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A Human Alloantibody Interferes With Binding of Factor IXa to the
Factor VIII Light Chain
Karin Fijnvandraat,
Patrick H.N. Celie,
Ellen A.M. Turenhout,
Jan
W. ten Cate,
Jan A. van Mourik,
Koen Mertens,
Marjolein Peters, and
Jan Voorberg
From the Departments of Blood Coagulation and Plasma Protein
Technology, Central Laboratory of the Netherlands Red Cross Blood
Transfusion Service; the Academic Medical Center, University of
Amsterdam, Emma Children's Hospital AMC, Department of Pediatrics; and
the Academic Medical Center, University of Amsterdam, Center for
Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research,
Amsterdam, The Netherlands.
Inhibitory antibodies directed against factor VIII develop in a
substantial number of patients with hemophilia A as a consequence of
factor VIII replacement therapy. These antibodies usually recognize discrete epitopes within the A2 and/or the C2 domains of factor VIII. Here, we have characterized the antibodies present in the plasma
of a patient affected by severe hemophilia A. The antibodies reacted
readily with the metabolically labeled factor VIII light chain and
fragments thereof when analyzed by immunoprecipitation. The inhibitory
activity could be neutralized by the complete light chain, whereas only
slight neutralization occurred with a fragment comprising the isolated
C2 domain. Binding of the majority of antibodies to in vitro
synthesized factor VIII fragments was dependent on the presence of
amino acid residues Gln1778-Met1823, a region
known to contain a factor IXa binding site. Functional characterization
showed that purified IgG from the patient's serum inhibited binding of
factor IXa to immobilized factor VIII light chain in a dose-dependent
manner. These data indicate that human alloantibodies may inhibit
factor VIII activity by interfering with factor IXa-factor VIIIa
complex assembly.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2347-2352
© 1998 by The American Society of Hematology.
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