The role of platelets in coronary heart disease
- Jane E Freedman, MD
Jane E Freedman, MD
- Professor of Medicine
- UMass Memorial Heart and Vascular Center
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 "Antiplatelet agents in acute non-ST elevation acute coronary syndromes" and "Antiplatelet agents in acute ST elevation myocardial infarction" 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 and figure 2) .
The following is a brief summary of platelet adhesion and aggregation. These processes are discussed in detail separately. (See "Platelet biology".)
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 3) . Platelet activation produced in vivo is enhanced by circulating catecholamines .
- Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359:938.
- Ware, JA, Coller, BS. Platelet morphology, biochemistry and function. In: Williams' Hematology, Beutler, E, Lichtman, MA, Coller, BS, Kipps, TJ (Eds), McGraw Hill, New York 1994. p.1161.
- Lauri D, Cerletti C, de Gaetano G. Amplification of primary response of human platelets to platelet-activating factor: aspirin-sensitive and aspirin-insensitive pathways. J Lab Clin Med 1985; 105:653.
- Stein B, Fuster V, Israel DH, et al. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol 1989; 14:813.
- McFadden EP, Clarke JG, Davies GJ, et al. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med 1991; 324:648.
- Chen LY, Mehta JL. Further evidence of the presence of constitutive and inducible nitric oxide synthase isoforms in human platelets. J Cardiovasc Pharmacol 1996; 27:154.
- Freedman JE, Loscalzo J, Barnard MR, et al. Nitric oxide released from activated platelets inhibits platelet recruitment. J Clin Invest 1997; 100:350.
- Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988; 78:1157.
- Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984; 310:1137.
- Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983; 50:127.
- Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92:657.
- MacIsaac AI, Thomas JD, Topol EJ. Toward the quiescent coronary plaque. J Am Coll Cardiol 1993; 22:1228.
- DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303:897.
- Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985; 71:699.
- Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986; 73:418.
- Ueda Y, Asakura M, Hirayama A, et al. Intracoronary morphology of culprit lesions after reperfusion in acute myocardial infarction: serial angioscopic observations. J Am Coll Cardiol 1996; 27:606.
- Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 1986; 315:913.
- Moreno PR, Bernardi VH, López-Cuéllar J, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation 1996; 94:3090.
- Ardissino D, Merlini PA, Ariëns R, et al. Tissue-factor antigen and activity in human coronary atherosclerotic plaques. Lancet 1997; 349:769.
- Santos MT, Valles J, Marcus AJ, et al. Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment. J Clin Invest 1991; 87:571.
- Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315:983.
- Ikeda H, Takajo Y, Ichiki K, et al. Increased soluble form of P-selectin in patients with unstable angina. Circulation 1995; 92:1693.
- Merten M, Chow T, Hellums JD, Thiagarajan P. A new role for P-selectin in shear-induced platelet aggregation. Circulation 2000; 102:2045.
- Konstantopoulos K, Neelamegham S, Burns AR, et al. Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin. Circulation 1998; 98:873.
- Ault KA, Cannon CP, Mitchell J, et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1999; 33:634.
- Ueda Y, Asakura M, Yamaguchi O, et al. The healing process of infarct-related plaques. Insights from 18 months of serial angioscopic follow-up. J Am Coll Cardiol 2001; 38:1916.
- Freedman JE, Ting B, Hankin B, et al. Impaired platelet production of nitric oxide predicts presence of acute coronary syndromes. Circulation 1998; 98:1481.
- Frelinger AL 3rd, Furman MI, Linden MD, et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 2006; 113:2888.
- Montalescot G, Vicaut E, Collet JP. Bedside monitoring of antiplatelet therapy for coronary stenting. N Engl J Med 2013; 368:871.
- Erusalimsky JD, Martin JF. The regulation of megakaryocyte polyploidization and its implications for coronary artery occlusion. Eur J Clin Invest 1993; 23:1.
- Brown AS, Hong Y, de Belder A, et al. Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis. Arterioscler Thromb Vasc Biol 1997; 17:802.
- Endler G, Klimesch A, Sunder-Plassmann H, et al. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2002; 117:399.
- Mathur A, Robinson MS, Cotton J, et al. Platelet reactivity in acute coronary syndromes: evidence for differences in platelet behaviour between unstable angina and myocardial infarction. Thromb Haemost 2001; 85:989.
- Grande P, Grauholt AM, Madsen JK. Unstable angina pectoris. Platelet behavior and prognosis in progressive angina and intermediate coronary syndrome. Circulation 1990; 81:I16.
- O'Donnell CJ, Larson MG, Feng D, et al. Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation 2001; 103:3051.
- Simmonds RE, Hermida J, Rezende SM, Lane DA. Haemostatic genetic risk factors in arterial thrombosis. Thromb Haemost 2001; 86:374.
- Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ. Association of the platelet Pl(A) polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bbeta 448 polymorphism with myocardial infarction and extent of coronary artery disease. Circulation 1997; 96:1424.
- Moshfegh K, Wuillemin WA, Redondo M, et al. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study. Lancet 1999; 353:351.
- Casorelli I, De Stefano V, Leone AM, et al. The C807T/G873A polymorphism in the platelet glycoprotein Ia gene and the risk of acute coronary syndrome in the Italian population. Br J Haematol 2001; 114:150.
- Marian AJ, Brugada R, Kleiman NS. Platelet glycoprotein IIIa PlA polymorphism and myocardial infarction. N Engl J Med 1996; 335:1071.
- Zhu MM, Weedon J, Clark LT. Meta-analysis of the association of platelet glycoprotein IIIa PlA1/A2 polymorphism with myocardial infarction. Am J Cardiol 2000; 86:1000.
- Di Castelnuovo A, de Gaetano G, Donati MB, Iacoviello L. Platelet glycoprotein receptor IIIa polymorphism PLA1/PLA2 and coronary risk: a meta-analysis. Thromb Haemost 2001; 85:626.
- Kirchhofer D, Riederer MA, Baumgartner HR. Specific accumulation of circulating monocytes and polymorphonuclear leukocytes on platelet thrombi in a vascular injury model. Blood 1997; 89:1270.
- Ostrovsky L, King AJ, Bond S, et al. A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood 1998; 91:3028.
- Li N, Hu H, Lindqvist M, et al. Platelet-leukocyte cross talk in whole blood. Arterioscler Thromb Vasc Biol 2000; 20:2702.
- Hu H, Varon D, Hjemdahl P, et al. Platelet-leukocyte aggregation under shear stress: differential involvement of selectins and integrins. Thromb Haemost 2003; 90:679.
- Faraday N, Scharpf RB, Dodd-o JM, et al. Leukocytes can enhance platelet-mediated aggregation and thromboxane release via interaction of P-selectin glycoprotein ligand 1 with P-selectin. Anesthesiology 2001; 94:145.
- Del Maschio A, Evangelista V, Rajtar G, et al. Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents. Am J Physiol 1990; 258:H870.
- Tamminen M, Lassila R, Westerbacka J, et al. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Int J Obes Relat Metab Disord 2003; 27:907.
- Konstantinides S, Schäfer K, Koschnick S, Loskutoff DJ. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108:1533.
- Gkaliagkousi E, Gavriilaki E, Yiannaki E, et al. Platelet activation in essential hypertension during exercise: pre- and post-treatment changes with an angiotensin II receptor blocker. Am J Hypertens 2014; 27:571.
- Zhu W, Li W, Silverstein RL. Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36. Blood 2012; 119:6136.
- Hoak JC. Platelets and atherosclerosis. Semin Thromb Hemost 1988; 14:202.
- Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357:2482.
- CHANDLER AB, HAND RA. Phagocytized platelets: a source of lipids in human thrombi and atherosclerotic plaques. Science 1961; 134:946.
- Mendelsohn ME, Loscalzo J. Role of platelets in cholesteryl ester formation by U-937 cells. J Clin Invest 1988; 81:62.
- Elwood PC, Renaud S, Beswick AD, et al. Platelet aggregation and incident ischaemic heart disease in the Caerphilly cohort. Heart 1998; 80:578.
- Furman MI, Benoit SE, Barnard MR, et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31:352.
- PLATELET ADHESION AND AGGREGATION
- PATHOGENESIS OF THE ACUTE ISCHEMIC SYNDROME
- Coronary thrombosis
- Polymorphisms of platelet glycoprotein receptor genes
- Interaction of thrombosis and inflammation
- THE EFFECT OF CARDIOVASCULAR RISK FACTORS ON PLATELET FUNCTION
- POSSIBLE ROLE OF PLATELETS IN ATHEROSCLEROSIS
- Possible role in stable coronary disease