Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients

Blood coagulation factor VIII functions in the intrinsic pathway of blood coagulation as a cofactor by enhancing the assembly of its complex with factors IX and X on the surface of activated platelets. This requires factor VIII interaction with these two proteins, von Willebrand factor (vWF), and phospholipids on the platelet surface. Once factor VIII and factor IX are activated by proteolytic cleavage, the complex is able to activate factor X to factor Xa by proteolysis. In hemophilia A patients with severe factor VIII deficiency, about 30% respond to factor VIII infusion therapy immunologically to produce antibodies that inactivate the infused factor VIII and others that are noninhibitory. An assay that measures only the inhibitor antibodies demonstrated that the factor VIII A2, A3, and C2 domains are the most immunogenic, and domains Al and B are poorly immunogenic or not immunogenic. The specific antibody responses to A2, A3, and C2 vary considerably among individuals, and epitopes for inhibitor antibodies have been determined for all three. The anti-C2 inhibitors prevent factor VIII binding to phospholipids and vWF, and anti-A3 inhibitors prevent binding to factor IX (IXa). An inhibitor binding site for factor X has been localized to the Al domain acidic region, leading to inhibition of factor VIII/factor X binding by antibodies. This inhibitor mechanism is rare. Beause a second binding site for factor IX was localized to the factor VIII A2 domain, it is likely but not proven that prevention of factor IX binding to factor VIII is the inhibitor mechanism for this epitope.