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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Effect of gonadectomy and anticoagulation on the disease progression and...
Effect of gonadectomy and anticoagulation on the disease progression and death in TMLox mice. (a) Gonadectomy before age 3 weeks did not prevent disease onset or death but reversed the sex-specific disease progression (inset). Gonadectomized TMLox mice, filled circles (n = 18); sham-operated TMLox mice, open diamonds (n = 14). Inset: gonadectomized males, filled squares (n = 10); gonadectomized females, open triangles (n = 8). (b and c) Warfarin treatment effectively prevents the overt thrombosis over an 8-week period (b, shaded area: warfarin treatment period), whereas typical lesions occur in mice from the placebo group (c, right; arrow: autoamputation of toes; arrowheads: hemorrhagic tail necrosis; double arrow: necrosis of the ear). The phenotype onset (“overt thrombosis”) does not included warfarin-induced hemorrhage. After termination of warfarin treatment at age 11 weeks, mice rapidly succumb to the prothrombotic challenge. The overall survival of warfarin-treated TMLox mice is not improved secondary to warfarin-induced hemorrhagic side effects (inset). Warfarin-treated TMLox mice, filled circles (n = 18); water-treated (placebo-treated) TMLox mice, open diamonds (n = 14). (d) During the warfarin treatment period, the body weight of TMLox mice normalizes, and after 8 weeks of anticoagulation, the weight difference between TMLox mice and TMwt littermates (age 11 weeks) loses significance. Yet mice again fail to thrive once treatment is terminated. TMLox mice, filled circles; TMwt mice, open diamonds (n = 12). Paired t-test; *P < 0.05. Shaded area: warfarin treatment period.