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

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.

Endothelial Cell Recovery Between Comparator Polymer-Based Drug-Eluting Stents

“…In particular, PECAM-1 expression over struts in 14-and 28-day SES and PES was generally poor, suggesting an inhibition of endothelial cell migration and proliferation, endothelial injury, and/or increased cell turnover. The expression of TM, a physiologically relevant regulator of platelets and coagulation, was also examined because the loss of TM function causes spontaneous thrombosis in the arterial and venous circulation (32). Overall staining for TM was absent or only weakly expressed in 14-and 28-day DES, and was even reduced in ML Vision control stents compared with nonstented segments.…”

Proteomic analysis reveals that apolipoprotein A1 levels are decreased in patients with Budd–Chiari syndrome

“…Consequently, when apo A1 concentration in plasma is decreased, this may potentially result in an impaired hemostatic balance and, thereby an increased tendency for thrombosis. Previous studies have shown that defects in the protein C pathway may, indeed, result in BCS, both in an experimental animal model [30] and in humans [5]. Another potential mode of action, recently published by Dahlbäck and colleagues, is that anionic phospholipids lose their procoagulant properties when incorporated into HDL [31].…”

Cre/loxP-mediated CTLA4IgG gene transfer induces clinically relevant immunosuppression via on–off gene recombination in vivo

“…Temporal, spatial, and cell type-specific control of Cre-mediated DNA recombination has been reported [24]. In particular, cardiac myocyte-specific [39] or endothelium-specific [40] recombination has been demonstrated using Cre cDNA, which is controlled by either cardiac-specific a-myosin heavy chain promoter or endothelial cell lineage-specific Tie2 promoter, respectively. Moreover, utilizing the cardiac-specific gene recombination system, the function of GATA4 gene [41] and serum response factor gene [39] required for cardiac development have recently been revealed.…”