Synergistic Effect of Thrombin on Collagen-Induced Platelet Procoagulant Activity Is Mediated Through Protease-Activated Receptor-1
- 1 July 2005
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 25 (7), 1499-1505
- https://doi.org/10.1161/01.atv.0000167526.31611.f6
Abstract
Objective— In the blood coagulation process, the rate of thrombin formation is critically dependent on phosphatidylserine (PtdSer) at the surface of activated platelets. Thrombin synergistically enhances the collagen-induced platelet procoagulant response. The objective of this study is to elucidate the mechanism of this synergistic action with a focus on the intracellular Ca 2+ concentration ([Ca 2+ ] i ) and the various platelet receptors for thrombin. Methods and Results— We demonstrate that procoagulant activity is related to a sustained increased [Ca 2+ ] i , which in turn depends on extracellular Ca 2+ influx. Increased PtdSer exposure coincides with increased [Ca 2+ ] i and was observed in a subpopulation (≈14%) of the platelets after stimulation with thrombin plus collagen. 2D2-Fab fragments against the thrombin binding site on GPIbα made clear that this receptor did not signal for platelet procoagulant activity. Inhibition of protease-activated receptor 1 (PAR-1) and PAR-4 by selective intracellular inhibitors and selective desensitization of these receptors revealed that PAR-1, but not PAR-4, activation is a prerequisite for both sustained elevations in [Ca 2+ ] i and procoagulant activity induced by collagen plus thrombin. Conclusions— The interaction of thrombin with PAR-1 mediates a synergistic effect on collagen-induced procoagulant activity by inducing a sustained elevation in [Ca 2+ ] i in a subpopulation of platelets.Keywords
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