Role of Platelets in Arterial Thrombosis

The exposure of subendothelial matrix leads to almost instantaneous adhesion of platelets to the site of vascular injury. Two molecules in the subendothelium are critical to this step: von Willebrand factor (vWF) and collagen. Platelets bind to vWF and collagen fibrils via the receptors glycoprotein (GP) Ib and Ia/IIa, respectively. This receptor-ligand interaction starts the process of platelet activation; it triggers a series of intracellular signaling events that result in cytoskeletal rearrangement, shape change, and release of alpha and dense granules. These storage granules contain substances, such as adenosine diphosphate (ADP), serotonin, fibrinogen, and thrombospondin, that promote aggregation and recruitment of additional platelets to the growing hemostatic plug. In addition, thromboxane A_2, formed after cyclooxygenase cleavage of arachidonic acid and released during platelet activation, is both a potent platelet agonist and vasoconstrictor.

The platelet receptor GPIIb/IIIa then undergoes a calcium (Ca⁺⁺)-dependent conformational change that allows it to bind to additional vWF and circulating fibrinogen. GPIIb/IIIa is the most abundant glycoprotein on the platelet surface, with approximately 50,000 copies expressed on resting platelets, and additional GPIIb/IIIa receptors within the cytosol that are mobilized to the surface after activation. Fibrinogen can simultaneously bind two GPIIb/IIIa receptors, thereby linking neighboring platelets. This results in platelet aggregation, formation of a fibrin network, and ultimately stabilization of the mass into a white thrombus. Red blood cells eventually become enmeshed in the platelet-fibrin aggregate and produce a more fully formed red thrombus. Aggregated platelets then provide cell-surface phospholipid for the assembly of coagulation factor complexes, forming a link with the processes of secondary hemostasis.

Platelets are particularly relevant in the high-pressure arterial circulation, where minor vascular damage can rapidly lead to major hemorrhage. The hemostatic system must therefore promptly control bleeding. Platelets assume a critical role in this response, because they initially contain blood loss and, as a second step, provide an active surface for rapid fibrin and, ultimately, clot formation. In contrast, in the low-pressure venous circulation, platelets are less relevant as the pivotal reaction controlling hemostats is the rate of thrombin generation.

These pathophysiologic differences define the antithrombotic or anticoagulant agents used in each situation. Antiplatelet agents are the treatment of choice to prevent coronary artery disease or arterial ischemic stroke, whereas antithrombin-based interventions, such as heparin and warfarin, are used for prophylaxis and treatment of systemic and cerebral venous thrombosis. Aspirin is an irreversible inhibitor of platelet cyclooxygenase-1 (COX-1) activity, thereby blocking thromboxane A₂ formation for the lifetime of that platelet. Clopidogrel inhibits platelet activation and aggregation through the irreversible binding of its active metabolite to the ADP receptors on platelets, preventing activation of the GPIIb/IIIa receptor. Dipyridamole inhibits platelet phosphodiesterase, thereby raising cyclic adenosine monophosphate (cAMP) levels, thus interfering with platelet aggregation. Nonsteroidal anti-inflammatory drugs (NSAIDs) bind to COX-1 reversibly and competitively, and thus their effects are dependent on plasma levels of the drug, unlike aspirin.

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