title: Functional thrombomodulin deficiency causes enhanced thrombus growth in a murine model of carotid artery thrombosis.
abstract: Thrombomodulin (TM) bound thrombin initiates the protein C anticoagulant pathway and defects in TM result in enhanced coagulation. Recent studies suggest a role for TM in arterial vascular disease. In order to corroborate this association we studied arterial thrombus formation in mice with a functional TM defect. We used mice homozygous for a (404)Glu-to-Pro mutation in the TM gene (TM(pro/pro)) and compared these with wildtype littermates in a model of FeCl(3) induced carotid artery thrombosis. Time-to-occlusion (TTO) was assessed by arterial blood flow measurement, using a Doppler flow probe. Complete occlusion occurred in 8/10 (80%) TM(pro/pro) mice and in 3/11 (27%) littermate controls. Mean time to occlusion (TTO) [+/- SE] was 767 +/- 196 s in the F2-TM(pro/pro) mice, versus 1507 +/- 159 s in controls (p = 0.007, Mann Whitney U test). Histology and immunostaining for tissue factor did not reveal any differences in thrombus morphology or thrombogenicity between the two groups. These data confirm and extend the finding that a functional deficiency in TM results in enhanced thrombus formation in a murine model of carotid artery thrombosis and support a role for TM defects in arterial thrombotic disease.
authors.affiliation: Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Janine
authors.initials: J
authors.lastname: Dörffler-Melly
authors.forename: Martijn
authors.initials: M
authors.lastname: de Kruif
authors.forename: Lothar A
authors.initials: LA
authors.lastname: Schwarte
authors.forename: Rendrik F
authors.initials: RF
authors.lastname: Franco
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
authors.forename: Can
authors.initials: C
authors.lastname: Ince
authors.forename: Pieter H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: Hugo
authors.initials: H
authors.lastname: ten Cate
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology*; D002341:Carotid Artery Thrombosis / Q000473:pathology*; D004195:Disease Models, Animal; D006439:Hemodynamics; D051379:Mice; D008822:Mice, Transgenic; D018180:Thrombomodulin / Q000172:deficiency*
chemical_list: D018180:Thrombomodulin