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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

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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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Figure 1

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(a) Targeted mutagenesis of the wild-type TM gene (TMwt) results in the ...
(a) Targeted mutagenesis of the wild-type TM gene (TMwt) results in the insertion of a loxP site immediately 5′ of the translation initiation codon and 3′ of the neomycin gene-expression cassette (neo). TK, thymidine kinase expression cassette. (b) Correctly targeted ES cells were identified by Southern blot hybridization analysis with external probe A (see a). (c) Mouse DNA was analyzed by PCR using the sense primer P1 (5′- aggttgtgatagaggctagctgctgtc -3′) and the antisense primer P2 (5′- ggccctaaatccatactgctct -3′), resulting in a 376-bp fragment for the TM wild-type allele, and the antisense primer P3 (5′- atgtgctgcaaggcgattaagttgg -3′), resulting in a 199-bp fragment for the TMlacZ allele (primer P3 is derived from the TMlacZ gene and is not shown in Figure 1a). The antisense primer P4 (5′- ggcccagtatgtctcaagatagcaatg -3′) yielded a 408-bp fragment only after deletion of the endogenous TM gene by Cre-recombinase. Immunohistochemical detection of TM in the lung (d and g), the brain (e and h), and the placenta (f and i) in TMwt (d–f) and TMLox (g–i) mice. Brown-black horseradish peroxidase reaction product identifies TM antigen. In TMLox mice, TM is absent in almost all lung capillaries (g) and brain endothelial cells (h, arrows), whereas nonendothelial cells such as meninges (h, arrowheads), giant trophoblast and parietal endoderm cells (i, arrowheads identify parietal endoderm) stain for TM. Arrows in e and f indicate meninges (top) and blood vessels. Original magnification is indicated at lower right.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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