Arterial thrombosis—insidious, unpredictable and deadly

Article metrics

Abstract

The formation of blood clots—thrombosis—at sites of atherosclerotic plaque rupture is a major clinical problem despite ongoing improvements in antithrombotic therapy. Progress in identifying the pathogenic mechanisms regulating arterial thrombosis has led to the development of newer therapeutics, and there is general anticipation that these treatments will have greater efficacy and improved safety. However, major advances in this field require the identification of specific risk factors for arterial thrombosis in affected individuals and a rethink of the 'one size fits all' approach to antithrombotic therapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Adhesion and activation mechanisms supporting the hemostatic and prothrombotic function of platelets.
Figure 2: Differential composition and localization of arterial thrombi relative to hemostatic plugs.
Figure 3: The antiadhesive phenotype of endothelial cells is maintained through four intrinsic pathways: ecto-ADPase, prostaglandin I2 (PGI2), nitric oxide (NO) and the thrombomodulin (TM)-activated protein C (APC) pathways.
Figure 4: Arterial thrombosis and the rapid progression of atherosclerotic lesions.
Figure 5: Platelet procoagulant activity necessary for α-thrombin generation, fibrin formation and thrombus stability.

References

  1. 1

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

  2. 2

    Alwan, A. et al. Burden: mortality, morbidity and risk factors. in Global Status Report on Noncommunicable Diseases 2010 (ed. Alwan, A.) (WHO Press, Geneva, Switzerland, 2011).

  3. 3

    Antithrombotic-Trialists-Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br. Med. J. 324, 71–86 (2002).

  4. 4

    Bhatt, D.L. What makes platelets angry: diabetes, fibrinogen, obesity, and impaired response to antiplatelet therapy? J. Am. Coll. Cardiol. 52, 1060–1061 (2008).

  5. 5

    Furie, B. & Furie, B.C. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938–949 (2008).

  6. 6

    Ruggeri, Z.M. Platelets in atherothrombosis. Nat. Med. 8, 1227–1234 (2002).

  7. 7

    Gawaz, M., Langer, H. & May, A.E. Platelets in inflammation and atherogenesis. J. Clin. Invest. 115, 3378–3384 (2005).

  8. 8

    de Boer, O.J., van der Wal, A.C., Teeling, P. & Becker, A.E. Leucocyte recruitment in rupture prone regions of lipid-rich plaques: a prominent role for neovascularization? Cardiovasc. Res. 41, 443–449 (1999).

  9. 9

    Kolodgie, F.D. et al. Intraplaque hemorrhage and progression of coronary atheroma. N. Engl. J. Med. 349, 2316–2325 (2003).

  10. 10

    Burke, A.P. et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 103, 934–940 (2001).

  11. 11

    Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

  12. 12

    Davies, M.J., Fulton, W.F. & Robertson, W.B. The relation of coronary thrombosis to ischaemic myocardial necrosis. J. Pathol. 127, 99–110 (1979).

  13. 13

    Falk, E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br. Heart J. 50, 127–134 (1983).

  14. 14

    Falk, E. 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 71, 699–708 (1985).

  15. 15

    Jackson, S.P. The growing complexity of platelet aggregation. Blood 109, 5087–5095 (2007).

  16. 16

    Denis, C.V. & Wagner, D.D. Platelet adhesion receptors and their ligands in mouse models of thrombosis. Arterioscler. Thromb. Vasc. Biol. 27, 728–739 (2007).

  17. 17

    Varga-Szabo, D., Pleines, I. & Nieswandt, B. Cell adhesion mechanisms in platelets. Arterioscler. Thromb. Vasc. Biol. 28, 403–412 (2008).

  18. 18

    Ruggeri, Z.M. Platelet adhesion under flow. Microcirculation 16, 58–83 (2009).

  19. 19

    Moroi, M. et al. Analysis of platelet adhesion to a collagen-coated surface under flow conditions: the involvement of glycoprotein VI in the platelet adhesion. Blood 88, 2081–2092 (1996).

  20. 20

    Nieswandt, B. & Watson, S.P. Platelet-collagen interaction: is GPVI the central receptor? Blood 102, 449–461 (2003).

  21. 21

    Santoro, S.A. Identification of a 160,000 dalton platelet membrane protein that mediates the initial divalent cation-dependent adhesion of platelets to collagen. Cell 46, 913–920 (1986).

  22. 22

    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).

  23. 23

    Ruggeri, Z.M. Structure and function of von Willebrand factor. Thromb. Haemost. 82, 576–584 (1999).

  24. 24

    Barg, A. et al. Soluble plasma-derived von Willebrand factor assembles to a haemostatically active filamentous network. Thromb. Haemost. 97, 514–526 (2007).

  25. 25

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

  26. 26

    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).

  27. 27

    Nesbitt, W.S. et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat. Med. 15, 665–673 (2009).

  28. 28

    Hantgan, R.R. Fibrin protofibril and fibrinogen binding to ADP-stimulated platelets: evidence for a common mechanism. Biochim. Biophys. Acta 968, 24–35 (1988).

  29. 29

    Ruggeri, Z.M., Bader, R. & de Marco, L. Glanzmann thrombasthenia: deficient binding of von Willebrand factor to thrombin-stimulated platelets. Proc. Natl. Acad. Sci. USA 79, 6038–6041 (1982).

  30. 30

    Bennett, J.S. & Vilaire, G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J. Clin. Invest. 64, 1393–1401 (1979).

  31. 31

    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).

  32. 32

    López, J.A., Andrews, R.K., Afshar-Kharghan, V. & Berndt, M.C. Bernard-Soulier syndrome. Blood 91, 4397–4418 (1998).

  33. 33

    Shattil, S.J., Kim, C. & Ginsberg, M.H. The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell Biol. 11, 288–300 (2010).

  34. 34

    Hartwig, J.H., Barkalow, K., Azim, A. & Italiano, J. The elegant platelet: signals controlling actin assembly. Thromb. Haemost. 82, 392–398 (1999).

  35. 35

    Reed, G.L. Platelet secretory mechanisms. Semin. Thromb. Hemost. 30, 441–450 (2004).

  36. 36

    Jin, J., Daniel, J.L. & Kunapuli, S.P. Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J. Biol. Chem. 273, 2030–2034 (1998).

  37. 37

    Hollopeter, G. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409, 202–207 (2001).

  38. 38

    Huang, J.S., Ramamurthy, S.K., Lin, X. & Le Breton, G.C. Cell signalling through thromboxane A2 receptors. Cell. Signal. 16, 521–533 (2004).

  39. 39

    Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br. Med. J. 324, 71–86 (2002).

  40. 40

    CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348, 1329–1339 (1996).

  41. 41

    Michelson, A.D. Antiplatelet therapies for the treatment of cardiovascular disease. Nat. Rev. Drug Discov. 9, 154–169 (2010).

  42. 42

    Patrono, C., Baigent, C., Hirsh, J. & Roth, G. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 8th edn., Chest 133, 199S–233S (2008).

  43. 43

    Coughlin, S.R. How the protease thrombin talks to cells. Proc. Natl. Acad. Sci. USA 96, 11023–11027 (1999).

  44. 44

    Boucher, P. & Gotthardt, M. LRP and PDGF signaling: a pathway to atherosclerosis. Trends Cardiovasc. Med. 14, 55–60 (2004).

  45. 45

    Davì, G. & Patrono, C. Platelet activation and atherothrombosis. N. Engl. J. Med. 357, 2482–2494 (2007).

  46. 46

    Davies, M.J. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 82, II38–II46 (1990).

  47. 47

    Mann, J. & Davies, M.J. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart 82, 265–268 (1999).

  48. 48

    Kuijpers, M.J. et al. Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model. J. Thromb. Haemost. 7, 152–161 (2009).

  49. 49

    Arbustini, E. et al. Coronary thrombosis in non-cardiac death. Coron. Artery Dis. 4, 751–759 (1993).

  50. 50

    Bruschke, A.V. et al. The dynamics of progression of coronary atherosclerosis studied in 168 medically treated patients who underwent coronary arteriography three times. Am. Heart J. 117, 296–305 (1989).

  51. 51

    Yokoya, K. et al. Process of progression of coronary artery lesions from mild or moderate stenosis to moderate or severe stenosis: a study based on four serial coronary arteriograms per year. Circulation 100, 903–909 (1999).

  52. 52

    Hackett, D., Davies, G. & Maseri, A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur. Heart J. 9, 1317–1323 (1988).

  53. 53

    Libby, P. Molecular bases of the acute coronary syndromes. Circulation 91, 2844–2850 (1995).

  54. 54

    Badimon, J.J. 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 99, 1780–1787 (1999).

  55. 55

    Toschi, V. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95, 594–599 (1997).

  56. 56

    Rekhter, M.D. Collagen synthesis in atherosclerosis: too much and not enough. Cardiovasc. Res. 41, 376–384 (1999).

  57. 57

    Siess, W. Athero- and thrombogenic actions of lysophosphatidic acid and sphingosine-1-phosphate. Biochim. Biophys. Acta 1582, 204–215 (2002).

  58. 58

    Siess, W. et al. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. Proc. Natl. Acad. Sci. USA 96, 6931–6936 (1999).

  59. 59

    Mallat, Z. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99, 348–353 (1999).

  60. 60

    Arai, M. et al. Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency. Br. J. Haematol. 89, 124–130 (1995).

  61. 61

    Boylan, B. et al. Anti-GPVI-associated ITP: an acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRγ-chain complex from the human platelet surface. Blood 104, 1350–1355 (2004).

  62. 62

    Jandrot-Perrus, M. et al. Absent collagen-induced platelet activation in a patient double heterozygous for two GPVI mutations. in American Society for Hematology, Vol. 112, Abstract 88 (Blood, American Society for Hematology, 2008).

  63. 63

    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).

  64. 64

    Ryo, R. et al. Deficiency of P62, a putative collagen receptor, in platelets from a patient with defective collagen-induced platelet aggregation. Am. J. Hematol. 39, 25–31 (1992).

  65. 65

    He, L. et al. The contributions of the α2 β1 integrin to vascular thrombosis in vivo. Blood 102, 3652–3657 (2003).

  66. 66

    Massberg, S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J. Exp. Med. 197, 41–49 (2003).

  67. 67

    Grüner, S. et al. Anti-glycoprotein VI treatment severely compromises hemostasis in mice with reduced α2β1 levels or concomitant aspirin therapy. Circulation 110, 2946–2951 (2004).

  68. 68

    Gkaliagkousi, E. & Ferro, A. Nitric oxide signalling in the regulation of cardiovascular and platelet function. Front. Biosci. 16, 1873–1897 (2011).

  69. 69

    Cheng, Y. et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296, 539–541 (2002).

  70. 70

    Enjyoji, K. et al. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat. Med. 5, 1010–1017 (1999).

  71. 71

    Marcus, A.J. et al. The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39. J. Clin. Invest. 99, 1351–1360 (1997).

  72. 72

    Pinsky, D.J. et al. Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. J. Clin. Invest. 109, 1031–1040 (2002).

  73. 73

    Esmon, C.T. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J. 9, 946–955 (1995).

  74. 74

    Trip, M.D., Cats, V.M., van Capelle, F.J. & Vreeken, J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N. Engl. J. Med. 322, 1549–1554 (1990).

  75. 75

    Hirsh, J. Hyperactive platelets and complications of coronary artery disease. N. Engl. J. Med. 316, 1543–1544 (1987).

  76. 76

    Rathbone, R.L., Ardlie, N.G. & Schwartz, C.J. Platelet aggregation and thrombus formation in diabetes mellitus: an in vitro study. Pathology 2, 307–316 (1970).

  77. 77

    Lincoff, A.M. Important triad in cardiovascular medicine: diabetes, coronary intervention, and platelet glycoprotein IIb/IIIa receptor blockade. Circulation 107, 1556–1559 (2003).

  78. 78

    Roffi, M. et al. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation 104, 2767–2771 (2001).

  79. 79

    Hamet, P., Skuherska, R., Pang, S.C. & Tremblay, J. Abnormalities of platelet function in hypertension and diabetes. Hypertension 7, II135–II142 (1985).

  80. 80

    Kjeldsen, S.E., Rostrup, M., Gjesdal, K. & Eide, I. The epinephrine-blood platelet connection with special reference to essential hypertension. Am. Heart J. 122, 330–336 (1991).

  81. 81

    Opper, C. et al. Increased number of high sensitive platelets in hypercholesterolemia, cardiovascular diseases, and after incubation with cholesterol. Atherosclerosis 113, 211–217 (1995).

  82. 82

    Terres, W., Becker, P. & Rosenberg, A. Changes in cardiovascular risk profile during the cessation of smoking. Am. J. Med. 97, 242–249 (1994).

  83. 83

    Terres, W., Weber, K., Kupper, W. & Bleifeld, W. Age, cardiovascular risk factors and coronary heart disease as determinants of platelet function in men. A multivariate approach. Thromb. Res. 62, 649–661 (1991).

  84. 84

    Ma, Y., Ashraf, M.Z. & Podrez, E.A. Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia. Blood 116, 1932–1941 (2010).

  85. 85

    Podrez, E.A. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat. Med. 13, 1086–1095 (2007).

  86. 86

    Falk, E. Morphologic features of unstable atherothrombotic plaques underlying acute coronary syndromes. Am. J. Cardiol. 63, 114E–120E (1989).

  87. 87

    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).

  88. 88

    Deplano, V. & Siouffi, M. Experimental and numerical study of pulsatile flows through stenosis: wall shear stress analysis. J. Biomech. 32, 1081–1090 (1999).

  89. 89

    Long, Q., Xu, X.Y., Ramnarine, K.V. & Hoskins, P. Numerical investigation of physiologically realistic pulsatile flow through arterial stenosis. J. Biomech. 34, 1229–1242 (2001).

  90. 90

    Wootton, D.M. & Ku, D.N. Fluid mechanics of vascular systems, diseases, and thrombosis. Annu. Rev. Biomed. Eng. 1, 299–329 (1999).

  91. 91

    Lowe, G.D. Blood rheology in arterial disease. Clin. Sci. (Lond.) 71, 137–146 (1986).

  92. 92

    O'Brien, J.R. Shear-induced platelet aggregation. Lancet 335, 711–713 (1990).

  93. 93

    Brown, B.G. et al. Incomplete lysis of thrombus in the moderate underlying atherosclerotic lesion during intracoronary infusion of streptokinase for acute myocardial infarction: quantitative angiographic observations. Circulation 73, 653–661 (1986).

  94. 94

    Mizuno, K. et al. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet 337, 809–812 (1991).

  95. 95

    Mizuno, K. et al. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N. Engl. J. Med. 326, 287–291 (1992).

  96. 96

    Owens, A.P. III & Mackman, N. Microparticles in hemostasis and thrombosis. Circ. Res. 108, 1284–1297 (2011).

  97. 97

    Gross, P.L., Furie, B.C., Merrill-Skoloff, G., Chou, J. & Furie, B. Leukocyte-versus microparticle-mediated tissue factor transfer during arteriolar thrombus development. J. Leukoc. Biol. 78, 1318–1326 (2005).

  98. 98

    Kleinschnitz, C. et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J. Exp. Med. 203, 513–518 (2006).

  99. 99

    Renné, T. et al. Defective thrombus formation in mice lacking coagulation factor XII. J. Exp. Med. 202, 271–281 (2005).

  100. 100

    Rosen, E.D., Gailani, D. & Castellino, F.J. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thromb. Haemost. 87, 774–776 (2002).

  101. 101

    Salomon, O., Steinberg, D.M., Koren-Morag, N., Tanne, D. & Seligsohn, U. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 111, 4113–4117 (2008).

  102. 102

    Zhang, H. et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 116, 4684–4692 (2010).

  103. 103

    Caen, J. & Wu, Q. Hageman factor, platelets and polyphosphates: early history and recent connection. J. Thromb. Haemost. 8, 1670–1674 (2010).

  104. 104

    Müller, F. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 139, 1143–1156 (2009).

  105. 105

    Hagedorn, I. et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 121, 1510–1517 (2010).

  106. 106

    Bevers, E.M. & Williamson, P.L. Phospholipid scramblase: an update. FEBS Lett. 584, 2724–2730 (2010).

  107. 107

    Weiss, H.J., Vicic, W.J., Lages, B.A. & Rogers, J. Isolated deficiency of platelet procoagulant activity. Am. J. Med. 67, 206–213 (1979).

  108. 108

    Suzuki, J., Umeda, M., Sims, P.J. & Nagata, S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468, 834–838 (2010).

  109. 109

    Bergmeier, W. et al. R93W mutation in Orai1 causes impaired calcium influx in platelets. Blood 113, 675–678 (2009).

  110. 110

    Braun, A. et al. Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 113, 2056–2063 (2009).

  111. 111

    Jackson, S.P. & Schoenwaelder, S.M. Procoagulant platelets: are they necrotic? Blood 116, 2011–2018 (2010).

  112. 112

    Schoenwaelder, S.M. et al. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 114, 663–666 (2009).

  113. 113

    Denis, C. et al. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc. Natl. Acad. Sci. USA 95, 9524–9529 (1998).

  114. 114

    Falati, S., Gross, P., Merrill-Skoloff, G., Furie, B.C. & Furie, B. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat. Med. 8, 1175–1181 (2002).

  115. 115

    Kulkarni, S. et al. A revised model of platelet aggregation. J. Clin. Invest. 105, 783–791 (2000).

  116. 116

    Nieswandt, B., Aktas, B., Moers, A. & Sachs, U.J. Platelets in atherothrombosis: lessons from mouse models. J. Thromb. Haemost. 3, 1725–1736 (2005).

  117. 117

    Holtkötter, O. et al. Integrin α2-deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen. J. Biol. Chem. 277, 10789–10794 (2002).

  118. 118

    Kato, K. et al. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion. Blood 102, 1701–1707 (2003).

  119. 119

    Kato, K. et al. Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size. Blood 104, 2339–2344 (2004).

  120. 120

    Mangin, P. et al. Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRγ deficiency. Blood 107, 4346–4353 (2006).

  121. 121

    Nieswandt, B. et al. Glycoprotein VI but not α2β1 integrin is essential for platelet interaction with collagen. EMBO J. 20, 2120–2130 (2001).

  122. 122

    Poole, A. et al. The Fc receptor γ-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen. EMBO J. 16, 2333–2341 (1997).

  123. 123

    Ware, J., Russell, S. & Ruggeri, Z.M. Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc. Natl. Acad. Sci. USA 97, 2803–2808 (2000).

  124. 124

    Hodivala-Dilke, K.M. et al. β3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J. Clin. Invest. 103, 229–238 (1999).

  125. 125

    Smyth, S.S., Reis, E.D., Vaananen, H., Zhang, W. & Coller, B.S. Variable protection of β3-integrin–deficient mice from thrombosis initiated by different mechanisms. Blood 98, 1055–1062 (2001).

  126. 126

    Tronik-Le Roux, D. et al. Thrombasthenic mice generated by replacement of the integrin αIIb gene: demonstration that transcriptional activation of this megakaryocytic locus precedes lineage commitment. Blood 96, 1399–1408 (2000).

  127. 127

    Wei, A.H., Schoenwaelder, S.M., Andrews, R.K. & Jackson, S.P. New insights into the haemostatic function of platelets. Br. J. Haematol. 147, 415–430 (2009).

  128. 128

    Sugidachi, A. et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite. J. Thromb. Haemost. 5, 1545–1551 (2007).

  129. 129

    Jernberg, T. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur. Heart J. 27, 1166–1173 (2006).

  130. 130

    van Giezen, J.J. & Humphries, R.G. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin. Thromb. Hemost. 31, 195–204 (2005).

  131. 131

    Anderson, J.L. et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 116, e148–e304 (2007).

  132. 132

    Kushner, F.G. et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 120, 2271–2306 (2009).

  133. 133

    Fisher, M. & Loscalzo, J. The perils of combination antithrombotic therapy and potential resolutions. Circulation 123, 232–235 (2011).

  134. 134

    Sørensen, R. et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 374, 1967–1974 (2009).

  135. 135

    Sobieraj-Teague, M., Gallus, A.S. & Eikelboom, J.W. The risk of iatrogenic bleeding in acute coronary syndromes and long-term mortality. Curr. Opin. Cardiol. 23, 327–334 (2008).

  136. 136

    Rao, S.V. et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. J. Am. Med. Assoc. 292, 1555–1562 (2004).

  137. 137

    Doyle, B.J., Rihal, C.S., Gastineau, D.A. & Holmes, D.R. Jr. Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervention: implications for contemporary practice. J. Am. Coll. Cardiol. 53, 2019–2027 (2009).

  138. 138

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

  139. 139

    Becker, R.C. et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 373, 919–928 (2009).

  140. 140

    Hurlen, M., Abdelnoor, M., Smith, P., Erikssen, J. & Arnesen, H. Warfarin, aspirin, or both after myocardial infarction. N. Engl. J. Med. 347, 969–974 (2002).

  141. 141

    Yousuf, O. & Bhatt, D.L. The evolution of antiplatelet therapy in cardiovascular disease. Nat. Rev. Cardiol. 8, 547–559 (2011).

  142. 142

    Dubois, C., Panicot-Dubois, L., Merrill-Skoloff, G., Furie, B. & Furie, B.C. Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo. Blood 107, 3902–3906 (2006).

  143. 143

    Konstantinides, S. et al. Distinct antithrombotic consequences of platelet glycoprotein Ibα and VI deficiency in a mouse model of arterial thrombosis. J. Thromb. Haemost. 4, 2014–2021 (2006).

  144. 144

    Falati, S. et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J. Exp. Med. 197, 1585–1598 (2003).

  145. 145

    Miszti-Blasius, K., Debreceni, I.B., Felszeghy, S., Dezso, B. & Kappelmayer, J. Lack of P-selectin glycoprotein ligand-1 protects mice from thrombosis after collagen/epinephrine challenge. Thromb. Res. 127, 228–234 (2011).

  146. 146

    Hechler, B. et al. A role of the fast ATP-gated P2X1 cation channel in thrombosis of small arteries in vivo. J. Exp. Med. 198, 661–667 (2003).

  147. 147

    Ghosh, A. et al. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice. J. Clin. Invest. 118, 1934–1943 (2008).

  148. 148

    Nanda, N. et al. Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling. Blood 106, 3028–3034 (2005).

  149. 149

    Zhu, L. et al. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc. Natl. Acad. Sci. USA 104, 1621–1626 (2007).

  150. 150

    Ni, H. et al. Plasma fibronectin promotes thrombus growth and stability in injured arterioles. Proc. Natl. Acad. Sci. USA 100, 2415–2419 (2003).

  151. 151

    Matuskova, J. et al. Decreased plasma fibronectin leads to delayed thrombus growth in injured arterioles. Arterioscler. Thromb. Vasc. Biol. 26, 1391–1396 (2006).

  152. 152

    André, P. et al. CD40L stabilizes arterial thrombi by a β3 integrin–dependent mechanism. Nat. Med. 8, 247–252 (2002).

  153. 153

    Angelillo-Scherrer, A. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat. Med. 7, 215–221 (2001).

  154. 154

    Li, D., D'Angelo, L., Chavez, M. & Woulfe, D.S. Arrestin-2 differentially regulates PAR4 and ADP receptor signaling in platelets. J. Biol. Chem. 286, 3805–3814 (2011).

  155. 155

    Elvers, M. et al. Impaired αIIbβ3 integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Sci. Signal. 3, ra1 (2010).

  156. 156

    Martin, V. et al. Deletion of the p110β isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood 115, 2008–2013 (2010).

  157. 157

    Nagy, B. Jr. et al. Impaired activation of platelets lacking protein kinase C-θ isoform. Blood 113, 2557–2567 (2009).

  158. 158

    Wang, X. et al. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. J. Thromb. Haemost. 3, 695–702 (2005).

  159. 159

    Goto, S., Ogawa, H., Takeuchi, M., Flather, M.D. & Bhatt, D.L. Double-blind, placebo-controlled phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur. Heart J. 31, 2601–2613 (2010).

  160. 160

    Lesault, P.-F. et al. Daily administration of the TP receptor antagonist terutroban improved endothelial function in high-cardiovascular-risk patients with atherosclerosis. Br. J. Clin. Pharmacol. 71, 844–851 (2011).

  161. 161

    Muller, J.E. Coronary artery thrombosis: historical aspects. J. Am. Coll. Cardiol. 1, 893–896 (1983).

  162. 162

    Weisse, A.B. The elusive clot: the controversy over coronary thrombosis in myocardial infarction. J. Hist. Med. Allied Sci. 61, 66–78 (2006).

  163. 163

    Hammer, A. Ein Fall von thrombotischem Verschlusse einer der Kranzarterien des Herzens. Wien. Med. Wochenschr. 28, 97–102 (1878).

  164. 164

    Payne, J.F. Two cases of sudden death from affection of the heart, examined in post mortem theatre. BMJ 1, 130–131 (1870).

  165. 165

    Vulpian, E.F.A. Ramollissement cerebral. Caillot ancien dans l'auricle gauche. Infarctus de la paroi du ventircule gauche du coeur coincidant avec l'existence d'un caillot ancien dans l'une des arteres coronaires, etc. Case Report from the Salpetriere. L'Union Medical (Paris) 29, 417–419 (1866).

  166. 166

    Herrick, J.B. Clinical features of sudden obstruction of the coronary arteries. J. Am. Med. Assoc. 59, 2015–2020 (1912).

  167. 167

    Ehrlich, J.C. & Shinohara, Y. Low incidence of coronary thrombosis in myocardial infarction. A restudy by serial block technique. Arch. Pathol. 78, 432–445 (1964).

  168. 168

    Friedberg, C.K. & Horn, H. Myocardial infarction with and without acute coronary occlusion. J. Am. Med. Assoc. 112, 1675–1679 (1939).

  169. 169

    Miller, R.D., Burchell, H.B. & Edwards, J.E. Myocardial infarction with and without acute coronary occlusion; a pathologic study. AMA Arch. Intern. Med. 88, 597–604 (1951).

  170. 170

    DeWood, M.A. et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N. Engl. J. Med. 303, 897–902 (1980).

  171. 171

    Chazov, E.I. et al. Intracoronary administration of fibrinolysin in acute myocardial infarct. Ter. Arkh. 48, 8–19 (1976).

  172. 172

    Rentrop, K.P. et al. Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase. Clin. Cardiol. 2, 354–363 (1979).

  173. 173

    Bizzozero, G. Su di un nuovo elemento morfologico del sangue de mammiferi e della sua importanza nella trombosi e nella coagulazione. L'Osservatore 17, 785–787 (1881).

  174. 174

    Bizzozero, G. Ueber einen neunen Forrnbestandteil des Blutes und dessen Rolle bei der Thrombose und Blut perinnung. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 90, 261–332 (1882).

Download references

Acknowledgements

I would like to thank S. Schoenwaelder for preparation of the figures, constructive advice and for assistance with the manuscript. I also acknowledge H. Salem, M. Cooper and Z. Kaplan for their constructive advice and assistance with the manuscript. This work was supported by the National Health and Medical Research Council of Australia (NHMRC). I am an NHMRC Australia Fellow.

Author information

Correspondence to Shaun P Jackson.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading