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(Received for publication, March 15, 1996, and in revised form, July 10, 1996)
From the The anti-factor VIII (fVIII) C2 domain monoclonal
antibody ESH8 inhibits fVIII activity only when fVIII is bound to von
Willebrand factor (vWf). However, ESH8 binds with similar affinity to
fVIII and fVIII·vWf complex, and it does not affect the kinetics of
thrombin cleavage at positions 372 and 740 within the fVIII heavy chain
and at 1689 within the light chain. The latter is required for fVIII
release from vWf. We showed that ESH8 reduced the initial rate of
thrombin-activated fVIII (fVIIIa) release from vWf by 4.3-fold compared
to that in the absence of antibody. The complex of vWf·fVIII·ESH8
was activated, and the rate constant determined for fVIIIa dissociation
from vWf was 4 × 10
Volume 271, Number 44,
Issue of November 1, 1996
pp. 27424-27431
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
Holland Laboratory, American Red Cross,
Rockville, Maryland 20855, § Department of Pediatrics, Nara
Medical University, Nara, Japan, and ¶ Brockton-West Roxbury
Veterans Administration Medical Center, Brigham and Women's Hospital,
and Harvard Medical School, Boston, Massachusetts 02115
3 s1. We
constructed a mathematical model incorporating the measured rates for
fVIIIa release from vWf and for inactivation of heterotrimeric fVIIIa
due to the spontaneous loss of the A2 subunit and found that the
decreased release rate is sufficient to explain our experimentally
observed inhibition of fVIII activity by ESH8. We hypothesize that the
slowed rate of fVIIIa release from vWf in the presence of ESH8 allows
time for inactivation of unstable fVIIIa prior its participation in the
formation of the factor Xase complex. The relevance of these findings
is illustrated by our observation that reduction of fVIIIa release from
vWf represents an additional mechanism of fVIII inhibition by an
anti-C2 domain antibody (epitope 2218-2307) from a hemophilia A
patient. This rare antibody binds to a more amino-terminal epitope than
other human anti-C2 inhibitors, resulting in its lack of inhibition of
fVIII binding to vWf but not to phospholipid. These two fVIII ligands
therefore bind to C2 sites which do not overlap completely.
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