Role of Microparticles in Hemostasis and Thrombosis

Abstract SCI-10

Microparticles (MPs) (also known as or microvesicles) are submicron plasma membrane vesicles released from activated or apoptotic cells. Current estimates indicate that MPs are ∼200 nm in diameter. They are formed as membrane blebs and have phosphatidylserine exposed on the surface due to a loss of membrane asymmetry. MPs containing tissue factor (TF) are highly procoagulant. We recently developed an assay to measure TF activity of MPs isolated from plasma. We found that healthy individuals contain low levels of TF+ MPs, but levels are increased in many pathological conditions associated with thrombosis, such as sepsis, cardiovascular disease, sickle cell disease, diabetes mellitus, and cancer. We have analyzed the role of TF+ MPs in various murine models of thrombosis and in different patient populations. Work in collaboration with Bruce and Barbara Furie demonstrated that leukocyte-derived TF+ MPs contributed to microvascular thrombosis in a model of laser injured cremaster arterioles using healthy mice. Further studies have been performed using different murine models of disease. Arterial thrombosis is mostly caused by rupture of atherosclerotic plaques and leads to myocardial infarction and stroke. In hypercholesterolemic LDLR−/− mice we observed increased levels of hematopoietic cell-derived TF+ MPs that were associated with a prothrombotic state. These TF+ MPs may enhance thrombosis after plaque rupture. Indeed, we observed more fibrin deposition in the laser injury model of thrombosis in hypercholesterolemic mice than controls. Importantly, we found that simvastatin reduced TF expression in mononuclear cells and levels of TF+ MPs in the plasma in these hypercholesterolemic mice. Venous thrombosis occurs without significant damage to the vessel wall and is associated with embolization of clot fragments that can block pulmonary arteries. Venous clots appear to form due to changes in the vessel wall, stasis, and/or increased coagulability of the blood. We have analyzed levels of TF+ MPs in murine cancer models and cancer patient samples. We and other have found that tumors release TF+ MPs into the circulation. In one study, we found that pancreatic patients with the highest levels of MP TF activity develop thrombosis. These results suggest that TF+ MPs may enhance venous thrombosis in cancer patients by binding to activated endothelium. Further studies are needed to determine if levels of TF+ MPs in the circulation can be used to identify patients at risk for thrombosis.