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.
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References
Ware, J.A. & Heistad, D.D. Platelet-endothelium interactions. N. Engl. J. Med. 328, 628–635 (1993).
Gross, P.L. & Aird, W.C. The endothelium and thrombosis. Semin. Thromb. Hemost. 26, 463–478 (2000).
Olsen, B.R. in Guidebook to the Extracellular Matrix and Adhesion Proteins (eds, Kreis, T. & Vale, R.) 35–37 (Oxford University Press, Oxford, 1993).
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).
Clemetson, K.J. & Clemetson, J.M. Platelet collagen receptors. Thromb. Haemost. 86, 189–197 (2001).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Timpl, R. & Brown, J.C. The laminins. Matrix Biol. 14, 275–281 (1994).
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).
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).
Godyna, S., Diaz-Ricart, M. & Argraves, W.S. Fibulin-1 mediates platelet adhesion via a bridge of fibrinogen. Blood 88, 2569–2577 (1996).
Hynes, R.O. Fibronectins (Springer-Verlag, New York, 1989).
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).
Beumer, S. et al. Platelet adhesion to fibronectin in flow: the importance of von Willebrand factor and glycoprotein Ib. Blood 86, 3452–3460 (1995).
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).
Savage, B., Cattaneo, M. & Ruggeri, Z.M. Mechanisms of platelet aggregation. Curr. Opin. Hematol. 8, 270–276 (2001).
Coughlin, S.R. Thrombin signalling and protease-activated receptors. Nature 407, 258–264 (2000).
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).
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).
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).
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).
Soslau, G. et al. Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib. J. Biol. Chem. 276, 21173–21183 (2001).
Gachet, C. Platelet activation by ADP: the role of ADP antagonists. Ann. Med. 32 Suppl 1, 15–20 (2000).
Woodside, D.G., Liu, S. & Ginsberg, M.H. Integrin activation. Thromb. Haemost. 86, 316–323 (2001).
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).
Andre, P. et al. CD40L stabilizes arterial thrombi by a β3 integrin-dependent mechanism. Nature Med. 8, 247–252 (2002).
Garlichs, C.D. et al. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation 104, 2395–2400 (2001).
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).
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).
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).
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).
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).
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).
Ruggeri, Z.M., Dent, J.A. & Saldivar, E. Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood 94, 172–178 (1999).
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).
Siediecki, C.A. et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand Factor. Blood 88, 2939–2950 (1996).
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).
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).
Furlan, M. et al. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 89, 3097–3103 (1997).
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).
Levy, G.G. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413, 488–494 (2001).
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).
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).
Talley, J.D. Clinical trials of glycoprotein IIb/IIIa inhibitors. J. Interv. Cardiol. 14, 129–142 (2001).
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).
Abumiya, T. et al. Integrin αIIbβ3 inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia. Stroke 31, 1402–1410 (2000).
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).
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).
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).
Bornstein, N.M. Antiplatelet drugs: how to select them and possibilities of combined treatment. Cerebrovasc. Dis. Suppl 1, 96–99 (2001).
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).
Laird, J.R. The management of acute limb ischemia: techniques for dealing with thrombus. J. Interv. Cardiol. 14, 539–546 (2001).
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).
Ruberg, F.L., Leopold, J.A. & Loscalzo, J. Atherothrombosis: plaque instability and thrombogenesis. Prog. Cardiovasc. Dis. 44, 381–394 (2002).
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).
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).
Goto, S. et al. Enhanced shear-induced platelet aggregation in acute myocardial infarction. Circulation 99, 608–613 (1999).
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).
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).
Kunicki, T.J. & Ruggeri, Z.M. Platelet collagen receptors and risk prediction in stroke and coronary artery disease. Circulation 104, 1451–1453 (2001).
Lusis, A.J. Atherosclerosis. Nature 407, 233–241 (2000).
Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).
Sachais, B.S. Platelet-endothelial interactions in atherosclerosis. Curr. Atheroscler. Rep. 3, 412–416 (2001).
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).
Theilmeier, G. et al. Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia. Blood 99, 4486–4493 (2002).
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).
Willerson, J.T. Systemic and local inflammation in patients with unstable atherosclerotic plaques. Prog. Cardiovasc. Dis. 44, 469–478 (2002).
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).
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).
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).
Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993).
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).
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).
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The author is supported by grants from the National Heart, Lung and Blood Institute.
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Ruggeri, Z. Platelets in atherothrombosis. Nat Med 8, 1227–1234 (2002). https://doi.org/10.1038/nm1102-1227
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DOI: https://doi.org/10.1038/nm1102-1227
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