Platelets in Atherothrombosis
2006; Elsevier BV; Volume: 81; Issue: 1 Linguagem: Inglês
10.4065/81.1.59
ISSN1942-5546
AutoresDavid Vorchheimer, Richard Becker,
Tópico(s)Platelet Disorders and Treatments
ResumoAtherosclerosis is a diffuse, systemic disease that affects the coronary, cerebral, and peripheral arterial trees. Disruption of atherosclerotic plaques leads to thrombus formation and arterial occlusion. This unpredictable and potentially life-threatening atherothrombotic sequence underlies clinical events such as angina, myocardial infarction, transient ischemic attacks, and stroke. One of the key components of a clot is the platelet. Although it was previously thought that platelets were relatively inactive cells that merely provided a framework for the attachment of other cells and proteins to mechanically stop bleeding due to injury, it is now known that this is not the case. Platelets secrete and express a large number of substances that are crucial mediators of both coagulation and inflammation. This article reviews the centrality of the platelet in atherothrombosis and briefly looks at the efficacy of antiplatelet agents in preventing and treating cardiovascular disease. Atherosclerosis is a diffuse, systemic disease that affects the coronary, cerebral, and peripheral arterial trees. Disruption of atherosclerotic plaques leads to thrombus formation and arterial occlusion. This unpredictable and potentially life-threatening atherothrombotic sequence underlies clinical events such as angina, myocardial infarction, transient ischemic attacks, and stroke. One of the key components of a clot is the platelet. Although it was previously thought that platelets were relatively inactive cells that merely provided a framework for the attachment of other cells and proteins to mechanically stop bleeding due to injury, it is now known that this is not the case. Platelets secrete and express a large number of substances that are crucial mediators of both coagulation and inflammation. This article reviews the centrality of the platelet in atherothrombosis and briefly looks at the efficacy of antiplatelet agents in preventing and treating cardiovascular disease. In general, atherosclerosis describes the hardening of an artery due to a loss of elasticity in its intimal and medial layers. Flexibility is lost when yellowish plaques made up of cholesterol, lipids, and cellular debris form in these inner layers. Atherosclerosis is a diffuse, systemic disease because plaques can arise in the large and medium arteries of any arterial tree, affecting the coronary, cerebral, and/or peripheral vascular beds. It is also a lifelong progressive disorder, with its precursor components, known as fatty streaks, universally present by late childhood. The development of atherosclerotic lesions over time and their close association with thrombotic complications are collectively known as atherothrombosis. Although the fatty streak constitutes the initial lesion, subsequent plaque formation and growth are heavily influenced by factors that damage and/or disrupt the normal functioning of the endothelial lining of the artery. Such factors include smoking (which introduces chemical irritants into the artery), diabetes mellitus (advanced glycation end products), hypercholesterolemia (increased circulation of lipids and monocytes), and hypertension (increased shear forces at arterial branches or points of curvature). Damage can also be caused by circulating vasoactive amines, immune complexes, and, possibly, infectious pathogens.1Fuster V Gotto AM Libby P Loscalzo J McGill HC 27th Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events, Task Force 1: pathogenesis of coronary disease: the biologic role of risk factors.J Am Coll Cardiol. 1996; 27: 964-976Abstract Full Text PDF PubMed Scopus (102) Google Scholar, 2Yusuf S Hawken S Ounpuu S INTERHEART Study Investigators et al.Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet. 2004; 364: 937-952Abstract Full Text Full Text PDF PubMed Scopus (8413) Google Scholar Atherothrombosis has essentially 5 phases.3Fuster V Lewis A Conner Memorial Lecture: mechanisms leading to myocardial infarction: insights from studies of vascular biology [published correction appears in Circulation. 1995;91:256].Circulation. 1994; 90: 2126-2146Crossref PubMed Google Scholar In the first phase, endothelial dysfunction stimulates the deposition, accumulation, and oxidation of low-density lipoprotein cholesterol within the cells of the intima. The second and third phases are the recruitment of inflammatory cells to the endothelium and the growth of a plaque; during these phases, smooth muscle cells migrate to the lesion and replicate, and lipid-laden foam cells accumulate, held together by extracellular matrix macromolecules such as collagen and elastin. As these processes occur and the plaque matures, its surface calcifies to form a fibrous cap. During the fourth stage of atherothrombosis, the balance of smooth muscle cell proliferation and removal changes, and breakdown outstrips formation. The fibrous cap then ruptures, or the lesion surface erodes, exposing the prothrombotic contents of the plaque to the circulating blood. This triggers a dynamic coagulatory response in which the platelet plays a primary role, resulting in the formation of a platelet-rich thrombus over the disrupted lesion (the fifth phase) and mechanical disruption of the diseased artery. If blood flow is sufficiently impeded, clinical manifestations (acute coronary syndromes, ischemic stroke, and critical limb ischemia) result.4Munger MA Hawkins DW Atherothrombosis: epidemiology, pathophysiology, and prevention.J Am Pharm Assoc (Wash DC). 2004; 44: S5-S12PubMed Scopus (58) Google Scholar Such a succinct summary of these phases belies the fact that the pathology of atherothrombosis is extremely complex and there is still much to learn. Not all plaques produce clinically overt ischemic events when they rupture or erode.5Pasterkamp G Falk E Atherosclerotic plaque rupture: an overview.J Clin Basic Cardiol. 2000; 3: 81-86Google Scholar The surface of an unstable plaque undergoes continualrenovation, and many cycles of rupture, thrombosis, and healing may occur before symptoms manifest. Because the platelet is central to these processes, it is a prime therapeutic target for the management and prevention of adverse clinical sequelae related to atherothrombosis, and it is therefore the topic of this review. Platelets, also known as thrombocytes, are fragments of large bone marrow-derived cells called megakaryocytes. As the megakaryocyte ages, its cytoplasm becomes compartmentalized, and its plasma membrane ruptures. The membranes associated with each fragment then quickly close to form anucleate, disk-shaped platelets, which have a lifespan of approximately 8 to 10 days.6Willoughby S Holmes A Loscalzo J Platelets and cardiovascular disease.Eur J Cardiovasc Nurs. 2002; 1: 273-288Crossref PubMed Scopus (180) Google Scholar The main function of the platelet is to scan the vascular system and respond to endothelial damage by tethering to the site of injury or lesion. Thus, it is an essential component of the clotting process. To this end, platelets contain several elements crucial to coagulation. Negatively charged elements within its phospholipid membrane provide a surface on which coagulation enzymes can function efficiently, whereas glycoprotein (GP) receptors on the platelet's surface act as points of attachment for both other platelets and various plasma components that are necessary for the clot mass to grow.6Willoughby S Holmes A Loscalzo J Platelets and cardiovascular disease.Eur J Cardiovasc Nurs. 2002; 1: 273-288Crossref PubMed Scopus (180) Google Scholar, 7Ferguson JJ Quinn M Moake JL The physiology of normal platelet function.in: Ferguson III, JJ Chronos NAF Harrington RA Antiplatelet Therapy in Clinical Practice. Martin Dunitz, London, England2000: 15-34Google Scholar The platelet is intimately involved in the successive phases of atherothrombosis that are triggered by damage to the endothelial lining of the arterial wall. The following is a simplified summary of these complex processes, and although they are conveniently divided into 3 stages, the degree of overlap among them is considerable. Under normal (nonhemostatic) conditions, platelets are at rest and flow through blood vessels without interacting with any other cells.8Samara WM Gurbel PA The role of platelet receptors and adhesion molecules in coronary artery disease.Coron Artery Dis. 2003; 14: 65-79Crossref PubMed Scopus (37) Google Scholar However, once a site of vessel damage is detected, passing platelets will adhere to the endothelium within seconds of the injury occurring (Figure 1).7Ferguson JJ Quinn M Moake JL The physiology of normal platelet function.in: Ferguson III, JJ Chronos NAF Harrington RA Antiplatelet Therapy in Clinical Practice. Martin Dunitz, London, England2000: 15-34Google Scholar The catalysts for this interaction are the constituents of the exposed subendothelium, including collagen, von Willebrand factor (vWF), fibronectin, laminin, and thrombospondin. Platelets have a range of surface membrane receptors that interact with these constituents,8Samara WM Gurbel PA The role of platelet receptors and adhesion molecules in coronary artery disease.Coron Artery Dis. 2003; 14: 65-79Crossref PubMed Scopus (37) Google Scholar helping the platelet to overcome the high shear forces generated by blood flow and so attach itself to the target site. Collagen is the most thrombogenic component of the subendothelial matrix, but it requires vWF to stabilize its interaction with the platelet's GP Ia/IIa receptor. Once the platelet has bound to both the exposed collagen and vWF (via the GP Ib/IX/V receptor complex), it changes shape from a disk to a ball (Figure 2).9Kuwahara M Sugimoto M Tsuji S et al.Platelet shape changes and adhesion under high shear flow.Arterioscler Thromb Vasc Biol. 2002; 22: 329-334Crossref PubMed Scopus (66) Google Scholar This conformational change triggers an internal signaling network that encourages further morphing of the cell into a hemispherical shape, increasing the surface area in contact with the artery wall. Thus, the platelet becomes more firmly anchored, but its adhesion remains reversible. Irreversible adhesion is achieved as a result of another signaling cascade, which causes extensive flattening of the platelet over the injured site.9Kuwahara M Sugimoto M Tsuji S et al.Platelet shape changes and adhesion under high shear flow.Arterioscler Thromb Vasc Biol. 2002; 22: 329-334Crossref PubMed Scopus (66) Google ScholarFIGURE 2Platelet shape changes and aggregation. From Arterioscler Thromb Vasc Biol,9Kuwahara M Sugimoto M Tsuji S et al.Platelet shape changes and adhesion under high shear flow.Arterioscler Thromb Vasc Biol. 2002; 22: 329-334Crossref PubMed Scopus (66) Google Scholar with permission from Lippincott Williams & Wilkins.View Large Image Figure ViewerDownload (PPT) The process by which a resting platelet changes shape and becomes an integral part of clot formation is known as activation. The binding of collagen and vWF to plateletreceptors triggers intracellular signals within the platelet mediated by calcium. This in turn causes degranulation of storage vesicles (which contain the platelet-activating substances adenosine diphosphate [ADP] and serotonin), synthesis of thromboxane A2 (also a platelet activator and a vasoconstrictor), and an increase in the surface population of the GP IIb/IIIa receptor. At the same time, circulating thromboxane A2 and ADP, in concert with other soluble agonists (eg, α-thrombin and epinephrine), bind to adherent platelets and synergistically induce their activation. Thus, platelet activation is amplified by several secondary feedback pathways. Another important step in platelet activation is the exposure of phospholipid membrane components on the platelet's surface. This triggers the well-known coagulation cascade (Figure 3),10Roberts HR Monroe DM Escobar MA Current concepts of hemostasis: implications for therapy.Anesthesiology. 2004; 100: 722-730Crossref PubMed Scopus (105) Google Scholar eventually resulting in the generation of insoluble fibrin, which provides stabilizing cross-links between adjacent platelets. However, this traditional model reflects only the interactions of the proteins involved in blood coagulation. More recently, a cell-based model was proposed to elucidate the key role of the activated platelet in the coagulation process (Figure 4).10Roberts HR Monroe DM Escobar MA Current concepts of hemostasis: implications for therapy.Anesthesiology. 2004; 100: 722-730Crossref PubMed Scopus (105) Google Scholar Interactions among activated platelets, coagulation cofactors, and their associated enzymes result in the generation of large amounts of thrombin, which is itself a potent stimulant of platelet activation.FIGURE 4Cell-based model of coagulation. Activated cofactors Va and VIIIa occupy sites in the activated platelet before binding of the respective enzymes, factors Xa and IXa. Factor Xa on the activated platelets is recruited from circulating factor X. The burst of thrombin generation takes place on the platelet surface. Thrombin generation can be boosted by further activation of factor IX by factor XIa. The burst of thrombin is sufficient to convert fibrinogen to fibrin. TF = tissue factor. From Anesthesiology,10Roberts HR Monroe DM Escobar MA Current concepts of hemostasis: implications for therapy.Anesthesiology. 2004; 100: 722-730Crossref PubMed Scopus (105) Google Scholar with permission from Lippincott Williams & Wilkins.View Large Image Figure ViewerDownload (PPT) The next phase of platelet activity, known as aggregation, is interwoven with the last stages of the coagulation cascade and overlaps somewhat with the platelet's activation phase. Aggregation is primarily mediated by GP IIb/IIIa receptors on the platelet surface that bind various adhesion proteins. These receptors have low affinity for their ligands under resting conditions but are up-regulated during platelet activation and become operational. One of the most important adhesion molecules bound by GP IIb/IIIa receptors is fibrinogen. Because platelet activation increases the surface density of these receptors, more fibrinogen can be bound, making higher concentrations accessible for thrombin-mediated conversion into fibrin. Concurrently, the GP IIb/IIIa receptors on the surface of adherent platelets immobilize other soluble adhesion proteins such as vWF, fibronectin, and vitronectin. Altogether, these processes attract more platelets to the site of injury, and the binding of fibrinogen encourages fibrin cross-linking with these newcomers. Fibrin then strengthens the structure, allowing continued platelet aggregation, thrombus formation, and growth.6Willoughby S Holmes A Loscalzo J Platelets and cardiovascular disease.Eur J Cardiovasc Nurs. 2002; 1: 273-288Crossref PubMed Scopus (180) Google Scholar, 7Ferguson JJ Quinn M Moake JL The physiology of normal platelet function.in: Ferguson III, JJ Chronos NAF Harrington RA Antiplatelet Therapy in Clinical Practice. Martin Dunitz, London, England2000: 15-34Google Scholar Once a plaque ruptures or erodes, 3 factors determine the extent of thrombus formation: the degree of plaque disruption, the degree of stenosis, and the physicochemical properties of the surface exposed to the circulating blood.11Cimminiello C Toschi V Atherothrombosis: the role of platelets.Eur Heart J Suppl. 1999; 1: A8-A13Google Scholar Platelet deposition increases greatly with increasing stenosis, whereas the exact site of deposition can be influenced by the placement of the lesion relative to blood flow.12Badimon L Badimon JJ Mechanisms of arterial thrombosis in nonparallel streamlines: platelet thrombi grow on the apex of stenotic severely injured vessel wall: experimental study in the pig model.J Clin Invest. 1989; 84: 1134-1144Crossref PubMed Scopus (181) Google Scholar, 13Lassila R Badimon JJ Vallabhajosula S Badimon L Dynamic monitoring of platelet deposition on severely damaged vessel wall in flowing blood: effects of different stenoses on thrombus growth.Arteriosclerosis. 1990; 10: 306-315Crossref PubMed Google Scholar Platelets aggregate most thickly at the top of the lesion, which may have clinical importance if the area of disruption is large and the remodeled shape of the lesion causes more severe stenosis. The continued narrowing of the artery encourages a larger, more platelet-rich thrombus toform, which may in turn occlude the vessel to a point where clinical events are induced, although this is highly dependent on the stability of the platelet aggregates and the rate of growth of the thrombus. These factors interplay with the thrombogenicity of the lesion itself. Plaques are notoriously heterogeneous with regard to their relative components, but studies have found that their thrombogenic potential is closely related to their tissue factor content14Toschi V Gallo R Lettino M et al.Tissue factor modulates the thrombogenicity of human atherosclerotic plaques.Circulation. 1997; 95: 594-599Crossref PubMed Scopus (599) Google Scholar and how lipid rich the lesion core is.15Fernandez-Ortiz A Badimon JJ Falk E et al.Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture.J Am Coll Cardiol. 1994; 23: 1562-1569Abstract Full Text PDF PubMed Scopus (513) Google Scholar It is well proved that atherothrombosis is a fundamental underlying factor in acute coronary syndromes.16Fuster V Badimon L Badimon JJ Chesebro JH The pathogenesis of coronary artery disease and the acute coronary syndromes (first of two parts).N Engl J Med. 1992; 326: 242-250Crossref PubMed Scopus (2909) Google Scholar, 17Badimon JJ Zaman A Helft G Fayad Z Fuster V Acute coronary syndromes: pathophysiology and preventive priorities.Thromb Haemost. 1999; 82: 997-1004PubMed Google Scholar Platelet reactivity is increased in these syndromes and is a significant predictor of cardiac outcomes after myocardial infarction (MI).18Trip MD Cats VM van Capelle FJ Vreeken J Platelet hyperreactivity and prognosis in survivors of myocardial infarction.N Engl J Med. 1990; 322: 1549-1554Crossref PubMed Scopus (539) Google Scholar Even when thrombi are only transiently occlusive, they can cause rest angina in the setting of non-ST-segment elevation MI; patients with more stable thrombotic vascular occlusion may develop ST-segment elevation MI. Furthermore, atherothrombi are the most prevalent cause of cardiac arrest or sudden death.19Falk E Shah PK Fuster V Coronary plaque disruption.Circulation. 1995; 92: 657-671Crossref PubMed Scopus (3139) Google Scholar Platelet-rich thrombi have also long been implicated in stroke and acute peripheral ischemia, although a more detailed picture of the pathogenic role of platelets is only now coming to light. For example, an investigation of hemostatic stroke markers revealed that vWF levels were elevated in participants who subsequently experienced ischemic stroke. The authors of the study suggested that increased vWF levels might augment platelet adhesion and aggregation, thereby enhancing the risk of cerebral thrombosis.20Folsom AR Rosamond WD Shahar E Atherosclerosis Risk in Communities (ARIC) Study Investigators et al.Prospective study of markers of hemostatic function with risk of ischemic stroke.Circulation. 1999; 100: 736-742Crossref PubMed Scopus (383) Google Scholar Patients with symptomatic peripheral arterial disease have increased mortality due to both coronary and cerebrovascular causes,21Criqui MH Langer RD Fronek A et al.Mortality over a period of 10 years in patients with peripheral arterial disease.N Engl J Med. 1992; 326: 381-386Crossref PubMed Scopus (2209) Google Scholar but the extent to which platelet-composed thrombi affect limb circulation is not fully understood. It was previously thought that the processes of thrombosis and inflammation were situated at opposite ends of the atherothrombosis spectrum. Inflammation was thought to contribute to early atherogenesis, whereas thrombosis was thought to be responsible for the onset of acute coronary syndromes. However, growing evidence now links the 2 processes much more closely. Platelets themselves have been shown to produce several inflammatory mediators and growth factors that play a role in atherothrombosis, including CD40 ligand (CD40L), cyclooxygenase (COX), epithelial neutrophil-activating protein 78 (ENA-78), interleukin (IL) 1β, macrophage inflammatory protein 1α (MIP-1α), platelet-derived growth factor (PDGF), platelet factor 4 (PF-4), P-selectin, RANTES (regulated on activation, normal T-cell expressed and secreted), and transforming growth factor β. Of the inflammatory molecules listed herein, 4 of the most potent secreted by platelets are the chemokines PF-4, RANTES, MIP-1α, and ENA-78.22Weyrich AS Lindemann S Zimmerman GA The evolving role of platelets in inflammation.J Thromb Haemost. 2003; 1: 1897-1905Crossref PubMed Scopus (245) Google Scholar Surface-expressed PF-4 attracts both monocytes and leukocytes and enhances the binding of oxidized low-density lipoprotein to endothelial and smooth muscle cells.23Nassar T Sachais BS Akkawi S et al.Platelet factor 4 enhances the binding of oxidized low-density lipoprotein to vascular wall cells.J Biol Chem. 2003; 278: 6187-6193Crossref PubMed Scopus (123) Google Scholar When PF-4 and oxidized low-density lipoprotein are confined together within the atherosclerotic lesion (in particular within foam cells), macrophage esterification of oxidized low-density lipoprotein is intensified.23Nassar T Sachais BS Akkawi S et al.Platelet factor 4 enhances the binding of oxidized low-density lipoprotein to vascular wall cells.J Biol Chem. 2003; 278: 6187-6193Crossref PubMed Scopus (123) Google Scholar At the same time, PF-4 facilitates macrophage differentiation22Weyrich AS Lindemann S Zimmerman GA The evolving role of platelets in inflammation.J Thromb Haemost. 2003; 1: 1897-1905Crossref PubMed Scopus (245) Google Scholar and recruits and activates monocytes.24Huo Y Schober A Forlow SB et al.Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E.Nat Med. 2003; 9: 61-67Crossref PubMed Scopus (853) Google Scholar RANTES is also a powerful chemoattractant, drawing monocytes and memory T lymphocytes. Once secreted, RANTES is deposited by platelets on the endothelial surface, enabling mononuclear cells to be tethered to the disrupted vascular wall.25von Hundelshausen P Weber KS Huo Y et al.RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium.Circulation. 2001; 103: 1772-1777Crossref PubMed Scopus (494) Google Scholar In addition, RANTES directly stimulates genes that control inflammatory pathways in monocytes, provoking the synthesis of more inflammatory mediators, such as IL-8, monocyte chemoattractant protein 1, MIP-1α, and tumor necrosis factor α.26Weyrich AS McIntyre TM McEver RP Prescott SM Zimmerman GA Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-α secretion: signal integration and NF-κB translocation.J Clin Invest. 1995; 95: 2297-2303Crossref PubMed Scopus (357) Google Scholar, 27Weyrich AS Elstad MR McEver RP et al.Activated platelets signal chemokine synthesis by human monocytes.J Clin Invest. 1996; 97: 1525-1534Crossref PubMed Scopus (541) Google Scholar Activated platelets not only secrete MIP-1α, a monocyte chemo-attractantattractant and macrophage activator,28Adams DH Lloyd AR Chemokines: leucocyte recruitment and activation cytokines.Lancet. 1997; 349: 490-495Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar but also induce its production by endothelial cells.29Cha J-K Jeong M-H Bae H-R et al.Activated platelets induce secretion of interleukin-1β, monocyte chemotactic protein-1, and macrophage inflammatory protein-1α and surface expression of intercellular adhesion molecule-1 on cultured endothelial cells.J Korean Med Sci. 2000; 15: 273-278PubMed Google Scholar This raises the possibility that adhesion of activated platelets to the vascular endothelium may up-regulate MIP-1α expression by endothelial cells and that MIP-1α may fulfill a chemotactic function in the endothelium by activating platelets. The last of the 4 chemokines produced by platelets, ENA-78, is probably less well known, but it is equally potent. The ENA-78 induces β2-integrin signaling, which greatly increases neutrophil adhesion to the endothelium.30Imaizumi T Albertine KH Jicha DL McIntyre TM Prescott SM Zimmerman GA Human endothelial cells synthesize ENA-78: relationship to IL-8 and to signaling of PMN adhesion.Am J Respir Cell Mol Biol. 1997; 17: 181-192Crossref PubMed Scopus (84) Google Scholar It is also synthesized by endothelial cells in response to platelet expression of IL-1β. Interleukin 1β is produced when platelets are activated, and its expression on the platelet membrane triggers the production not only of ENA-78 but also of E-selectin and IL-8, all of which encourage endothelial cell adhesiveness.22Weyrich AS Lindemann S Zimmerman GA The evolving role of platelets in inflammation.J Thromb Haemost. 2003; 1: 1897-1905Crossref PubMed Scopus (245) Google Scholar, 24Huo Y Schober A Forlow SB et al.Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E.Nat Med. 2003; 9: 61-67Crossref PubMed Scopus (853) Google Scholar Two other important molecules that are stored in platelets and provoke inflammation are the transmembrane protein CD40L and P-selectin. CD40 ligand is rapidly cleaved to soluble CD40L after its presentation on the platelet surface.31Hermann A Rauch BH Braun M Schror K Weber AA Platelet CD40 ligand (CD40L)—subcellular localization, regulation of expression, and inhibition by clopidogrel.Platelets. 2001; 12: 74-82Crossref PubMed Scopus (245) Google Scholar This protein is capable of instigating several inflammatory responses by endothelial cells, most notably the production of reactive oxygen species,32Urbich C Dernbach E Aicher A Zeiher AM Dimmeler S CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species.Circulation. 2002; 106: 981-986Crossref PubMed Scopus (193) Google Scholar chemokines and cytokines (IL-6 and tissue factor),33Henn V Slupsky JR Grafe M et al.CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.Nature. 1998; 391: 591-594Crossref PubMed Scopus (1739) Google Scholar and the expression of adhesion molecules (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin).34Slupsky JR Kalbas M Willuweit A Henn V Kroczek RA Muller-Berghaus G Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40.Thromb Haemost. 1998; 80: 1008-1014Crossref PubMed Scopus (218) Google Scholar Vesicle-stored P-selectin migrates to the platelet's outer membrane during adhesion.35Zimmerman GA Two by two: the pairings of P-selectin and P-selectin glycoprotein ligand 1.Proc Natl Acad Sci U S A. 2001; 98: 10023-10024Crossref PubMed Scopus (28) Google Scholar There it engages the P-selectin GP 1 receptor expressed on leukocytes, enabling the leukocyte to roll, adhere (Figure 5),22Weyrich AS Lindemann S Zimmerman GA The evolving role of platelets in inflammation.J Thromb Haemost. 2003; 1: 1897-1905Crossref PubMed Scopus (245) Google Scholar and eventually transmigrate into the vascular wall.36McEver RP Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation.Thromb Haemost. 2001; 86: 746-756Crossref PubMed Scopus (360) Google Scholar Macrophage accumulation in the vessel wall is also accomplished by P-selectin-mediated amplification of monocyte adhesion to the endothelium.37Ramos CL Huo Y Jung U et al.Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice.Circ Res. 1999; 84: 1237-1244Crossref PubMed Scopus (232) Google Scholar Other proinflammatory functions of P-selectin include up-regulation of tissue factor expression on monocytes38Tousoulis D Davies G Stefanadis C Toutouzas P Ambrose JA Inflammatory and thrombotic mechanisms in coronary atherosclerosis.Heart. 2003; 89: 993-997Crossref PubMed Scopus (143) Google Scholar, 39Wagner DD Burger PC Platelets in inflammation and thrombosis.Arterioscler Thromb Vasc Biol. 2003; 23: 2131-2137Crossref PubMed Scopus (442) Google Scholar and facilitation of RANTES and PF-4 deposition by platelets.25von Hundelshausen P Weber KS Huo Y et al.RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium.Circulation. 2001; 103: 1772-1777Crossref PubMed Scopus (494) Google Scholar The 2 PDGFs mentioned at the beginning of this section (PDGF and transforming growth factor β) work by stimulating the migration and proliferation of vascular smooth muscle cells. However, PDGF can be produced by macrophages and foam cells as well, so there is uncertainty regarding what proportion of PDGF found within atherosclerotic lesions is of platelet origin.40Huo Y Ley KF Role of platelets in the development of atherosclerosis.Trends Cardiovasc Med. 2004; 14: 18-22Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar Levels of several inflammatory molecules stored in platelets are elevated in coronary artery disease and are of prognostic value. For example, high P-selectin levels were recently found to predict the risk
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