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Received April 8, 2004
Revised May 4, 2004
Accepted after revision May 14, 2004
IIb
3 in phosphatidylserine exposure during vWF/collagen-induced thrombus formation
1 Department of Biochemistry, Maastricht University, the Netherlands
2 Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Germany
3 Center for Molecular and Vascular Biology, KU Leuven, Belgium
4 Department of Molecular Cell Biology and Genetics, Maastricht University, the Netherlands
* To whom correspondence should be addressed. E-mail: jwm.heemskerk{at}bioch.unimaas.nl.
Vessel wall damage exposes collagen fibres, to which platelets adhere directly by the collagen receptors glycoprotein (GP)VI and integrin 
2
1, and indirectly to collagen-bound von Willebrand factor (vWF) via GPIb-V-IX and integrin IIb3. Platelet-collagen interaction under shear stimulates thrombus formation in two ways, by integrin-dependent formation of platelet aggregates and by surface exposure of procoagulant phosphatidylserine (PS). GPVI is involved in both processes complemented by 21. In mouse blood flowing over collagen, we investigated the additional role of platelet-vWF binding via GPIb and IIb3. Inhibition of GPIb as well as blocking of vWF binding to collagen reduced stable platelet adhesion at high shear rate. This was accompanied by delayed platelet Ca2+ responses and reduced PS exposure, while micro-aggregates were still formed. Inhibition of integrin IIb3 with JON/A antibody, which blocks IIb3 binding to both vWF and fibrinogen, reduced PS exposure and aggregate formation. The JON/A effects were not enhanced by combined blocking of GPIb-vWF binding, suggesting a function for IIb3 downstream of GPIb. Typically, with blood from FcR 
-chain +/- mice, expressing 50% of normal platelet GPVI levels, GPIb blockage almost completely abolished platelet adhesion and PS exposure. Together, these data indicate that, under physiological conditions of flow, both adhesive receptors, GPIb and IIb3, facilitate GPVI-mediated PS exposure by stabilising platelet binding to collagen. Hence, these glycoproteins have an assistant procoagulant role in collagen-dependent thrombus formation, which is most prominent at reduced GPVI activity and is independent of thrombin.
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