title: Thrombomodulin is required for the antithrombotic activity of thrombin mutant W215A/E217A in a mouse model of arterial thrombosis.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), São Paulo, Brazil.
authors.forename: Cristina P
authors.initials: CP
authors.lastname: Vicente
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: Enrico
authors.initials: E
authors.lastname: Di Cera
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Tollefsen
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000627:therapeutic use*; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D017354:Point Mutation; D015202:Protein Engineering; D013917:Thrombin / Q000235:genetics / Q000627:therapeutic use*; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D005343:Fibrinolytic Agents; D018180:Thrombomodulin; D013917:Thrombin