Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Badimon, L.
Right arrow Articles by Duran, X.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Badimon, L.
Right arrow Articles by Duran, X.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


Atheromatous plaque formation and thrombogenesis: formation, risk factors and therapeutic approaches

L. Badimon*, G. Vilahur, S. Sanchez and X. Duran

Cardiovascular Research Center, Instituto de Investigaciones Biomédicas de Barcelona and Consejo Superior de Investigaciones Científicas, Hospital Santa Creu i San Pau-Universidad Autómoma de Barcelona, 08034 Barcelona, Spain

* Correspondence: Professor Lina Badimon, Centro de Investigación y Desarrollo-CSIC, Jordi Girona, 18-26, 08034 Barcelona, Spain.

Abstract

Angiographic and ultrasound analyses of the coronary arteries have confirmed the importance of acute thrombosis as the primary cause of myocardial infarction and acute coronary syndromes. Intravenous treatments aimed at recanalizing the obstructed arteries can help achieve acute reperfusion of the organ, but often a thrombus-triggering plaque remains active for some time. It is not yet known how long a plaque remains active, but it has been shown that systemic markers of coagulation remain elevated as long as 6 months after the event. The presence of a residual mural thrombus overlying an active plaque predisposes to recurrent thrombosic vessel occlusion. A fragmented thrombus appears to be one of the most powerful thrombogenic substrates, and residual thrombus may predispose to recurrent thrombosis. Non-acute, chronic antithrombotic treatments and pharmacological interventions should aim to block thrombosis and preserve vascular prostacyclin formation. Experimental work has shown that both aspirin and triflusal inhibit the growth of a thrombus on a fresh mural thrombus to the same extent, but triflusal was found to preserve cyclooxygenase-2 activity in the vessel wall. Research to uncover the mechanism of action of triflusal at the vascular level is in progress.

Key Words: Atherogenesis • lipids • platelets • thrombosis • triflusal

References

  1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (Part I). N Engl J Med. 1992;326:242–250[Web of Science][Medline]
  2. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (Part II). N Engl J Med. 1992;326:310–318[Web of Science][Medline]
  3. Fernandez-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;23:1562–1569[Abstract]
  4. Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594–599[Abstract/Free Full Text]
  5. Badimon JJ, Lettino M, Toschi V, et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques. Effects of TFP1 on plaque thrombogenicity under flow conditions. Circulation. 1999;99:1780–1787[Abstract/Free Full Text]
  6. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA. 1989. p. 2839–2843
  7. Thiruvikraman SV, Guha A, Roboz J, et al. In situ localization of tissue factor in human atherosclerotic plaques by binding of digoxigenin-labeled factors VIM and X. Lab Invest. 1996;75:451–461[Web of Science][Medline]
  8. Annex BH, Denning SM, Channon KM, et al. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation. 1995;91:619–622[Abstract/Free Full Text]
  9. Moreno PR, Falk E, Palacios IF, et al. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation. 1994;90:775–778[Abstract/Free Full Text]
  10. Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94:3090–3097[Abstract/Free Full Text]
  11. Mallat Z, Hugel B, Ohan J, et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999;99:348–353[Abstract/Free Full Text]
  12. Giesen PL, Rauch U, Bohrmann B, et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA. 1999. p. 2311–2315
  13. Badimon L, Martinez-Gonzalez J, Royo T, Lassila R, Badimon JJ. A sudden increase in plasma epinephrine levels transiently enhances platelet deposition on severely damaged arterial wall. Thromb Haemost. 1999;82:1736–1742[Web of Science][Medline]
  14. Spalding A, Vaitkevicius H, Dill S, et al. Mechanism of epinephrine-induced platelet aggregation. Hypertension. 1998;31:603–607[Abstract/Free Full Text]
  15. Goto S, Handa S, Takahashi E, et al. Synergistic effect of epinephrine and shearing on platelet activation. Thromb Res. 1996;84:351–359[CrossRef][Web of Science][Medline]
  16. Krantz DS, Kop WJ, Santiago HT, Gottdiener JS. Mental stress as a trigger of myocardial ischemia and infarction. Cardiol Clin. 1996;14:271–287[Medline]
  17. Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313:1315–1322[Abstract]
  18. Johnstone MT, Mittleman M, Tofler G, Muller JE. The pathophysiology of the onset of morning cardiovascular events. Am J Hypertens. 1996;9:22S–28S[Medline]
  19. Willich SN, Linderer T, Wegscheider K, et al. Increased morning incidence of myocardial infarction in the ISAM Study: absence with prior beta-adrenergic blockade. ISAM Study Group. Circulation. 1989;80:853–858[Abstract/Free Full Text]
  20. Winniford MD, Wheelan KR, Kremers MS, et al. Smokinginduced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone. Circulation. 1986;73:662–667[Abstract/Free Full Text]
  21. Fuster V, Chesebro JH, Frye RL, Elveback LR. Platelet survival and the development of coronary artery disease in the young adult: effects of cigarette smoking, strong family history and medical therapy. Circulation. 1981;63:546–551[Abstract/Free Full Text]
  22. Blann AD, Kirkpatrick U, Devine C, et al. The influence of acute smoking on leucocytes, platelets and the endothelium. Atherosclerosis. 1998;141:133–139[CrossRef][Web of Science][Medline]
  23. Paul O. Background of the prevention of cardiovascular disease. 11. Arteriosclerosis, hypertension, and selected risk factors. Circulation. 1989;80:206–214[Abstract/Free Full Text]
  24. Buhler FR, Vesanen K, Watters JT, Bolli P. Impact of smoking on heart attacks, strokes, blood pressure control, drug dose, and quality of life aspects in the international Prospective Primary Prevention Study in Hypertension. Am Heart J. 1988;115:282–288[CrossRef][Web of Science][Medline]
  25. Hunt BJ. The relation between abnormal hemostatic function and the progression of coronary disease. Curr Opin Cardiol. 1990;5:758–765[CrossRef][Web of Science]
  26. Thompson SG, Kienast J, Pyke SD, et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med. 1995;332:635–641[Abstract/Free Full Text]
  27. Pueyo Palazon C, Alfón J, Gaffney P, Berrozpe M, Royo T, Badimon L. Effects of reducing LDL and increasing HDL with Gemfibrozil in experimental coronary lesion development and thrombotic risk. Atherosclerosis. 1998;136:333–345[CrossRef][Web of Science][Medline]
  28. Alfón J, Pueyo-Palazón C, Royo T, Badimon L. Effects of statins in thrombosis and aortic lesion development in a dyslipemic rabbit model. Thromb Haemost. 1999;81:822–827[Web of Science][Medline]
  29. Alfón J, Royo T, Garcia-Moll X, Badimon L. Platelet deposition on eroded vessel wall at stenotic shear rate is inhibited by lipid-lowering treatment with atorvastatin. Arterioscler Thromb Vasc Biol. 1999;19:1812–1817[Abstract/Free Full Text]
  30. Alfón J, Guasch JF, Berrozpe M, Badimon L. NOSH gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors. Atherosclerosis. 1999;145:325–331[CrossRef][Web of Science][Medline]
  31. Badimon JJ, Badimon L, Turitto VT, Fuster V. Platelet deposition at high shear rates is enhanced by high plasma cholesterol levels. In vivo study in the rabbit model. Arterioscler Thromb. 1991;11:395–402[Abstract/Free Full Text]
  32. Henry PD, Cabello OA, Chen CH. Hypercholesterolemia and endothelial dysfunction. Curr Opin Lipidol. 1995;6:190–195[Web of Science][Medline]
  33. Lacoste L, Lam JY, Hung J, et al. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation. 1995;92:3172–3177[Abstract/Free Full Text]
  34. Rauch U, Osende JI, Chesebro JH, et al. Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins. Atherosclerosis. 2000;153:181–189[CrossRef][Web of Science][Medline]
  35. Boers GH. Hyperhomocysteinemia as a risk factor for arterial and venous disease. A review of evidence and relevance. Thromb Haemost. 1997;78:520–522[Web of Science][Medline]
  36. de Jong SC, van den Berg M, Rauwerda JA, Stehouwer CD. Hyperhomocysteinemia and atherothrombotic disease. Semin Thromb Hemost. 1998;24:381–385[Web of Science][Medline]
  37. Vaughan DE. Plasminogen activator inhibitor-1: a common denominator in cardiovascular disease. J Invest Med. 1998;46:370–376[Web of Science][Medline]
  38. Geppert A, Graf S, Beckmann R, et al. Concentration of endogenous tPA antigen in coronary artery disease: relation to thrombotic events, aspirin treatment, hyperlipidemia, and multivessel disease. Arterioscler Thromb Vase Biol. 1998;18:1634–1642
  39. Salomaa V, Stinson V, Kark JD, et al. Association of fibrinolytic parameters with early atherosclerosis. The ARIC Study. Atherosclerosis Risk in Communities Study. Circulation. 1995;91:284–290[Abstract/Free Full Text]
  40. Meade TW. Fibrinogen and cardiovascular disease. J Clin Pathol. 1997;50:13–15[Free Full Text]
  41. Maseri A, L'Abbate A, Baroldi G, et al. Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of ‘preinfarction’ angina. N Engl J Med. 1978;299:1271–1277[Abstract]
  42. de Feyter PJ, Ozaki Y, Baptista J, et al. Ischemia-related lesion characteristics in patients with stable or unstable angina. A study with intracoronary angioscopy and ultrasound. Circulation. 1995;92:1408–1413[Abstract/Free Full Text]
  43. Silva JA, Escobar A, Collins TJ, et al. Unstable angina. A comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation. 1995;92:1731–1736[Abstract/Free Full Text]
  44. Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986;315:913–919[Abstract]
  45. Mizuno K, Satomura K, Miyamoto A, et al. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med. 1992;326:287–291[Abstract]
  46. Nesto RW, Waxman S, Mittleman MA, et al. Angioscopy of culprit coronary lesions in unstable angina pectoris and correlation of clinical presentation with plaque morphology. Am J Cardiol. 1998;81:225–228[CrossRef][Web of Science][Medline]
  47. Van Belle E, Lablanche JM, Bauters C, et al. Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction: natural history and the effect of thrombolysis. Circulation. 1998;97:26–33[Abstract/Free Full Text]
  48. Uchida Y, Tomaru T, Nakamura F, et al. Percutaneous coronary angioscopy in patients with ischemic heart disease. Am Heart J. 1987;114:1216–1222[CrossRef][Web of Science][Medline]
  49. Theroux P, Fuster V. Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation. 1998;97:1195–1206[Free Full Text]
  50. Braunwald E, Jones RH, Mark DB, et al. Diagnosing and managing unstable angina. Agency for Health Care Policy and Research. Circulation. 1994;90:613–622[Abstract/Free Full Text]
  51. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–671[Free Full Text]
  52. Alderman EL, Corley SD, Fisher LD, et al. Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS). CASS Participating Investigators and Staff. J Am Coll Cardiol. 1993;22:1141–1154[Abstract]
  53. Danchin N. Is myocardial revascularisation for tight coronary stenoses always necessary? Lancet. 1993;342:224–225[CrossRef][Web of Science][Medline]
  54. Mehta D, Curwin J, Gomes JA, Fuster V. Sudden death in coronary artery disease: acute ischemia versus myocardial substrate. Circulation. 1997;96:3215–3223[Free Full Text]
  55. Badimon L, Badimon JJ, Fuster V. Pathogenesis of thrombosis. Verstraete M, Fuster V. Cardiovascular thrombosis: Thrombocardiology. Philadelphia: Lippincott-Raven; 1998. p. 23–44
  56. Kieffer N, Phillips DR. Platelet membrane glycoproteins: functions in cellular interactions. Annu Rev Biol. 1990;6:329–357
  57. Kunicki TJ. Organization of glycoproteins within the platelet plasma membrane. George JN, Nurden AT, Philips DR. Platelet membrane glycoproteins. New York: Plenum Press; 1985. p. 87–101
  58. Marcus A, Safier LB. Thromboregulation: multicellular modulation of platelet reactivity in hemostasis and thrombosis. FASEB J. 1993;7:516–522[Abstract]
  59. Fitzgerald LA, Phillips DR. Calcium regulation of the platelet membrane glycoprotein lib 111a complex. J Biol Chem. 1985;260:11366–11376[Abstract/Free Full Text]
  60. Plow EF, Ginsberg MIL, Marguerie GA. Expression and function of adhesive proteins on the platelet surface. Phillips DR, Shuman MA. Biochemistry of platelets. New York: Academic Press; 1986. p. 225–256
  61. Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion : RGD and integrins. Science. 1987;238:491–497[Abstract/Free Full Text]
  62. Doolittle RF, Watt KWK, Cottrell BA, Strong DD, Riley M. The amino acid sequence of the a-chain of human fibrinogen. Nature (London). 1979;280:464–467[CrossRef][Medline]
  63. Vu TH, Hung DT, Wheaton NJ, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991;64:1057–1068[CrossRef][Web of Science][Medline]
  64. Coughlin SR. Thrombin receptor structure and function. Thromb Haemost. 1993;70:184–187[Web of Science][Medline]
  65. Rentrop KP, Feit F, Blanke H, Sherman W, Thornton JC. Serial angiographic assessment of coronary artery obstruction and collateral flow in acute myocardial infarction. Circulation. 1989;80:1166–1175[Abstract/Free Full Text]
  66. European Cooperative Study Group for Recombinant Tissue-Type Plasminogen Activator (rt-PA)Van de Werf F, Arnold AER. Effect of intravenous tissue plasminogen activator on infarct size, left ventricular function and survival in patients with acute myocardial infarction. Br Med J. 1988;297:374–379[Free Full Text]
  67. Van Lierde De Geest H, Verstraete M, et al. Angiographic assessment of the infarct-related residual coronary stenosis after spontaneous or therapeutic thrombolysis. J Am Coll Cardiol. 1990;16:1545–1549[Abstract]
  68. Fuster V, Stein B, Badimon L, Badimon JJ, Ambrose JA, Chesebro JH. Atheroscerotic plaque rupture and thrombosis: evolving concepts. Circulation. 1990;82(Suppl 11):47–59
  69. Davies SW, Marchant B, Lyon JP, et al. Coronary lesion morphology in acute myocardial infarction: demonstration of early remodeling after streptokinase treatment. J Am Coll Cardiol. 1990;16:1079–1086[Abstract]
  70. Gulba DC, Barthels M, Westhoff-Bleck M, et al. Increased thrombin levels during acute myocardial infarction. Relevance for the success of therapy. Circulation. 1991;83:937–944[Abstract/Free Full Text]
  71. Badimon L, Badimon JJ. Mechanism of arterial thrombosis in non-parallel strealines: platelet grow at the apex of stenotic severely injured vessel wall. Experimental study in the pig model. J Clin Invest. 1989;84:1134–1144
  72. Lassila R, Badimon JJ, Vallabhajosula S, Badimon L. Dynamic monitoring of platelet deposition on severely damaged vessel wall in flowing blood. Effects of different stenosis on thrombus growth. Arteriosclerosis. 1990;10:306–315[Abstract/Free Full Text]
  73. Fitzgerald DJ, Fitzgerald GA. Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator. Proc Natl Acad Sci USA. 1989. p. 7585
  74. Meyer BJ, Badimon JJ, Mailhac A, et al. Inhibition of growth of thrombus on fresh mural thrombus: targeting optimal therapy. Circulation. 1994;90:2432–2438[Abstract/Free Full Text]
  75. Meyer B, Badimon JJ, Chesebro JH, Fallon JT, Fuster V, Badimon L. Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin. Circulation. 1998;97:681–685[Abstract/Free Full Text]
  76. De la Cruz JP, Pavia J, Garcia-Arnes J, et al. Effects of triflusal and acetylsalicylic acid on platelet aggregation in whole blood of diabetic patients. Eur J Haematol. 1998;40:232–236
  77. Garcia-Rafanell J, Ramis J, Gomez L, et al. Effect of triflusal and other salicylic acid derivatives on cyclic AMP levels in rat platelets. Arch Int Pharmacodyn Ther. 1986;284:155–165[Web of Science][Medline]
  78. Ramis J, Mis R, Forn J, Torrent J, Gorina E, Jané F. Pharmacokinetics of triflusal and its main metabolite HTB in healthy subjects following a single oral dose. Eur J Drug Metab Pharmacokinet. 1991;16:269–273[Web of Science][Medline]
  79. Ramis J, Torrent J, Mis R, et al. Pharmacokinetics of triflusal after single and repeated doses in man. Int J Clin Pharmacol Ther Toxicol. 1990;28:344–349[Medline]
  80. Mis R, Ramis J, Conte L, Forn J. In vitro protein binding interaction between a metabolite of triflusal, 2-hydroxy-4trifluoromethylbenzoic acid and other drugs. J Pharm Pharmacol. 1992;44:935–937[Web of Science][Medline]
  81. Putz Ph, Buyes H, Delvauz D, et al. Triflusal versus acetylsalicylic acid: a double-blind study for the prophylaxis of deep vein thrombosis after hip surgery. Acta Chir Belg. 1991;91:269–276[Medline]
  82. Cruz-Fernández JM, López-Bescós L, Garcia-Dorado D, et al. Randomized comparative trial of triflusal and aspirin following acute myocardial infarction. Eur Heart J. 2000;21:457–465[Abstract/Free Full Text]
  83. López-Bescós L, Calades O'Callaghan A, Castro Beiras A, et al. Incidence of vascular stroke in patients with acute myocardial infarction receiving fibrinolytic treatment. Eur Heart J Suppl. 1999;1(Suppl F):F19–F23[Web of Science]
  84. Sanchez-Gomez S, Alfón J, Badimon L. Thrombus growth on residual thrombus is inhibited and vascular wall Cox2 upregulated by treatment with Triflusal. Eur Heart J (Abstract Suppl). 2000;21(79):546

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Badimon, L.
Right arrow Articles by Duran, X.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Badimon, L.
Right arrow Articles by Duran, X.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?