New insights into the mechanisms of venous thrombosis (original) (raw)
A blood clot contains a mixture of platelets and fibrin and in some cases red blood cells (1, 33). Importantly, the etiologies of arterial and venous clots are very different (1). Arterial clots are formed under high shear stress, typically after rupture of an atherosclerotic plaque or other damage to the blood vessel wall (34–36). They are platelet-rich (so called “white clots”) and are generally treated with antiplatelet drugs. In contrast, venous clots form under lower shear stress on the surface of a largely intact endothelium (36–39). They are fibrin-rich (so called “red clots” because they also contain red blood cells) and are treated with anticoagulant drugs.
The blood coagulation cascade can be divided into three parts: the extrinsic, intrinsic, and common pathways (Figure 1 and reviewed in refs. 39–42). Under pathological conditions, tissue factor (TF) is expressed on circulating leukocytes and possibly activated endothelial cells (40). In addition, TF is present on microvesicles (MVs), which are small membrane vesicles released from activated cells (43–45). These intravascular sources of TF may trigger the formation of venous clots. Recent studies have shown that FXII can be activated by extracellular RNA and polyphosphates and this activation of the intrinsic pathway may also contribute to venous thrombosis (46–49).
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.
The coagulation cascade is regulated at several levels by different anticoagulant pathways (50). TF pathway inhibitor blocks the TF/FVIIa complex, whereas antithrombin inhibits all coagulation proteases, including thrombin (51, 52). Binding of thrombin to thrombomodulin on the surface of endothelial cells changes its substrate specificity from fibrinogen to protein C and therefore plays a key role in shutting down the clotting cascade (53). Binding of protein C to the endothelial cell protein C receptor enhances its conversion to activated protein C, which in association with its cofactor protein S, cleaves and inactivates both FVa and FVIIIa (54). Importantly, loss of a single anticoagulant pathway leads to embryonic lethality (50). One explanation for this observation is that different tissues use distinct anticoagulant pathways to regulate clotting (50, 55). Clots in blood vessels are removed by proteolytic digestion of fibrin by plasmin (56). Levels of plasmin are regulated by plasminogen activators and inhibitors, particularly plasminogen activator inhibitor 1 (PAI-1) (57). This explains why elevated levels of PAI-1 are associated with thrombosis (8).
Traditionally, VTE is treated with anticoagulant drugs to prevent growth and embolization of the thrombus. Patients initially receive some form of injectable heparin, which acts rapidly, followed by a more prolonged course of an oral vitamin K antagonist (58–60). These drugs have been used for over 50 years. Heparins inhibit FXa and thrombin in an antithrombin-dependent manner, whereas vitamin K antagonists reduce the activity of vitamin K–dependent proteins, including FVIIa, FIXa, FXa, and thrombin. The limitations of these drugs have fueled the search for new anticoagulant therapies. Over the past 5 years, several new oral drugs have been developed, the two most advanced of which are rivaroxaban (Xarelto), which selectively inhibits FXa, and dabigatran etexilate (Pradaxa), which selectively inhibits thrombin (Figure 1 and refs. 61–65). Rivaroxaban was shown to be superior to the low-molecular-weight heparin enoxaparin in reducing VTE in four clinical trials involving total knee and hip replacement (65); in 2011, it was approved by the FDA for thrombosis prophylaxis to reduce the risk of DVT and PE following knee and hip replacement surgery. Dabigatran showed non-inferiority to enoxaparin in 3 out of 4 trials for high-risk orthopedic patients but has not been approved for thrombosis prophylaxis in this population (60).