© 2000 American Heart Association, Inc.
Thrombosis |
Antithrombotic Effect of Platelet Glycoprotein Ib–Blocking Monoclonal Antibody Fab Fragments in Nonhuman Primates
From the Laboratory for Thrombosis Research (N.C., S.V., H.D.), Interdisciplinary Research Center, KU Leuven Campus Kortrijk, Kortrijk, Belgium; the Department of Haematology and Cell Biology (N.C., M.M., V.v.W., S.L., J.P.R., H.F.K.), University of the Orange Free State, Bloemfontein, South Africa; and the Department of Clinical Biochemistry and Molecular Pathology (L.N., J.H.), Medical School, University of Debrecen, Debrecen Hungary.
Correspondence to Nancy Cauwenberghs, Laboratory for Thrombosis Research-IRC. K U Leuven Campus Kortrijk, E Sabbelaan 53, B-8500 Kortrijk, Belgium. E-mail Nancy.Cauwenberghs{at}kulak.ac.be
Abstract—Platelet adhesion in
arterial blood flow is mainly supported by the platelet
receptor glycoprotein (GP) Ib, which interacts with von
Willebrand factor (vWF) that is bound to collagen at the site
of vessel wall injury. Antibody 6B4 is a monoclonal antibody (MoAb)
raised against purified human GPIb. MoAb 6B4 inhibits both ristocetin-
and botrocetin-induced, vWF-dependent human platelet agglutination.
MoAb 6B4 furthermore blocks shear-induced adhesion of human
platelets to collagen I. We studied the antithrombotic effect of
this inhibitory murine MoAb 6B4 in a baboon model of
arterial thrombosis. When injected into baboons, intact IgG
and its F(ab')2 fragments caused almost immediate
thrombocytopenia, whereas injection of the Fab fragments alone did not.
Fab fragments were subsequently used to investigate their in vivo
effect on platelet deposition onto a thrombogenic device,
consisting of collagen-rich, glutaraldehyde-fixed
bovine pericardium (0.6 cm2), at a wall shear
rate ranging from 700 to 1000 s-1. Baboons were
either pretreated with Fabs to study the effect of inhibition on
platelet adhesion or treated 6 minutes after placement of the
thrombogenic device to investigate the effect on interplatelet
cohesion. Pretreatment of the animals with bolus doses ranging from 80
to 640 µg/kg Fab fragments significantly reduced
111In-labeled platelet deposition onto the
collagen surface by 
43% to 65%. Only the highest dose caused a
significant prolongation (doubling) of the bleeding time. Ex vivo
ristocetin-induced platelet agglutination was equally reduced.
Treatment with a bolus of 110 µg/kg Fab fragments after a thrombus
was allowed to form for 6 minutes had no effect on further platelet
deposition. We therefore conclude that Fab fragments or
derivatives of inhibitory anti-GPIb antibodies may be
useful compounds to prevent thrombosis.
Key Words: platelet adhesion • platelet aggregation • thrombosis • glycoprotein Ib • monoclonal antibodies
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