Antifactor VIII antibody inhibiting allogeneic but not antologous factor VIII in patients with mild hemophilia A

Two unrelated patients with the same Arg2150His mutation in the factor VIII (FVIII) C1 domain, a residual FVIII activity of 0.09 IU/mL, and inhibitor titres of 300 and 6 Bethesda Units, respectively, were studied. Further ana lysis of patient LE, with the highest inhibitor titer, showed that (1) plas ma or polyclonal IgG antibodies prepared from LE plasma inhibited the activ ity of allogeneic (wild-type) but not of self FVIII; (2) the presence of vo n Willebrand factor (VWF) increased by over 10-fold the inhibitory activity on wild-type FVIII; (3) the kinetics of FVIII inhibition followed a type I I pattern, but in contrast to previously described type II inhibitors, LE I gG was potentiated by the presence of vWF instead of being in competition w ith it; (4) polyclonal LE IgG recognized the FVIII light chain in enzyme-li nked immunosorbent assay and the recombinant A3-C1 domains in an immunoprec ipitation assay, indicating that at least part of LE antibodies reacted wit h the FVIII domain encompassing the mutation site; and (5) LE IgG inhibited FVIII activity by decreasing the rate of FVIIIa release from vWF but LE Ig G recognized an epitope distinct from ESH8, a murine monoclonal antibody ex hibiting the same property. We conclude that the present inhibitors are uni que in that they clearly distinguish wild-type from self, mutated FVIII. Th e inhibition of wild-type FVIII by LE antibody is enhanced by vWF and is as sociated with an antibody-dependent reduced rate of FVIIIa release from vWF . (C) 1999 by The American Society of Hematology.