Faculty Collaboration Database

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis. J Clin Invest 2001 Aug;108(4):537-46

Date

08/24/2001

Pubmed ID

11518727

Pubmed Central ID

PMC209404

DOI

10.1172/JCI13077

Scopus ID

2-s2.0-0034892611 (requires institutional sign-in at Scopus site)   119 Citations

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.

Author List

Isermann B, Hendrickson SB, Zogg M, Wing M, Cummiskey M, Kisanuki YY, Yanagisawa M, Weiler H

Author

Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Age Factors
Animals
Anticoagulants
Blood Coagulation
Cardiomegaly
Disease Models, Animal
Disease Progression
Disseminated Intravascular Coagulation
Endothelium, Vascular
Female
Gene Expression Regulation
Gene Targeting
Genes, Lethal
Genes, Synthetic
Humans
Integrases
Male
Mice
Mice, Transgenic
Myocardium
Organ Specificity
Protein C
Receptor Protein-Tyrosine Kinases
Receptor, TIE-2
Recombinant Fusion Proteins
Recombination, Genetic
Sexual Maturation
Thrombomodulin
Thrombophilia
Thrombosis
Viral Proteins
Warfarin