Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Platelets in atherothrombosis

Nature Medicine volume 8, pages 1227–1234 (2002)Cite this article

The participation of platelets in atherogenesis and the subsequent formation of occlusive thrombi depend on platelets' adhesive properties and the inability to respond to stimuli with rapid activation. By understanding the multifaceted mechanisms involved in platelet interactions with vascular surfaces and aggregation, new approaches can be tailored to selectively inhibit the pathways most relevant to the pathological aspects of atherothrombosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: False color scanning electron micrograph of an activated platelet.

© SPL, PHOTO RESEARCHERS, INC.

Figure 2: Balance between antithrombotic and prothrombotic molecules synthesized by endothelial cells.

D. Maizels

Figure 3: Platelet adhesion, activation and aggregation.

D. Maizels

Figure 4: Possible model for the arrest of platelets on a developing atherosclerotic plaque.

D. Maizels

References

  1. Ware, J.A. & Heistad, D.D. Platelet-endothelium interactions. N. Engl. J. Med. 328, 628–635 (1993).

    Article  CAS  Google Scholar 

  2. Gross, P.L. & Aird, W.C. The endothelium and thrombosis. Semin. Thromb. Hemost. 26, 463–478 (2000).

    Article  CAS  Google Scholar 

  3. Olsen, B.R. in Guidebook to the Extracellular Matrix and Adhesion Proteins (eds, Kreis, T. & Vale, R.) 35–37 (Oxford University Press, Oxford, 1993).

    Google Scholar 

  4. Saelman, E.U.M. et al. Platelet adhesion to collagen types I through VIII under conditions of stasis and flow is mediated by GPIa/IIa (α2β1-Integrin). Blood 83, 1244–1250 (1994).

    CAS  PubMed  Google Scholar 

  5. Clemetson, K.J. & Clemetson, J.M. Platelet collagen receptors. Thromb. Haemost. 86, 189–197 (2001).

    Article  CAS  Google Scholar 

  6. Nieuwenhuis, H.K., Akkerman, J.W.N., Houdijk, W.P.M. & Sixma, J.J. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 318, 470–472 (1985).

    Article  CAS  Google Scholar 

  7. Nieuwenhuis, H.K., Sakariassen, K.S., Houdijk, W.P.M., Nievelstein, P.F.E.M. & Sixma, J.J. Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: A defect in platelet spreading. Blood 68, 692–695 (1986).

    CAS  PubMed  Google Scholar 

  8. Moroi, M., Jung, S.M., Okuma, M. & Shinmyozu, K. A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J. Clin. Invest. 84, 1440–1445 (1989).

    Article  CAS  Google Scholar 

  9. Holtkotter, O. et al. Integrin α 2-deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen. J. Biol. Chem. 277, 10789–10794 (2002).

    Article  CAS  Google Scholar 

  10. Savage, B., Ginsberg, M.H. & Ruggeri, Z.M. Influence of fibrillar collagen structure on the mechanisms of platelet thrombus formation under flow. Blood 94, 2704–2715 (1999).

    CAS  PubMed  Google Scholar 

  11. Watson, S., Berlanga, O., Best, D. & Frampton, J. Update on collagen receptor interactions in platelets: Is the two-model still valid? Platelets 11, 252–258 (2000).

    Article  CAS  Google Scholar 

  12. Keely, P.J. & Parise, L.V. The α2β1 integrin is a necessary co-receptor for collagen-induced activation of syk and subsequent phosphorylation of phospholipase Cγ2 in platelets. J. Biol. Chem. 271, 26668–26676 (1996).

    Article  CAS  Google Scholar 

  13. Patil, S., Newman, D.K. & Newman, P.J. Platelet endothelial cell adhesion molecule-1 serves as an inhibitor receptor that modulates platelet responses to collagen. Blood 97, 1727–1732 (2001).

    Article  CAS  Google Scholar 

  14. Savage, B., Saldivar, E. & Ruggeri, Z.M. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 84, 289–297 (1996).

    Article  CAS  Google Scholar 

  15. Savage, B., Almus-Jacobs, F. & Ruggeri, Z.M. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 94, 657–666 (1998).

    Article  CAS  Google Scholar 

  16. Timpl, R. & Brown, J.C. The laminins. Matrix Biol. 14, 275–281 (1994).

    Article  CAS  Google Scholar 

  17. Balbona, K. et al. Fibulin binds to itself and to the carboxy-terminal heparin-binding region of fibronectin. J. Biol. Chem. 267, 20120–20125 (1992).

    CAS  PubMed  Google Scholar 

  18. Tran, H. et al. The interaction of fibulin-1 with fibrinogen: A potential role in hemostasis and thrombosis. J. Biol. Chem. 270, 19458–19464 (1995).

    Article  CAS  Google Scholar 

  19. Godyna, S., Diaz-Ricart, M. & Argraves, W.S. Fibulin-1 mediates platelet adhesion via a bridge of fibrinogen. Blood 88, 2569–2577 (1996).

    CAS  PubMed  Google Scholar 

  20. Hynes, R.O. Fibronectins (Springer-Verlag, New York, 1989).

    Google Scholar 

  21. Beumer, S., IJsseldijk, M.J., de Groot, P.G. & Sixma, J.J. Platelet adhesion to fibronectin in flow: dependence on surface concentration and shear rate, role of platelet membrane glycoproteins GP IIb/IIIa and VLA-5, and inhibition by heparin. Blood 84, 3724–3733 (1994).

    CAS  PubMed  Google Scholar 

  22. Beumer, S. et al. Platelet adhesion to fibronectin in flow: the importance of von Willebrand factor and glycoprotein Ib. Blood 86, 3452–3460 (1995).

    CAS  PubMed  Google Scholar 

  23. Ni, H. et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J. Clin. Invest. 106, 385–392 (2000).

    Article  CAS  Google Scholar 

  24. Savage, B., Cattaneo, M. & Ruggeri, Z.M. Mechanisms of platelet aggregation. Curr. Opin. Hematol. 8, 270–276 (2001).

    Article  CAS  Google Scholar 

  25. Coughlin, S.R. Thrombin signalling and protease-activated receptors. Nature 407, 258–264 (2000).

    Article  CAS  Google Scholar 

  26. Sambrano, G.R., Weiss, E.J., Zheng, Y.-W., Huang, W. & Coughlin, S.R. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 413, 74–78 (2001).

    Article  CAS  Google Scholar 

  27. Covic, L., Gresser, A.L. & Kuliopulos, A. Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 39, 5458–5467 (2000).

    Article  CAS  Google Scholar 

  28. Mazzucato, M. et al. Characterization of the initial α-thrombin interaction with glycoprotein Ibα in relation to platelet activiation. J. Biol. Chem. 273, 1880–1887 (1998).

    Article  CAS  Google Scholar 

  29. Ramakrishnan, V. et al. A thrombin receptor function for platelet glycoprotein Ib-IX unmasked by cleavage of glycoprotein V. Proc. Natl. Acad. Sci. USA 98, 1823–1828 (2001).

    Article  CAS  Google Scholar 

  30. Soslau, G. et al. Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib. J. Biol. Chem. 276, 21173–21183 (2001).

    Article  CAS  Google Scholar 

  31. Gachet, C. Platelet activation by ADP: the role of ADP antagonists. Ann. Med. 32 Suppl 1, 15–20 (2000).

    CAS  PubMed  Google Scholar 

  32. Woodside, D.G., Liu, S. & Ginsberg, M.H. Integrin activation. Thromb. Haemost. 86, 316–323 (2001).

    Article  CAS  Google Scholar 

  33. Ni, H. et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J. Clin. Invest. 106, 385–392 (2000).

    Article  CAS  Google Scholar 

  34. Andre, P. et al. CD40L stabilizes arterial thrombi by a β3 integrin-dependent mechanism. Nature Med. 8, 247–252 (2002).

    Article  CAS  Google Scholar 

  35. Garlichs, C.D. et al. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation 104, 2395–2400 (2001).

    Article  CAS  Google Scholar 

  36. Tangelder, G.J., Slaaf, D.W., Arts, T. & Reneman, R.S. Wall shear rate in arterioles in vivo: least estimates from platelet velocity profiles. Am. J. Physiol. 254, H1059–H1064 (1988).

    CAS  PubMed  Google Scholar 

  37. Savage, B., Saldivar, E. & Ruggeri, Z.M. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 84, 289–297 (1996).

    Article  CAS  Google Scholar 

  38. Savage, B., Almus-Jacobs, F. & Ruggeri, Z.M. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 94, 657–666 (1998).

    Article  CAS  Google Scholar 

  39. Mazzucato, M., Pradella, P., Cozzi, M.R., De Marco, L. & Ruggeri, Z.M. Sequential cytoplasmic calcium signals in a two-stage platelet activation process induced by the glycoprotein Ibα mechanoreceptor. Blood, 100, 2793–2800 (2002).

    Article  CAS  Google Scholar 

  40. Ruggeri, Z.M., De Marco, L., Gatti, L., Bader, R. & Montgomery, R.R. Platelets have more than one binding site for von Willebrand factor. J. Clin. Invest. 72, 1–12 (1983).

    Article  CAS  Google Scholar 

  41. Goto, S., Salomon, D.R., Ikeda, Y. & Ruggeri, Z.M. Characterization of the unique mechanism mediating the shear-dependent binding of soluble von Willebrand factor to platelets. J. Biol. Chem. 270, 23352–23361 (1995).

    Article  CAS  Google Scholar 

  42. Ruggeri, Z.M., Dent, J.A. & Saldivar, E. Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood 94, 172–178 (1999).

    CAS  PubMed  Google Scholar 

  43. Savage, B., Sixma, J.J. & Ruggeri, Z.M. Functional self-association of von Willebrand factor during platelet adhesion under flow. Proc. Natl. Acad. Sci. USA 99, 425–430 (2002).

    Article  CAS  Google Scholar 

  44. Siediecki, C.A. et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand Factor. Blood 88, 2939–2950 (1996).

    Google Scholar 

  45. Zimmerman, T.S., Dent, J.A., Ruggeri, Z.M. & Nannini, L.H. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (Types IIC, IID and IIE). J. Clin. Invest. 77, 947–951 (1986).

    Article  CAS  Google Scholar 

  46. Dent, J.A., Berkowitz, S.D., Ware, J., Kasper, C.K. & Ruggeri, Z.M. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc. Natl. Acad. Sci. USA 87, 6306–6310 (1990).

    Article  CAS  Google Scholar 

  47. Furlan, M. et al. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 89, 3097–3103 (1997).

    CAS  PubMed  Google Scholar 

  48. Tsai, H.M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 87, 4235–4244 (1996).

    CAS  Google Scholar 

  49. Levy, G.G. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413, 488–494 (2001).

    Article  CAS  Google Scholar 

  50. Xie, L., Chesterman, C.N. & Hogg, P.J. Control of von Willebrand factor multimer size by thrombospondin-1. J. Exp. Med. 193, 1341–1349 (2001).

    Article  CAS  Google Scholar 

  51. Vivekananthan, D.P., Patel, V.B. & Moliterno, D.J. Glycoprotein IIb/IIa antagonism and fibrinolytic therapy for acute myocardial infarction. J. Interv. Cardiol. 15, 131–139 (2002).

    Article  Google Scholar 

  52. Talley, J.D. Clinical trials of glycoprotein IIb/IIIa inhibitors. J. Interv. Cardiol. 14, 129–142 (2001).

    Article  CAS  Google Scholar 

  53. Quinn, M.J., Plow, E.F. & Topol, E.J. Platelet glycoprotein IIb/IIa inhibitors: recognition of a two-edged sword? Circulation 106, 379–385 (2002).

    Article  CAS  Google Scholar 

  54. Abumiya, T. et al. Integrin αIIbβ3 inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia. Stroke 31, 1402–1410 (2000).

    Article  CAS  Google Scholar 

  55. Barnett, H.J.M. et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N. Engl. J. Med. 339, 1415–1425 (1998).

    Article  CAS  Google Scholar 

  56. Inzitari, D., Eliasziw, M., Sharpe, B.L., Fox, A.J. & Barnett, H.J.M. Risk factors and outcome of patients with carotid artery stenosis presenting with lacunar stroke. Neurology 54, 660–666 (2000).

    Article  CAS  Google Scholar 

  57. Inzitari, D. et al. The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. N. Engl. J. Med. 342, 1693–1700 (2000).

    Article  CAS  Google Scholar 

  58. Bornstein, N.M. Antiplatelet drugs: how to select them and possibilities of combined treatment. Cerebrovasc. Dis. Suppl 1, 96–99 (2001).

    Article  Google Scholar 

  59. Taylor, D.W. et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. Lancet 353, 2179–2184 (1999).

    Article  CAS  Google Scholar 

  60. Laird, J.R. The management of acute limb ischemia: techniques for dealing with thrombus. J. Interv. Cardiol. 14, 539–546 (2001).

    Article  CAS  Google Scholar 

  61. Matsagas, M.I., Geroulakos, G. & Mikhailidis, D.P. The role of platelets in peripheral arterial disease: therapeutic implications. Ann. Vasc. Surg. 16, 246–258 (2002).

    Article  CAS  Google Scholar 

  62. Ruberg, F.L., Leopold, J.A. & Loscalzo, J. Atherothrombosis: plaque instability and thrombogenesis. Prog. Cardiovasc. Dis. 44, 381–394 (2002).

    Article  CAS  Google Scholar 

  63. Strony, J., Beaudoin, A., Brands, D. & Adelman, B. Analysis of shear stress and hemodynamic factors in a model of coronary artery stenosis and thrombosis. Am. J. Physiol. Heart Circ. Physiol. 265, H1787–H1796 (1993).

    Article  CAS  Google Scholar 

  64. Mailhac, A. et al. Effect of an eccentric severe stenosis on fibrin(ogen) deposition on severely damaged vessel wall in arterial thrombosis. Relative contribution of fibrin(ogen) and platelets. Circulation 90, 988–996 (1994).

    Article  CAS  Google Scholar 

  65. Goto, S. et al. Enhanced shear-induced platelet aggregation in acute myocardial infarction. Circulation 99, 608–613 (1999).

    Article  CAS  Google Scholar 

  66. Balasubramanian, V., Grabowski, E., Bini, A. & Nemerson, Y. Platelets, circulating tissue factor, and fibrin colocalize in ex vivo thrombi: Real-time fluorescence images of thrombus formation and propagation under defined flow conditions. Blood 100, 2787–2792 (2002).

    Article  CAS  Google Scholar 

  67. Weiss, E.J. et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N. Engl. J. Med. 334, 1090–1094 (1996).

    Article  CAS  Google Scholar 

  68. Kunicki, T.J. & Ruggeri, Z.M. Platelet collagen receptors and risk prediction in stroke and coronary artery disease. Circulation 104, 1451–1453 (2001).

    Article  CAS  Google Scholar 

  69. Lusis, A.J. Atherosclerosis. Nature 407, 233–241 (2000).

    Article  CAS  Google Scholar 

  70. Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  CAS  Google Scholar 

  71. Sachais, B.S. Platelet-endothelial interactions in atherosclerosis. Curr. Atheroscler. Rep. 3, 412–416 (2001).

    Article  CAS  Google Scholar 

  72. Pratico, D., Tillmann, C., Zhang, Z.-B., Li, H. & Fitzgerald, G.A. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc. Natl. Acad. Sci. USA 98, 3358–3363 (2001).

    Article  CAS  Google Scholar 

  73. Theilmeier, G. et al. Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia. Blood 99, 4486–4493 (2002).

    Article  CAS  Google Scholar 

  74. Methia, N., Andre, P., Denis, C.V., Economopoulos, M. & Wagner, D.D. Localized reduction of atherosclerosis in von Willebrand factor-deficient mice. Blood 98, 1424–1428 (2001).

    Article  CAS  Google Scholar 

  75. Willerson, J.T. Systemic and local inflammation in patients with unstable atherosclerotic plaques. Prog. Cardiovasc. Dis. 44, 469–478 (2002).

    Article  CAS  Google Scholar 

  76. Sjobring, U., Ringdahl, U. & Ruggeri, Z.M. Induction of platelet thrombi by bacteria and antibodies. (Blood, published online August 1, 2002, doi:10.1182/blood-2002-01-0069).

  77. Shpilberg, O. et al. Patients with Glanzmann thrombasthenia lacking platelet glycoprotein αIIbβ3 (GPIIb/IIIa) and αvβ3 receptors are not protected from atherosclerosis. Circulation 105, 1044–1048 (2002).

    Article  CAS  Google Scholar 

  78. Celi, A., Lorenzet, R., Furie, B. & Furie, B.C. Platelet-leukocyte-endothelial cell interaction on the blood vessel wall. Sem. Hematol. 34, 327–335 (1997).

    CAS  Google Scholar 

  79. Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993).

    Article  CAS  Google Scholar 

  80. Sachais, B.S. et al. Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic machinery, resulting in retention of low-density lipoprotein on the cell surface. Blood 99, 3613–3622 (2002).

    Article  CAS  Google Scholar 

  81. De Meyer, G.R. et al. Platelet phagocytosis and processing of β-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis. Circ. Res. 90, 1145–1146 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

The author is supported by grants from the National Heart, Lung and Blood Institute.

Author information

Authors and Affiliations

  1. Department of Molecular and Experimental Medicine The Scripps Research Institute, La Jolla, California, USA

    Zaverio M. Ruggeri

Authors
  1. Zaverio M. Ruggeri
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruggeri, Z. Platelets in atherothrombosis. Nat Med 8, 1227–1234 (2002). https://doi.org/10.1038/nm1102-1227

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1102-1227

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing