A murine model of myocardial microvascular thrombosis

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gen e products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvascul ature. This study used mice with modifications of the thrombomodulin (TM) g ene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-ty pe plasminogen activator (uPA) gene. The results revealed that tPA played t he most important role in local regulation of fibrin deposition in the hear t, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomit ant modifications of tPA and TM, resulting in myocardial necrosis and depre ssed cardiac function. The data were fit to a statistical model that may of fer a foundation for examination of hemostasis-regulating gene interactions .