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Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 564-570
Fibrin-Dependent Platelet Procoagulant Activity Requires GPIb
Receptors and von Willebrand Factor
S. Béguin,
R. Kumar,
I. Keularts,
U. Seligsohn,
B.S. Coller, and
H.C. Hemker
From the Department of Biochemistry, Cardiovascular Research
Institute Maastricht (CARIM) and Medical Faculty University of
Maastricht, Maastricht, The Netherlands; the Department of Hematology,
Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine,
Tel-Aviv University, Tel-Aviv, Israel; and the Department of Medicine,
Mount Sinai School of Medicine, New York, NY.
Thrombin generation in platelet-rich plasma (PRP) involves complex
interactions between platelets and coagulation proteins. We previously
reported that the addition of fibrin to PRP enhances tissue-factor
initiated thrombin generation by  40%, and the current
studies were designed to assess the mechanism(s) underlying thrombin
generation in the absence and presence of fibrin. Blocking platelet
GPIIb/IIIa +  v 3 receptors with a monoclonal antibody (MoAb)
inhibited basal thrombin generation, but did not affect the enhancement
produced by fibrin. In contrast, blocking GPIb with any of three
different MoAbs had no effect on basal thrombin generation, but
essentially eliminated fibrin enhancement of thrombin generation. When
thrombin generation was tested in PRP deficient in von Willebrand
factor (vWF), both basal and fibrin-enhanced thrombin generation were
markedly reduced, and the addition of factor VIII did not normalize
thrombin generation. Botrocetin, which induces the binding of vWF to
GPIb, enhanced thrombin generation. In all studies, the ability of PRP
to support thrombin generation correlated with the production of
platelet-derived microparticles and serum platelet-derived procoagulant
activity. Thus, two separate mechanisms, both of which depend on vWF,
appear to contribute to platelet-derived procoagulant activity: one is
independent of fibrin and relies primarily on GPIIb/IIIa, but with a
minor contribution from v3; and the other is fibrin-dependent and relies on GPIb. These data may have implications for understanding the
mechanisms of the abnormalities in serum prothrombin times reported in
Bernard-Soulier syndrome, hemorrhage in von Willebrand disease (vWD),
and the increased risk of thrombosis associated with elevated vWF
levels.
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