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

The thrombomodulin (TM) gene was ablated in mice in a cell type-restricted manner from vascular endothelium by Cre-recombinase-mediated excision contr olled 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 mic e survive beyond birth, but invariably succumb to a severe hypercoagulable state and massive thrombosis after 3 weeks, terminating in a lethal consump tive coagulopathy. The progression of thrombosis was age- and sex-dependent . Disruption of the TM/protein C pathway was not associated with a latent p roinflammatory state. Disease onset and progression could be prevented by w arfarin anticoagulation. These results show that in mice, loss of endotheli al cell TM function causes spontaneous and fatal thrombosis in the arterial and venous circulation, resulting from unfettered activation of the coagul ation system. The combination of complete disease penetrance, uniform disea se onset at young age, large vessel thrombosis of the extremities and multi ple organ systems, and consumptive coagulopathy as the disease end-point pr ovides a unique mouse model of human thrombotic disease.