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This Article Full Text Full Text (PDF) All Versions of this Article: 558/2/403    most recent jphysiol.2004.062414v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kuijpers, M. J. E. Articles by Heemskerk, J. W. M. Search for Related Content PubMed PubMed Citation Articles by Kuijpers, M. J. E. Articles by Heemskerk, J. W. M.

Departments of ¹ Biochemistry, Cardiovascular Research Institute Maastricht⁴ Molecular Cell Biology & Genetics, University of Maastricht, Maastricht, The Netherlands² Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Germany³ Center for Molecular and Vascular Biology, KU Leuven, Belgium

Vessel wall damage exposes collagen fibres, to which platelets adhere directly via the collagen receptors glycoprotein (GP) VI and integrin ₂ß₁ and indirectly by collagen-bound von Willebrand factor (vWF) via the GPIb-V-IX and integrin IIbß3 receptor complexes. 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 2ß1. In mouse blood flowing over collagen, we investigated the additional role of platelet–vWF binding via GPIb and IIbß3. 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 microaggregates were still formed. Inhibition of integrin IIbß3 with JON/A antibody, which blocks IIbß3 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 IIbß3 downstream of GPIb. Typically, with blood from FcR -chain +/– mutant 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 IIbß3 facilitate GPVI-mediated PS exposure by stabilizing 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 the presence of thrombin.

(Received 8 April 2004; accepted after revision 14 May 2004; first published online 21 May 2004)
Corresponding author J. W. M. Heemskerk: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands. Email: jwm.heemskerk{at}bioch.unimaas.nl

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