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Platelet Aggregation Induced by a Monoclonal Antibody to the A1
Domain of von Willebrand Factor
Hilde Depraetere,
Nadine Ajzenberg,
Jean-Pierre Girma,
Catherine Lacombe,
Dominique Meyer,
Hans Deckmyn, and
Dominique Baruch
From INSERM U143, Paris, France; Laboratory for Thrombosis Research,
KU Leuven, Campus Kortrijk, Belgium; and Biorheology URA CNRS 343, Paris, France.
Shear-induced platelet aggregation (SIPA) involves von Willebrand
Factor (vWF) binding to platelet glycoprotein (GP)Ib at high shear
stress, followed by the activation of
 IIb 3. The purpose of this study was to
determine the vWF sequences involved in SIPA by using monoclonal
antibodies (MoAbs) to vWF known to interfere with its binding to GPIb
and to IIb3. Washed platelets were exposed to shear rates between 100 and 4,000 seconds 1 in
a rotational viscometer. SIPA was quantitated by flow cytometry as the
disappearance of single platelets (DSP) in the sheared sample in the
presence of vWF, relative to a control in the absence of shear and vWF.
At a shear rate of 4,000 seconds1, DSP was increased
from 5.9% ± 3.5% in the absence of vWF to 32.7% ± 6.3% in the
presence of vWF. This increase in SIPA was not associated with an
elevation of P-selectin expression. vWF-dependent SIPA was completely
abolished by MoAb 6D1 to GPIb and partially inhibited by MoAb 10E5 to
IIb3. Three MoAbs to vWF were compared for their effect on SIPA at 4,000 seconds1 in the
presence of vWF: MoAb 328, known to block vWF binding to GPIb in the
presence of ristocetin, MoAb 724 blocking vWF binding to GPIb in the
presence of botrocetin, and MoAb 9, an inhibitor of vWF binding to
IIb3. Similar to the effect of MoAb 6D1,
MoAb 328 completely inhibited the effect of vWF, whereas MoAb 9 had a
partial inhibitory effect, as MoAb 10E5 did. In contrast, MoAb 724, as
well as its F(ab )2 fragments, promoted
shear-dependent platelet aggregation (165% of the DSP value obtained
in the absence of MoAb 724), indicating that MoAb 724 was responsible
for an enhanced aggregation, which was independent of binding to the platelet Fc receptor. In addition, the enhancement of aggregation induced by MoAb 724 was abrogated by MoAb 6D1 or 10E5 to the level of
SIPA obtained in the presence of vWF incubated with a control MoAb to
vWF. Finally, the activating effect of MoAb 724 was also found under
static conditions at ristocetin concentrations too low to induce
platelet aggregation. Our results suggested that on binding to a
botrocetin-binding site on vWF, MoAb 724 mimics the effect of
botrocetin by inducing an active conformation of vWF that is more
sensitive to shear stress or to low ristocetin concentration.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3792-3799
© 1998 by The American Society of Hematology.
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