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 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.
Isermann
B
B
Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin 53226, USA.
Hendrickson
S B
SB
Zogg
M
M
Wing
M
M
Cummiskey
M
M
Kisanuki
Y Y
YY
Yanagisawa
M
M
Weiler
H
H
D000367:Age Factors; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001777:Blood Coagulation / Q000502:physiology*; D006332:Cardiomegaly / Q000209:etiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy / Q000209:etiology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D018390:Gene Targeting; D005804:Genes, Lethal; D005813:Genes, Synthetic; D006801:Humans; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D009928:Organ Specificity; D011486:Protein C / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D042787:Receptor, TIE-2; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D011995:Recombination, Genetic; D012741:Sexual Maturation; D018180:Thrombomodulin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019851:Thrombophilia / Q000188:drug therapy / Q000209:etiology; D013927:Thrombosis / Q000209:etiology* / Q000517:prevention & control; D014764:Viral Proteins / Q000235:genetics; D014859:Warfarin / Q000627:therapeutic use
D000925:Anticoagulants; D011486:Protein C; D011993:Recombinant Fusion Proteins; D018180:Thrombomodulin; D014764:Viral Proteins; D014859:Warfarin; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C045073:Cre recombinase; D019426:Integrases