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The causal role of megakaryocyte–platelet hyperactivity in acute coronary syndromes

Nature Reviews Cardiology volume 9, pages 658–670 (2012)Cite this article

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Abstract

Platelets are causally involved in coronary artery obstruction in acute coronary syndromes (ACS). This cell type is unique to mammals and its production, which is unlike that of any other mammalian cell, involves polyploid nuclear change in the mother cell (megakaryocyte) and the production of anucleate cells with a log Gaussian distribution of volume. Platelets vary more in cellular volume than any other circulating blood element in mammals. Larger platelets are denser, contain more secretory granules, and are more reactive than their smaller counterparts. A causal relationship between the presence of large, dense, reactive platelets in the circulation and ACS is supported by many clinical studies. Furthermore, the results of two large, prospective, epidemiological studies have demonstrated that mean platelet volume was the strongest independent predictor of outcome in patients with acute myocardial infarction. Notably, evidence indicates that an increase in mean platelet volume in the pathogenesis of ACS can potentially overwhelm current therapeutics. The control system for the physiological and pathophysiological production of large platelets should, therefore, be researched. An understanding of this system might give rise to new therapeutics that could control platelet reactivity and thereby comprehensively prevent ACS.

Key Points

  • The megakaryocyte–platelet hemostatic system is unique to mammals, and has a complex control system that is not yet fully understood

  • Larger platelets are denser and more reactive than smaller platelets, and are associated with megakaryocyte change

  • Large clinical studies have shown a relationship between large platelets and incidence of acute coronary syndromes

  • Two large prospective epidemiological studies have shown that the presence of large platelets can independently predict outcome related to acute myocardial infarction, including death

  • Platelet physiological change has the potential to overwhelm current therapeutic interventions

  • Future research should address the physiological and pathological production of large platelets

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Figure 1: The platelet.
Figure 2: Megakaryocyte endomitosis.
Figure 3: Platelet release from megakaryocytes.
Figure 4: Log Gaussian platelet volume distribution curve.
Figure 5: Changes in normalized platelet count (pink) and mean platelet volume (blue) following cardiopulmonary bypass surgery.
Figure 6: Average platelet volume distribution of patients with AMI compared with a control population.
Figure 7: Inappropriate activation of the thrombopoietic response to hemorrhage might lead to acute coronary syndromes.

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References

  1. Bonaca, M. P. et al. Antithrombotics in acute coronary syndromes. J. Am. Coll. Cardiol. 54, 969–984 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Radomski, M. W., Martin, J. F. & Moncada, S. Synthesis of nitric oxide by the hemocytes of the American horseshoe crab (Limulus polyphemus). Phil. Trans. R. Soc. Lond. B Biol. Sci. 334, 129–133 (1991).

    Article  CAS  Google Scholar 

  3. Ratnoff, O. D. The evolution of hemostatic mechanisms. Perspect. Biol. Med. 31, 4–33 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. Martin, J. F. Punctuated equilibrium in evolution and the platelet. Eur. J. Clin. Invest. 24, 291 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Cohen, J. A. & Leeksma, C. H. Determination of the life span of human blood platelets using labeled diisopropylfluorophosphonate. J. Clin. Invest. 35, 964–969 (1956).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Peters, A. M. & Lavender, J. P. Platelet kinetics with indium-111 platelets: comparison with chromium-51 platelets. Semin. Thromb. Hemost. 9, 100–114 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. Trowbridge, E. A. & Harley, P. J. A computer model of the random binary sequential division of megakaryocyte cytoplasm to produce platelets. Phys. Med. Biol. 29, 1477–1487 (1984).

    Article  CAS  PubMed  Google Scholar 

  8. Harrison, P. & Martin-Cramer, E. Platelet alpha-granules. Blood Rev. 7, 52–62 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Harker, L. A. & Finch, C. A. Thrombokinetics in man. J. Clin. Invest. 48, 963–974 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Martin, J. F., Trowbridge, E. A., Salmon, G. L. & Slater, D. N. The relationship between platelet and megakaryocyte volumes. Thromb. Res. 28, 447–459 (1982).

    Article  CAS  PubMed  Google Scholar 

  11. Nagl, W. Endopolyploidy and Polyteny in Differentiation and Evolution: Towards an Understanding of Quantitative and Qualitative Variation of Nuclear DNA in Ontogeny and Phylogeny (North-Holland Publishing Company, Amsterdam, 1978).

    Google Scholar 

  12. Nagata, Y., Muro, Y. & Todokoro, K. Thrombopoietin-induced polyploidization of bone marrow megakaryocytes is due to a unique regulatory mechanism in late mitosis. J. Cell Biol. 139, 449–457 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lordier, L. et al. Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling. Blood 112, 3164–3174 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Wang, Z., Zhang, Y., Kamen, D., Lees, E. & Ravid, K. Cyclin D3 is essential for megakaryocytopoiesis. Blood 86, 3783–3788 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Sun, S. et al. Overexpression of cyclin D1 moderately increases ploidy in megakaryocytes. Hematologica 86, 17–23 (2001).

    CAS  Google Scholar 

  16. Geng, Y. et al. Cyclin E ablation in the mouse. Cell 114, 431–443 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Minoshima, Y. et al. Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis. Dev. Cell 4, 549–560 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Guse, A., Mishima, M. & Glotzer, M. Phosphorylation of ZEN-4/MKLP1 by aurora B regulates completion of cytokinesis. Curr. Biol. 15, 778–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Steigemann, P. et al. Aurora B-mediated abscission checkpoint protects against tetraploidization. Cell 136, 473–484 (2009).

    Article  PubMed  CAS  Google Scholar 

  20. Lordier, L. et al. Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process. Blood 116, 2345–2355 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Bartley, T. D. et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell 77, 1117–1124 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. de Sauvage, F. J. et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369, 533–538 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Kaushansky, K. The molecular mechanisms that control thrombopoiesis. J. Clin. Invest. 115, 3339–3347 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Solberg, L. A. Jr. Biologic aspects of thrombopoietins and the development of therapeutic agents. Curr. Hematol. Rep. 4, 423–428 (2005).

    CAS  PubMed  Google Scholar 

  25. Zauli, G. et al. In vitro senescence and apoptotic cell death of human megakaryocytes. Blood 90, 2234–2243 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Gurney, A. L., Carver-Moore, K., de Sauvage, F. J. & Moore, M. W. Thrombocytopenia in c-mpl-deficient mice. Science 265, 1445–1447 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Kimura, H. et al. Interleukin-1 beta (IL-1 beta) induces thrombocytosis in mice: possible implication of IL-6. Blood 76, 2493–2500 (1990).

    Article  CAS  PubMed  Google Scholar 

  28. Debili, N. et al. Effects of the recombinant hematopoietic growth factors interleukin-3, interleukin-6, stem cell factor, and leukemia inhibitory factor on the megakaryocytic differentiation of CD34+ cells. Blood 82, 84–95 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Mukaida, N. Interleukin-8: an expanding universe beyond neutrophil chemotaxis and activation. Int. J. Hematol. 72, 391–398 (2000).

    CAS  PubMed  Google Scholar 

  30. Podolak-Dawidziak, M., Hancock, V., Lelchuk, R., Kotlarek-Haus, S. & Martin, J. F. The expression of mRNA for fibrinogen in megakaryocytes isolated from patients with T-cell lymphoma. Br. J. Hematol. 91, 362–366 (1995).

    Article  CAS  Google Scholar 

  31. Gladwin, A. M. et al. Identification of mRNA for PDGF B-chain in human megakaryocytes isolated using a novel immunomagnetic separation method. Br. J. Hematol. 76, 333–339 (1990).

    Article  CAS  Google Scholar 

  32. Hancock, V., Martin, J. F. & Lelchuk, R. The relationship between human megakaryocyte nuclear DNA content and gene expression. Br. J. Hematol. 85, 692–697 (1993).

    Article  CAS  Google Scholar 

  33. Ault, K. A. et al. The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am. J. Clin. Path. 98, 637–646 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Ault, K. A. & Knowles, C. In vivo biotinylation demonstrates that reticulated platelets are the youngest platelets in circulation. Exp. Hematol. 23, 996–1001 (1995).

    CAS  PubMed  Google Scholar 

  35. Radley, J. M. & Scurfield, G. The mechanism of platelet release. Blood 56, 996–999 (1980).

    Article  CAS  PubMed  Google Scholar 

  36. Paulus, J. M., Bury, J. & Grosdent, J. C. Control of platelet territory development in megakaryocytes. Blood Cells 5, 59–88 (1979).

    CAS  PubMed  Google Scholar 

  37. Junt, T. et al. Dynamic visualization of thrombopoiesis within bone marrow. Science 317, 1767–1770 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Kinosita, R. & Ohno, S. in Blood Platelets (Johnson, S. A. et al.) 611–616 (Little Brown and Company, Boston, 1961).

    Google Scholar 

  39. Slater, D. N., Trowbridge, E. A. & Martin, J. F. The megakaryocyte in thrombocytopenia: a microscopic study which supports the theory that platelets are produced in the pulmonary circulation. Thromb. Res. 31, 163–176 (1983).

    Article  CAS  PubMed  Google Scholar 

  40. Hansen, K. B. & Aabo, K. Megakaryocytes in pulmonary blood vessels. 2. Relations to malignant hematological diseases especially leukaemia. Acta Pathol. Microbiol. Scand. A. 86, 293–295 (1978).

    CAS  PubMed  Google Scholar 

  41. Zucker-Franklin, D. & Philipp, C. S. Platelet production in the pulmonary capillary bed: new ultrastructural evidence for an old concept. Am. J. Pathol. 157, 69–74 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pedersen, N. T. Occurrence of megakaryocytes in various vessels and their retention in the pulmonary capillaries in man. Scand. J. Hematol. 21, 369–375 (1978).

    Article  CAS  Google Scholar 

  43. Fox, S. B., Day, C. A. & Gatter, K. C. Association between platelet microthrombi and finger clubbing. Lancet 338, 313–314 (1991).

    Article  CAS  PubMed  Google Scholar 

  44. Silveri, F. et al. Hypertrophic osteoarthropathy: endothelium and platelet function. Clin. Rheumatol. 15, 435–439 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Dickinson, C. J. & Martin, J. F. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 2, 1434–1435 (1987).

    Article  CAS  PubMed  Google Scholar 

  46. Huaux, J. P. et al. Hypertrophic osteoarthropathy related to end stage cholestatic cirrhosis: reversal after liver transplantation. Ann. Rheum. Dis. 46, 342–345 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stoller, J. K. et al. Reduction of intrapulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation. Hepatology 11, 54–58 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Martin, J. F. & Levine, R. P. in The Platelet in Health and Disease (ed. Page, C. P.) 1–9 (Wiley-Blackwell, London, 1991).

    Google Scholar 

  49. Trowbridge, E. A., Martin, J. F. & Slater, D. N. Evidence for a theory of physical fragmentation of megakaryocytes, implying that all platelets are produced in the pulmonary circulation. Thromb. Res. 28, 461–475 (1982).

    Article  CAS  PubMed  Google Scholar 

  50. Born, G. V. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194, 927–929 (1962).

    Article  CAS  PubMed  Google Scholar 

  51. Martin, J. F., Shaw, T., Heggie, J. & Penington, D. G. Measurement of the density of human platelets and its relationship to volume. Br. J. Hematol. 54, 337–352 (1983).

    Article  CAS  Google Scholar 

  52. Trowbridge, E. A., Reardon, D. M., Hutchinson, D. & Pickering, C. The routine measurement of platelet volume: a comparison of light-scattering and aperture-impedance technologies. Clin. Phys. Physiol. Meas. 6, 221–238 (1985).

    Article  CAS  PubMed  Google Scholar 

  53. Martin, J. F., Plumb, J., Kilbey, R. S. & Kishk, Y. T. Changes in volume and density of platelets in myocardial infarction. BMJ 287, 456–459 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Karpatkin, S. Heterogeneity of human platelets. VI. Correlation of platelet function with platelet volume. Blood 51, 307–316 (1978).

    Article  CAS  PubMed  Google Scholar 

  55. Haver, V. M. & Gear, A. R. Functional fractionation of platelets. J. Lab. Clin. Med. 97, 187–204 (1981).

    CAS  PubMed  Google Scholar 

  56. Martin, J. F., Trowbridge, E. A., Salmon, G. & Plumb, J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb. Res. 32, 443–460 (1983).

    Article  CAS  PubMed  Google Scholar 

  57. Thompson, C. B., Eaton, K. A., Princiotta, S. M., Rushin, C. A. & Valeri, C. R. Size dependent platelet subpopulations: relationship of platelet volume to ultrastructure, enzymatic activity, and function. Br. J. Hematol. 50, 509–519 (1982).

    Article  CAS  Google Scholar 

  58. Thompson, C. B., Jakubowski, J. A., Quinn, P. G., Deykin, D. & Valeri, C. R. Platelet size as a determinant of platelet function. J. Lab. Clin. Med. 101, 205–213 (1983).

    CAS  PubMed  Google Scholar 

  59. Giles, H., Smith, R. E. & Martin, J. F. Platelet glycoprotein IIb-IIIa and size are increased in acute myocardial infarction. Eur. J. Clin. Invest. 24, 69–72 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Klovaite, J., Benn, M., Yazdanyar, S. & Nordestgaard, B. G. High platelet volume and increased risk of myocardial infarction: 39, 531 participants from the general population. J. Thromb. Hemost. 9, 49–56 (2011).

    Article  CAS  Google Scholar 

  61. Chu, S. G. et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J. Thromb. Hemost. 8, 148–156 (2010).

    Article  CAS  Google Scholar 

  62. von Behrens, W. E. Evidence of phylogenetic canalisation of the circulating platelet mass in man. Thromb. Diath. Hemorrh. 27, 159–172 (1972).

    CAS  Google Scholar 

  63. Paulus, J. M. Platelet size in man. Blood 46, 321–336 (1975).

    Article  CAS  PubMed  Google Scholar 

  64. Karpatkin, S. & Charmatz, A. Heterogeneity of human Platelets. I. Metabolic and kinetic evidence suggestive of young and old platelets. J. Clin. Invest. 48, 1073–1082 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Martin, J. F. & Trowbridge, E. A. Theoretical requirements for the density separation of platelets with comparison of continuous and discontinuous gradients. Thromb. Res. 27, 513–522 (1982).

    Article  CAS  PubMed  Google Scholar 

  66. Thompson, C. B., Love, D. G., Quinn, P. G. & Valeri, C. R. Platelet size does not correlate with platelet age. Blood 62, 487–494 (1983).

    Article  CAS  PubMed  Google Scholar 

  67. Johnson, C. A., Abildgaard, C. F. & Schulman, I. Functional studies of young versus old platelets in a patient with chronic thrombocytopenia. Blood 37, 163–171 (1971).

    Article  Google Scholar 

  68. Martin, J. F. & Penington, D. G. The relationship between the age and density of circulating 51Cr labeled platelets in the sub-human primate. Thromb. Res. 30, 157–164 (1983).

    Article  CAS  PubMed  Google Scholar 

  69. Savage, B., McFadden, P. R., Hanson, S. R. & Harker, L. A. The relation of platelet density to platelet age: survival of low- and high-density 111indium-labeled platelets in baboons. Blood 68, 386–393 (1986).

    Article  CAS  PubMed  Google Scholar 

  70. Boughton, B. J., Macwhannell, A., Simpson, A. & Hawker, R. Platelet size and adenine nucleotides in patients undergoing bone marrow ablation: a useful model for studying platelet ageing. Platelets 1, 21–24 (1990).

    Article  CAS  PubMed  Google Scholar 

  71. Wright, J. H. The histogenesis of the blood platelets. J. Morphol. 21, 263–278 (1910).

    Article  Google Scholar 

  72. Ingram, M. & Coopersmith, A. Reticulated platelets following acute blood loss. Br. J. Hematol. 17, 225–229 (1969).

    Article  CAS  Google Scholar 

  73. Martin, J. F., Daniel, T. D. & Trowbridge, E. A. Acute and chronic changes in platelet volume and count after cardiopulmonary bypass induced thrombocytopenia in man. Thromb. Haemost. 57, 55–58 (1987).

    Article  CAS  PubMed  Google Scholar 

  74. Mazur, E. M., Lindquist, D. L., de Alarcon, P. A. & Cohen, J. L. Evaluation of bone marrow megakaryocyte ploidy distributions in persons with normal and abnormal platelet counts. J. Lab. Clin. Med. 111, 194–202 (1988).

    CAS  PubMed  Google Scholar 

  75. Trowbridge, E. A. & Martin, J. F. An analysis of the platelet and polyploid megakaryocyte response to acute thrombocytopenia and its biological implications. Clin. Phys. Physiol. Meas. 5, 263–277 (1984).

    Article  CAS  PubMed  Google Scholar 

  76. Gladwin, A. M. & Martin, J. F. The control of megakaryocyte ploidy and platelet production: biology and pathology. Int. J. Cell Cloning 8, 291–298 (1990).

    Article  CAS  PubMed  Google Scholar 

  77. Harris, R. A. & Penington, D. G. The effects of low-dose vincristine on megakaryocyte colony-forming cells and megakaryocyte ploidy. Br. J. Hematol. 57, 37–48 (1984).

    Article  CAS  Google Scholar 

  78. Corash, L. & Levin, J. The relationship between megakaryocyte ploidy and platelet volume in normal and thrombocytopenic C3H mice. Exp. Hematol. 18, 985–989 (1990).

    CAS  PubMed  Google Scholar 

  79. Stenberg, P. E., Levin, J., Baker, G., Mok, Y. & Corash, L. Neuraminidase-induced thrombocytopenia in mice: effects on thrombopoiesis. J. Cell Physiol. 147, 7–16 (1991).

    Article  CAS  PubMed  Google Scholar 

  80. Sola-Visner, M. C., Christensen, R. D., Hutson, A. D. & Rimsza, L. M. Megakaryocyte size and concentration in the bone marrow of thrombocytopenic and nonthrombocytopenic neonates. Pediatr. Res. 61, 479–484 (2007).

    Article  PubMed  Google Scholar 

  81. Penington, D. G., Streatfield, K. & Roxburgh, A. E. Megakaryocytes and the heterogeneity of circulating platelets. Br. J. Hematol. 34, 639–653 (1976).

    Article  CAS  Google Scholar 

  82. Bessman, J. D. The relation of megakaryocyte ploidy to platelet volume. Am. J. Hematol. 16, 161–170 (1984).

    Article  CAS  PubMed  Google Scholar 

  83. Trowbridge, E. A. et al. The origin of platelet count and volume. Clin. Phys. Physiol. Meas. 5, 145–170 (1984).

    Article  CAS  PubMed  Google Scholar 

  84. Dalby Kristensen, S., Bath, P. M. & Martin, J. F. The bleeding time is inversely related to megakaryocyte nuclear DNA content and size in man. Thromb. Haemost. 59, 357–359 (1988).

    Article  CAS  PubMed  Google Scholar 

  85. Corash, L. et al. Regulation of thrombopoiesis: effects of the degree of thrombocytopenia on megakaryocyte ploidy and platelet volume. Blood 70, 177–185 (1987).

    Article  CAS  PubMed  Google Scholar 

  86. Stenberg, P. E. & Levin, J. Ultrastructural analysis of acute immune thrombocytopenia in mice: dissociation between alterations in megakaryocytes and platelets. J. Cell. Physiol. 141, 160–169 (1989).

    Article  CAS  PubMed  Google Scholar 

  87. Kuter, D. J. & Rosenberg, R. D. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 85, 2720–2730 (1995).

    Article  CAS  PubMed  Google Scholar 

  88. Gieger, C. et al. New gene functions in megakaryopoiesis and platelet formation. Nature 480, 201–208 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Koch, R. Classics in infectious diseases. The etiology of tuberculosis: Robert Koch. Berlin, Germany 1882. Rev. Infect. Dis. 4, 1270–1274 (1982).

    Article  CAS  PubMed  Google Scholar 

  90. Monaco, C., Mathur, A. & Martin, J. F. What causes acute coronary syndromes? Applying Koch's postulates. Atherosclerosis 179, 1–15 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. Kragel, A. H., Gertz, S. D. & Roberts, W. C. Morphologic comparison of frequency and types of acute lesions in the major epicardial coronary arteries in unstable angina pectoris, sudden coronary death and acute myocardial infarction. J. Am. Coll. Cardiol. 18, 801–808 (1991).

    Article  CAS  PubMed  Google Scholar 

  93. Fox, K. A. et al. Scintigraphic detection of coronary artery thrombi in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 4, 975–986 (1984).

    Article  CAS  PubMed  Google Scholar 

  94. Folts, J. D., Crowell, E. B. Jr & Rowe, G. G. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 54, 365–370 (1976).

    Article  CAS  PubMed  Google Scholar 

  95. Badimon, L., Martínez-González, J., Royo, T., Lassila, R. & Badimon, J. J. A sudden increase in plasma epinephrine levels transiently enhances platelet deposition on severely damaged arterial wall—studies in a porcine model. Thromb. Haemost. 82, 1736–1742 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Hanson, S. R., Kotze, H. F., Savage, B. & Harker, L. A. Platelet interactions with Dacron vascular grafts. A model of acute thrombosis in baboons. Arteriosclerosis 5, 595–603 (1985).

    Article  CAS  PubMed  Google Scholar 

  97. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2, 349–360 (1988).

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

  99. Yusuf, S. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345, 494–502 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Chen, Z. M. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366, 1607–1621 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Schulman, S. P. et al. Effects of integrelin, a platelet glycoprotein IIb/IIIa receptor antagonist, in unstable angina. A randomized multicenter trial. Circulation 94, 2083–2089 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Stone, G. W. et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N. Engl. J. Med. 346, 957–966 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N. Engl. J. Med. 338, 1498–1505 (1998).

  104. Cameron, H. A., Phillips, R., Ibbotson, R. M. & Carson, P. H. Platelet size in myocardial infarction. BMJ 287, 449–451 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kishk, Y. T., Trowbridge, E. A. & Martin, J. F. Platelet volume subpopulations in acute myocardial infarction: an investigation of their homogeneity for smoking, infarct size and site. Clin. Sci. 68, 419–425 (1985).

    Article  CAS  Google Scholar 

  106. S¸enaran, H. et al. Thrombopoietin and mean platelet volume in coronary artery disease. Clin. Cardiol. 24, 405–408 (2001).

    Article  Google Scholar 

  107. Milner, P. C. & Martin, J. F. Shortened bleeding time in acute myocardial infarction and its relation to platelet mass. BMJ 290, 1767–1770 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kristensen, S. D., Bath, P. M. & Martin, J. F. Differences in bleeding time, aspirin sensitivity and epinephrine between acute myocardial infarction and unstable angina. Cardiovasc. Res. 24, 19–23 (1990).

    Article  CAS  PubMed  Google Scholar 

  109. Mathur, A., Robinson, M. S., Cotton, J., Martin, J. F. & Erusalimsky, J. D. Platelet reactivity in acute coronary syndromes: evidence for differences in platelet behavior between unstable angina and myocardial infarction. Thromb. Haemost. 85, 989–994 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Pizzulli, L., Yang, A., Martin, J. F. & Lüderitz, B. Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain. Eur. Heart J. 19, 80–84 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Endler, G. et al. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br. J. Hematol. 117, 399–404 (2002).

    Article  Google Scholar 

  112. López-Cuenca, A. A. et al. Prognostic value of mean platelet volume in patients with non-ST-elevation acute coronary syndrome. Angiology 63, 241–244 (2012).

    Article  PubMed  Google Scholar 

  113. Ranjith, M. P. et al. Significance of platelet volume indices and platelet count in ischaemic heart disease. J. Clin. Path. 62, 830–833 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Lippi, G. et al. Increased mean platelet volume in patients with acute coronary syndromes. Arch. Pathol. Lab. Med. 133, 1441–1443 (2009).

    Article  PubMed  Google Scholar 

  115. Chu, H. et al. Diagnostic performance of mean platelet volume for patients with acute coronary syndrome visiting an emergency department with acute chest pain: the Chinese scenario. Emerg. Med. J. 28, 569–574 (2011).

    Article  PubMed  Google Scholar 

  116. van der Lelie, J. & Brakenhoff, J. A. Mean platelet volume in myocardial infarction. BMJ (Clin. Res. Ed.) 287, 1471 (1983).

    Article  CAS  Google Scholar 

  117. Martin, J. F., Bath, P. M. & Burr, M. L. Influence of platelet size on outcome after myocardial infarction. Lancet 338, 1409–1411 (1991).

    Article  CAS  PubMed  Google Scholar 

  118. Huczek, Z. et al. Mean platelet volume on admission predicts impaired reperfusion and long-term mortality in acute myocardial infarction treated with primary percutaneous coronary intervention. J. Am. Coll. Cardiol. 46, 284–290 (2005).

    Article  PubMed  Google Scholar 

  119. Estévez-Loureiro, R. et al. Mean platelet volume predicts patency of the infarct-related artery before mechanical reperfusion and short-term mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Thromb. Res. 124, 536–540 (2009).

    Article  PubMed  CAS  Google Scholar 

  120. Pereg, D., Berlin, T. & Mosseri, M. Mean platelet volume on admission correlates with impaired response to thrombolysis in patients with ST-elevation myocardial infarction. Platelets 21, 117–121 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Yazici, H. U. et al. Relationship between mean platelet volume and left ventricular systolic function in patients with metabolic syndrome and ST-elevation myocardial infarction. Clin. Invest. Med. 34, E330 (2011).

    Article  PubMed  Google Scholar 

  122. Taglieri, N. et al. Prognostic significance of mean platelet volume on admission in an unselected cohort of patients with non ST-segment elevation acute coronary syndrome. Thromb. Haemost. 106, 132–140 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Aksu, H. et al. Significance of mean platelet volume on prognosis of patients with and without aspirin resistance in settings of non-ST-segment elevated acute coronary syndromes. Blood Coagul. Fibrinolysis 20, 686–693 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Azab, B. et al. Mean platelet volume/platelet count ratio as a predictor of long-term mortality after non-ST-elevation myocardial infarction. Platelets 22, 557–566 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Smyth, D. W., Martin, J. F., Michalis, L., Bucknall, C. A. & Jewitt, D. E. Influence of platelet size before coronary angioplasty on subsequent restenosis. Eur. J. Clin. Invest. 23, 361–367 (1993).

    Article  CAS  PubMed  Google Scholar 

  126. Yang, A., Pizzulli, L. & Lüderitz, B. Mean platelet volume as marker of restenosis after percutaneous transluminal coronary angioplasty in patients with stable and unstable angina pectoris. Thromb. Res. 117, 371–377 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Goncalves, S. C. et al. Usefulness of mean platelet volume as a biomarker for long-term outcomes after percutaneous coronary intervention. Am. J. Cardiol. 107, 204–209 (2011).

    Article  PubMed  Google Scholar 

  128. Lakkis, N. et al. Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J. Am. Coll. Cardiol. 44, 2091–2093 (2004).

    Article  PubMed  Google Scholar 

  129. Grove, E. L., Hvas, A. M. & Kristensen, S. D. Immature platelets in patients with acute coronary syndromes. Thromb. Haemost. 101, 151–156 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Cesari, F. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb. Haemost. 99, 930–935 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Guthikonda, S. et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J. Am. Coll. Cardiol. 52, 743–749 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Trowbridge, E. A. & Martin, J. F. The platelet volume distribution: a signature of the prethrombotic state in coronary heart disease? Thromb. Haemost. 58, 714–717 (1987).

    Article  CAS  PubMed  Google Scholar 

  133. Khandekar, M. M. et al. Platelet volume indices in patients with coronary artery disease and acute myocardial infarction: an Indian scenario. J. Clin. Path. 59, 146–149 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Trowbridge, E. A., Slater, D. N., Kishk, Y. T., Woodcock, B. W. & Martin, J. F. Platelet production in myocardial infarction and sudden cardiac death. Thromb. Haemost. 52, 167–171 (1984).

    Article  CAS  PubMed  Google Scholar 

  135. Kristensen, S. D., Roberts, K. M., Kishk, Y. T. & Martin, J. F. Accelerated atherogenesis occurs following platelet destruction and increases in megakaryocyte size and DNA content. Eur. J. Clin. Invest. 20, 239–247 (1990).

    Article  CAS  PubMed  Google Scholar 

  136. Brown, A. S. et al. Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 17, 802–807 (1997).

    Article  CAS  PubMed  Google Scholar 

  137. Pampus, E. C., Huijgens, P. C., Zevenbergen, A., Verheugt, F. W. & Langenhuijsen, M. Circulating human megakaryocytes in cardiac diseases. Eur. J. Clin. Invest. 24, 345–349 (1994).

    Article  PubMed  Google Scholar 

  138. Grove, E. L., Hvas, A. M., Mortensen, S. B., Larsen, S. B. & Kristensen, S. D. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J. Thromb. Hemost. 9, 185–191 (2011).

    Article  CAS  Google Scholar 

  139. Wurtz, M. et al. Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. JACC Cardiovasc. Interv. 3, 828–835 (2010).

    Article  PubMed  Google Scholar 

  140. Holmes, M. V., Perel, P., Shah, T., Hingorani, A. D. & Casas, J. P. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA 306, 2704–2714 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

J. F. Martin is an Adjunct Professor of Medicine at Yale University, New Haven, CT, USA. The authors would like to acknowledge Mattia Frontini, University of Cambridge, for his suggestions on megakaryocyte biology in revision of the manuscript.

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Authors and Affiliations

  1. Division of Medicine, Center for Cardiovascular Biology and Medicine, University College London, 5 University Street, WC1E 6JF, London, UK

    John F. Martin

  2. Department of Cardiology, Aarhus University Hospital Skejby, Brendstrupgaardsvej 100, DK-8200, Aarhus N, Denmark

    Steen D. Kristensen & Erik L. Grove

  3. NIHR Cardiovascular Biomedical Research Unit, Queen Mary, University of London, Bonner Road, E2 9JX, London, UK

    Anthony Mathur & Fizzah A. Choudry

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Contributions

J. F. Martin and F. A. Choudry wrote the article. J. F. Martin, S. D. Kristensen, E. L. Grove, and F. A. Choudry had a substantial contribution to the discussion of content. J. F. Martin, S. D. Kristensen, E. L. Grove, and F. A. Choudry researched data for the article, and all authors reviewed and edited the manuscript before submission.

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Correspondence to John F. Martin.

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Martin, J., Kristensen, S., Mathur, A. et al. The causal role of megakaryocyte–platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 9, 658–670 (2012). https://doi.org/10.1038/nrcardio.2012.131

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