American Journal of Cardiovascular Drugs

, Volume 5, Issue 6, pp 399–408

The Role of the Platelet in the Pathogenesis of Atherothrombosis

Review Article

Abstract

Platelet adhesion, activation, and aggregation at sites of vascular endothelial disruption caused by atherosclerosis are key events in arterial thrombus formation. Platelet tethering and adhesion to the arterial wall, particularly under high shear forces, are achieved through multiple high-affinity interactions between platelet membrane receptors (integrins) and ligands within the exposed subendothelium, most notably collagen and von Willebrand factor (vWF). Platelet adhesion to collagen occurs both indirectly, via binding of the platelet glycoprotein (GP) Ib-V-IX receptor to circulating vWF, which binds to exposed collagen, and directly, via interaction with the platelet receptors GP VI and GP Ia/IIb. Platelet activation, initiated by exposed collagen and locally generated soluble platelet agonists (primarily thrombin, ADP, and thromboxane A2), provides the stimulus for the release of platelet-derived growth factors, adhesion molecules and coagulation factors, activation of adjacent platelets, and conformational changes in the platelet αIIbβ3 integrin (GP IIb/IIIa receptor). Platelet aggregation, mediated primarily by interaction between the activated platelet GP IIb/IIIa receptor and its ligands, fibrinogen and vWF, results in the formation of a platelet-rich thrombus. Currently available antiplatelet drugs (aspirin [acetylsalicylic acid], dipyridamole, clopidogrel, ticlopidine, abciximab, eptifibatide, tirofiban) act on specific targets to inhibit platelet activation and aggregation. Elucidation of the multiple mechanisms involved in platelet thrombus formation provides opportunities for selectively inhibiting the pathways most relevant to the pathophysiology of atherothrombosis.

References

  1. 1.
    Duvall WL, Vorchheimer DA. Multi-bed vascular disease and atherothrombosis: scope of the problem. J Thromb Thrombolysis 2004; 17: 51–61.PubMedCrossRefGoogle Scholar
  2. 2.
    Viles-Gonzalez JF, Fuster V, Badimon JJ. Atherothrombosis: a widespread disease with unpredictable and life-threatening consequences. Eur Heart J 2004; 25: 1197–207.PubMedCrossRefGoogle Scholar
  3. 3.
    Sachais BS. Platelet-endothelial interactions in atherosclerosis. Curr Atheroscler Rep 2001; 3: 412–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Behnke O, Forer A. From megakaryocytes to platelets: platelet morphogenesis takes place in the bloodstream. Eur J Haematol 1998; 60: 3–23.CrossRefGoogle Scholar
  5. 5.
    Kaushansky K. Thrombopoietin and hematopoietic stem cell development. Ann NY Acad Sci 1999; 872: 314–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Gawaz M, Neumann FJ, Dickfeld T, et al. Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. Circulation 1998; 98: 1164–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Gawaz M, Brand K, Dickfeld T, et al. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an inter leukin-1-dependent mechanism: implications for atherogenesis. Atherosclerosis 2000; 148: 75–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Rosenfeld ME, Pestel E. Cellularity of atherosclerotic lesions. Coron Artery Dis 1994; 5: 189–97.PubMedCrossRefGoogle Scholar
  10. 10.
    Libby P, Simon D. Inflammation and thrombosis: the clot thickens. Circulation 2001; 103: 1715–20.CrossRefGoogle Scholar
  11. 11.
    Schönbeck U, Libby P. CD40 signaling and plaque instability. Circ Res 2001; 89: 1092–103.PubMedCrossRefGoogle Scholar
  12. 12.
    Phipps RP. Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system. Proc Natl Acad Sci U S A 2000; 97: 6930–2.PubMedCrossRefGoogle Scholar
  13. 13.
    Mach F, Schönbeck U, Sukhova GK, et al. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998; 394: 200–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Schönbeck U, Mach F, Sukhova GK, et al. CD40 ligation induces tissue factor expression in human vascular smooth muscle cells. Am J Pathol 2000; 156: 7–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Lindemann S, Tolley ND, Dixon DA, et al. Activated platelets mediate inflammatory signalling by regulated interleukin 1 beta synthesis. J Cell Biol 2001; 154: 485–90.PubMedCrossRefGoogle Scholar
  16. 16.
    McEver RP. Properties of GMP-140, an inducible granule membrane protein of platelets and endothelium. Blood Cells 1990; 16: 73–80.PubMedGoogle Scholar
  17. 17.
    Theilmeier G, Michiels C, Spaepen E, et al. Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia. Blood 2002; 99: 4486–93.PubMedCrossRefGoogle Scholar
  18. 18.
    Gu L, Okada Y, Clinton SK, et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998; 2: 275–81.PubMedCrossRefGoogle Scholar
  19. 19.
    Falk F. 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: 699–708.PubMedCrossRefGoogle Scholar
  20. 20.
    Davies MJ, Woolf N, Rowles PM, et al. Morphology of the endothelium over atherosclerotic plaques in human coronary arteries. Br Heart J 1988; 60: 459–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Lüscher TF. Platelet-vessel wall interaction: role of nitric oxide, prostaglandins and endothelins. Baillieres Clin Haematol 1993; 6: 609–27.PubMedCrossRefGoogle Scholar
  23. 23.
    Andrews RK, Lopez JA, Berndt MC. Molecular mechanisms of platelet adhesion and activation. Int J Biochem Cell Biol 1997; 29: 91–105.PubMedCrossRefGoogle Scholar
  24. 24.
    Barnes MJ, Knight CG, Farndale RW. The collagen-platelet interaction. Curr Opin Hematol 1998; 5: 314–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Ruggeri ZM. New insights into the mechanisms of platelet adhesion and aggregation. Semin Hematol 1994; 31: 229–39.PubMedGoogle Scholar
  26. 26.
    Van Zanten GH, de Graaf S, Slootweg PJ, et al. Increased platelet deposition on atherosclerotic coronary arteries. J Clin Invest 1994; 93: 615–32.PubMedCrossRefGoogle Scholar
  27. 27.
    Ruggieri ZM. Mechanisms initiating platelet thrombus formation. Thromb Haemost 1997; 78: 611–6.Google Scholar
  28. 28.
    Andre P, Denis CV, Ware J, et al. Platelets adhere to and translocate on von Willebrand factor presented by endothelium in stimulated veins. Blood 2000; 96: 3322–8.PubMedGoogle Scholar
  29. 29.
    Savage B, Saldivar E, Ruggieri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289–97.PubMedCrossRefGoogle Scholar
  30. 30.
    Jurk K, Clemetson KJ, De Groot PG, et al. Thrombospondin-1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor. FASEB J 2003; 17: 1490–2.PubMedGoogle Scholar
  31. 31.
    Moroi M, Jung SM, Shinmyozu K, et al. Analysis of platelet adhesion to a collagen-coated surface under flow conditions: the involvement of glycoprotein VI in the platelet adhesion. Blood 1996; 88: 2081–92.PubMedGoogle Scholar
  32. 32.
    Nieswandt B, Brakebusch C, Bergmeier W, et al. Glycoprotein VI but not alpha2betal integrin is essential for platelet interaction with collagen. EMBO J 2001; 20: 2120–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Chen H, Locke D, Liu Y, et al. The platelet receptor GPVI mediates both adhesion and signalling responses to collagen in a receptor density-dependent fashion. J Biol Chem 2002; 277: 301–9.Google Scholar
  34. 34.
    Massberg S, Gawaz M, Grüner S, et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med 2003; 197: 41–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Kasirer-Friede A, Ware J, Leng L, et al. Lateral clustering of platelet GP Ib-IX complexes leads to up-regulation of the adhesive function of integrin alphaIIbbeta3. J Biol Chem 2002; 277: 11949–56.PubMedCrossRefGoogle Scholar
  36. 36.
    Clemetson KJ. Platelet activation: signal transduction via membrane receptors. Thromb Haemost 1995; 74: 111–6.PubMedGoogle Scholar
  37. 37.
    Savage B, Cattaneo M, Ruggeri ZM. Mechanisms of platelet aggregation. Curr Opin Hematol 2001; 8: 270–6.PubMedCrossRefGoogle Scholar
  38. 38.
    George JN. Haemostasis and fibrinolysis. In: Stein JH, editor. Internal medicine. 5th ed. St Louis (MO): Mosby, 1998: 534–40.Google Scholar
  39. 39.
    Wu KK. Platelet activation mechanisms and markers in arterial thrombosis. J Intern Med 1996; 239: 17–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Glusa E. Vascular effects of thrombin. Semin Thromb Hemost 1992; 18: 296–304.PubMedCrossRefGoogle Scholar
  42. 42.
    Kahn ML. Platelet-collagen responses: molecular basis and therapeutic promise. Semin Thromb Hemost 2004; 30: 419–25.PubMedCrossRefGoogle Scholar
  43. 43.
    Jackson SP, Nesbitt WS, Kulkarni S. Signaling events underlying thrombus formation. J Thromb Haemost 2003; 1: 1602–12.PubMedCrossRefGoogle Scholar
  44. 44.
    Kato K, Kanaji T, Russell S, et al. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion. Blood 2003; 102: 1701–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Chen J, Diacovo TG, Grenache DG, et al. The alpha(2) integrin subunit-defective mouse: a multi-faceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 2002; 161: 337–44.PubMedCrossRefGoogle Scholar
  46. 46.
    Sugiyama T, Okuma M, Ushikubi F, et al. A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia. Blood 1987; 69: 1712–20.PubMedGoogle Scholar
  47. 47.
    Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor? Blood 2003; 102: 449–61.PubMedCrossRefGoogle Scholar
  48. 48.
    Gast A, Tschopp TB, Baumgartner HR. Thrombin plays a key role in late platelet thrombus growth and/or stability: effect of a specific thrombin inhibitor on thrombogenesis induced by aortic subendothelium exposed to flowing rabbit blood. Arterioscler Thromb 1994; 14: 1466–74.PubMedCrossRefGoogle Scholar
  49. 49.
    Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258–64.PubMedCrossRefGoogle Scholar
  50. 50.
    Mazzucato M, Marco LD, Masotti A, et al. Characterization of the initial αthrombin interaction with glycoprotein Ibα in relation to platelet activation. J Biol Chem 1998; 273: 1880–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227–34.PubMedCrossRefGoogle Scholar
  52. 52.
    Moritz MW, Reimers RC, Baker RK, et al. Role of cytoplasmic and releasable ADP in platelet aggregation induced by laminar shear stress. J Lab Clin Med 1983; 101: 537–44.PubMedGoogle Scholar
  53. 53.
    Turner NA, Moake JL, McIntire LV. Blockade of adenosine diphosphate receptors P2Y (12) and P2Y (1) is required to inhibit platelet aggregation in whole blood under flow. Blood 2001; 98: 3340–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Offermanns S, Laugwitz KL, Spicher K, et al. G Proteins of the G12 family are activated via thromboxane and thrombin receptors in human platelets. Proc Natl Acad Sci U S A 1994; 91: 504–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Barstad RM, Orvim U, Hamers MJ, et al. Reduced effect of aspirin on thrombus formation at high shear and disturbed laminar blood flow. Thromb Haemost 1996; 75: 827–32.PubMedGoogle Scholar
  56. 56.
    Maalejs N, Folts JD. Increased shear stress overcomes the antithrombotic platelet inhibitory effect of aspirin in stenosed dog coronary arteries. Circulation 1996; 93: 1201–5.CrossRefGoogle Scholar
  57. 57.
    Veen G, Meyer A, Verheugt FW, et al. Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. Antithrombotics in the prevention of reocclusion in coronary thrombolysis. J Am Coll Cardiol 1993; 22: 1755–62.PubMedCrossRefGoogle Scholar
  58. 58.
    Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22: 1381–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Roberts HR, Monroe DM, Escobar MA. Current concepts of hemostasis: implications for therapy. Anesthesiology 2004; 100: 722–30.PubMedCrossRefGoogle Scholar
  60. 60.
    Shattil SJ. Signaling through platelet integrin alpha IIb beta 3: inside-out, outside-in and sideways. Thromb Haemost 1999; 82: 318–25.PubMedGoogle Scholar
  61. 61.
    Nurden P, Poujol C, Durrieu-Jais C, et al. Labeling of the internal pool of GP Ilb-IIIa in platelets by c7E3 Fab fragments (abciximab): flow and endocytic mechanisms contribute to transport. Blood 1999; 93: 1622–33.PubMedGoogle Scholar
  62. 62.
    Ruggeri ZM. Old concepts and new developments in the study of platelet aggregation. J Clin Invest 2000; 105: 699–701.PubMedCrossRefGoogle Scholar
  63. 63.
    Frojmovic MM. Platelet aggregation in flow: differential roles for adhesive receptors and ligands. Am Heart J 1998; 135(Pt 2 Suppl. 5): S119–131.PubMedCrossRefGoogle Scholar
  64. 64.
    Goto S, Ikeda Y, Saldivar E, et al. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J Clin Invest 1998; 101: 479–86.PubMedCrossRefGoogle Scholar
  65. 65.
    Kulkarni S, Dopheide SM, Yap CL, et al. A revised model of platelet aggregation. J Clin Invest 2000; 105: 783–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Stack S, Gonzales-Gronow M, Pizzo SV. Regulation of plasminogen activation by components of extracellular matrix. Biochemistry 1990; 29: 4966–70.PubMedCrossRefGoogle Scholar
  67. 67.
    Maksimenko AV. Molecular interactions during fibrinolysis: search for new plasminogen activators. Mol Biol (Mosk) 1995; 29: 38–60.Google Scholar
  68. 68.
    Lambers JWJ, Cammenga M, Konig BW, et al. Activation of human endothelial cell-type plasminogen activator inhibitor (PAI-1) by negatively charged phospholipids. J Biol Chem 1987; 262: 17492–6.PubMedGoogle Scholar
  69. 69.
    Nguyen CM, Harrington RA. Glycoprotein IIb/IIIa receptor antagonists: a comparative review of their use in percutaneous coronary intervention. Am J Cardiovasc Drugs 2003; 3: 423–36.PubMedCrossRefGoogle Scholar
  70. 70.
    Massberg S, Enders G, Leiderer R, et al. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin. Blood 1998; 92: 507–15.PubMedGoogle Scholar
  71. 71.
    Massberg S, Enders G, Matos FC, et al. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood 1999; 94: 3829–38.PubMedGoogle Scholar
  72. 72.
    Gawaz M, Neumann FJ, Dickfeld T, et al. Vitronectin receptor (alpha(v)beta3) mediates platelet adhesion to the luminal aspect of endothelial cells: implications for reperfusion in acute myocardial infarction. Circulation 1997; 96: 1809–18.PubMedCrossRefGoogle Scholar
  73. 73.
    Merlini PA, Bauer KA, Oltrona L, et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Mehta SR, Yusuf S. Short- and long-term oral antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention. J Am Coll Car diol 2003; 41(4 Suppl. S): 79S–88S.CrossRefGoogle Scholar
  75. 75.
    Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 1986; 315: 913–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Le Breton H, Plow EF, Topol EJ. Role of platelets in restenosis after percutaneous coronary revascularization. J Am Coll Cardiol 1996; 28: 1643–51.PubMedCrossRefGoogle Scholar
  77. 77.
    Merino A, Cohen M, Badimon JJ, et al. Synergistic action of severe wall injury and shear forces on thrombus formation in arterial stenosis: definition of a thrombotic shear rate threshold. J Am Coll Cardiol 1994; 24: 1091–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Abumiya T, Fitridge R, Mazur C, et al. Integrin αIIbβ3 inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia. Stroke 2000; 31: 1402–10.PubMedCrossRefGoogle Scholar
  79. 79.
    Diener H-C, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Taylor DW, Barnett HJ, Haynes RB, et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. Lancet 1999; 353: 2179–84.PubMedCrossRefGoogle Scholar
  81. 81.
    Matsagas MI, Geroulakos G, Mikhailidis DP. The role of platelets in peripheral arterial disease: therapeutic implications. Ann Vasc Surg 2002; 16: 246–58.PubMedCrossRefGoogle Scholar
  82. 82.
    Fuster V, Ip JH, Badimon L. Importance of experimental models for the development of clinical trials on thromboatherosclerosis. Circulation 1991; 83: IV15–25.PubMedGoogle Scholar
  83. 83.
    Badimon L. Atherosclerosis and thrombosis: lessons from animal models. Thromb Haemost 2001; 86: 356–65.PubMedGoogle Scholar
  84. 84.
    Hughes A, Daunt S, Vass G, et al. In vivo platelet activation following myocardial infarction and acute coronary ischaemia. Thromb Haemost 1982; 48: 133–5.PubMedGoogle Scholar
  85. 85.
    De Boer AC, Turpie AG, Butt RW, et al. Platelet release and thromboxane synthesis in symptomatic coronary artery disease. Circulation 1982; 66: 327–33.PubMedCrossRefGoogle Scholar
  86. 86.
    Chakhtoura EY, Shamoon FE, Haft JI, et al. Comparison of platelet activation in unstable and stable angina pectoris and correlation with coronary angiographic findings. Am J Cardiol 2000; 86: 835–9.PubMedCrossRefGoogle Scholar
  87. 87.
    McEver R. Adhesive interactions of leucocytes, platelets and the vessel wall during hemostasis and inflammation. Thromb Haemost 2001; 86: 746–56.PubMedGoogle Scholar
  88. 88.
    Wang K, Zhou Z, Zhou X, et al. Prevention of intimai hyperplasia with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in the porcine coronary artery balloon injury model. J Am Coll Cardiol 2001; 38: 577–82.PubMedCrossRefGoogle Scholar
  89. 89.
    Wang K, Zhou X, Zhou Z, et al. Recombinant soluble P-selectin glycoprotein ligand-Ig (rPSGL-Ig) attenuates infarct size and myeloperoxidase activity in a canine model of ischemia-reperfusion. Thromb Haemost 2002; 88: 149–54.PubMedGoogle Scholar
  90. 90.
    Neumann FJ, Marx N, Gawaz M, et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation 1997; 95: 2387–94.PubMedCrossRefGoogle Scholar
  91. 91.
    Ault KA, Cannon CP, Mitchell M, et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. J Am Coll Cardiol 1999; 33: 634–9.PubMedCrossRefGoogle Scholar
  92. 92.
    May AE, Neumann FJ, Gawaz M, et al. Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation. Eur Heart J 1997; 18: 1913–20.PubMedCrossRefGoogle Scholar
  93. 93.
    Klinkhardt U, Bauersachs R, Adams J, et al. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Ther 2003; 73: 232–41.PubMedCrossRefGoogle Scholar
  94. 94.
    Prasad KS, Andre P, Yan Y, et al. The platelet CD40L/GP IIb-IIIa axis in atherothrombosis. Curr Opin Hematol 2003; 10: 356–61.PubMedCrossRefGoogle Scholar
  95. 95.
    Aukrust P, Muller F, Ueland T, et al. Enhanced levels of soluble and membranebound CD40 ligand in patients with unstable angina: possible reflection of T lymphocytes and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100: 614–20.PubMedCrossRefGoogle Scholar
  96. 96.
    Schönbeck U, Varo N, Libby P, et al. Soluble CD40 and cardiovascular risk in women. Circulation 2001; 104: 2266–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Herrmann A, Rauch BH, Braun M, et al. Platelet CD40 ligand (CD40L): subcellular localization, regulation of expression and inhibition by clopidogrel. Platelets 2001; 12: 74–82.CrossRefGoogle Scholar
  98. 98.
    Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 2: 15–28.PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.The Gill Heart Institute and Division of Cardiovascular MedicineUniversity of Kentucky College of MedicineLexingtonUSA

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