Summary
In order to clarify the potential role of von Willebrand factor (vWf) in attenuating
the inactivation of factor VIII (fVIII) by those antibodies with C2 domain specificity,
we investigated a panel of 14 human antibodies to fVIII. Immunoblotting analysis localized
light chain (C2 domain) epitopes for four cases, heavy chain (A2 domain) epitopes
in five cases, while the remaining five cases were both light and heavy chains. The
inhibitor titer was considerably higher for Kogenate, a recombinant fVIII concentrate,
than for Haemate P, a fVIII/vWf complex concentrate, in all inhibitor plasmas that
had C2 domain specificity. In five inhibitor plasmas with A2 domain specificity and
in five with both A2 and C2 domain specificities, Kogenate gave titers similar to
or lower than those with Haemate P. The inhibitory effect of IgG of each inhibitor
plasma was then compared with recombinant fVIII and its complex with vWf. When compared
to the other 10 inhibitor IgGs, IgG concentration, which inhibited 50% of fVIII activity
(IC50), was remarkably higher for the fVIII/vWf complex than for fVIII in all the
inhibitor IgGs that had C2 domain reactivity. Competition of inhibitor IgG and vWf
for fVIII binding was observed in an ELISA system. In 10 inhibitors that had C2 domain
reactivity, the dose dependent inhibition of fVIII-vWf complex formation was observed,
while, in the group of inhibitors with A2 domain specificity, there was no inhibition
of the complex formation except one case. We conclude that a subset of fVIII inhibitors,
those that bind to C2 domain determinants, are less inhibitory to fVIII when it is
complexed with vWf that binds to overlapping region in the C2 domain.
