In hemophilia A and autoantibody inhibitor patients: The factor VIII A2 domain and light chain are most immunogenic

Factor VIII (fVIII) is a protein cofactor essential for blood coagulation, and it binds in the factor Xase complex to factors IXa, X, and phospholipid . In about 30% of severe hemophilia A patients, treatment with fVIII leads to production of anti-fVIII antibodies. Anti-fVIII autoantibodies also rare ly appear in normal individuals. Those antibodies that inactivate fVIII (in hibitors) prevent optimal fVIII, therapy. Inhibitor epitopes were previousl y localized to the fVIII A2, A3, and C2 domains and to an acidic amino acid region between Al and A2. Such anti-fVIII antibodies interfere with fVIII binding to components of the factor Xase complex and prevent blood coagulat ion. When total anti-fVIII titers were determined for each fVIII domain in 43 inhibitor plasmas by immunoprecipitation (IP) and inhibitor neutralizati on assays, the anti-light chain (LCh) antibody titer was highest, anti-A2 w as intermediate, and anti-Al and anti-B were low. The relative immunogenici ty of the fVIII domains in hemophilic and autoantibody inhibiter patients w as similar. (C) 2001 Elsevier Science Ltd. All rights reserved.