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  • Review Article
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Arterial thrombus formation in cardiovascular disease

Abstract

The pathogenesis of arterial thrombosis is complex and dynamic. Unlike venous thrombi, arterial thrombi typically form under conditions of high blood flow and are mainly composed of platelet aggregates, giving them the appearance of 'white clots'. Strong evidence suggests that arterial thrombi originate as a consequence of an injured atherosclerotic plaque, and that their formation involves the release of prothrombotic material (such as tissue factor), platelet aggregation, and platelet adhesion to the vascular wall. The initially labile platelet plaque is then stabilized by insoluble fibrin produced upon activation of the coagulation cascade. Inherited genetic factors (gene polymorphisms) and acquired predisposing conditions (such as the concentration and activity of clotting factors) can influence both the composition and the size of an arterial thrombus. Further research is needed to elucidate the functions of blood coagulation proteins and cellular elements that are critical to the pathogenesis of arterial thrombosis. This Review explains mechanisms of pathological arterial thrombus formation and discusses genetic and acquired risk factors of atherothrombosis.

Key Points

  • Arterial thrombus formation is a complex and dynamic pathological process that is initiated at an injured atherosclerotic plaque

  • Several factors are involved in arterial thrombus formation, including the platelet glycoprotein VI, glycoprotein receptor Ia/IIa, collagenous plaque components, and blood coagulation protein

  • Coronary artery disease (CAD) in young individuals often has a genetic basis, but whether genetic variants or disorders predispose to an increased risk of CAD in adults remains unclear

  • Reliable associations have been demonstrated between CAD and acquired risk factors such as antiphospholipid antibodies, hyperhomocysteinemia, and elevated levels of fibrinogen, C-reactive protein, and lipoprotein(a)

  • Future research should aim to further elucidate the functions of blood coagulation proteins and cellular elements that are critical to thrombus formation

  • A better knowledge of the pathophysiological mechanisms of arterial thrombosis might open up new therapeutic options in the treatment of atherothrombosis

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Figure 1
Figure 2: Platelet activation and aggregation in the context of arterial thrombus formation.
Figure 3: The activation of blood coagulation in arterial thrombus formation.
Figure 4: Coagulatory and fibrinolytic systems.

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References

  1. Löwenberg, E. C., Meijers, J. C. & Levi, M. Platelet-vessel wall interaction in health and disease. Neth. J. Med. 65, 242–251 (2010).

    Google Scholar 

  2. Jerjes-Sanchez, C. Venous and arterial thrombosis: a continuous spectrum of the same disease? Eur. Heart J. 26, 3–4 (2005).

    Article  PubMed  Google Scholar 

  3. Franchini, M. & Mannucci, P. M. Venous and arterial thrombosis: different sides of the same coin? Eur. J. Intern. Med. 19, 476–481 (2008).

    Article  PubMed  Google Scholar 

  4. Lundberg, A. M. & Hansson, G. K. Innate immune signals in atherosclerosis. Clin. Immunol. 134, 5–24 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Andersson, J., Libby, P. & Hansson, G. K. Adaptive immunity and atherosclerosis. Clin. Immunol. 134, 33–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Libby, P. Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis. J. Lipid. Res. 50, S352–S357 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. WHO. World Health Statistics 2010 [online], (2010).

  9. Hodgkinson, C. P. & Ye, S. Toll-like receptors, their ligands, and atherosclerosis. ScientificWorldJournal 14, 437–453 (2011).

    Article  CAS  Google Scholar 

  10. Badimon, J. J., Ibanez, B. & Cimmino, G. Genesis and dynamics of atherosclerotic lesions: implications for early detection. Cerebrovasc. Dis. 27, 38–47 (2009).

    Article  PubMed  Google Scholar 

  11. Penz, S. et al. Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI. FASEB J. 19, 898–909 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Reininger, A. J. et al. A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. J. Am. Coll. Cardiol. 55, 1147–1158 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Mega, J. L. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 374, 29–38 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Aird, W. C. Vascular bed-specific thrombosis. J. Thromb. Haemost. 5, 283–291 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Andrews, R. K., Gardiner, E. E., Shen, Y. & Berndt, M. C. Platelet interactions in thrombosis. IUBMB Life 56, 13–18 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cheli, Y. et al. The Modifier of hemostasis (Mh) locus on chromosome 4 controls in vivo hemostasis of Gp6−/− mice. Blood 111, 1266–1273 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nergiz-Unal, R., Rademakers, T., Cosemans, J. M & Heemskerk, J. W. CD36 as a multiple-ligand signaling receptor in atherothrombosis. Cardiovasc. Hematol. Agents Med. Chem. 9, 42–55 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, K., Febbraio, M., Li, W. & Silverstein, R. L. A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein. Circ. Res. 102, 1512–1519 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ofosu, F. A. Protease activated receptors 1 and 4 govern the responses of human platelets to thrombin. Transfus. Apher. Sci. 28, 265–268 (2003).

    Article  PubMed  Google Scholar 

  23. 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  PubMed  Google Scholar 

  24. Gupta, A., Williams, M. D., Macias, W. L., Molitoris, B. A. & Grinnell, B. W. Activated protein C and acute kidney injury: Selective targeting of PAR-1. Curr. Drug Targets 10, 1212–1226 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Yang, J. Xu, K. & Seiffert, D. Challenges and promises of developing thrombin receptor antagonists. Recent Pat. Cardiovasc. Drug Discov. 5, 162–170 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Lippi, G., Franchini, M. & Guidi, G. C. Diagnostic approach to inherited bleeding disorders. Clin. Chem. Lab. Med. 45, 2–12 (2007).

    CAS  PubMed  Google Scholar 

  28. MacFarlane, R. G. An enzyme cascade in the blood clotting mechanism and its function as a biochemical amplifier. Nature 202, 498–499 (1964).

    Article  CAS  PubMed  Google Scholar 

  29. Davie, E. W. & Ratnoff, O. D. Waterfall sequence for intrinsic blood clotting. Science 145, 1310–1312 (1964).

    Article  CAS  PubMed  Google Scholar 

  30. Monroe, D. M., Hoffman, M. & Roberts, H. R. Platelets and thrombin generation. Arterioscler. Thromb. Vasc. Biol. 22, 1381–1389 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Stavrou, E. & Schmaier, A. H. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb. Res. 125, 210–215 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gailani, D. & Renné, T. Intrinsic pathway of coagulation and arterial thrombosis. Arterioscler. Thromb. Vasc. Biol. 27, 2507–2513 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Celi, A. et al. Thrombus formation: direct real-time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy. J. Thromb. Haemost. 1, 60–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Furie, B. & Furie, B. C. In vivo thrombus formation. J. Thromb. Haemost. 5, 12–17 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Palabrica, T. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P selectin on adherent platelets. Nature 359, 848–851 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Boden, G., Vaidyula, V., Homko, C., Mozzoli, M. & Rao, A. K. Differential effects of somatostatin on circulating tissue factor procoagulant activity and protein. Am. J. Physiol. Endocrinol. Metab. 292, E1333–E1339 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Marsik, C. et al. Polymorphism in the tissue factor region is associated with basal but not endotoxin-induced tissue factor-mRNA levels in leukocytes. J. Thromb. Haemost. 4, 745–749 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Sidelmann, J. J., Gram, J., Jespersen, J. & Kluft, C. Fibrin clot formation and lysis: basic mechanisms. Semin. Thromb. Hemost. 26, 605–618 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Bouma, B. N. & Mosnier, L. O. Thrombin activatable fibrinolysis inhibitor (TAFI)—how does thrombin regulate fibrinolysis? Ann. Med. 38, 378–388 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Muszbek, L., Bereczky, Z., Bagoly, Z., Shemirani, A. H. & Katona, E. Factor XIII and atherothrombotic diseases. Semin. Thromb. Hemost. 36, 18–33 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Muszbek, L., Bagoly, Z., Bereczky, Z. & Katona, E. The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis. Cardiovasc. Hematol. Agents Med. Chem. 6, 190–205 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. de Moerloose, P., Boehlen, F. & Neerman-Arbez, M. Fibrinogen and the risk of thrombosis. Semin. Thromb. Hemost. 36, 7–17 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. von Hundelshausen, P. & Weber, C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ. Res. 100, 27–40 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Faber, D. R., de Groot, P. G. & Visseren, F. L. Role of adipose tissue in haemostasis, coagulation and fibrinolysis. Obes. Rev. 10, 554–563 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Targher, G., Zoppini, G., Moghetti, P. & Day, C. P. Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Semin. Thromb. Hemost. 36, 41–48 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Matsuda, S. et al. Human C-reactive protein enhances thrombus formation after neointimal balloon injury in transgenic rabbits. J. Thromb. Haemost. 9, 201–208 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Teupser, D. et al. No reduction of atherosclerosis in C-reactive protein (CRP)-deficient mice. J. Biol. Chem. 286, 6272–6279 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Koike, T. et al. Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation 120, 2088–2094 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pepys, M. B., Baltz, M., Gomer, K., Davies, A. J. & Doenhoff, M. et al. Serum amyloid P component is an acute-phase reactant in the mouse. Nature 278, 259–261 (1979).

    Article  CAS  PubMed  Google Scholar 

  51. Reifenberg, K. et al. Role of C-reactive protein in atherogenesis: can the apolipoprotein E knockout mouse provide the answer? Arterioscler. Thromb. Vasc. Biol. 28, 1641–1646 (2005).

    Article  CAS  Google Scholar 

  52. Liotta, L. A. et al. Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. Cancer Res. 41, 4629–4636 (1981).

    CAS  PubMed  Google Scholar 

  53. Mochan, E. & Keler, T. Plasmin degradation of cartilage proteoglycan. Biochim. Biophys. Acta. 800, 312–315 (1984).

    Article  CAS  PubMed  Google Scholar 

  54. Mackay, A. R., Corbitt, R. H., Hartzler, J. L. & Thorgeirsson, U. P. Basement membrane type IV collagen degradation: evidence for the involvement of a proteolytic cascade independent of metalloproteinases. Cancer Res. 50, 5997–6001 (1990).

    CAS  PubMed  Google Scholar 

  55. Zorio, E. et al. Fibrinolysis: the key to new pathogenetic mechanisms. Curr. Med. Chem. 15, 923–929 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Gebbink, M. F., Bouma, B., Maas, C. & Bouma, B. N. Physiological responses to protein aggregates: fibrinolysis, coagulation and inflammation (new roles for old factors). FEBS Lett. 583, 2691–2699 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Meltzer M. E., Doggen, C. J., de Groot, P. G., Rosendaal, F. R. & Lisman, T. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin. Thromb. Hemost. 35, 468–477 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Ha, H., Oh, E. Y. & Lee, H. B. The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases. Nat. Rev. Nephrol. 5, 203–211 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Franchini, M., Lippi, G., Manzato, F., Vescovi, P. P. & Targher, G. Hemostatic abnormalities in endocrine and metabolic disorders. Eur. J. Endocrinol. 162, 439–451 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Murata, M. et al. Genetic polymorphisms and risk of coronary artery disease. Semin. Thromb. Hemost. 24, 245–250 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Boekholdt, S. M. & Kramer, M. H. Arterial thrombosis and the role of thrombophilia. Semin. Thromb. Hemost. 33, 588–596 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Borecki, I. B. Contemporary approach to gene discovery: progress toward personalized medicine? Circ. Cardiovasc. Genet. 2, 1–2 (2009).

    Article  PubMed  Google Scholar 

  63. Kullo, I. J. & Cooper, L. T. Early identification of cardiovascular risk using genomics and proteomics. Nat. Rev. Cardiol. 7, 309–317 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Franchini, M., Peyvandi, F. & Mannucci, P. M. The genetic basis of coronary artery disease: from candidate genes to whole genomic analysis. Trends Cardiovasc. Med. 18, 157–162 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Voetsch, B. & Loscalzo, J. Genetic determinants of arterial thrombosis. Arterioscler. Thromb. Vasc. Biol. 24, 216–229 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Patay, B. A. & Topol, E. J. Is there a genetic basis for acute coronary syndrome? Nat. Clin. Pract. Cardiovasc. Med. 4, 596–597 (2007).

    Article  PubMed  Google Scholar 

  67. Parè G. et al. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol. Am. J. Hum. Genet. 80, 673–682 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Morgan, T. M., Krumholz, H. M., Lifton, R. P. & Spertus, J. A. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA 297, 1551–1561 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Song, Y., Stampfer M. J. & Liu, S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann. Intern. Med. 141, 137–147 (2004).

    Article  PubMed  Google Scholar 

  70. Ye, Z. et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 367, 651–658 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group. No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age. Circulation 107, 1117–1122 (2003).

  72. The International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  73. The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  74. The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  75. Ding, K. & Kullo, I. J. Genome-wide association studies for atherosclerotic vascular disease and its risk factors. Circ. Cardiovasc. Genet. 2, 63–72 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Arking, D. E. & Chakravarti, A. Understanding cardiovascular disease through the lens of genome-wide association studies. Trends Genet. 25, 387–394 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Baudhuin, L. M. Genetics of coronary artery disease: focus on genome-wide association studies. Am. J. Transl. Res. 1, 221–234 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. McCarthy, M. I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9, 356–369 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Herrington, D. M. Cardiovascular genomics: outcome and implications. Can. J. Cardiol. 26, 60A–63A (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Ozaki, K. et al. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650–654 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Ozaki, K. et al. Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-α secretion in vitro. Nature 429, 72–75 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Ozaki, K. et al. SNPs in BRAP associated with risk of myocardial infarction in Asian populations. Nat. Genet. 41, 329–333 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Girelli, D., Martinelli, N., Peyvandi, F. & Olivieri, O. Genetic architecture of coronary artery disease in the genome-wide era: implications for the emerging “golden dozen” loci. Semin. Thromb. Hemost. 35, 671–682 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Helgadottir, A. et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat. Genet. 40, 217–224 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Samani, N. J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  89. Shen, G. Q. et al. Association between four SNPs on chromosome 9p21 and myocardial infarction is replicated in an Italian population. J. Hum. Genet. 53, 144–150 (2008).

    Article  PubMed  CAS  Google Scholar 

  90. Larson, M. G. et al. Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes. BMC Med. Genet. 8, S5 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Broadbent, H. M. et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum. Mol. Genet. 17, 906–914 (2008).

    Article  CAS  Google Scholar 

  92. The Myocardial Infarction Genetics Consortium. Genome wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).

  93. Erdmann, J. et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280–282 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Trégouët, D. A. et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat. Genet. 41, 283–285 (2009).

    Article  PubMed  CAS  Google Scholar 

  95. Lippi, G. & Guidi, G. Lipoprotein(a): an emerging cardiovascular risk factor. Crit. Rev. Clin. Lab. Sci. 40, 1–42 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Vokó, Z. Bereczky, Z., Katona, E., Adány, R. & Muszbek, L. Factor XIII Val34Leu variant protects against coronary artery disease. A meta-analysis. Thromb. Haemost. 97, 458–463 (2007).

    Article  PubMed  CAS  Google Scholar 

  97. Laffan, M. A. Fibrinogen polymorphisms and disease. Eur. Heart J. 22, 2224–2226 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Gorog, D. A. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J. Am. Coll. Cardiol. 55, 2701–2709 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Feinbloom, D. & Bauer, K. A. Assessment of hemostatic risk factors in predicting arterial thrombotic events. Arterioscler. Thromb. Vasc. Biol. 25, 2043–2053 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Ghaddar, H. M. et al. Correlation of factor VIIa values with factor VII gene polymorphism, fasting and postprandial triglyceride levels, and subclinical carotid atherosclerosis. Circulation 98, 2815–2821 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Feng, D. et al. Factor VII gene polymorphism, factor VII levels, and prevalent cardiovascular disease: the Framingham Heart Study. Arterioscler. Thromb. Vasc. Biol. 20, 593–600 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Ridker, P. M. Hennekens, C. H., Schmitz, C., Stampfer, M. J. & Lindpaintner, K. et al. PIA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 349, 385–388 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Herrmann, S. M. et al. The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l'Infarctus du Myocarde. Thromb. Haemost. 77, 1179–1181 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. Ito, T., Ishida, F., Shimodaira, S. & Kitano, K. Polymorphisms of platelet membrane glycoprotein Ib alpha and plasma von Willebrand factor antigen in coronary artery disease. Int. J. Hematol. 70, 47–51 (1999).

    CAS  PubMed  Google Scholar 

  105. Mercier, B. et al. Myocardial infarction: absence of association with VNTR polymorphism of platelet glycoprotein (GP) Ibα. Thromb. Haemost. 84, 921–922 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Ozelo, M. C. et al. Platelet glycoprotein Ibα polymorphisms modulate the risk for myocardial infarction. Thromb. Haemost. 92, 384–386 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 294, 1799–1809 (2005).

  108. Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375, 132–140 (2010).

  109. Lühmann, D., Schramm, S. & Raspe, H. The role of homocysteine as a predictor for coronary heart disease. GMS Health. Technol. Assess. 3, Doc11 (2007).

    PubMed  PubMed Central  Google Scholar 

  110. Lippi, G. & Guidi, G. Lipoprotein(a): from ancestral benefit to modern pathogen? QJM 93, 75–84 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Kucharska-Newton, A. M. et al. Hemostasis, inflammation, and fatal and nonfatal coronary heart disease: long-term follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Arterioscler. Thromb. Vasc. Biol. 29, 2182–2190 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Miyakis, S. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Ben-Ami, D., Bar-Meir, E. & Shoenfeld, Y. Stenosis in antiphospholipid syndrome: a new finding with clinical implications. Lupus 15, 466–472 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Espinosa, G. & Cervera, R. Morbidity and mortality in the antiphospholipid syndrome. Curr. Opin. Pulm. Med. 15, 413–417 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Ridker, P. M., Hennekens, C. H., Lindpaintner, K., Stampfer, M. J. & Miletich, J. P. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 95, 59–62 (1997).

    Article  CAS  PubMed  Google Scholar 

  116. Wang, T. J. et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N. Engl. J. Med. 355, 2631–2639 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Turpie, A. G. & Esmon, C. Venous and arterial thrombosis—pathogenesis and the rationale for anticoagulation. Thromb. Haemost. 105, 586–596 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Helgadottir, A. et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat. Genet. 36, 233–239 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Zwicker, J. I. et al. The thrombospondin-1 N700S polymorphism is associated with early myocardial infarction without altering von Willebrand factor multimer size. Blood 108, 1280–1283 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Helgadottir, A. et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat. Genet. 38, 68–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Gudbjartsson, D. F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Trégouët, D. A. et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat. Genet. 41, 283–285 (2009).

    Article  PubMed  CAS  Google Scholar 

  123. He, M. et al. Functional SNPs in HSPA1A gene predict risk of coronary heart disease. PLoS One 4, e4851 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

    Article  CAS  PubMed  Google Scholar 

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All authors contributed equally to the research of data and the writing of the article, provided substantial contributions to the discussion of content, and reviewed/edited the manuscript before submission.

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Correspondence to Giuseppe Lippi.

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Lippi, G., Franchini, M. & Targher, G. Arterial thrombus formation in cardiovascular disease. Nat Rev Cardiol 8, 502–512 (2011). https://doi.org/10.1038/nrcardio.2011.91

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