After the cloning of thrombopoietin (c-mpl ligand, Tpo) in 1994, 2 recombinant thrombopoietic growth factors, full-length glycosylated recombinant human Tpo (reHuTPO) and polyethylene glycol conjugated megakaryocyte growth and development factor (PEG-reHuMGDF), have been studied in humans in a variety of clin- ical settings. Both thrombopoietins are generally well tolerated if ad- ministered intravenously (IV). The c-mpl ligands produce a dose-re- lated enhancement of platelet levels, reduce nonmyeloablative chemotherapy-induced mild thrombocytopenia, and mobilize hematopoietic progenitors. On September 11, 1998, the development of PEG-reHuMGDF was suspended in the U.S., due to formation of the neutralizing anti-Tpo antibody. Those neutralizing antibodies lead to thrombocytopenia and pancytopenia in some patients receiv- ing subcutaneous (SC) PEG-reHuMGDF. Japanese investigators in- dicate that the probability of antibody formation against PEG- reHuMGDF is low when the drug is administered IV instead of SC. reHuTPO has a more favorable safety profile from the point of anti- body production. The c-mpl ligands can improve apheresis yields when administered to normal platelet donors. Preliminary data about the use of PEG-reHuMGDF in myelodysplasia, aplastic anemia, and immune thrombocytopenic purpura are promising. Tpo is usually not effective in myeloablative thrombocytopenia when bone marrow hematopoietic progenitors are not present. The major obstacle for the thrombopoietins is their delayed action for managing clinical thrombocytopenia. This review will focus on the biologic basis, cur- rent clinical experience, and future directions for the use of throm- bopoietic molecules as drugs. The identification of a safe, effective, and potent pharmacologic platelet growth factor could significantly improve the management of thrombocytopenia-induced bleeding.
8. Kaushansky K.Thrombopoietin: The primary regulator of megakaryocyte and platelet production. Thromb Haemost1995;74:521-521.
9.
9. Kaushansky K.Thrombopoietin. N Engl J Med1998; 339:746-746.
10.
10. Kaushansky K.Thrombopoietin: The primary regulator of platelet production. Blood1995;86:419-419.
11.
11. Wendling F, Varlet P, Charon M, Tambourin P.MPLV: A retrovirus complex inducing an acute myeloproliferative leukemic disorder in adult mice. Virology1986;149:242-242.
12.
12. Souyri M, Vigon I, Penciolelli JF, Heard JM, Tambourin P, Wendling F.A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell1990;63:1137-1137.
13.
13. Vigon I, Mornon JP, Cocault L, Mitjavila MT, Tambourin P, Gisselbrecht S, 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 USA1992;89:5640-5640.
14.
14. Methia N, Louache F, Vainchenker W, Wendling F.Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood1993;82:1395-1395.
15.
15. Alexander WS, Roberts AW, Nicola NA, Li R, Metcalf D.Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-mpl. Blood1996;87:2162-2162.
16.
16. de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-mpl ligand. Nature1994;369:533-533.
17.
17. de Sauvage FJ, Villeval JL, Shivdasani RA. Regulation of megakaryocytopoiesis and platelet production: Lessons from animal models. J Lab Clin Med1998;131:496-496.
18.
18. Gurney AL, Carver-Moore K, de Sauvage FJ, Moore MW.Thrombocytopenia in c-mpl-deficient mice. Science1994;265: 1445-1445.
19.
19. Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell1994;77:1117-1117.
20.
20. Kato T, Ogami K, Shimada Y, Iwamatsu A, Sohma Y, Akahori H, et al. Purification and characterization of thrombopoietin. J Biochem1995;118:229-229.
21.
21. Kaushansky K, Lok S, Holly RD, Broudy VC, Lin N, Bailey MC, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-mpl ligand thrombopoietin. Nature1994;369:568-568.
22.
22. Lok S, Kaushansky K, Holly RD, Kuijper JL, Lofton-Day CE, Oort PJ, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature1994;369:565-565.
23.
23. Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: A physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA1994;91:11104-11104.
24.
24. Sohma Y, Akahori H, Seki N, Hori T, Ogami K, Kato T, et al. Molecular cloning and chromosomal localization of the human thrombopoietin gene. FEBS Lett1994;353:57-57.
25.
25. Solar GP, Kerr WG, Zeigler FC, Hess D, Donahue C, de Sauvage FJ, et al. Role of c-mpl in early hematopoiesis. Blood1998;92:4-4.
26.
26. Kaushansky K.Thrombopoietin and the hematopoietic stem cell. Blood1998;92:1-1.
28. 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. Blood2002;99:2599-2599.
29.
29. Haznedaroglu IC, Benekli M, Dundar S.Thrombopoietin, megakaryocytopoietic cytokines, and reactive versus clonal megakaryocytopoiesis: An enigma complex. Blood1996;87:1654-1654.
30.
30. Haznedaroglu IC, Ertenli I, Ozcebe 01, Kiraz S, Ozdemir 0, Sayinalp NM, et al. Megakaryocyte-related interleukins in reactive thrombocytosis versus autonomous thrombocythemia. Acta Haematol1996;95:107-107.
31.
31. Haznedaroglu IC, Gullu IH, Dundar S, Kirazli S.The significance and distinct interactions of various growth factors in physiologic and pathologic megakaryocytopoiesis/thrombocytopoiesis. Aust NZJ Med.1997;27:191-191.
32.
32. Zucker-Franklin D, Kaushansky K.Effect of thrombopoietin on the development of megakaryocytes and platelets: an ultrastructural analysis. Blood1996;88:1632-1632.
33.
33. Kaushansky K, Broudy VC, Lin N, Jorgensen MJ, McCarty J, Fox N, et al. Thrombopoietin, the Mpl ligand, is essential for full megakaryocyte development. Proc Natl Acad Sci USA.1995;92:3234-3234.
34.
34. Bunting S, Widmer R, Lipari T, Rangell L, Steinmetz H, Carver-Moore K, et al. Normal platelets and megakaryocytes are produced in vivo in the absence of thrombopoietin. Blood1997;90:3423-3423.
35.
35. Drayer AL, Sibinga CT, Blom NR, De Wolf JT, Vellenga E.The in vitro effects of cytokines on expansion and migration of megakaryocyte progenitors. Br J Haematol2000; 109:776-776.
36.
36. Gainsford T, Roberts AW, Kimura S, Metcalf D, Dranoff G, Mulligan RC, et al. Cytokine production and function in c-mpl-deficient mice: No physiologic role for interleukin-3 in residual megakaryocyte and platelet production. Blood1998;91:2745-2745.
37.
37. Sui X, Tsuji K, Ebihara Y, Tanaka R, Muraoka K, Yoshida M, et al. Soluble interleukin-6 (IL-6) receptor with IL-6 stimulates megakaryopoiesis from human CD34(+) cells through glycoprotein (gp)130 signaling. Blood1999;93:2525-2525.
38.
38. Gainsford T, Nandurkar H, Metcalf D, Robb L, Begley CG, Alexander WS.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. Blood2000;95:528-528.
39.
39. Kaye JA. FDA licensure of NEUMEGA to prevent severe chemotherapy-induced thrombocytopenia. Stem Cells1998;16(suppl 2):207-207.
40.
40. Chang MS, McNinch J, Basu R, Shutter J, Hsu RY, Perkins C, et al. Cloning and characterization of the human megakaryocyte growth and development factor (MGDF) gene. J Biol Chem1995;270:511-511.
41.
41. Foster DC, Sprecher CA, Grant FJ, Kramer JM, Kuijper JL, Holly RD, et al. Human thrombopoietin: Gene structure, cDNA sequence, expression, and chromosomal localization. Proc Natl Acad Sci USA1994;91:13023-13023.
42.
42. Suzukawa K, Satoh H, Taniwaki M, Yokota J, Morishita K.The human thrombopoietin gene is located on chromosome 3q26.33-q27, but is not transcriptionally activated in leukemia cells with 3q21 and 3q26 abnormalities (3q21q26 syndrome). Leukemia1995;9:1328-1328.
43.
43. Skoda RC, Seldin DC, Chiang MK, Peichel CL, Vogt TF, Leder P.Murine c-mpl: A member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal. EMBO J1993; 12:2645-2645.
44.
44. Mignotte V, Deveaux S, Filipe A.Transcriptional regulation in megakaryocytes: The thrombopoietin receptor gene as a model. Stem Cells1996;14(suppl 1):232-232.
45.
45. Debili N, Wendling F, Cosman D, Titeux M, Florindo C, Dusanter-Fourt I, et al. The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood1995;85:391-391.
46.
46. Vigon I, Florindo C, Fichelson S, Guenet JL, Mattei MG, Souyri M, et al. Characterization of the murine Mpl proto-oncogene, a member of the hematopoietic cytokine receptor family: Molecular cloning, chromosomal location and evidence for a function in cell growth. Oncogene1993;8:2607-2607.
47.
47. Le Coniat M, Souyri M, Vigon I, Wendling F, Tambourin P, Berger R.The human homolog of the myeloproliferative virus maps to chromosome band 1p34. Hum Genet1989;83:194-194.
48.
48. Alexander WS, Dunn AR.Structure and transcription of the genomic locus encoding murine c-mpl, a receptor for thrombopoietin. Oncogene1995;10:795-795.
49.
49. Drachman JG, Kaushansky K.Dissecting the thrombopoietin receptor: Functional elements of the Mpl cytoplasmic domain. Proc Natl Acad Sci USA1997;94:2350-2350.
50.
50. Drachman JG, Sabath DF, Fox NE, Kaushansky K.Thrombopoietin signal transduction in purified murine megakaryocytes. Blood1997;89:483-483.
51.
51. Drachman JG, Millett KM, Kaushansky K.Thrombopoietin signal transduction requires functional JAK2, not TYK2. J Biol Chem1999;274:13480-13480.
52.
52. Ezumi Y, Takayama H, Okuma M.Thrombopoietin, cmpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists-induced aggregation in platelets in vitro. FEBS Lett1995;374:48-48.
53.
53. Ward AC, Touw I, Yoshimura A.The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood2000;95:19-19.
54.
54. Rojnuckarin P, Drachman JG, Kaushansky K.Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: Role in endomitosis. Blood.1999;94:1273-1273.
55.
55. Kato T, Matsumoto A, Ogami K, Tahara T, Morita H, Miyazaki H.Native thrombopoietin: Structure and function. Stem Cells1998;16(suppl 2):11-11.
56.
56. Foster D, Lok S.Biological roles for the second domain of thrombopoietin. Stem Cells1996;14(suppl 1):102-102.
57.
57. Gurney AL, Kuang WJ, Xie MH, Malloy BE, Eaton DL, de Sauvage FJ. Genomic structure, chromosomal localization, and conserved alternative splice forms of thrombopoietin. Blood1995;85:981-981.
58.
58. Eaton DL, de Sauvage FJ. Thrombopoietin: The primary regulator of megakaryocytopoiesis and thrombopoiesis. Exp Hematol1997;25:1-1.
59.
59. Linden HM, Kaushansky K.The glycan domain of thrombopoietin enhances its secretion. Biochemistry2000; 39:3044-3044.
60.
60. Basser RL.Early Australian clinical studies with pegylated recombinant human megakaryocyte growth and development factor. Stem Cells1998;16(suppl 2):225-225.
61.
61. Harker LA, Marzec UM, Hunt P, Kelly AB, Tomer A, Cheung E, et al. Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. Blood1996;88:511-511.
62.
62. Harker LA, Roskos LK, Marzec UM, Carter RA, Cherry JK, Sundell B, et al. Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers. Blood2000;95:2514-2514.
63.
63. Jones DV, Jr, Ashby M, Vadhan-Raj S, Somlo G, Champlin R, Gajewski J, et al. Recombinant human thrombopoietin clinical development. Stem Cells1998;16 (suppl 2):199-199.
64.
64. Vadhan-Raj S.Clinical experience with recombinant human thrombopoietin in chemotherapy-induced thrombocytopenia. Semin Hematol2000;37:28-28.
65.
65. Farese AM, Smith WG, Giri JG, Siegel N, McKearn JP, MacVittie TJ. Promegapoietin-la, an engineered chimeric IL-3 and Mpl-L receptor agonist, stimulates hematopoietic recovery in conventional and abbreviated schedules following radiation-induced myelosuppression in nonhuman primates. Stem Cells2001;19:329-329.
66.
66. Cwirla SE, Balasubramanian P, Duffin DJ, Wagstrom CR, Gates CM, Singer SC, et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science1997;276:1696-1696.
67.
67. Kimura T, Kaburaki H, Miyamoto S, Katayama J, Watanabe Y.Discovery of a novel thrombopoietin mimic agonist peptide. J Biochem1997;122:1046-1046.
68.
68. Kimura T, Kaburaki H, Tsujino T, Ikeda Y, Kato H, Watanabe Y.A non-peptide compound which can mimic the effect of thrombopoietin via c-mpl. FEBS Lett1998;428:250-250.
69.
69. Kimura T, Kaburaki H, Tsujino T, Watanabe Y, Kato H.Signal transduction by the peptide which mimics the activity of thrombopoietin. Biochem Mol Biol Int1998;44:1203-1203.
70.
70. Kaushansky K.Hematopoietic growth factor mimetics. Ann NYAcad Sci2001;938:131-131.
71.
71. Kaushansky K.Small molecule mimics of hematopoietic growth factors: Improving on Mother Nature?Leukemia2001;15:673-673.
72.
72. Martin TG, III, Somberg KA, Meng YG, Cohen RL, Heid CA, de Sauvage FJ, et al. Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation. Ann Intern Med1997;127:285-285.
73.
73. Sungaran R, Markovic B, Chong BH. Localization and regulation of thrombopoietin mRNa expression in human kidney, liver, bone marrow, and spleen using in situ hybridization. Blood.1997;89:101-101.
74.
74. Cardier JE, Dempsey J.Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: Evidence of thrombopoietin as a growth factor for liver endothelial cells. Blood1998;91:923-923.
75.
75. Cardier JE. Effects of megakaryocyte growth and development factor (thrombopoietin) on liver endothelial cells in vitro. Microvasc Res1999;58:108-108.
76.
76. Peck-Radosavljevic M, Zacherl J, Meng YG, Pidlich J, Lipinski E, Langle F, et al. Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver?J Hepatol1997;27:127-127.
77.
77. Goker H, Egesel T, Karakus S, Haznedaroglu IC, Apras S, Buyukasic Y, et al. Plasma thrombopoietin in patients with cavernous transformation of the portal vein. Int J Hematol2002;75:91-91.
78.
78. Altun B, Arici M, Haznedaroglu IC, Usalan C, Erdem Y, Yasavul U, et al. Serum thrombopoietin levels in haemodialysis patients: Involvement of arteriovenous fistula. Nephrol Dial Transplant1999;14:2173-2173.
79.
79. Altun B, Usalan C, Haznedaroglu IC, Arici M, Ulusoy S, Erdem Y, et al. Thrombopoietin and thrombospondin in renal allograft recipients. Blood Coagul Fibrinolysis1999;10:233-233.
80.
80. Jelkmann W.The role of the liver in the production of thrombopoietin compared with erythropoietin. Eur J Gastroenterol Hepatol2001;13:791-791.
81.
81. 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. Blood1996;87:567-567.
82.
82. Cohen-Solal K, Villeval JL, Titeux M, Lok S, Vainchenker W, Wendling F.Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis. Blood1996;88:2578-2578.
83.
83. Cohen-Solal K, Vitrat N, Titeux M, Vainchenker W, Wendling F.High-level expression of Mpl in platelets and megakaryocytes is independent of thrombopoietin. Blood1999;93:2859-2859.
84.
84. 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. Blood1995;85:2720-2720.
85.
85. Fielder PJ, Gurney AL, Stefanich E, Marian M, Moore MW, Carver-Moore K, et al. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood.1996;87:2154-2154.
86.
86. de Sauvage FJ, Carver-Moore K, Luoh SM, Ryan A, Dowd M, Eaton DL, et al. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med1996; 183:651-651.
87.
87. Fielder PJ, Hass P, Nagel M, Stefanich E, Widmer R, Bennett GL, et al. Human platelets as a model for the binding and degradation of thrombopoietin. Blood1997;89:2782-2782.
88.
88. De Gabriele G, Penington DG. Regulation of platelet production: “Thrombopoietin.”Br J Haematol1967; 13:210-210.
89.
89. Broudy VC, Lin NL, Sabath DF, Papayannopoulou T, Kaushansky K.Human platelets display high-affinity receptors for thrombopoietin. Blood.1997;89:1896-1896.
90.
90. Stefanich E, Senn T, Widmer R, Fratino C, Keller GA, Fielder PJ. Metabolism of thrombopoietin (TPO) in vivo: Determination of the binding dynamics for TPO in mice. Blood.1997;89:4063-4063.
91.
91. Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, Jackson CW, Hunt P, Saris CJ, et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell1995;81:695-695.
92.
92. Shivdasani RA, Fielder P, Keller GA, Orkin SH, de Sauvage FJ. Regulation of the serum concentration of thrombopoietin in thrombocytopenic NF-E2 knockout mice. Blood1997;90:1821-1821.
93.
93. Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood1996;87:4068-4068.
94.
94. Kosar A, Haznedaroglu IC, Buyukasik Y, Ozcebe 0, Kirazli S, Dundar S.Circulating thrombopoietin and interleukin-6 in newly diagnosed autoimmune versus aplastic thrombocytopenia. Haematologica1998; 83:1055-1055.
95.
95. Sato T, Fuse A, Niimi H, Fielder PJ, Avraham H.Binding and regulation of thrombopoietin to human megakaryocytes. Br J Haematol1998;100:704-704.
96.
96. Folman CC, Linthorst GE, van Mourik J, van Willigen G, de Jonge E, Levi M, et al. Platelets release thrombopoietin (Tpo) upon activation: Another regulatory loop in thrombocytopoiesis?Thromb Haemost2000;83:923-923.
97.
97. Haznedaroglu IC, Buyukasik Y, Kosar A, Kirazli S, Dundar SV. Thrombopoietin, interleukin-6, and P-selectin at diagnosis and during post-steroid recovery period of patients with autoimmune thrombocytopenic purpura. Ann Hematol1998;77:165-165.
98.
98. Nichol JL. Endogenous TPO (eTPO) levels in health and disease: Possible clues for therapeutic intervention. Stem Cells1998;16(suppl 2):165-165.
99.
99. O'Malley CJ, Rasko JE, Basser RL, McGrath KM, Cebon J, Grigg AP, et al. Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation. Blood1996;88:3288-3288.
100.
100. Dale DC, Nichol JL, Rich DA, Best DM, Slichter SJ, Sheridan W, et al. Chronic thrombocytopenia is induced in dogs by development of cross-reacting antibodies to the MpL ligand. Blood.1997;90:3456-3456.
101.
101. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood2001;98:3241-3241.
102.
102. Dan K, Nomura S, Hotta T, et al. Biological effect of pegylated recombinant megakaryocyte growth and development factor (PEG-MGDF) in patients with idiopathic thrombocytopenic purpura. Blood2001;98:299a-299a.
103.
103. Vadhan-Raj S, Murray LJ, Bueso-Ramos C, Patel S, Reddy SP, Hoots WK, et al. Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med1997;126:673-673.
104.
104. Kuter DJ. The use of PEG-rhuMGDF in platelet apheresis. Stem Cells1998;16(suppl 2):231-231.
106. Goodnough LT, Kuter DJ, McCullough J, Slichter SJ, DiPersio J, Romo J, et al. Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin. Blood2001;98:1346-1346.
107.
107. Rasko JE, Basser RL, Boyd J, Mansfield R, O'Malley CJ, Hussein S, et al. Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG-rHuMGDF. Br J Haematol1997;97:871-871.
108.
108. Geissler K, Kabrna E, Stengg S, Schwarzinger I, Knobl P, Valent P, et al. Recombinant human megakaryocyte growth and development factor increases levels of circulating haemopoietic progenitor cells post chemotherapy in patients with acute myeloid leukaemia. Br J Haematol1998; 102:535-535.
109.
109. Nash RA, Kurzrock R, DiPersio J, Vose J, Linker C, Maharaj D, et al. A phase I trial of recombinant human thrombopoietin in patients with delayed platelet recovery after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant2000;6:25-25.
110.
110. Lazzari L, Henschler R, Lecchi L, Rebulla P, Mertelsmann R, Sirchia G. Interleukin-6 and interleukin-11 act synergistically with thrombopoietin and stem cell factor to modulate ex vivo expansion of human CD41 + and CD61 + megakaryocytic cells. Haematologica2000; 85:25-25.
111.
111. Maurer AM, Liu Y, Caen JP, Han ZC. Ex vivo expansion of megakaryocytic cells. Int J Hematol2000; 71:203-203.
112.
112. Qiu L, Meagher R, Welhausen S, Heye M, Brown R, Herzig RH. Ex vivo expansion of CD34+ umbilical cord blood cells in a defined serum-free medium (QBSF-60) with early effect cytokines. J Hematother Stem Cell Res1999;8:609-609.
113.
113. Kratz-Albers K, Scheding S, Mohle R, Buhring HJ, Baum CM, Mc Kearn JP, et al. Effective ex vivo generation of megakaryocytic cells from mobilized peripheral blood CD34(+) cells with stem cell factor and promegapoietin. Exp Hematol2000;28:335-335.
114.
114. Archimbaud E, Thomas X.Thrombopoietic factors potentially useful in the treatment of acute leukemia. Leuk Res1998;22:1155-1155.
115.
115. Archimbaud E, Ottmann OG, Yin JA, Lechner K, Dombret H, Sanz MA, et al. A randomized, double-blind, placebo-controlled study with pegylated recombinant human megakaryocyte growth and development factor (PEGrHuMGDF) as an adjunct to chemotherapy for adults with de novo acute myeloid leukemia. Blood1999;94:3694-3694.
116.
116. Geissler K, Yin J, Ganser A, et al. Prior and concurrent administration of recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients receiving consolidation chemotherapy for de novo acute myeloid leukemia: A randomized, placebo-controlled, double blind, safety and efficacy study. Blood2001;98:3324a-3324a.
117.
117. Schiffer CA, Miller K, Larson RA, Amrein PC, Antin JH, Zani VJ, et al. A double-blind, placebo-controlled trial of pegylated recombinant human megakaryocyte growth and development factor as an adjunct to induction and consolidation therapy for patients with acute myeloid leukemia. Blood2000;95:2530-2530.
118.
118. Tokunaga Y, Miyamoto T, Gondo H, Okamura T, Niho Y.Effect of thrombopoietin on acute myelogenous leukemia blasts. Leuk Lymphoma2000;37:27-27.
119.
119. Geissler RG, Schulte P, Ganser A.Clinical use of hematopoietic growth factors in patients with myelodysplastic syndromes. Int J Hematol1997;65:339-339.
120.
120. Komatsu N, Okamoto T, Yoshida T, et al. Pegylated recombinant human megakaryocyte growth and development factor (Peg-reHuMGDF) increased platelet counts (Plt) in patients (Pts) with aplastic anemia (AA) and myelodysplastic syndrome (MDS). Blood.2000;96:296a-296a.
121.
121. Urabe A, Komatsu N, Okamoto T, Yoshida T, Nakao S, Nagasawa T, et al. Effects of pegylated recombinant megakaryocyte growth and development factor on haematopoiesis in patients with aplastic anemia and myelodysplastic syndrome. Exp Hematol2001;29:112a-112a.
122.
122. Iki S, Usuki K, Urabe A.Trilineage response in a refractory anemia patient by pegylated recombinant megakayocyte growth and development factor (PEG-rHuMGDF). Exp Hematol2001;29:46a-46a.
123.
123. Hashimoto S, Toba K, Fuse I, Watanabe K, Takahashi H, Abe T, et al. Thrombopoietin activates the growth of megakaryoblasts in patients with chronic myeloproliferative disorders and myelodysplastic syndrome. Eur J Haematol2000;64:225-225.
124.
124. Yan XQ, Lacey D, Hill D, Chen Y, Fletcher F, Hawley RG, et al. A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): Reversal of disease by bone marrow transplantation. Blood.1996;88:402-402.
126. Haznedaroglu IC, Savas CM, Benkli M, Gullu IH, Dundar SV. The significance of megakaryocytopoietic cytokines and thrombopoietin in immune thrombocytopenic purpura: a hypothesis. NZ Med J1996;109:389-389.
127.
127. Basser RL, Rasko JE, Clarke K, Cebon J, Green MD, Hussein S, et al. Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer. Lancet1996;348:1279-1279.
128.
128. Basser RL, Rasko JE, Clarke K, Cebon J, Green MD, Grigg AP, et al. Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer. Blood1997;89:3118-3118.
129.
129. Fanucchi M, Glaspy J, Crawford J, Garst J, Figlin R, Sheridan W, et al. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med1997;336:404-404.
130.
130. Vadhan-Raj S, Verschraegen CF, Bueso-Ramos C, Broxmeyer HE, Kudelka AP, Freedman RS, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med2000;132:364-364.
131.
131. Abraham R, Basser RL. Megakaryocyte growth and development factor: A review of early clinical studies. Oncologist1997;2:311-311.
132.
132. Miyazaki H, Kato T.Thrombopoietin: Biology and clinical potentials. Int J Hematol1999;70:216-216.
133.
133. Dan K, Nomura S, Hotta T, et al. Biological effect of pegylated recombinant megakaryocyte growth and development factor (PEG-MGDF) in patients with idiopathic thrombocytopenic purpura. Blood.2001;98: 299a-299a.
134.
134. Harker LA, Marzec UM, Novembre F, Sundell IB, Waller EK, Karpatkin S, et al. Treatment of thrombocytopenia in chimpanzees infected with human immunodeficiency virus by pegylated recombinant human megakaryocyte growth and development factor. Blood1998;91:4427-4427.
135.
135. Nakamura M, Toombs CF, Duarte IG, Ronson RS, Schmarkey LS, Katzmark SL, et al. Recombinant human megakaryocyte growth and development factor attenuates postbypass thrombocytopenia. Ann Thorac Surg1998;66:1216-1216.
137. Case BC, Hauck ML, Yeager RL, Simkins AH, de Serres M, Schmith VD, et al. The pharmacokinetics and pharmacodynamics of GW395058, a peptide agonist of the thrombopoietin receptor, in the dog, a large-animal model of chemotherapy-induced thrombocytopenia. Stem Cells2000;18:360-360.
138.
138. Farese AM, Casey DB, Smith WG, Vigneulle RM, McKearn JP, MacVittie TJ. Leridistim, a chimeric dual GCSF and IL-3 receptor agonist, enhances multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression: Effect of schedule, dose, and route of administration. Stem Cells2001;19:522-522.
139.
139. Basser RL, Begley CG. Failing to live up to the fanfare? A personal perspective on obstacles to the clinical development of thrombopoietic agents. Int J Hematol2001;74:390-390.
