Skip to main content
Log in

Evolving Concepts in the Triad of Atherosclerosis, Inflammation and Thrombosis

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Recent developments into antherothrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis. Thrombosis may lead to a complete occlusion or, in the case of mural thrombus or intraplaque hemorrhage, to plaque progression.

Disruption of a vulnerable or unstable plaque (type IV and Va lesions of the AHA classification) with a subsequent change in plaque geometry and thrombosis may result in an acute coronary syndrome. The high-risk plaque tend to be relatively small, but soft or vulnerable to “passive” disruption because of high lipid content. Inflammatory processes are important components of all stages of atherosclerotic development, including plaque initiation and disruption. As such the early steps in atherosclerotic lesion formation are the over expression of endothelial adhesive protein (i.e. selectins, VCAM and ICAM), chemotactic factors (MCP-1), growth factors (M-CSF), and cytokines (IL-2) that will facilitate the recruitment, internalization and survival of blood-borne inflammatory cells into the vascular wall. Macrophages, following what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with release of MMPs and TF. Specific cell recruitment in the vessel wall and build-up of the extracellular matrix are coordinated by a wide variety of stimulators and inhibitors. Active interaction of immune competent cells within the atherosclerotic lesions appears to play a pivotal role in the control of atherosclerotic plaque evolution and, therefore, deserves particular attention from the research community with the ultimate goal of improving preventive and therapeutic medical approaches. Inflammation, thrombosis and atherosclerosis are interdependent and define a triad within the complex pathogenic process of atherothrombosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992;326:310–318.

    Google Scholar 

  2. Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: Biology. Lancet 1999;353(Suppl 2):SII5–SII9.

    Google Scholar 

  3. Ross R. Atherosclerosis-An inflammatory disease.NEngl J Med 1999;340:115–126.

    Google Scholar 

  4. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001;104:365–372.

    Google Scholar 

  5. Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: Pathogenesis and clinical consequences. Ann Intern Med 2001;134:224–238.

    Google Scholar 

  6. Fuster V, Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: Insights from studies of vascular biology. Circulation 1994;90:2126–2146.

    Google Scholar 

  7. Stary HC. Composition and classification of human atherosclerotic lesions. Virchows Arch A Pathol Anat Histopathol 1992;421:277–290.

    Google Scholar 

  8. Davies MJ. Stability and instability: Two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation 1996;94:2013–2020.

    Google Scholar 

  9. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994;90:775–778.

    Google Scholar 

  10. Ambrose JA. Angiographic correlations of advanced coronary lesions in acute coronary syndromes. In Fuster V, ed. Syndromes of Atherosclerosis: Correlations of Clinical Imaging and Pathology. Armonk, NY: Futura Publishing Company, Inc. 1996:105–122.

    Google Scholar 

  11. Corti R, Fuster V, Badimon JJ, Hutter R, Fayad ZA. New understanding of atherosclerosis (clinically and experimentally) with evolving MRI technology in vivo. Ann NY Acad Sci 2001:181–195.

  12. Fuster V. Mechanisms leading to myocardial infarction: Insights from studies of vascular biology. Circulation 1994;90:2126–2146.

    Google Scholar 

  13. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92:1355–1374.

    Google Scholar 

  14. Price DT, Loscalzo J. Cellular adhesion molecules and atherogenesis. Am J Med 1999;107:85–97.

    Google Scholar 

  15. McEver RP, Moore KL, Cummings RD. Leukocyte trafficking mediated by selectin-carbohydrate interactions. J Biol Chem 1995;270:11025–11028.

    Google Scholar 

  16. Cybulsky MI, Iiyama K, Li H, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 2001;107:1255–1262.

    Google Scholar 

  17. Sartore S, Chiavegato A, Faggin E, et al. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: From innocent bystander to active participant. Circ Res 2001;89:1111–1121.

    Google Scholar 

  18. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995;92:657–671.

    Google Scholar 

  19. Michel JB. Contrasting outcomes of atheroma evolution: Intimal accumulation versus medial destruction. Arterioscler Thromb Vasc Biol 2001;21:1389–1392.

    Google Scholar 

  20. Silence J, Lupu F, Collen D, Lijnen HR. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb Vasc Biol 2001;21:1440–1445.

    Google Scholar 

  21. Moreno PR, Purushothaman K-R, Fuster V. Internal elastic lamina in the process of plaque disruption.J Am Coll Cardiol 2001;37:288A–298A.

    Google Scholar 

  22. Mallat Z, Tedgui A. Current perspective on the role of apoptosis in atherothrombotic disease. Circ Res 2001;88:998–1003.

    Google Scholar 

  23. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276–1282.

    Google Scholar 

  24. 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.

    Google Scholar 

  25. Toschi V, Gallo R, Lettino M, et al.Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997;95:594–599.

    Google Scholar 

  26. 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.

    Google Scholar 

  27. Nemerson Y. Tissue factor and hemostasis. Blood 1988;71:1–8.

    Google Scholar 

  28. 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.

    Google Scholar 

  29. Bauriedel G, Hutter R, Welsch U, Bach R, Sievert H, Luderitz B. Role of smooth muscle cell death in advanced coronary primary lesions: Implications for plaque instability. Cardiovasc Res 1999;41:480–488.

    Google Scholar 

  30. Hutter R, Sauter B, Fallon JT, Fuster V, Badimon JJ. Macrophages and vascular stellate cells in human carotid plaques are prone to apoptosis and tissue factor expression. J AmColl Cardiol 2001;37:288A.

    Google Scholar 

  31. Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: A role for apoptosis in plaque thrombogenicity. Circulation 1999;99:348–353.

    Google Scholar 

  32. Badimon JJ, Lettino M, Toschi V, et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: Effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999;99:1780–1787.

    Google Scholar 

  33. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: A comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262–1275.

    Google Scholar 

  34. Dangas G, Badimon JJ, Smith DA, et al. Pravastatin therapy in hyperlipidemia: Effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 1999;33:1294–1304.

    Google Scholar 

  35. 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.

    Google Scholar 

  36. Rauch U, Crandall J, Osende JI, et al. Increased thrombus formation relates to ambient blood glucose and leukocyte count in diabetes mellitus type 2. Am J Cardiol 2000;86:246–249.

    Google Scholar 

  37. Osende JI, Badimon JJ, Fuster V, et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol 2001;38:1307–1312.

    Google Scholar 

  38. Fuster V, Gotto AM, Jr. Risk reduction. Circulation 2000;102:IV94-IV102.

    Google Scholar 

  39. Corti R, Badimon JJ. Value and/or desirability ofhemorheologic-hemostatic parameter changes as end points in blood lipid regulating trials. Curr Opin Lipidol 2001:629–637.

  40. Rao AK, Chouhan V, Chen X, Sun L, Boden G. Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. Diabetes 1999;48:1156–1161.

    Google Scholar 

  41. Kaikita K, Ogawa H, Yasue H, et al. Tissue factor expression on macrophages in coronary plaques in patients with unstable angina. Arterioscler Thromb Vasc Biol 1997;17:2232–2237.

    Google Scholar 

  42. Saito Y, Wada H, Yamamuro M, et al. Changes of plasma hemostatic markers during percutaneous transluminal coronary angioplasty in patients with chronic coronary artery disease. Am J Hematol 1999;61:238–242.

    Google Scholar 

  43. Soejima H, Ogawa H, Yasue H, et al. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation 1999;99:2908–2913.

    Google Scholar 

  44. Drew AF, Davenport P, Apostolopoulos J, Tipping PG. Tissue factor pathway inhibitor expression in atherosclerosis. Lab Invest 1997;77:291–298.

    Google Scholar 

  45. Giesen PL, Rauch U, Bohrmann B, et al. Blood-borne tissue factor: Another view of thrombosis. Proc Natl Acad Sci USA1999;96:2311–2315.

    Google Scholar 

  46. Ridker PM. High-sensitivity C-reactive protein: Potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001;103:1813–1818.

    Google Scholar 

  47. Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: More than an epiphenomenon? Circulation 1999;100:96–102.

    Google Scholar 

  48. Pasceri V, Chang J, Willerson JT, Yeh ET. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by antiatherosclerosis drugs. Circulation 2001;103:2531–2534.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Corti, R., Hutter, R., Badimon, J.J. et al. Evolving Concepts in the Triad of Atherosclerosis, Inflammation and Thrombosis. J Thromb Thrombolysis 17, 35–44 (2004). https://doi.org/10.1023/B:THRO.0000036027.39353.70

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:THRO.0000036027.39353.70

Navigation