Characterization of a mouse model for thrombomodulin deficiency. Arterioscler Thromb Vasc Biol 2001 Sep;21(9):1531-7
Date
09/15/2001Pubmed ID
11557684DOI
10.1161/hq0901.094496Scopus ID
2-s2.0-0035572892 (requires institutional sign-in at Scopus site) 132 CitationsAbstract
Mutations in the gene encoding thrombomodulin (TM), a thrombin regulator, are suspected risk factors for venous and arterial thrombotic disease. We have previously described the generation of TM(Pro/Pro) mice carrying a TM gene mutation that disrupts the TM-dependent activation of protein C. Here, it is shown that inbred C57BL/6J TM(Pro/Pro) mice exhibit a hypercoagulable state and an increased susceptibility to thrombosis and sepsis. Platelet thrombus growth after FeCl(3)-induced acute endothelial injury was accelerated in mutant mice. Vascular stasis after permanent ligation of the carotid artery precipitated thrombosis in mutant but not in normal mice. Mutant mice showed increased mortality after exposure to high doses of endotoxin and demonstrated altered cytokine production in response to low-dose endotoxin. The severity of the hypercoagulable state and chronic microvascular thrombosis caused by the TM(Pro) mutation is profoundly influenced by mouse strain-specific genetic differences between C57BL/6 and 129SvPas mice. These data demonstrate that in mice, TM is a physiologically relevant regulator of platelet- and coagulation-driven large-vessel thrombosis and modifies the response to endotoxin-induced inflammation. The phenotypic penetrance of the TM(Pro) mutation is determined by as-yet-uncharacterized genetic modifiers of thrombosis other than TM.
Author List
Weiler H, Lindner V, Kerlin B, Isermann BH, Hendrickson SB, Cooley BC, Meh DA, Mosesson MW, Shworak NW, Post MJ, Conway EM, Ulfman LH, von Andrian UH, Weitz JIMESH terms used to index this publication - Major topics in bold
AnimalsBlood Coagulation
Carotid Artery Thrombosis
Chlorides
Cytokines
Ferric Compounds
Fibrin
Genetic Predisposition to Disease
Ligation
Lipopolysaccharides
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Sepsis
Survival Analysis
Thrombomodulin
Thrombosis
