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Some Human Inhibitor Antibodies Interfere With Factor VIII
Binding to Factor IX
Degang Zhong,
Evgueni L. Saenko,
Midori Shima,
Matthew Felch, and
Dorothea Scandella
From the American Red Cross, Holland Laboratory, Rockville, MD; and
Nara Medical College, Japan.
Factor VIII (fVIII) functions as a cofactor of factor IXa in the
intrinsic pathway of blood coagulation. Its absence or abnormality causes the bleeding disorder hemophilia A. About 23% of hemophiliacs who receive therapeutic fVIII infusions develop antibodies that inhibit
its activity. We previously showed by inhibitor neutralization assays
that the fVIII A2 and C2 domain polypeptides contain common inhibitor
epitopes. Often hemophilic inhibitor plasmas were partially neutralized
by C2 and more completely neutralized by fVIII light chain (A3-C1-C2),
suggesting the presence of an additional major inhibitor epitope(s)
within the A3-C1 domains. In immunoprecipitation assays, 17 of 18 inhibitor IgGs bound to recombinant 35S-A3-C1. Amino acids
1811-1818 of the A3 domain comprise a binding site for factors IX and
IXa. Three inhibitor IgGs prevented binding of factor IXa to fVIII
light chain, and the binding of each IgG to light chain was competed by
A3 peptide 1804-1819. The generation of factor Xa by the fVIIIa/fIXa
complex in a chromogenic assay was prevented by these inhibitors.
Therefore, we propose that another important mechanism of fVIII
inactivation by human inhibitors is the prevention of fVIIIa/fIXa
association.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 136-142
© 1998 by The American Society of Hematology.
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