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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3701-3709
Residues Glu2181-Val2243 Contain a Major Determinant of the
Inhibitory Epitope in the C2 Domain of Human Factor VIII
John F. Healey,
Rachel T. Barrow,
Hiba M. Tamim,
Ira M. Lubin,
Midori Shima,
Dorothea Scandella, and
Pete Lollar
From Emory University, Atlanta, GA; Holland Laboratory, American Red
Cross, Rockville, MD; and the Department of Pediatrics, Nara Medical
College, Kashihara Nara, Japan.
The human blood coagulation factor VIII C2 domain (Ser2173-Tyr2332)
contains an epitope recognized by most polyclonal inhibitory anti-factor VIII alloantibodies and autoantibodies. We took advantage of the differential reactivity of inhibitory antibodies with human and
porcine factor VIII and mapped a major determinant of the C2 epitope by
using a series of active recombinant hybrid human/porcine factor VIII
molecules. A series of five C2-specific human antibodies and a murine
anti-factor VIII monoclonal antibody, NMC-VIII/5, inhibited a hybrid
containing a substitution of porcine sequence for Glu2181-Val2243
significantly less than human factor VIII. In contrast, four of the
five patient antibodies and NMC-VIII/5 inhibited a hybrid containing a
substitution of porcine sequence for Thr2253-Tyr2332 equally well as
human factor VIII. Thus, a major factor VIII inhibitor epitope
determinant is bounded by Glu2181-Val2243 at the
NH2-terminal end of the C2 domain. Because C2 inhibitors
block the binding of factor VIII to phospholipid and von Willebrand
factor, for which binding sites have been localized to Thr2303-Tyr2332,
these results imply that the segment bounded by Glu2181-Val2243 also is
involved in these macromolecular interactions.
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