Arterial and venous thromboses are major causes of morbidity and mortality rates. Arterial thrombosis is the most common cause of acute myocardial infarction (MI), ischemic stroke, and limb gangrene, whereas deep-vein thrombosis (DVT) leads to pulmonary embolism (PE), which can be fatal, and to the postphlebitic syndrome. Most arterial thrombi are superimposed on disrupted atherosclerotic plaque because plaque rupture exposes thrombogenic material in the plaque core to the blood. This material then triggers platelet aggregation and fibrin formation, which results in the generation of a platelet-rich thrombus that can temporarily or permanently occlude blood flow. In contrast to arterial thrombi, venous thrombi rarely form at sites of obvious vascular disruption. Although they can develop after surgical trauma to veins or secondary to indwelling venous catheters, venous thrombi usually originate in the valve cusps of the deep veins of the calf or in the muscular sinuses, where they are triggered by stasis. Sluggish blood flow in these veins reduces the oxygen supply to the avascular valve cusps. Endothelial cells lining these valve cusps become activated and express adhesion molecules on their surface. Tissue factor–bearing leukocytes and microparticles adhere to these activated cells and induce coagulation. Local thrombus formation is exacerbated by reduced clearance of activated clotting factors as a result of impaired blood flow. If the thrombi extend into more proximal veins of the leg, thrombus fragments can dislodge, travel to the lungs, and produce a PE.
Arterial and venous thrombi are composed of platelets and fibrin, but the proportions differ. Arterial thrombi are rich in platelets because of the high shear in the injured arteries. In contrast, venous thrombi, which form under low shear conditions, contain relatively few platelets and are predominantly composed of fibrin and trapped red cells. Because of the predominance of platelets, arterial thrombi appear white, whereas venous thrombi are red in color, reflecting the trapped red cells.
Antithrombotic drugs are used for prevention and treatment of thrombosis. Targeting the components of thrombi, these agents include (1) antiplatelet drugs, (2) anticoagulants, and (3) fibrinolytic agents (Fig. 118-1). With the predominance of platelets in arterial thrombi, strategies to inhibit or treat arterial thrombosis focus mainly on antiplatelet agents, although, in the acute setting, they often include anticoagulants and fibrinolytic agents. Anticoagulants are the mainstay of prevention and treatment of venous thromboembolism because fibrin is the predominant component of venous thrombi. Antiplatelet drugs are less effective than anticoagulants in this setting because of the limited platelet content of venous thrombi. Fibrinolytic therapy is used in selected patients with venous thromboembolism. For example, patients with massive or submassive PE can benefit from systemic or catheter-directed fibrinolytic therapy. The latter can also be used as an adjunct to anticoagulants for treatment of patients with extensive iliofemoral-vein thrombosis.
Classification of antithrombotic drugs.
Role of Platelets in Arterial Thrombosis
In healthy vasculature, circulating platelets are maintained in an inactive state by nitric oxide (NO) and prostacyclin released by endothelial cells lining the blood vessels. In addition, endothelial cells also express CD39 on their surface, a membrane-associated ecto-adenosine diphosphatase (ADPase) that degrades ADP released from activated platelets. When the vessel wall is damaged, release of these substances is impaired and subendothelial matrix is exposed. Platelets adhere to exposed collagen via α2β1 and glycoprotein (GP)V1 and to von Willebrand factor (vWF) via GPIbα and GPIIb/IIIa (αIIbβ3)—receptors that are constitutively expressed on the platelet surface. Adherent platelets undergo a change in shape, secrete ADP from their dense granules, and synthesize and release thromboxane A2. Released ADP and thromboxane A2, which are platelet agonists, activate ambient platelets and recruit them to the site of vascular injury (Fig. 118-2).
Coordinated role of platelets and the coagulation system in thrombogenesis. Vascular injury simultaneously triggers platelet activation and aggregation and activation of the coagulation system. Platelet activation is initiated by exposure of subendothelial collagen and von Willebrand factor (vWF), onto which platelets adhere. Adherent platelets become activated and release ADP and thromboxane A2, platelet agonists that activate ambient platelets and recruit them to the site of injury. When platelets are activated, glycoprotein IIb/IIIa on their surface undergoes a conformational change that enables it to ligate fibrinogen and mediate platelet aggregation. Coagulation is triggered by tissue factor exposed at the site of injury. Tissue factor triggers thrombin generation. As a potent platelet agonist, thrombin amplifies platelet recruitment to the site of injury. Thrombin also converts fibrinogen to fibrin, and the fibrin strands then weave the platelet aggregates together to form a platelet/fibrin thrombus.
Disruption of the vessel wall also exposes tissue factor–expressing cells to the blood. Tissue factor initiates coagulation. Activated platelets potentiate coagulation by binding clotting factors and supporting the assembly of activation complexes that enhance thrombin generation. In addition to converting fibrinogen to fibrin, thrombin also serves as a potent platelet agonist and recruits more platelets to the site of vascular injury.
When platelets are activated, GPIIb/IIIa, the most abundant receptor on the platelet surface, undergoes a conformational change that enables it to bind fibrinogen and, under high shear conditions, vWF. Divalent fibrinogen or multivalent vWF molecules bridge adjacent platelets together to form platelet aggregates. Fibrin strands, generated through the action of thrombin, then weave these aggregates together to form a platelet/fibrin mesh.
Antiplatelet drugs target various steps in this process. The commonly used drugs include aspirin, thienopyridines (clopidogrel, prasugrel, and ticlopidine), dipyridamole, and GPIIb/IIIa antagonists.
The most widely used antiplatelet agent worldwide is aspirin. As a cheap and effective antiplatelet drug, aspirin serves as the foundation ...