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

Thromb Res. 2012 Oct;130(4):646-8. doi: 10.1016/j.thromres.2011.11.026. Epub 2011 Dec 16.


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 ≥10μg/kg prolonged the thrombosis time of wild-type mice (>1.6-fold), while doses ≥100μg/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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carotid Arteries / drug effects*
  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Carotid Artery Thrombosis / drug therapy*
  • Carotid Artery Thrombosis / metabolism
  • Carotid Artery Thrombosis / pathology*
  • Fibrinolytic Agents / metabolism
  • Fibrinolytic Agents / therapeutic use*
  • Gene Deletion
  • Mice
  • Mice, Inbred C57BL
  • Point Mutation
  • Protein Engineering
  • Thrombin / genetics
  • Thrombin / therapeutic use*
  • Thrombomodulin / genetics
  • Thrombomodulin / metabolism*


  • Fibrinolytic Agents
  • Thrombomodulin
  • Thrombin