Human Anti-Factor VIII Antibodies: Epitope Localization and Inhibitory Function

Abstract

Recombinant polypeptides derived from coagulation factor Vili (fVIII) have been used to determine the epitopes and characteristics of human pathologic anti-fVIII antibodies. The results of immunoprecipitation assays indicate that 70% of patient plasmas contain antibodies to the A2 as well as the C2 domains of the fVIII protein. The same polypeptides were used for inhibitor neutralization assays to demonstrate that about 60% of plasmas contain 2 or 3 different antibodies which collectively make up the inhibitor titer. The results of neutralization assays indicate that there is a third important inhibitor epitope within the light chain outside C2. Anti-A2 antibodies prevent normal function of the factor Xase complex of the intrinsic pathway of blood coagulation. Anti-C2 antibodies prevent the binding of fVIII to phospholipid and to von Willebrand factor, both of which are important for normal fVIII function.