Fatal thrombotic disease in designer mice lacking vascular thrombomodulin

The protein C pathway, which is initiated by the interaction of thrombin with the vascular surface protein thrombomodulin (TM), provides an important brake on blood clotting. Although defects in protein C, protein S, and clotting factor V, other players in this pathway, are known causes of thrombosis, the physiological role of TM in adult hemostasis has proved difficult to pin down, in part because TM serves an early, essential role in development. Indeed, Weiler and his colleagues have found that deletion of the Tm gene in mice causes early death of embryos and that the critical site of this protein’s developmental function is not the blood vessel endothelium, but the placenta. Now the same group has used the Cre/LoxP system to generate mice lacking the Tm gene specifically in endothelial cells. Many of these mice survive gestation but develop flagrant thrombosis in early adulthood and eventually die with a consumptive coagulopathy. Continuous low-dose exposure to the coagulation inhibitor warfarin prevents these symptoms and allows mice to survive despite the lack of TM, confirming that the disease is one of uncontrolled thrombosis. Males and females show different rates of disease progression in this strain, but the basis of this effect and the possible relation with the coincidence of disease and sexual maturity remain mysterious.

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