of inhibition, management and perspectives.
abstract: 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.
authors.affiliation: Department of Biochemistry, J. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, Maryland 20855, USA. ananyeve@usa.redcross.org
authors.forename: Natalya M
authors.initials: NM
authors.lastname: Ananyeva
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
authors.forename: Charlotte A E
authors.initials: CA
authors.lastname: Hauser
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Ovanesov
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Khrenov
authors.forename: Evgueni L
authors.initials: EL
authors.lastname: Saenko
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use; D017151:Antibodies, Catalytic / Q000276:immunology; D000918:Antibody Specificity; D017951:Antigen Presentation; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001779:Blood Coagulation Factors / Q000627:therapeutic use; D003888:Desensitization, Immunologic; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D015316:Genetic Therapy; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007108:Immune Tolerance; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000888:Antibodies, Anti-Idiotypic; D017151:Antibodies, Catalytic; D001323:Autoantibodies; D001779:Blood Coagulation Factors; D000939:Epitopes; D007518:Isoantibodies; D010446:Peptide Fragments; C025667:prothrombin complex concentrates; D005169:Factor VIII