Functional thrombomodulin deficiency causes enhanced thrombus growth in a murine model of carotid artery thrombosis.
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.
Dörffler-Melly
Janine
J
Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.
de Kruif
Martijn
M
Schwarte
Lothar A
LA
Franco
Rendrik F
RF
Florquin
Sandrine
S
Spek
C Arnold
CA
Ince
Can
C
Reitsma
Pieter H
PH
ten Cate
Hugo
H
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*
D018180:Thrombomodulin