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Blood, 1 January 2005, Vol. 105, No. 1, pp. 186-191.
Prepublished online as a Blood First Edition Paper on August 31, 2004; DOI 10.1182/blood-2004-07-2842.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Platelet activation induces metalloproteinase-dependent GP VI cleavage to down-regulate platelet reactivity to collagen
Gillian Stephens,
Yibing Yan,
Martine Jandrot-Perrus,
Jean-Luc Villeval,
Kenneth J. Clemetson, and
David R. Phillips
From the Portola Pharmaceuticals Inc, San Francisco, CA; the Institut National de la Santé et de la Recherche Médicale (INSERM) E348, Faculté Xavier Bichat, Paris, France; INSERM U 362, Institut Gustave Roussy, Villejuif, France; Millennium Pharmaceuticals Inc, Cambridge, MA; and the Theodor Kocher Institute, University of Berne, Switzerland.
Glycoprotein (GP) VI, the primary collagen receptor on platelets, has been shown to have variable expression, possibly as a consequence of immune modulation. The present study was designed to determine the mechanism by which GP VI clearance occurs. We found that direct activation of GP VI both by a GP VI–specific antibody and by GP VI ligands (collagen and convulxin) reduced binding of biotinylated convulxin to the stimulated platelets. Analysis of immunoblots of platelets and supernatants showed that the stimulated platelets contained less GP VI, while the soluble fraction contained a 57-kDa cleavage product. Stimulation of platelets with PAR-1 agonists (TRAP peptide and thrombin) also caused GP VI cleavage, although the amount of GP VI loss was less than that observed with direct GP VI ligands. The metalloproteinase (MMP) inhibitors GM6001 and TAPI prevented both the clearance of GP VI from the platelet surface and the appearance of the soluble cleavage product. Induction of GP VI cleavage caused specific down-regulation of collagen-induced platelet aggregation, providing a mechanism for the modulation of platelet responsiveness to this important platelet agonist.
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