Triggers, targets and treatments for thrombosis

Abstract

Thrombosis--localized clotting of the blood--can occur in the arterial or the venous circulation and has a major medical impact. Acute arterial thrombosis is the proximal cause of most cases of myocardial infarction (heart attack) and of about 80% of strokes, collectively the most common cause of death in the developed world. Venous thromboembolism is the third leading cause of cardiovascular-associated death. The pathogenic changes that occur in the blood vessel wall and in the blood itself resulting in thrombosis are not fully understood. Understanding these processes is crucial for developing safer and more effective antithrombotic drugs.

Figures

Figure 1. Triggers of arterial and venous thrombosis

a, Artery. The primary trigger of arterial thrombosis is rupture of an atherosclerotic plaque. This involves disruption of the endothelium and release of constituents of the plaque into the lumen of the blood vessel. b, Vein. By contrast, in venous thrombosis, the endothelium remains intact but can be converted from a surface with anticoagulant properties to one with procoagulant properties. Venous thrombosis can be triggered by several factors: abnormal blood flow (such as the absence of blood flow); altered properties of the blood itself (thrombophilia); and alterations in the endothelium.

Figure 2. Targets of antiplatelet drugs

Platelets have a variety of cell-surface receptors that mediate their activation (green shading), their adhesion to the blood vessel wall (red) and their aggregation with each other (blue). The ligands for various receptors are shown. Antiplatelet drugs and their targets are also indicated; targets include thromboxane A2 (TXA2), protease-activated receptor 1 (PAR1), the ADP receptor P2Y12 and αIIbβ3-integrin.

Figure 3. Targets of anticoagulant drugs

Tissue factor is present at high concentrations in atherosclerotic plaques. When exposed to the blood — for example, when a plaque ruptures — tissue factor binds to the plasma protein factor VIIa (the extrinsic pathway, red), and this complex triggers activation of the coagulation cascade through the proteolytic cleavage of both factor X and factor IX. This cascade ultimately generates fibrin (through the common pathway, orange), which (on polymerization) stabilizes platelet thrombi. The coagulation cascade is amplified by the tenase complex, which consists of factor VIIIa and factor IXa (components of the intrinsic pathway, blue). Factor XIa and factor XIIa might also help to activate the coagulation cascade under pathological conditions. Triggers of thrombosis are shown in bold face. Anticoagulant drugs that are in current use (black) and in development (grey) are listed, and their targets are also indicated (red blocking arrows).