Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis
Berend Isermann, … , Masashi Yanagisawa, Hartmut Weiler
Berend Isermann, … , Masashi Yanagisawa, Hartmut Weiler
Published August 15, 2001
Citation Information: J Clin Invest. 2001;108(4):537-546. https://doi.org/10.1172/JCI13077.
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Article

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis

Abstract

The thrombomodulin (TM) gene was ablated in mice in a cell type–restricted manner from vascular endothelium by Cre-recombinase–mediated excision controlled by the endothelial cell lineage–specific Tie2 promoter. Forty percent of mutant (TMLox-) mice display a distinct lethal embryonic phenotype not observed in completely TM-deficient embryos. The remaining 60% of TMLox mice survive beyond birth, but invariably succumb to a severe hypercoagulable state and massive thrombosis after 3 weeks, terminating in a lethal consumptive coagulopathy. The progression of thrombosis was age- and sex-dependent. Disruption of the TM/protein C pathway was not associated with a latent proinflammatory state. Disease onset and progression could be prevented by warfarin anticoagulation. These results show that in mice, loss of endothelial cell TM function causes spontaneous and fatal thrombosis in the arterial and venous circulation, resulting from unfettered activation of the coagulation system. The combination of complete disease penetrance, uniform disease onset at young age, large vessel thrombosis of the extremities and multiple organ systems, and consumptive coagulopathy as the disease end-point provides a unique mouse model of human thrombotic disease.

Authors

Berend Isermann, Sara B. Hendrickson, Mark Zogg, Mark Wing, Marjorie Cummiskey, Yaz Y. Kisanuki, Masashi Yanagisawa, Hartmut Weiler

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Disease progression and death in TMLox mice. Reduced body weight, phenot...
Disease progression and death in TMLox mice. Reduced body weight, phenotypical disease onset, and death in TMLox mice at young age. (a) Body weight in TMwt and TMLox littermates. The body weight of TMLox mice is reduced at weaning age and remains low thereafter. TMLox mice (excluding runt animals), filled circles; TMwt mice, open diamonds. Paired t test; n = 27; error bars = SEM. *P < 0.05, **P < 0.01. Manifestation of phenotypes (b) and death (c) approaches 100% within 20 and 30 weeks, respectively, and occurs earlier in male than in female mice. Males, filled squares; n = 23. Females, open triangles; n = 25.