on April 21, 2005
Published online before print April 21, 2005, doi: 10.1161/01.ATV.0000167526.31611.f6
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 1, 2004
Accepted on April 7, 2005
Synergistic Effect of Thrombin on Collagen-Induced Platelet Procoagulant Activity Is Mediated Through Protease-Activated Receptor-1
Jeffrey F.W. Keuren ;
From the Sanquin (J.F.W.K.), Blood Bank region South-East, Maastricht, and the Department of Biochemistry (S.J.H.W., T.H., J.W.M.H., E.M.B., T.L.), Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands; and the Laboratory for Thrombosis Research (H.U., H.D.), K.U. Leuven, Campus Kortrijk, Belgium.
* To whom correspondence should be addressed. E-mail: t.lindhout{at}bioch.unimaas.nl.
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 Ca2+ concentration ([Ca2+]i) and the various platelet receptors for thrombin.
Methods and Results--We demonstrate that procoagulant activity is related to a sustained increased [Ca2+]i, which in turn depends on extracellular Ca2+ influx. Increased PtdSer exposure coincides with increased [Ca2+]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 GPIb
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 [Ca2+]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 [Ca2+]i in a subpopulation of platelets.
This article has been cited by other articles:
 |
|
 |
|
  A. Arachiche, D. Kerbiriou-Nabias, I. Garcin, T. Letellier, and J. Dachary-Prigent Rapid Procoagulant Phosphatidylserine Exposure Relies on High Cytosolic Calcium Rather Than on Mitochondrial Depolarization Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1883 - 1889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Maroney, S. L. Haberichter, P. Friese, M. L. Collins, J. P. Ferrel, G. L. Dale, and A. E. Mast Active tissue factor pathway inhibitor is expressed on the surface of coated platelets Blood, March 1, 2007; 109(5): 1931 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Hughan, C. E. Hughes, O. J.T. McCarty, E. Schweighoffer, I. Soultanova, J. Ware, V. L.J. Tybulewicz, and S. P. Watson GPVI Potentiation of Platelet Activation by Thrombin and Adhesion Molecules Independent of Src Kinases and Syk Arterioscler Thromb Vasc Biol, February 1, 2007; 27(2): 422 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Wolfs, S. J. Wielders, P. Comfurius, T. Lindhout, J. C. Giddings, R. F. Zwaal, and E. M. Bevers Reversible inhibition of the platelet procoagulant response through manipulation of the Gardos channel Blood, October 1, 2006; 108(7): 2223 - 2228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Leger, L. Covic, and A. Kuliopulos Protease-Activated Receptors in Cardiovascular Diseases Circulation, September 5, 2006; 114(10): 1070 - 1077. [Abstract] [Full Text] [PDF]
|
|