Thrombus composition varies greatly between arteries and veins. An arterial clot is primarily triggered by the rupture of an artherosclerotic plaque (Figure 4a). Upon plaque rupture, platelets are rapidly recruited to the site through interaction of specific platelet cell-surface receptors with collagen and von Willebrand factor. Platelets adherant to the vessel wall then propagate thrombus growth by binding additional platelets in a receptor-dependent manner. This induces platelets to release factors that further promote platelet recruitment, adhesion, aggregation, and activation. Acute arterial thrombosis is the most common cause of death in the developed world and antiplatelet drugs are used prophylactically to reduce the incidence of arterial thrombosis in patients with cardiovascular disease. These drugs target platelet activation and aggregation. Atherosclerotic plaques also contain high levels of TF that trigger the activation of the clotting cascade upton plaque rupture.
Figure 4: Triggers of arterial and venous thrombosis*
Thrombi that occur in the veins are rich in fibrin and primarily occur without damage to the vessel wall (Figure 4b). Venous thromboembolism (VTE) occurs due to changes in the composition of the blood, changes that reduce or abolish blood flow, and/or changes to the endothelium. In addition, genetic and enviornmental factors can increase the risk of developing venous thromboembolism. A genetic predisposition to thrombosis, termed thrombophilia, results from an increased activity or abundance of proteins that promote coagulation and/or decreased abundance of proteins that inhibit coagulation. Acquired risk factors include cancer, obesity, oral contraceptives and major surgery. Increased amounts of circulating TF in the form of microparticles may also contribute to venous thrombosis. Venous thrombosis is treated with anticoagulant drugs to reduce the activity of various proteases within the coagulation cascade. There are three classes of anticoagulant drugs: 1) direct inhibitors of FXa and thrombin; 2) vitamin K antagonists which inhibit post-translational modification of FVII, FIX, FX and thrombin; 3) indirect thrombin inhibitors (heparin) bind to antithrombin and increase its affinity for thrombin.
*Figure 4 reproduced from Mackman, N. Triggers, targets, and treatments for thrombosis. Nature, 2008, 451 (7181): 914-8.