New insights into the mechanisms of venous thrombosis

Abstract

Venous thrombosis is a leading cause of morbidity and mortality in industrialized countries, especially in the elderly. Many risk factors have been identified for venous thrombosis that alter blood flow, activate the endothelium, and increase blood coagulation. However, the precise mechanisms that trigger clotting in large veins have not been fully elucidated. The most common site for initiation of the thrombus appears to be the valve pocket sinus, due to its tendency to become hypoxic. Activation of endothelial cells by hypoxia or possibly inflammatory stimuli would lead to surface expression of adhesion receptors that facilitate the binding of circulating leukocytes and microvesicles. Subsequent activation of the leukocytes induces expression of the potent procoagulant protein tissue factor that triggers thrombosis. Understanding the mechanisms of venous thrombosis may lead to the development of new treatments.

Figure 1. Activation of the coagulation cascade.

The coagulation cascade can be divided into the extrinsic (TF, FVIIa), intrinsic (FXIIa, FXIa, FIXa), and common (FXa and thrombin) pathways. The FIXa and FXa cofactors (FVIIIa and FVa, respectively) are not shown. Pathological activation of the extrinsic pathway is via TF expression in activated monocytes, monocyte-derived MVs, and possibly activated endothelial cells. Cellular RNA and polyphosphate (PolyP) released from activated platelets or bacteria activate FXIIa in the intrinsic pathway. The two new FDA-approved anticoagulant drugs rivaroxaban and dabigatran inhibit FXa and thrombin, respectively.

Figure 2. Proposed mechanisms for venous thrombosis.

My group proposed that formation of a venous thrombosis can be divided into distinct steps. First, the endothelium is activated by hypoxia and/or inflammatory mediators and expresses the adhesion proteins P-selectin, E-selectin, and vWF. Second, circulating leukocytes, platelets, and TF⁺ MVs bind to the activated endothelium. Third, the bound leukocytes become activated and express TF. The local activation of the coagulation cascade overwhelms the protective anticoagulant pathways and triggers thrombosis. The fibrin-rich clot also contains platelets and red blood cells.