doi: 10.1161/hq0901.094496
© 2001 American Heart Association, Inc.
Thrombosis |
Characterization of a Mouse Model for Thrombomodulin Deficiency
From the Blood Research Institute (H.W., B.H.I., S.B.H., D.A.M., M.W.M.), Blood Center of Southeastern Wisconsin, and Medical College of Wisconsin (H.W., B.K., B.C.C.), Milwaukee; Maine Medical Center Research Institute (V.L.), Portland; Angiogenesis Research Center (N.W.S., M.J.P.), Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass; the Center for Transgene Technology and Gene Therapy (E.M.C.), Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium; The Center for Blood Research and Department of Pathology (L.H.U., U.H.v.A.), Harvard Medical School, Boston, Mass; and McMaster University and Hamilton Civic Hospitals Research Centre (J.I.W.), Hamilton, Ontario, Canada. Dr Ulfman is now at the University Medical Center, Department of Pulmonary Diseases, Utrecht, the Netherlands.
Correspondence to Dr Hartmut Weiler, Blood Research Institute, Blood Center of Southeastern Wisconsin, 8727 Watertown Plank Rd, Milwaukee, WI 53226-3548. E-mail hweiler{at}bcsew.edu
Abstract—— 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 TMPro/Pro mice carrying a TM gene mutation that disrupts the TM-dependent activation of protein C. Here, it is shown that inbred C57BL/6J TMPro/Pro mice exhibit a hypercoagulable state and an increased susceptibility to thrombosis and sepsis. Platelet thrombus growth after FeCl3-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 TMPro 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 TMPro mutation is determined by as-yet-uncharacterized genetic modifiers of thrombosis other than TM.
Key Words: transgenic mice • thrombomodulin • thrombosis • inflammation • thrombosis modifier genes
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