Microparticles in hemostasis and thrombosis

Abstract

Blood contains microparticles (MPs) derived from a variety of cell types, including platelets, monocytes, and endothelial cells. In addition, tumors release MPs into the circulation. MPs are formed from membrane blebs that are released from the cell surface by proteolytic cleavage of the cytoskeleton. All MPs are procoagulant because they provide a membrane surface for the assembly of components of the coagulation protease cascade. Importantly, procoagulant activity is increased by the presence of anionic phospholipids, particularly phosphatidylserine (PS), and the procoagulant protein tissue factor (TF), which is the major cellular activator of the clotting cascade. High levels of platelet-derived PS(+) MPs are present in healthy individuals, whereas the number of TF(+), PS(+) MPs is undetectable or very low. However, levels of PS(+), TF(+) MPs are readily detected in a variety of diseases, and monocytes appear to be the primary cellular source. In cancer, PS(+), TF(+) MPs are derived from tumors and may serve as a useful biomarker to identify patients at risk for venous thrombosis. This review will summarize our current knowledge of the role of procoagulant MPs in hemostasis and thrombosis.

Figure 1. Assembly of coagulation complexes on a PS⁺ phospholipid membrane

Coagulation complexes (TF:FVIIa; FVIIIa:FIXa; and FVa:FXa) assemble on a membrane surface. The presence of anionic phospholipids, such as PS (red), facilitate the binding of FVIIa, FIXa, FXa, and prothrombin (PT) by interaction with the Gla domains within the proteins. Phospholipids originating from the outer membrane before disruption of membrane asymmetry are shown in grey.

Figure 2. Surface markers of MPs released by different vascular cells

Figure 3. Proposed roles of platelet-derived and monocyte-derived MPs in hemostasis and thrombosis

PS⁺ MPs derived from platelets may play a role in hemostasis and may enhance thrombosis in certain diseases. Conversely, PS⁺, TF⁺ MP derived from monocytes may contribute to thrombosis and have a minor role in hemostasis.

Figure 4. Role of TF⁺ MPs in microvascular and venous thrombosis

A. Microvascular thrombosis in healthy mice. Leukocyte-derived TF⁺ MPs and vessel wall TF both appear to contribute to thrombosis induced by laser injury to cremaster arterioles. B. Cancer associated venous thrombosis. Tumors release TF⁺ MPs into the circulation where they are proposed to bind to activated endothelium and trigger venous thrombosis.