A murine model of myocardial microvascular thrombosis

Abstract

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene 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 microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statis tical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking

“…3,17 This is consistent with the enhanced macrovascular fibrin deposition and atherogenesis seen in genetic murine models of tPA and plasminogen deficiency. 5,18 It is likely, however, that both processes, impaired fibrinolysis and atherogenesis, cooperate and interact to damage vascular function and structure.…”

“…4 Indeed, in genetic murine models, tPA deficiency is associated with myocardial necrosis and the development of regional wall motion abnormalities. 5 Recently, Rosenberg and Aird 4 postulated that vascular bed-specific defects in hemostasis exist and that coronary thrombosis critically depends on the local fibrinolytic balance. To date, however, no clinical studies have directly assessed the acute local fibrinolytic capacity of the coronary vascular bed in patients with coronary artery disease.…”

Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo

“…Tissues were harvested, weighed, and stored frozen in liquid N 2 . Fibrin was extracted exactly as described (26,27). Proteins were resolved by 7.5% SDS-PAGE and transferred to nitrocellulose membranes.…”

Association of G-33A Polymorphism in the Thrombomodulin Gene with Myocardial Infarction in Koreans.

“…The TM-thrombin complex can activate protein C, which then acts as a potent anticoagulant (1). Studies on mice without functional TM (2) as well as on rare mutations in the TM gene reported in patients of myocardial infarction (MI) (3,4) have suggested that dysfunction of TM plays an important role in the pathorisk for MI (6). According to the latter study, the three SNPs may be more common in Asians than Caucasians, although the authors did not provide precise frequencies of the polymorphisms in clearly defined ethnic populations.…”