HUMAN ANTI-FACTOR-VIII ANTIBODIES - EPITOPE LOCALIZATION AND INHIBITORY FUNCTION

Recombinant polypeptides derived from coagulation factor VIII (fVIII) have been used to determine the epitopes and characteristics of human pathologic anti-fVIII antibodies. The results of immunoprecipitation a ssays indicate that 70% of patient plasmas contain antibodies to the A 2 as well as the C2 domains of the fVIII protein. The same polypeptide s were used for inhibitor neutralization assays to demonstrate that ab out 60% of plasmas contain 2 or 3 different antibodies which collectiv ely 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 t o von Willebrand factor, both of which are important for normal fVIII function.