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Biology and physiology of thrombopoietin

INTRODUCTION

Thrombopoietin is the physiologically relevant regulator of platelet production. Although the concept of a platelet growth factor analogous to erythropoietin had been proposed in the 1950s, it was not until 1994 that the existence of this hematopoietic growth factor was demonstrated and the protein purified [1-5]. Although historically called "thrombopoietin" [6], its discoverers also called it by several other names, including megapoietin [3], megakaryocyte growth and development factor (MGDF) [4], and c-Mpl ligand [2]. The last name is often used instead of thrombopoietin because the receptor for thrombopoietin, called c-Mpl, was discovered prior to the identification of thrombopoietin [7] and was instrumental in helping to purify the ligand (ie, the c-Mpl ligand) that bound to it.

This topic will review the biology and physiology of thrombopoietin. The potential clinical applications of thrombopoietin, ranging from the management of thrombocytopenic states to improving yields from platelet apheresis, are discussed separately [8]. (See "Clinical applications of thrombopoietic growth factors".)

STRUCTURE OF THROMBOPOIETIN

Thrombopoietin is produced primarily in liver parenchymal cells with much smaller amounts being made in the kidney and bone marrow [9,10]. It is synthesized as a 353 amino acid precursor protein with a molecular weight of 36 kDa [2,4,11]. Following the removal of the 21 amino acid signal peptide, the remaining 332 amino acids undergo glycosylation to produce a 95 kDa glycoprotein (figure 1). The glycoprotein is then released into the circulation with no apparent intracellular storage in the liver or kidney.

Thrombopoietin is an unusual hematopoietic growth factor in a number of ways:

It is much larger than most other regulators of blood cell production such as G-CSF (granulocyte colony-stimulating factor) and erythropoietin.

                

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Literature review current through: Jul 2014. | This topic last updated: Apr 8, 2014.
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References
Top
  1. Kato T, Ogami K, Shimada Y, et al. Purification and characterization of thrombopoietin. J Biochem 1995; 118:229.
  2. de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 1994; 369:533.
  3. Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A 1994; 91:11104.
  4. 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.
  5. Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 1994; 369:565.
  6. KELEMEN E, CSERHATI I, TANOS B. Demonstration and some properties of human thrombopoietin in thrombocythaemic sera. Acta Haematol 1958; 20:350.
  7. Vigon I, Mornon JP, Cocault L, et al. Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc Natl Acad Sci U S A 1992; 89:5640.
  8. Kaushansky K. Thrombopoietin. N Engl J Med 1998; 339:746.
  9. Nomura S, Ogami K, Kawamura K, et al. Cellular localization of thrombopoietin mRNA in the liver by in situ hybridization. Exp Hematol 1997; 25:565.
  10. Qian S, Fu F, Li W, et al. Primary role of the liver in thrombopoietin production shown by tissue-specific knockout. Blood 1998; 92:2189.
  11. Foster DC, Sprecher CA, Grant FJ, et al. Human thrombopoietin: gene structure, cDNA sequence, expression, and chromosomal localization. Proc Natl Acad Sci U S A 1994; 91:13023.
  12. Gurney AL, Kuang WJ, Xie MH, et al. Genomic structure, chromosomal localization, and conserved alternative splice forms of thrombopoietin. Blood 1995; 85:981.
  13. Hokom MM, Lacey D, Kinstler OB, et al. Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice. Blood 1995; 86:4486.
  14. Spivak JL, Hogans BB. The in vivo metabolism of recombinant human erythropoietin in the rat. Blood 1989; 73:90.
  15. Feese MD, Tamada T, Kato Y, et al. Structure of the receptor-binding domain of human thrombopoietin determined by complexation with a neutralizing antibody fragment. Proc Natl Acad Sci U S A 2004; 101:1816.
  16. Schnittger S, de Sauvage FJ, Le Paslier D, Fonatsch C. Refined chromosomal localization of the human thrombopoietin gene to 3q27-q28 and exclusion as the responsible gene for thrombocytosis in patients with rearrangements of 3q21 and 3q26. Leukemia 1996; 10:1891.
  17. Souyri M, Vigon I, Penciolelli JF, et al. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell 1990; 63:1137.
  18. Debili N, Wendling F, Cosman D, et al. The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood 1995; 85:391.
  19. Methia N, Louache F, Vainchenker W, Wendling F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood 1993; 82:1395.
  20. Li J, Xia Y, Kuter DJ. Interaction of thrombopoietin with the platelet c-mpl receptor in plasma: binding, internalization, stability and pharmacokinetics. Br J Haematol 1999; 106:345.
  21. Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood 1995; 86:419.
  22. Kuter DJ. Thrombopoietin: Biology and Clinical Applications. Oncologist 1996; 1:98.
  23. Kuter DJ. Thrombopoietin: biology, clinical applications, role in the donor setting. J Clin Apher 1996; 11:149.
  24. 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.
  25. Fielder PJ, Hass P, Nagel M, et al. Human platelets as a model for the binding and degradation of thrombopoietin. Blood 1997; 89:2782.
  26. Fielder PJ, Gurney AL, Stefanich E, et al. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood 1996; 87:2154.
  27. Saur SJ, Sangkhae V, Geddis AE, et al. Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood 2010; 115:1254.
  28. Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med 2006; 354:2034.
  29. Kuter DJ. Milestones in understanding platelet production: a historical overview. Br J Haematol 2014; 165:248.
  30. Alexander WS, Roberts AW, Nicola NA, et al. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood 1996; 87:2162.
  31. Gurney AL, Carver-Moore K, de Sauvage FJ, Moore MW. Thrombocytopenia in c-mpl-deficient mice. Science 1994; 265:1445.
  32. de Sauvage FJ, Carver-Moore K, Luoh SM, et al. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med 1996; 183:651.
  33. Carver-Moore K, Broxmeyer HE, Luoh SM, et al. Low levels of erythroid and myeloid progenitors in thrombopoietin-and c-mpl-deficient mice. Blood 1996; 88:803.
  34. Gainsford T, Nandurkar H, Metcalf D, et al. The residual megakaryocyte and platelet production in c-mpl-deficient mice is not dependent on the actions of interleukin-6, interleukin-11, or leukemia inhibitory factor. Blood 2000; 95:528.
  35. Zauli G, Vitale M, Falcieri E, et al. In vitro senescence and apoptotic cell death of human megakaryocytes. Blood 1997; 90:2234.
  36. Choi ES, Nichol JL, Hokom MM, et al. Platelets generated in vitro from proplatelet-displaying human megakaryocytes are functional. Blood 1995; 85:402.
  37. Choi ES, Hokom MM, Chen JL, et al. The role of megakaryocyte growth and development factor in terminal stages of thrombopoiesis. Br J Haematol 1996; 95:227.
  38. Harker LA, Marzec UM, Hunt P, et al. Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. Blood 1996; 88:511.
  39. Harker LA, Hunt P, Marzec UM, et al. Regulation of platelet production and function by megakaryocyte growth and development factor in nonhuman primates. Blood 1996; 87:1833.
  40. Basser RL, Rasko JE, Clarke K, et al. Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer. Lancet 1996; 348:1279.
  41. Kuter DJ, Goodnough LT, Romo J, et al. Thrombopoietin therapy increases platelet yields in healthy platelet donors. Blood 2001; 98:1339.
  42. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther 2004; 76:628.
  43. Chen J, Herceg-Harjacek L, Groopman JE, Grabarek J. Regulation of platelet activation in vitro by the c-Mpl ligand, thrombopoietin. Blood 1995; 86:4054.
  44. Kubota Y, Arai T, Tanaka T, et al. Thrombopoietin modulates platelet activation in vitro through protein-tyrosine phosphorylation. Stem Cells 1996; 14:439.
  45. Montrucchio G, Brizzi MF, Calosso G, et al. Effects of recombinant human megakaryocyte growth and development factor on platelet activation. Blood 1996; 87:2762.
  46. Kaushansky K, Lin N, Grossmann A, et al. Thrombopoietin expands erythroid, granulocyte-macrophage, and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol 1996; 24:265.
  47. Kaushansky K. Thrombopoietin and the hematopoietic stem cell. Blood 1998; 92:1.
  48. Solar GP, Kerr WG, Zeigler FC, et al. Role of c-mpl in early hematopoiesis. Blood 1998; 92:4.
  49. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood 2014; 123:1818.
  50. Stoffel R, Ziegler S, Ghilardi N, et al. Permissive role of thrombopoietin and granulocyte colony-stimulating factor receptors in hematopoietic cell fate decisions in vivo. Proc Natl Acad Sci U S A 1999; 96:698.
  51. Kuter DJ. The regulation of platelet production. In: Thrombosis and Thrombopoietins: Molecular, Cellular, Preclinical and Clinical Biology, Kuter DJ, Hunt P, Sheridan W, et al. (Eds), Humana Press, Totowa 1997. p.377.
  52. Stoffel R, Wiestner A, Skoda RC. Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. Blood 1996; 87:567.
  53. Yang C, Li YC, Kuter DJ. The physiological response of thrombopoietin (c-Mpl ligand) to thrombocytopenia in the rat. Br J Haematol 1999; 105:478.
  54. Scheding S, Bergmann M, Shimosaka A, et al. Human plasma thrombopoietin levels are regulated by binding to platelet thrombopoietin receptors in vivo. Transfusion 2002; 42:321.
  55. Wiestner A, Padosch SA, Ghilardi N, et al. Hereditary thrombocythaemia is a genetically heterogeneous disorder: exclusion of TPO and MPL in two families with hereditary thrombocythaemia. Br J Haematol 2000; 110:104.
  56. Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat Genet 1998; 18:49.
  57. Siemensma NP, Bathal PS, Penington DG. The effect of massive liver resection on platelet kinetics in the rat. J Lab Clin Med 1975; 86:817.
  58. Peck-Radosavljevic M, Zacherl J, Meng YG, et al. Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver? J Hepatol 1997; 27:127.
  59. Peck-Radosavljevic M, Wichlas M, Zacherl J, et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood 2000; 95:795.
  60. Basser RL, O'Flaherty E, Green M, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood 2002; 99:2599.
  61. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001; 98:3241.
  62. Shiozaki H, Miyawaki S, Kuwaki T, et al. Autoantibodies neutralizing thrombopoietin in a patient with amegakaryocytic thrombocytopenic purpura. Blood 2000; 95:2187.
  63. Aledort LM, Hayward CP, Chen MG, et al. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol 2004; 76:205.
  64. Heckl D, Wicke DC, Brugman MH, et al. Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia. Blood 2011; 117:3737.
  65. Ihara K, Ishii E, Eguchi M, et al. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A 1999; 96:3132.
  66. van den Oudenrijn S, Bruin M, Folman CC, et al. Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia. Br J Haematol 2000; 110:441.
  67. Pinto MR, King MA, Goss GD, et al. Acute megakaryoblastic leukaemia with 3q inversion and elevated thrombopoietin (TSF): an autocrine role for TSF? Br J Haematol 1985; 61:687.
  68. Bouscary D, Fontenay-Roupie M, Chretien S, et al. Thrombopoietin is not responsible for the thrombocytosis observed in patients with acute myeloid leukemias and the 3q21q26 syndrome. Br J Haematol 1995; 91:425.
  69. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369:2379.
  70. Emmons RV, Reid DM, Cohen RL, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood 1996; 87:4068.
  71. Horikawa Y, Matsumura I, Hashimoto K, et al. Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia. Blood 1997; 90:4031.