Thrombomodulin is required for the antithrombotic activity of thrombin mutant W215A/E217A in a mouse model of arterial thrombosis

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• 作者：Cristina P. Vicente ; Hartmut Weiler ; Enrico Di Cera ; Douglas M. Tollefsen
• 关键词：PAR ; protease-activated receptor ; WE thrombin ; mutant thrombin W215A/E217A ; APC ; activated protein C ; TMPro/Pro ; homozygous mutant thrombomodulin E404P
• 刊名：Thrombosis Research
• 出版年：2012
• 出版时间：October, 2012
• 年：2012
• 卷：130
• 期：4
• 页码：646-648
• 全文大小：219 K

文摘

Introduction

The thrombin mutant W215A/E217A (WE thrombin) has greatly reduced procoagulant activity, but it activates protein C in the presence of thrombomodulin and inhibits binding of platelet glycoprotein Ib to von Willebrand factor and collagen under flow conditions. Both thrombomodulin-dependent protein C activation and inhibition of platelet adhesion could contribute to the antithrombotic activity of WE thrombin.

Materials and methods

To assess the role of thrombomodulin, we administered WE thrombin to thrombomodulin-deficient (TM^Pro/Pro) mice and measured the time to occlusive thrombus formation in the carotid artery after photochemical injury of the endothelium.

Results and conclusions

Doses of WE thrombin ¡Ý 10 ¦Ìg/kg prolonged the thrombosis time of wild-type mice (> 1.6-fold), while doses ¡Ý 100 ¦Ìg/kg only slightly prolonged the thrombosis time of TM^Pro/Pro mice. We conclude that thrombomodulin plays a predominate role in mediating the antithrombotic effect of WE thrombin in the arterial circulation of mice after endothelial injury. Thrombomodulin-independent effects may occur only when high doses of WE thrombin are administered.