Acute coronary syndromes result from coronary plaque disruption that exposes the vascular basement membrane to circulating blood cells and plasma components. Exposure of the basement membrane leads to generation of a thrombus.
The formation of a thrombus consists of four distinct phases: platelet adhesion, activation, aggregation, and stabilization. The first step in this process is endothelial disruption, or plaque rupture, which exposes subendothelial collagen and other platelet-adhering ligands, such as von Willebrand factor (vWF) and fibronectin. Platelet receptors bind these ligands, causing adhesion of a thin platelet monolayer. Adhesion occurs primarily through binding of platelet glycoprotein IIb/IIIa receptors to collagen and GP Ib receptors to von Willebrand factor. The adhered platelets become activated and release alpha granules, which contain adenosine diphosphate (ADP), thromboxane, and serotonin. These substances, as well as other platelet agonists, cause local vasoconstriction and further activate surrounding platelets. Aspirin, a cyclooxygenase inhibitor, inhibits the synthesis of some of these thrombogenic substances, therefore slowing thrombogenesis activation. Platelets skimming along blood vessel walls recognize and adhese to certain proteins in the basement membrane including collagen, fibronectin and others. These and other platelets in this microenvironment are then activated by platelet agonists (ADP, epinephrine, thrombin, thromboxane A2, etc). Plaque disruption releases tissue factors that activate factor VII and the extrinsic coagulation pathway. The platelet surface activates both the extrinsic and intrinsic coagulation pathways, leading to the formation of thrombin. Thrombin converts fibrinogen to fibrin, thus providing a fibrin mesh that stabilizes the aggregate. Heparin inhibits this stabilization phase of thrombogenesis by combining with antithrombin III to inactivate factor X and prevent thrombin formation.
Platelet activation results in a conformational change of the platelet glycoprotein IIb/IIIa receptor on the surface and promotes externalization of the IIb/IIIa glycoproteins within. Each platelet contains 40,000 to 80,000 surface IIb/IIIa receptors and an additional 20,000 IIb/IIIa glycoproteins stored interiorly. Once platelet activation occurs, the glycoprotein IIb/IIIa receptor readily binds divalent fibrinogen molecules, thus cross-linking the adjacent platelets. Known as "platelet aggregation," this process results in a local platelet plug at the site of endothelial injury.
Activated platelets express 40,000-80,0000 glycoprotein IIb/IIIa inhibitors on their cell surfaces. Fibrinogen, a bivalent protein freely circulating in the serum, can then bind at each end to a glycoprotein IIb/IIIa receptor on two different platelets. This will quickly lead to a platelet –fibrinogen –rich thrombus in a coronary artery at the site of the initial plaque rupture.
If the thrombus obstructs flow of blood to downstream myocardium, ischemia or frank infarction is the result.
The formation of a thrombus consists of four distinct phases: platelet adhesion, activation, aggregation, and stabilization. The first step in this process is endothelial disruption, or plaque rupture, which exposes subendothelial collagen and other platelet-adhering ligands, such as von Willebrand factor (vWF) and fibronectin. Platelet receptors bind these ligands, causing adhesion of a thin platelet monolayer. Adhesion occurs primarily through binding of platelet glycoprotein IIb/IIIa receptors to collagen and GP Ib receptors to von Willebrand factor. The adhered platelets become activated and release alpha granules, which contain adenosine diphosphate (ADP), thromboxane, and serotonin. These substances, as well as other platelet agonists, cause local vasoconstriction and further activate surrounding platelets. Aspirin, a cyclooxygenase inhibitor, inhibits the synthesis of some of these thrombogenic substances, therefore slowing thrombogenesis activation. Platelets skimming along blood vessel walls recognize and adhese to certain proteins in the basement membrane including collagen, fibronectin and others. These and other platelets in this microenvironment are then activated by platelet agonists (ADP, epinephrine, thrombin, thromboxane A2, etc). Plaque disruption releases tissue factors that activate factor VII and the extrinsic coagulation pathway. The platelet surface activates both the extrinsic and intrinsic coagulation pathways, leading to the formation of thrombin. Thrombin converts fibrinogen to fibrin, thus providing a fibrin mesh that stabilizes the aggregate. Heparin inhibits this stabilization phase of thrombogenesis by combining with antithrombin III to inactivate factor X and prevent thrombin formation.
Platelet activation results in a conformational change of the platelet glycoprotein IIb/IIIa receptor on the surface and promotes externalization of the IIb/IIIa glycoproteins within. Each platelet contains 40,000 to 80,000 surface IIb/IIIa receptors and an additional 20,000 IIb/IIIa glycoproteins stored interiorly. Once platelet activation occurs, the glycoprotein IIb/IIIa receptor readily binds divalent fibrinogen molecules, thus cross-linking the adjacent platelets. Known as "platelet aggregation," this process results in a local platelet plug at the site of endothelial injury.
Activated platelets express 40,000-80,0000 glycoprotein IIb/IIIa inhibitors on their cell surfaces. Fibrinogen, a bivalent protein freely circulating in the serum, can then bind at each end to a glycoprotein IIb/IIIa receptor on two different platelets. This will quickly lead to a platelet –fibrinogen –rich thrombus in a coronary artery at the site of the initial plaque rupture.
If the thrombus obstructs flow of blood to downstream myocardium, ischemia or frank infarction is the result.
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