Characterization of a mouse model for thrombomodulin deficiency.
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.
Weiler
H
H
Blood Research Institute, Blood Center of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.
Lindner
V
V
Kerlin
B
B
Isermann
B H
BH
Hendrickson
S B
SB
Cooley
B C
BC
Meh
D A
DA
Mosesson
M W
MW
Shworak
N W
NW
Post
M J
MJ
Conway
E M
EM
Ulfman
L H
LH
von Andrian
U H
UH
Weitz
J I
JI
D000818:Animals; D001777:Blood Coagulation; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000473:pathology; D002712:Chlorides; D016207:Cytokines / Q000096:biosynthesis; D005290:Ferric Compounds; D005337:Fibrin / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D008026:Ligation; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology; D016019:Survival Analysis; D018180:Thrombomodulin / Q000235:genetics* / Q000502:physiology*; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000473:pathology
D002712:Chlorides; D016207:Cytokines; D005290:Ferric Compounds; D008070:Lipopolysaccharides; D018180:Thrombomodulin; D005337:Fibrin; C024555:ferric chloride