Role of tissue factor in venous thrombosis

Abstract

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality worldwide. However, the mechanisms by which clots are formed in the deep veins have not been determined. Tissue factor (TF) is the primary initiator of the coagulation cascade and is essential for hemostasis. Under pathological conditions, TF is released into the circulation on small-membrane vesicles termed microparticles (MPs). Recent studies suggest that elevated levels of MP TF may trigger thrombosis. This review provides an overview of the role of TF in VTE.

Figure 1

Formation of a venous clot. Venous thrombi are fibrin-rich clots that develop in the absence of gross endothelial damage. In a healthy vein (left), high levels of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), and endothelial cell protein C receptor (EPCR) maintain an antithrombotic phenotype (normal endothelium). In pathological conditions (right), elevated levels of tissue factor (TF)-positive microparticles (MPs) are present in the blood, and reduced blood flow, activation of the venous endothelium, and deposition of platelets may conspire to trigger formation of a thrombotic clot. Here we present two potential mechanisms that initiate activation of the coagulation system: (a) TF-positive MPs expressing P-selectin glycoprotein-1 (PSGL-1) dock to an activated endothelium expressing P-selectin, and (b) TF-positive MPs bind to activated platelets that adhere to the activated endothelium. In both cases, the presence of MP TF serves as a potent trigger of coagulation activation, and the continuous delivery of TF-positive MPs may enhance propagation of the thrombus.