Version May 2024
INTRODUCTION — Platelets play an important role in cardiovascular disease both in the pathogenesis of atherosclerosis and in the development of acute thrombotic events. Their importance in coronary disease and in acute coronary syndromes is indirectly confirmed by the benefit of antiplatelet agents (particularly aspirin, clopidogrel, and the glycoprotein IIb/IIIa inhibitors) in these disorders. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Aspirin in the primary prevention of cardiovascular disease and cancer".)
PLATELET ADHESION AND AGGREGATION — Both superficial and deep intimal injury disrupt the intact endothelium, which normally prevents the adherence of platelets by the production of the antiplatelet agents nitric oxide and prostacyclin. Disruption of the endothelium also exposes collagen. These factors lead to the adherence of platelets to the subendothelium, both directly and via von Willebrand factor, and, subsequently, to platelet activation (figure 1) [1].
The following is a brief summary of platelet adhesion and aggregation. These processes are discussed in detail separately. (See "Platelet biology and mechanism of anti-platelet drugs".)
Adhesion — Platelet adhesion is mediated by the binding of platelet receptors to a number of arterial wall receptors, including subendothelial collagen (whose corresponding platelet receptor is glycoprotein [GP] Ia/IIa), von Willebrand factor (GP Ib/IX and GP IIb/III), and fibrinogen (GP IIb/IIIa).
Activation — Binding of platelets to these structural proteins in concert with the action of soluble receptor-mediated stimulants, such as thrombin, adenosine diphosphate (ADP), and thromboxane A2 (TxA2), induces platelet activation. This process involves the mobilization of calcium from intracellular stores, the activation of several intracellular kinases, and the release of arachidonic acid from membrane phospholipids, resulting in the generation of TxA2 (figure 2) [2]. Platelet activation produced in vivo is enhanced by circulating catecholamines [3].
Aggregation — Platelet aggregation results from conversion of the IIb/IIIa receptor to a form that can bind adhesive proteins, such as fibrinogen. This process is normally opposed by the secretion of nitric oxide and of prostacyclin (PGI2), another product of arachidonic acid metabolism, from the vascular endothelium.
Secretion — During and after aggregation, platelets release many substances that can induce further platelet accumulation and activation, vasoconstriction, thrombosis, and mitogenesis, including adenosine diphosphate (ADP), serotonin, platelet-derived growth factor, fibroblast growth factor, platelet factor 4, and beta-thromboglobulin [2,4]. Platelet-released serotonin normally causes vasodilation; however, it can induce vasoconstriction in the presence of damaged or abnormal (dysfunctional) endothelium [5].
Activated platelets also release nitric oxide [6,7]. This response may prevent an excessive response by inhibiting platelet recruitment to the growing thrombus [7].
PATHOGENESIS OF THE ACUTE ISCHEMIC SYNDROME — Angiographic severity of coronary stenosis does not adequately predict the location of subsequent coronary artery occlusion [8]. Thus, rupture of atheromatous plaque and subsequent occlusive thrombus formation are believed to be responsible for most acute myocardial ischemic events, such as unstable angina and acute myocardial infarction [9-12]. However, systemic effects, such as inflammation due to systemic disease or infection, are more widespread within the coronary circulation and lead to instability of multiple plaques. (See 'Interaction of thrombosis, inflammation, and infection' below and "Mechanisms of acute coronary syndromes related to atherosclerosis".)
Coronary thrombosis — Coronary artery thrombosis is the final pathogenic mechanism of acute ischemic events, including myocardial infarction and sudden cardiac arrest. There are complex interactions among the atherosclerotic artery, endothelial injury and dysfunction, vasospasm, and platelet activation. Plaque rupture exposes thrombogenic subendothelial components, leading to platelet deposition and activation.
The following observations are compatible with the importance of platelet thrombus formation in acute ischemic syndromes:
●Thrombus formation within a coronary vessel is the acute precipitating event in most unstable ischemic coronary syndromes, as documented by angiographic and pathologic studies [13,14]. Among patients with sudden death due to coronary thrombosis, the thrombi typically have a layered appearance indicative of episodic growth [14]. Episodic growth may alternate with intermittent fragmentation of the thrombus, leading to distal embolization of both thrombus and platelet aggregates and microinfarction [14,15]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
●Aggregating platelets form the core of the growing thrombotic mass (white thrombus) at the disrupted plaque; the associated reduction in blood flow promotes upstream and/or downstream propagation of fibrin and red blood cell and leukocyte rich red thrombus [16,17]. Both subendothelial tissue factor and activated platelets themselves serve as stimuli for thrombin generation [18-20]. Platelets provide a membrane surface for the assembly of procoagulants, two of which (factors V and VIII) are released with activation. Persistent thrombotic occlusion of the coronary vessel leads to acute myocardial infarction.
●Increased platelet-derived thromboxane A2 and other prothrombotic prostaglandin metabolites have been found in patients with acute myocardial infarction and unstable angina, providing biochemical support for platelet activation as the cause of these events [14,21]. One prospective study, for example, found a phasic increase in the excretion of thromboxane A2 metabolites in 84 percent of episodes of unstable angina [21].
●Patients with unstable angina have elevated levels of P-selectin, an integral membrane protein involved in platelet adhesion, as well as adherence to immune cells [22]. Pulsatile shear stress, as occurs in stenotic arteries, can cause platelet aggregation via an increased expression of P-selectin [23]. Hydrodynamic shear stress, resulting from plaque rupture, can activate platelets and cause both platelet aggregation (via glycoprotein [GP] IIb/IIIa and von Willebrand factor) and platelet-mediated neutrophil aggregation via upregulation of P-selectin [24]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)
●Although levels of P-selectin decrease during the first month after treatment, levels remain higher than normal even with therapy with GP IIb/IIIa inhibitors, suggesting continued platelet activation [25]. This finding is consistent with serial angioscopic studies showing persistence of complex yellow plaque and thrombus after successful reperfusion at one month and later [26]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
●Aggregating platelets from patients with acute coronary syndromes produce less nitric oxide than those from patients with stable or no angina [27]. Why this might occur is not known, but impaired nitric oxide production can enhance platelet aggregation and thrombus formation.
●Despite treatment with platelet inhibitors, patients with acute cardiovascular events have enhanced platelet reactivity even at baseline [28]. However, no benefit for platelet function testing with corresponding medication adjustment was found in the setting of coronary disease when the testing was conducted before and soon after stenting [29], and the use of widespread platelet function testing for medication guidance remains unclear.
These findings are consistent with another platelet-related factor that has been associated with cardiovascular thrombosis, which is the presence of larger, more reactive platelets in patients with acute ischemic events [30-32]. The increase in platelet size, which may be in compensation for a persistent decrease in platelet count, results from the ongoing consumption of platelets in unstable angina; this is not seen in acute myocardial infarction [33]. In addition, platelets from patients with unstable angina, as determined by studying platelet aggregability ex vivo, are hyperaggregable [34]. These effects promote thrombus growth, limitation of blood flow, and acute ischemia.
Platelet reactivity is altered by a number of environmental factors, such as age, serum cholesterol, diabetes, catecholamine levels, cigarette smoking, obesity, and alcohol consumption. However, data from the Framingham Heart Study suggest that these factors play only a minor role, accounting for only 4 to 7 percent of variance; in contrast, estimates suggest that heritable factors play a major role, accounting for 20 to 30 percent of the overall variance in platelet aggregation [35].
Polymorphisms of platelet glycoprotein receptor genes — The functions of the platelet GP receptors have been described above. It has been suggested that polymorphisms in these receptors are a risk factor for coronary artery thrombosis [36], although data from Framingham suggest that these polymorphisms contribute minimally to platelet function [35]. Associations have been described for GP IIIa polymorphisms [37] and GP Ia/IIa polymorphisms [38,39]. However, many of these findings have not been confirmed in larger studies [35,40] or meta-analyses [41,42].
Interaction of thrombosis, inflammation, and infection — The mechanism of action of most platelet inhibitors is inhibition of fibrinogen-dependent platelet-platelet association.
Platelets are also involved in the inflammatory response and produce proinflammatory mediators such as platelet-derived growth factor, platelet factor 4, and transforming growth factor-beta, as well as CD40 ligand. Platelets possess many innate immune receptors that may be activated in the setting of infection. Patients with acute coronary syndromes have increased interactions between platelets (homotypic aggregates) and between platelets and leukocytes/neutrophils (heterotypic aggregates). These latter aggregates form when platelets are activated and adhere to circulating leukocytes or neutrophils.
Accumulating information suggests that inflammation plays an important role during the thrombotic phase of acute coronary syndromes. Leukocytes and neutrophils bind to platelets via P-selectin and beta-2-integrin, a process that requires platelet production of platelet-activating factor [43-46]. Leukocytes in turn may be able to enhance platelet aggregation [47,48], and the relationship between platelet-dependent thrombosis and inflammation is also governed, in part, by the platelet-surface receptor CD40 and its binding of CD40 ligand. These interactions suggest a mechanism for the coupling of thrombosis and inflammation during cardiac ischemia and are consistent with the increase in unstable coronary syndromes seen post-infection that is widely thought to be platelet mediated [49,50]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)
Clinically, acute infections are associated with a transient increase in the risk of thrombotic vascular events, many due to platelet activation [51]. In addition to thrombosis, platelets perform various immune functions during acute and chronic infections. For instance, patients with COVID-19 have been consistently noted to have enhanced clinical thrombosis presumed to be due to increased coagulation, enhanced platelet function inflammatory cytokines, endothelial damage, and activated immunity. Previous studies of patients with COVID-19 report hyperactive platelets with increased interleukin content [52].
THE EFFECT OF CARDIOVASCULAR RISK FACTORS ON PLATELET FUNCTION — Growing evidence suggests that enhanced platelet reactivity and thrombosis seen in acute coronary syndromes may be partially due to cardiovascular risk factors. Data have demonstrated that obese subjects may have hyper-reactive platelets or have a blunted response to platelet-inhibitory effect of aspirin [53] and the mechanism has been suggested to be leptin-dependent [54]. Information on blood pressure is mixed, but it appears platelet reactivity is exaggerated in hypertensive patients in the setting of exercise [55]. Lastly, diabetes has been associated with platelet hyperreactivity and the mechanism may be due to advanced glycation end products [56]. Other evolving risk factors attributed to platelet-dependent arterial thrombosis include systemic lupus erythematosus and hormone replacement therapy [49].
POSSIBLE ROLE OF PLATELETS IN ATHEROSCLEROSIS — A role for platelets in the evolutionary phase of the atherosclerotic plaque is suggested by the following observations:
●Platelets adhere to exposed subendothelium after endothelial injury and release vasoactive substances that induce smooth muscle cell migration and proliferation [57,58].
●Platelets may serve as a lipid source in the development of the fatty streak [59].
●Platelets can promote foam cell formation even in the absence of hyperlipidemia [60].
However, there is no direct clinical evidence that platelets contribute to coronary atherosclerosis [61].
Possible role in stable coronary disease — Platelets may play a role in stable coronary artery disease. This hypothesis is supported by a study in which circulating degranulated or activated platelets, enhanced platelet reactivity, and an increase in circulating monocyte-platelet aggregates were demonstrated in such patients [62].
SUMMARY
●Platelet activation – Platelets are activated by sequential steps, including adhesion, platelet-platelet interaction, and recruitment, which leads to thrombus formation.
●Coronary artery thrombosis – This is the final pathogenic mechanism of acute ischemic events, including myocardial infarction and sudden cardiac arrest. There are complex interactions within the atherosclerotic artery, endothelial injury and dysfunction, vasospasm, and platelet activation. Plaque rupture exposes thrombogenic subendothelial components, leading to platelet deposition and activation. (See 'Pathogenesis of the acute ischemic syndrome' above.)
●Platelet function – In the setting of arterial thrombosis, platelet function may be mediated by its interaction with immune cells and can be influenced by active infection.
●Role in early atherosclerosis – Platelets may also have a role in the evolutionary phase of the atherosclerotic plaque. (See 'Possible role of platelets in atherosclerosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Joseph Loscalzo for his past contributions as an author to this topic review.
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