Abstract

Procoagulant Extracellular Vesicles in Hemostasis and Thrombosis

Nigel Mackman, , University of North Carolina at Chapel Hill

The coagulation cascade consists of a series of cofactor/protease complexes (tissue factor (TF)/FVIIa; FVIIIa/FIXa; FVa/FXa) that assemble on membrane surfaces and result in the formation of fibrin. TF is a transmembrane receptor for FVII/FVIIa and the TF/FVIIa complex is the major initiator of the clotting cascade. The clotting cascade plays an essential role in hemostasis but also contributes to pathologic thrombosis. Several coagulation proteases (FIX, FX, FVII and prothrombin) contain a Gla domain that is positively-charged. Normal cells have an asymmetric membrane with negatively-charged phospholipids, such as phosphatidylserine (PS), located on the inner leaflet of the membrane. However, after cell damage PS flips to the outer leaflet of the membrane where it facilitates the binding and assembly of Gla-containing coagulation proteases and activation of coagulation at sites of injury. Extracellular vesicles (EVs) are small vesicles derived from activated or apoptotic cells. There are several types of EVs that can enhance coagulation depending on the presence of exposed PS and TF. For instance, PS^-,TF^- EVs have the lowest procoagulant activity (PCA) whereas PS⁺,TF⁺ EVs have the highest PCA. The majority of EVs in blood are derived from platelets and were originally described as platelet dust. These PS⁺ and PS^-EVs can enhance ongoing coagulation but cannot trigger coagulation. In contrast, EVs derived from activated monocytes and many types of tumors express PS and TF and can activate coagulation. PS⁺,TF⁺ EVs have been detected in the blood of patients with experimental endotoxemia, liver injury, cirrhosis, sickle cell disease, influenza A infection and cancer. These EVs likely contribute to thrombosis in these patients. Several prospective studies found that increased levels of TF⁺ EV precede venous thrombosis in pancreatic cancer patients. These studies suggest that TF⁺EVs could be used as a biomarker to identify patients at increased risk for venous thrombosis.