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

B. Isermann, S. B. Hendrickson, M. Zogg, M. Wing, M. Cummiskey, Y. Y. Kisanuki, M. Yanagisawa, H. Weiler

Research output: Contribution to journalArticle

100 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)537-546
Number of pages10
JournalJournal of Clinical Investigation
Volume108
Issue number4
DOIs
StatePublished - 2001

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Thrombomodulin
Protein C
Anticoagulants
Endothelium
Thrombosis
Endothelial Cells
Penetrance
Vascular Endothelium
Cell Lineage
Warfarin
Age of Onset
Disease Progression
Embryonic Structures
Extremities
Parturition
Phenotype
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis. / Isermann, B.; Hendrickson, S. B.; Zogg, M.; Wing, M.; Cummiskey, M.; Kisanuki, Y. Y.; Yanagisawa, M.; Weiler, H.

In: Journal of Clinical Investigation, Vol. 108, No. 4, 2001, p. 537-546.

Research output: Contribution to journalArticle

Isermann, B. ; Hendrickson, S. B. ; Zogg, M. ; Wing, M. ; Cummiskey, M. ; Kisanuki, Y. Y. ; Yanagisawa, M. ; Weiler, H. / Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis. In: Journal of Clinical Investigation. 2001 ; Vol. 108, No. 4. pp. 537-546.
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AU - Hendrickson, S. B.

AU - Zogg, M.

AU - Wing, M.

AU - Cummiskey, M.

AU - Kisanuki, Y. Y.

AU - Yanagisawa, M.

AU - Weiler, H.

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