Fibrillar type I collagens enhance platelet-dependent thrombin generation via glycoprotein VI with direct support of α2β1 but not αIIbβ3 integrin

Christelle Lecut; Marion A. H. Feijge; Judith M. E. M. Cosemans; Martine Jandrot-Perrus; Johan W. M. Heemskerk

doi:10.1160/TH04-12-0783

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(01): 107-114
DOI: 10.1160/TH04-12-0783

Platelets and Blood Cells

Schattauer GmbH

Fibrillar type I collagens enhance platelet-dependent thrombin generation via glycoprotein VI with direct support of α2β1 but not αIIbβ3 integrin

Christelle Lecut

¹Departments of Biochemistry and Human Biology, CARIM, Maastricht University, The Netherlands

²INSERM E348, Faculté Xavier Bichat, Université Paris, France

,

Marion A. H. Feijge^*

¹Departments of Biochemistry and Human Biology, CARIM, Maastricht University, The Netherlands

,

Judith M. E. M. Cosemans^*

¹Departments of Biochemistry and Human Biology, CARIM, Maastricht University, The Netherlands

,

Martine Jandrot-Perrus

²INSERM E348, Faculté Xavier Bichat, Université Paris, France

,

Johan W. M. Heemskerk

¹Departments of Biochemistry and Human Biology, CARIM, Maastricht University, The Netherlands

› Author Affiliations

Abstract

Summary

The role of collagens and collagen receptors was investigated in stimulating platelet-dependent thrombin generation. Fibrillar type-I collagens, including collagen from human heart, were most potent in enhancing thrombin generation, in a way dependent on exposure of phosphatidylserine (PS) at the platelet surface. Soluble, non-fibrillar type-I collagen required pre-activation of integrin α2β1 with Mn²⁺ for enhancement of thrombin generation. With all preparations, blocking of glycoprotein VI (GPVI) with 9O12 antibody abrogated the collagen-enhanced thrombin generation, regardless of the α2β1 activation state. Blockade of α2β1 alone or antagonism of autocrine thromboxane A₂ and ADP were less effective. Blockade of αIIbβ3 with abciximab suppressed thrombin generation in platelet-rich plasma, but this did not abolish the enhancing effect of collagens. The high activity of type-I fibrillar collagens in stimulating GPVI-dependent procoagulant activity was confirmed in whole-blood flow studies, showing that these collagens induced relatively high expression of PS. Together, these results indicate that: i) fibrillar type-I collagen greatly enhances thrombin generation, ii) GPVI-induced platelet activation is principally responsible for the procoagulant activity of fibrillar and non-fibrillar collagens, iii) α2β1 and signaling via autocrine mediators facilitate and amplify this GPVI activity, and iv) αIIbβ3 is not directly involved in the collagen effect.

Keywords

Coagulation - collagen - glycoprotein VI - platelets - thrombin generation

Full Text

References

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