Historical Perspective and Overview

  • Eric M. Mazur


Although the normal peripheral platelet count varies considerably from person to person, it is clear that platelet production is a regulated physiological process. That such a regulatory system exists is evidenced by the constancy of the normal peripheral platelet count in individuals over time, the capacity of the bone marrow to increase platelet production in the setting of accelerated platelet turnover, and the other alterations that characterize platelets and megakaryocytes produced in the clinical context of varying peripheral platelet demand (1).


Platelet Production Human Megakaryocyte Megakaryocyte Growth Bone Marrow Megakaryocyte Megakaryocyte Maturation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mazur EM. Megakaryocytopoiesis and platelet production: a review. Exp Hematol. 1987; 15: 340–350.PubMedGoogle Scholar
  2. 2.
    Mazur EM. Megakaryocytes and megakaryocytopoiesis. In: Loscalzo J, Schafer A (eds). Throm bosis and Hemorrhage. Oxford: Blackwell Scientific Publications; 1994: 161–194.Google Scholar
  3. 3.
    Harker LA. Kinetics of thrombopoiesis. J Clin Invest. 1968; 47: 458–465.PubMedCrossRefGoogle Scholar
  4. 4.
    Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest. 1969; 48: 963–974.PubMedCrossRefGoogle Scholar
  5. 5.
    Ebbe S, Stohlman F Jr, Donovan J, Overcash J. Megakaryocyte maturation rate in thrombocy topenic rats. Blood. 1968; 32: 383–392.PubMedGoogle Scholar
  6. 6.
    Keleman E, Cserhati I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythemic sera. Acta Haematol. 1958; 20: 350–353.CrossRefGoogle Scholar
  7. 7.
    Odell TT Jr, McDonald TP, Detwiler TC. Stimulation of platelet production by serum of platelet-depleted rats. Proc Soc Exp Biol Med. 1961; 108: 428–431.PubMedGoogle Scholar
  8. 8.
    Spector B. In vivo transfer of a thrombopoietic factor. Proc Soc Exp Biol Med. 1961; 108: 146–149.PubMedGoogle Scholar
  9. 9.
    Odell TT Jr, McDonald TP, Howsden FL. Native and foreign stimulators of platelet production. J Lab Clin Med. 1964; 64: 418–424.PubMedGoogle Scholar
  10. 10.
    Evatt BL, Levin J. Measurement of thrombopoiesis in rabbits using selenomethionine. J Clin Invest. 1969; 48: 1615–1626.PubMedCrossRefGoogle Scholar
  11. 11.
    Harker LA. Regulation of thrombopoiesis. Am J Physiol. 1970; 218: 1376–1380.PubMedGoogle Scholar
  12. 12.
    Penington DG. Isotope bioassay for “thrombopoietin.” Br Med J. 1970; 1: 606–608.PubMedCrossRefGoogle Scholar
  13. 13.
    Shreiner DP, Levin J. Detection of thrombopoietic activity in plasma by stimulation of sup pressed thrombopoiesis. J Clin Invest. 1970; 49: 1709–1713.PubMedCrossRefGoogle Scholar
  14. 14.
    Levin J, Evatt BL, Shreiner DP. Measurement of plasma thrombopoiesis stimulating activity using selenomethionine-75Se: studies in rabbits and mice. In: Baldini MG, Ebbe S (eds). Platelets: Production, Function, Transfusion, and Storage. New York: Grune & Stratton; 1974: 63–72.Google Scholar
  15. 15.
    McDonald TP. Thrombopoietin: its biology, purification, and characterization. Exp Hematol. 1988; 16: 201–205.PubMedGoogle Scholar
  16. 16.
    Ebbe S. Biology of megakaryocytes. Prog Hemost Thromb. 1976; 3: 787–795.Google Scholar
  17. 17.
    Schulman I, Pierce M, Lukens A, Currimbhoy Z. Studies on thrombopoiesis. 1. A factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency. Blood. 1960; 16: 943–957.PubMedGoogle Scholar
  18. 18.
    Miura M, Koizumi S, Nakamura K, et al. Efficacy of several plasma components in a young boy with chronic thrombocytopenia and hemolytic anemia who responds repeatedly to normal plasma infusions. Am J Hematol 1984; 17: 307–319.PubMedCrossRefGoogle Scholar
  19. 19.
    McDonald TP, Green D. Demonstration of thrombopoietin production after plasma infusion in a patient with congenital thrombopoietin deficiency. Thromb Haemost. 1977; 37: 577–579.PubMedGoogle Scholar
  20. 20.
    McDonald TP, Miura M, Koizumi S. Thrombopoietin production in a patient with chronic thrombocytopenia after plasma infusion. Thromb Res. 1985; 38: 353–359.PubMedCrossRefGoogle Scholar
  21. 21.
    Adams WH, Liu YK, Sullivan LW. Humoral regulation of thrombopoiesis in man. J Lab Clin Med. 1978; 91: 141–147.PubMedGoogle Scholar
  22. 22.
    Shreiner DP, Weinberg J, Enoch D. Plasma thrombopoietic activity in humans with normal and abnormal platelet counts. Blood. 1980; 56: 183–188.PubMedGoogle Scholar
  23. 23.
    Kellar KL, Evatt BL, McGrath CR, Ramsey RB. Stimulation of DNA synthesis in megakaryo cytes by thrombopoietin in vitro. In: Evatt BL, Levine RF, Williams N (eds). Megakaryocyte Biology and Precursors: In Vitro Cloning and Cellular Properties. New York: Elsevier; 1981: 21–34.Google Scholar
  24. 24.
    Greenberg SM, Kuter DJ, Rosenberg RD. In vitro stimulation of megakaryocyte maturation by megakaryocyte stimulatory factor. J Biol Chem. 1987; 262: 3269–3277.PubMedGoogle Scholar
  25. 25.
    Hill RJ, Leven RM, Levin FC, Levin J. The effect of partially purified thrombopoietin on guinea pig megakaryocyte ploidy in vitro. Exp Hematol .1989; 17: 903–907.PubMedGoogle Scholar
  26. 26.
    Long MW, Williams N, Ebbe S. Immature megakaryocytes in the mouse: physical characteris tics, cell cycle status, and in vitro responsiveness to thrombopoietic stimulatory factor. Blood. 1982; 59: 569–575.PubMedGoogle Scholar
  27. 27.
    Leven RM, Yee MK. Megakaryocyte morphogenesis stimulated in vitro by whole and partially fractionated thrombocytopenic plasma: a model system for the study of platelet formation. Blood. 1987; 69: 1046–1052.PubMedGoogle Scholar
  28. 28.
    Hill R, Levin J. Partial purification of thrombopoietin using lectin chromatography. Exp Hematol. 1986; 14: 752–759.PubMedGoogle Scholar
  29. 29.
    Tagrien G, Rosenberg RD. Purification and properties of a megakaryocyte stimulatory factor present both in the serum-free conditioned medium of human embryonic kidney cells and in thrombocytopenic plasma. J Biol Chem. 1987; 262: 3262–3268.Google Scholar
  30. 30.
    Nakeff A, Daniels-McQueen S. In vitro colony assay for a new class of megakaryocyte precur sor: colony-forming unit megakaryocyte (CFU-M) (39265). Proc Soc Exp Biol Med. 1976; 151: 587–590.PubMedGoogle Scholar
  31. 31.
    Mazur EM, Hoffman R, Bruno E. Regulation of human megakaryocytopoiesis. An in vitro analysis. J Clin Invest. 1981; 68: 733–741.PubMedCrossRefGoogle Scholar
  32. 32.
    Mazur EM, Hoffman R, Chasis J, Marchesi S, Bruno E. Immunofluorescent identification of human megakaryocyte colonies using an antiplatelet glycoprotein antiserum. Blood. 1981; 57: 277–286.PubMedGoogle Scholar
  33. 33.
    Levin J, Levin FC, Hull DF III, Penington DG. The effects of thrombopoietin on megakaryocyte-CFC, megakaryocytes, and thrombopoiesis: with studies of ploidy and platelet size. Blood. 1982; 60: 989–998.PubMedGoogle Scholar
  34. 34.
    Mazur EM, Cohen JL, Newton J, et al. Human serum megakaryocyte colony-stimulating activity appears to be distinct from interleukin-3, granulocyte-macrophage colony-stimulating factor, and lymphocyte-conditioned medium. Blood. 1990; 76: 290–297.PubMedGoogle Scholar
  35. 35.
    Vainchenker W, Bouguet J, Guichard J, Breton-Gorius J. Megakaryocyte colony formation from human bone marrow precursors. Blood. 1979; 54: 940–945.PubMedGoogle Scholar
  36. 36.
    Hill RJ, Levin J, Levin FC. Correlation of in vitro and in vivo biological activities during the partial purification of thrombopoietin. Exp Hematol. 1992; 20: 354–360.PubMedGoogle Scholar
  37. 37.
    Williams N, Eger RR, Jackson HM, Nelson DJ. Two-factor requirement for murine mega karyocyte colony formation. J Cell Physiol. 1982; 110: 101–104.PubMedCrossRefGoogle Scholar
  38. 38.
    Hoffman R, Mazur E, Bruno E, Floyd V. Assay of an activity in the serum of patients with disorders of thrombopoiesis that stimulates formation of megakaryocytic colonies. N Engl J Med. 1981; 305: 533–538.PubMedCrossRefGoogle Scholar
  39. 39.
    Homans AC, Cohen JL, Mazur EM. Defective megakaryocytopoiesis in the syndrome of throm bocytopenia with absent radii. Br J Haematol .1988; 70: 205–210.PubMedCrossRefGoogle Scholar
  40. 40.
    Mazur EM, de Alarcon P, South K, Miceli L. Human serum megakaryocyte colony-stimulating activity increases in response to intensive cytotoxic chemotherapy. Exp Hematol. 1984; 12: 624–628.PubMedGoogle Scholar
  41. 41.
    de Alarcon P, Schmieder JA. Megakaryocyte colony stimulating activity (Mk-CSA) in serum from patients undergoing bone marrow transplantation. In: Levine RF, Williams N, Levin J, Evatt BL (eds). Megakaryocyte Development and Function. New York: Alan R. Liss; 1986: 335–340.Google Scholar
  42. 42.
    Hoffman R, Yang HH, Bruno E, Straneva JE. Purification and partial characterization of a megakaryocyte colony-stimulating factor from human plasma. J Clin Invest. 1985; 75: 1174–1182.PubMedCrossRefGoogle Scholar
  43. 43.
    Mazur EM, South K. Human megakaryocyte colony-stimulating factor in sera from aplastic dogs: partial purification, characterization, and determination of hematopoietic cell lineage specificity. Exp Hematol. 1985; 13: 1164–1172.PubMedGoogle Scholar
  44. 44.
    Hoffman R. Regulation of megakaryocytopoiesis. Blood. 1989; 74: 1196–1212.PubMedGoogle Scholar
  45. 45.
    Segal GM, Stueve T, Adamson JW. Analysis of murine megakaryocyte colony size and ploidy: effects of interleukin-3. J Cell Physiol. 1988; 137: 537–544.PubMedCrossRefGoogle Scholar
  46. 46.
    Mazur EM, Cohen JL, Bogart L, et al. Recombinant gibbon interleukin-3 stimulates mega karyocyte colony growth in vitro from human peripheral blood progenitor cells. J Cell Physiol. 1988; 136: 439–446.PubMedCrossRefGoogle Scholar
  47. 47.
    Williams N, Sparrow R, Gill K, Yasmeen D, McNiece I. Murine megakaryocyte colony stimu lating factor: its relationship to interleukin 3. Leukemia Res. 1985; 9: 1487–1496.CrossRefGoogle Scholar
  48. 48.
    Donahue RE, Seehra J, Metzger M, et al. Human IL-3 and GM-CSF act synergistically in stimulating hematopoiesis in primates. Science. 1988; 241: 1820–1823.PubMedCrossRefGoogle Scholar
  49. 49.
    Lindemann A, Ganser A, Herrmann F, et al. Biologic effects of recombinant human interleukin-3 in vivo. J Clin Oncol. 1991; 9: 2120–2127.PubMedGoogle Scholar
  50. 50.
    Warren MK, Conroy LB, Rose JS. The role of interleukin 6 and interleukin 1 in megakaryocyte development. Exp Hematol. 1989; 17: 1095–1099.PubMedGoogle Scholar
  51. 51.
    Navarro S, Debili N, Le Couedic JP, et al. Interleukin-6 and its receptor are expressed by human megakaryocytes: in vitro effects on proliferation and endoreplication. Blood. 1991; 77: 461–471.PubMedGoogle Scholar
  52. 52.
    Banu N, Fawcett J, Williams N De Giorgio T, Withy R. Tissue sources of murine megakaryo cyte potentiator: biochemical and immunological studies. Br J Haematol. 1990; 75: 313–318.PubMedCrossRefGoogle Scholar
  53. 53.
    Leven RM, Rodriguez A. Immunomagnetic bead isolation of megakaryocytes from guinea-pig bone marrow: effect of recombinant interleukin-6 on size, ploidy, and cytoplasmic fragmentation. Br J Haematol. 1991; 77: 267–273.PubMedCrossRefGoogle Scholar
  54. 54.
    Ravid K, Kuter DJ, Rosenberg RD. rmIL-6 stimulates the transcriptional activity of the rat PF4 gene. Exp Hematol. 1995; 23: 397–401.PubMedGoogle Scholar
  55. 55.
    Williams N, De Giorgio T, Banu N, Withy R, Hirano T, Kishimoto T. Recombinant interleukin 6 stimulates immature murine megakaryocytes. Exp Hematol. 1990; 18: 69–72.PubMedGoogle Scholar
  56. 56.
    Asano S, Okano A, Ozawa K, et al. In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood. 1990; 75: 1602–1605.PubMedGoogle Scholar
  57. 57.
    Stahl CP, Zucker-Franklin D, Evatt BL, Winton EF. Effects of human interleukin-6 on mega karyocyte development and thrombocytopoiesis in primates. Blood. 1991; 78: 1467–1475.PubMedGoogle Scholar
  58. 58.
    Mayer P, Geissler K, Valent P, Ceska M, Bettelheim P, Liehl E. Recombinant human interleukin 6 is a potent inducer of the acute phase response and elevates the blood platelets in nonhuman primates. Exp Hematol 1991; 19: 688–696.PubMedGoogle Scholar
  59. 59.
    Geissler K, Valent P, Bettelheim P, et al. In vivo synergism of recombinant human interleukin-3 and recombinant human interleukin-6 on thrombopoiesis in primates. Blood. 1992; 79: 1155–1160.PubMedGoogle Scholar
  60. 60.
    Ishibashi T, Shikama Y, Kimura H et al. Thrombopoietic effects of interleukin-6 in long-term administration in mice. Exp Hematol. 1993; 21: 640–646.PubMedGoogle Scholar
  61. 61.
    Straneva JE, van Besien KW, Derigs G, Hoffman R. Is interleukin 6 the physiological regulator of thrombopoiesis? Exp Hematol. 1992; 20: 47–50.PubMedGoogle Scholar
  62. 62.
    Hill RJ, Warren K, Levin J. Does interleukin 6 mediate the thrombopoietic response to acute immune thrombocytopenia? Exp Hematol. 1990; 18: 704 (abstract).Google Scholar
  63. 63.
    Tefferi A, Ho TC, Ahmann GJ, Katzmann JA, Greipp PR. Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis. Am J Med. 1994; 97: 374–378.PubMedCrossRefGoogle Scholar
  64. 64.
    Bruno E, Briddell RA, Cooper RJ, Hoffman R. Effects of recombinant interleukin 11 on human megakaryocyte progenitor cells. Exp Hematol. 1991; 19: 378–381.PubMedGoogle Scholar
  65. 65.
    Neben TY, Loebelenz J, Hayes L, et al. Recombinant human interleukin-11 stimulates megakaryocytopoiesis and increases peripheral platelets in normal and splenectomized mice. Blood. 1993; 81: 901–908.PubMedGoogle Scholar
  66. 66.
    Du XX, Neben T, Goldman S, Williams DA. Effects of recombinant human interleukin-11 on hematopoietic reconstitution in transplant mice: acceleration of recovery of peripheral blood neutrophils and platelets. Blood. 1993; 81: 27–34.PubMedGoogle Scholar
  67. 67.
    Mazur EM, Cohen JL, Wong GG, Clark SC. Modest stimulatory effect of recombinant human GM-CSF on colony growth from peripheral blood human megakaryocyte progenitor cells. Exp Hematol. 1987; 15: 1128–1133.PubMedGoogle Scholar
  68. 68.
    Arriaga M, South K, Cohen JL, Mazur EM. Interrelationship between mitosis and endomitosis in cultures of human megakaryocyte progenitor cells. Blood. 1987; 69: 486–492.PubMedGoogle Scholar
  69. 69.
    Kuter DJ, Rosenberg RD. Appearance of a megakaryocyte growth-promoting activity, megapoietin, during acute thrombocytopenia in the rabbit Blood. 1994; 84: 1464–1472.PubMedGoogle Scholar
  70. 70.
    Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood. 1995; 86: 419–431.PubMedGoogle Scholar
  71. 71.
    Wendling F, Maraskovsky E, Debill N, et al. c-Mpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994; 369: 571–574.PubMedCrossRefGoogle Scholar
  72. 72.
    de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and throm bopoiesis by the c-Mpl ligand. Nature. 1994; 369: 533–538.PubMedCrossRefGoogle Scholar
  73. 73.
    Bartley TD, Bogenberger J, Hunt P, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994; 77: 1117–1124.PubMedCrossRefGoogle Scholar
  74. 74.
    Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regu lator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA. 1994; 91: 11, 104–11, 108.Google Scholar
  75. 75.
    Kuter DJ, Rosenberg RD. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood. 1995; 85: 2720–2730.PubMedGoogle Scholar
  76. 76.
    Nichol JL, Hokom MM, Hornkohl A, et al. Megakaryocyte growth and development factor. Analyses of in vitro effects on human megakaryopoiesis and endogenous serum levels during chemotherapy induced thrombocytopenia. J Clin Invest. 1995; 95: 2973–2978.PubMedCrossRefGoogle Scholar
  77. 77.
    Farese AM, Hunt P, Boone T, MacVittie TJ. Recombinant human megakaryocyte growth and development factor stimulates thrombocytopoiesis in normal nonhuman primates. Blood. 1995; 86: 54–59.PubMedGoogle Scholar
  78. 78.
    McDonald TP, Wendling F, Vainchenker W, et al. Thrombopoietin from human embryonic kidney cells is the same factor as c-mpl-ligand. Blood. 1995; 85: 292–294.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 1997

Authors and Affiliations

  • Eric M. Mazur

There are no affiliations available

Personalised recommendations