New advances in the treatment of adult chronic immune thrombocytopenic purpura: Role of thrombopoietin receptor-stimulating agents

Biologics: Targets and Therapy

Volumn 3, Issue , 2009, Pages 499-513

  Metjian, Ara ^a   Abrams, Charles S ^b  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Eltrombopag; Immune mediated thrombocytopenia; Romiplostim; Thrombocytopenia; Thrombopoietin; Thrombopoietin receptor

Indexed keywords

EID: 77953591720     PISSN: 11775475     EISSN: 11775491     Source Type: Journal    
DOI: 10.2147/BTT.S5578     Document Type: Review

References (126)

1. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88(1):3-40.
2. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120(4):574-596.
3. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346(13):995-1008.
4. Whipple A. Splenectomy as a therapeutic measure in thrombocytopenic purpura hæmorrhagica. Surg Gynecol Obstetr. 1926;42:329-341.
5. Meyers MMS, Bethell FH. Administration of ACTH in hypersplenic syndromes. J Lab Clin Med. 1950;36(6):965-966.
6. Bethell FM, Miller S, Bullock WH. Effects of ACTH and cortisone on idiopathic thrombocytopenic purpura. Trans Assoc Am Physicians. 1951;64:199-203.
7. Verlin M, Laros RK Jr, Penner JA. Treatment of refractory thrombocytopenic purpura with cyclophosphamine. Am J Hematol. 1976;1(1): 97-104.
8. Sussman LN. Azathioprine in refractory idiopathic thrombocytopenic purpura. JAMA. 1967;202(4):259-263.
9. Proctor SJ, Jackson G, Carey P, Stark A. Short-course alpha-interferon therapy in severe unresponsive immune thrombocytopenic purpura. Lancet. 1988;1(8591):947.
10. Kelsey PR, Schofield KP, Geary CG. Refractory idiopathic thrombocytopenic purpura (ITP) treated with cyclosporine. Br J Haematol. 1985;60(1):197-198.
11. Howard J, Hoffbrand AV, Prentice HG, Mehta A. Mycophenolate mofetil for the treatment of refractory auto-immune haemolytic anaemia and auto-immune thrombocytopenia purpura. Br J Haematol. 2002;117(3):712-715.
12. Godeau B, Oksenhendler E, Bierling P. Dapsone for autoimmune thrombocytopenic purpura. Am J Hematol. 1993;44(1):70-72.
13. McMinn JR Jr, Cohen S, Moore J, et al. Complete recovery from refractory immune thrombocytopenic purpura in three patients treated with etanercept. Am J Hematol. 2003;73(2):135-140.
14. Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG. Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med. 1983;308(23):1396-1399.
15. George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost. 2006;4(8):1664-1672.
16. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood. 2001;97(9):2549-2554.
17. George JN, Vesely SK. Immune thrombocytopenic purpura-let the treatment fit the patient. N Engl J Med. 2003;349(9):903-905.
18. Dameshek W, Miller EB. The Megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism. Blood. 1946;1(1)27-51.
19. Stoll D, Cines DB, Aster RH, Murphy S. Platelet kinetics in patients with idiopathic thrombocytopenic purpura and moderate thrombocytopenia. Blood. 1985;65(3):584-588.
20. Heyns Adu P, Badenhorst PN, Lotter MG, Pieters H, Wessels P, Kotze HF. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Crlabeled platelets differ. Blood. 1986;67(1):86-92.
21. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest. 1987;80(1):33-40.
22. Gernsheimer T, Stratton J, Ballem PJ, Slichter SJ. Mechanisms of response to treatment in autoimmune thrombocytopenic purpura. N Engl J Med. 1989;320(15):974-980.
23. Keleman EC I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythaemic sera. Acta Haem. 1958;20(6):350-355.
24. De Gabriele G, Penington DG. Physiology of the regulation of platelet production. Br J Haematol. 1967;13(2):202-209.
25. Wendling F, Varlet P, Charon M, Tambourin P. MPLV: a retrovirus complex inducing an acute myeloproliferative leukemic disorder in adult mice. Virology. 1986;149(2):242-246.
26. 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 Genet. 1989;83(2):194-196.
27. 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. Cell. 1990;63(6):1137-1147.
28. 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(12): 5640-5644.
29. Methia N, Louache F, Vainchenker W, Wendling F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood. 1993;82(5):1395-1401.
30. Gurney AL, Carver-Moore K, de Sauvage FJ, Moore MW. Thrombocytopenia in c-mpl-deficient mice. Science. 1994;265(5177): 1445-1447.
31. 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. Blood. 1996;87(6):2162-2170.
32. Kimura S, Roberts AW, Metcalf D, Alexander WS. Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci U S A. 1998;95(3):1195-1200.
33. de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369(6481):533-538.
34. 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(6481):565-568.
35. Kaushansky K, Lok S, Holly RD, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994;369(6481):568-571.
36. 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(7):1117-1124.
37. Wendling F, Maraskovsky E, Debili N, et al. c-Mpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994;369(6481): 571-574.
38. Sohma Y, Akahori H, Seki N, et al. Molecular cloning and chromosomal localization of the human thrombopoietin gene. FEBS Let. 1994;353(1):57-61.
39. Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest. 2005;115(12):3339-3347.
40. Broudy VC, Lin NL, Kaushansky K. Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. Blood. 1995;85(7): 1719-1726.
41. van Willigen G, Gorter G, Akkerman JW. Thrombopoietin increases platelet sensitivity to alpha-thrombin via activation of the ERK2-cPLA2 pathway. Thromb Haemost. 2000;83(4):610-616.
42. Akkerman JW. Thrombopoietin and platelet function. Semin Thromb Hemost. 2006;32(3):295-304.
43. Kaushansky K. Thrombopoietin: a tool for understanding thrombopoiesis. J Thromb Haemost. 2003;1(7):1587-1592.
44. Alexander WS, Metcalf D, Dunn AR. Point mutations within a dimer interface homology domain of c-Mpl induce constitutive receptor activity and tumorigenicity. EMBO J, 1995;14(22):5569-5578.
45. Miyakawa Y, Oda A, Druker BJ, et al. Recombinant thrombopoietin induces rapid protein tyrosine phosphorylation of Janus kinase 2 and Shc in human blood platelets. Blood. 1995;86(1):23-27.
46. Drachman JG, Griffin JD, Kaushansky K. The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl. J Biol Chem. 1995;270(10):4979-4982.
47. Miyakawa Y, Drachman JG, Gallis B, Kaushansky A, Kaushansky K. A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl. J Biol Chem. 2000; 275(41):32214-32219.
48. Miyakawa Y, Oda A, Druker BJ, et al. Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets. Blood. 1996;87(2):439-446.
49. Gurney AL, Wong SC, Henzel WJ, de Sauvage FJ. Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. Proc Natl Acad Sci U S A. 1995;92(12):5292-5296.
50. Nagata Y, Todokoro K. Thrombopoietin induces activation of at least two distinct signaling pathways. FEBS Lett. 1995;377(3):497-501.
51. Kaushansky K, Drachman JG. The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production. Oncogene. 2002;21(21):3359-3367.
52. Yamada M, Komatsu N, Okada K, Kato T, Miyazaki H, Miura Y. Thrombopoietin induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in a human thrombopoietin-dependent cell line. Biochem Biophys Res Commun. 1995;217(1):230-237.
53. 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(4): 1273-1282.
54. Hunt P, Li YS, Nichol JL, et al. Purification and biologic characterization of plasma-derived megakaryocyte growth and development factor. Blood. 1995;86(2):540-547.
55. Hirayama Y, Sakamaki S, Matsunaga T, et al. Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stromal cells. Blood. 1998;92(1):46-52.
56. Kosugi S, Kurata Y, Tomiyama Y, et al. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol. 1996;93(3):704-706.
57. Tahara T, Usuki K, Sato H, et al. A sensitive sandwich ELISA for measuring thrombopoietin in human serum: serum thrombopoietin levels in healthy volunteers and in patients with haemopoietic disorders. Br J Haematol. 1996;93(4):783-788.
58. 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(10):4068-4071.
59. Corazza F, Hermans C, D'Hondt S, et al. Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia. Blood. 2006;107(6):2525-2530.
60. De Gabriele G, Penington DG. Regulation of platelet production: "thrombopoietin". Br J Haematol. 1967;13(2):210-215.
61. Dahlen DD; Broudy VC; Drachman J. Internalization of the thrombopoietin receptor is regulated by 2 cytoplasmic motifs. Blood. 2003;103(1):102-108.
62. Kuter DJ, Rosenberg RD. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfaninduced thrombocytopenia in the rabbit. Blood. 1995;85(10): 2720-2730.
63. Fielder PJ, Gurney AL, Stefanich E, et al. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood. 1996;87(6):2154-2161.
64. Nagasawa T, Hasegawa Y, Shimizu S, et al. Serum thrombopoietin level is mainly regulated by megakaryocyte mass rather than platelet mass in human subjects. Br J Haematol. 1998;101(2):242-244.
65. Terashi K, Oka M, Ohdo S, et al. Close association between clearance of recombinant human granulocyte colony-stimulating factor (G-CSF) and G-CSF receptor on neutrophils in cancer patients. Antimicrob Agents Chemother. 1999;43(1):21-24.
66. Harker LA. Therapeutic cytokine stimulation of thrombocytopoiesis. Transfus Sci. 1998;19(2):149-162.
67. 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(9037):1279-1281.
68. 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(12):4486-4492.
69. Fanucchi M, Glaspy J, Crawford J, 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 Med. 1997:336(6):404-409.
70. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100(10): 3457-3469.
71. Vadhan-Raj S, Verschraegen CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med. 2000;132(5) 364-368.
72. Vadhan-Raj S, Murray LJ, Bueso-Ramos C, et al. Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med. 1997;126(9):673-681.
73. Harker LA, Marzec UM, Novembre F, et al. Treatment of thrombocytopenia in chimpanzees infected with human immunodeficiency virus by pegylated recombinant human megakaryocyte growth and development factor. Blood. 1998;91(12):4427-4433.
74. Harker LACR, Marzec UM, Cherry JK, et al. Correction of thrombocytopenia and ineffective platelet production in patients infected with human immunodeficiency virus (HIV) by PEG-rHuMGDF therapy. Blood. 1998;92:707a.
75. Kuter DJ, Goodnough LT, Romo J, et al. Thrombopoietin therapy increases platelet yields in healthy platelet donors. Blood. 2001;98(5): 1339-1345.
76. Goodnough LT, Kuter DJ, McCullough J, et al. Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin. Blood. 2001;98(5):1346-1351.
77. Nomura S, Dan K, Hotta T, Fujimura K, Ikeda Y. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood. 2002;100(2):728-730.
78. Rice L, Nichol JL, McMillan R, Roskos LK, Bacile M. Cyclic immune thrombocytopenia responsive to thrombopoietic growth factor therapy. Am J Hematol. 2001;68(3):210-214.
79. Hua B, Zou N, Wang S, Zhu T, Zhao Y. Multiple cycles of recombinant human thrombopoietin therapy in a patient with chronic refractory idiopathic thrombocytopenic purpura. Blood Coagul Fibrinolysis. 2005;16(4):291-295.
80. Fontenay-Roupie M, Dupont JM, Picard F, et al. Analysis of megakaryocyte growth and development factor (thrombopoietin) effects on blast cell and megakaryocyte growth in myelodysplasia. Leuk Res. 1998;22(6):527-535.
81. Ferrajoli A, Talpaz M, Kurzrock R, et al. Thrombopoietin stimulates myelodysplastic syndrome granulocyte-macrophage and erythroid progenitor proliferation. Leuk Lymphoma. 1998;30(3-4): 279-292.
82. Kizaki M, Miyakawa Y, Ikeda Y. Long-term administration of pegylated recombinant human megakaryocyte growth and development factor dramatically improved cytopenias in a patient with myelodysplastic syndrome. Br J Haematol. 2003;122(5): 764-767.
83. Matsuda A, Misumi M, Ishikawa M, et al. Long-term improvement of anaemia in a patient with aplastic anaemia by short-term administration of pegylated recombinant human megakaryocyte growth and development factor. Br J Haematol. 2004;125(6):818-819.
84. Archimbaud E, Ottmann OG, Yin JA, et al. A randomized, doubleblind, placebo-controlled study with pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) as an adjunct to chemotherapy for adults with de novo acute myeloid leukemia. Blood. 1999;94(11):3694-3701.
85. Schiffer CA, Miller K, Larson RA, et al. A double-blind, placebocontrolled trial of pegylated recombinant human megakaryocyte growth and development factor as an adjunct to induction and consolidation therapy for patients with acute myeloid leukemia. Blood. 2000;95(8):2530-2535.
86. Bolwell B, Vredenburgh J, Overmoyer B, et al. Phase 1 study of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in breast cancer patients after autologous peripheral blood progenitor cell (PBPC) transplantation. Bone Marrow Transplant. 2000;26(2):141-145.
87. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98(12): 3241-3248.
88. 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(7):2599-2602.
89. Lollar P. Pathogenic antibodies to coagulation factors. Part one: factor VIII and factor IX. J Thromb Haemost. 2004;2:1082-1095.
90. Key NS. Inhibitors in congenital coagulation disorders. Br J Haematol. 2004;127(4):379-391.
91. Cwirla SE, Balasubramanian P, Duffin DJ, et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science. 1997;276(5319):1696-1699.
92. de Serres M, Ellis B, Dillberger JE, et al. Immunogenicity of thrombopoietin mimetic peptide GW395058 in BALB/c mice and New Zealand white rabbits: evaluation of the potential for thrombopoietin neutralizing antibody production in man. Stem Cells. 1999;17(4): 203-209.
93. Deng B, Banu N, Malloy B, et al. An agonist murine monoclonal antibody to the human c-Mpl receptor stimulates megakaryocytopoiesis. Blood. 1998;92(6):1981-1988.
94. Rice L. Drug evaluation: AMG-531 for the treatment of thrombocytopenias. Curr Opin Investig Drugs. 2006;7(9):834-841.
95. Nichol JL. AMG 531: an investigational thrombopoiesis-stimulating peptibody. Pediatr Blood Cancer. 2006;47(5 Suppl):723-725.
96. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76(6):628-638.
97. Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine. 2004;25(2):52-60.
98. Newland A, Caulier MT, Kappers-Klunne M, et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol. 2006;135(4):547-553.
99. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesisstimulating protein, for chronic ITP. N Engl J Med. 2006;355(16): 1672-1681.
100. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371(9610): 395-403.
101. George JN, Mathias SD, Go RS, et al. Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials. Br J Haematol. 2009;144(3):409-415.
102. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161-2171.
103. Yan XQ, Lacey D, Fletcher F, et al. Chronic exposure to retroviral vector encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice. Blood. 1995;86(11): 4025-4033.
104. Ulich TR, del Castillo J, Senaldi G, et al. Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice. Blood. 1996;87(12):5006-5015.
105. Yanagida M, Ide Y, Imai A, et al. The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats. Br J Haematol. 1997;99(4):739-745.
106. Chagraoui H, Komura E, Tulliez M, Giraudier S, Vainchenker W, Wendling F. Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood. 2002;100(10):3495-3503.
107. Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Rutstein M. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia (ITP) patients treated with romiplostim. Blood. 2009;114:3748-3756.
108. Amgen. Romiplostim package insert. 2008. http://www.nplatenexus. com/pdfs/misc/nplate_pi.pdf. Accessed on October 10, 2009.
109. Kumagai Y, Fujita T, Ozaki M, et al. Pharmacodynamics and pharmacokinetics of AMG 531, a thrombopoiesis-stimulating peptibody, in healthy Japanese subjects: a randomized, placebo-controlled study. J Clin Pharmacol. 2007;47(12):1489-1497.
110. Duffy KJ, Darcy MG, Delorme E, et al. Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis. J Med Chem. 2001;44(22): 3730-3745.
111. Luengo JI, Duffy KJ, Shaw AN, et al. Discovery of SB-497115, a small-molecule thrombopoietin (TPO) receptor agonist for the treatment of thrombocytopenia. Blood (ASH Annual Meeting Abstracts). 2004;104(11):2910.
112. Erickson-Miller C, Delorme E, Giampa L, et al. Biological activity and selectivity for TPO receptor of the orally bioavailable, small molecule TPO receptor agonist, SB-497115. Blood (ASH Annual Meeting Abstracts). 2004;104(11):2912.
113. Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009;27(2):424-430.
114. Erhardt J, Erickson-Miller CL, Tapley P. Agonist-induced platelet aggregation in vitro. ASH Annual Meeting Abstracts. 2004;104(11):3888.
115. Jenkins JM, Williams D, Deng Y, et al. Phase I clinical study of eltrombopag, an oral, non-peptide thrombopoietin receptor agonist. Blood. 2007;109:4739-4741.
116. Williams DD, Peng B, Bailey CK, et al. Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: Two single-dose, open-label, randomized-sequence, crossover studies. Clin Ther. 2009;31(4):764-776.
117. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237-2247.
118. McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357(22):2227-2236.
119. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9664):641-648.
120. GlaxoSmithKline. PROMACTA® (eltrombopag) tablets. 2008. Available from: http://www.promactacares.com/prescribing_information. pdf. Accessed on October 10, 222009.
121. Rice L. Treatment of immune thrombocytopenic purpura: focus on eltrombopag. Biologics. 2009;3:151-157.
122. Su SF, Peng B, Williams D, et al. A phase I study to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of an oral platelet growth factor (SB-559448) in healthy subjects. ASH Annual Meeting Abstracts. 2006;108(11):1072.
123. Desjardins RE, Tempel DL, Lucek R, Kuter DJ. Single and multiple oral doses of AKR-501 (YM477) increase the platelet count in healthy volunteers. ASH Annual Meeting Abstracts. 2006;108(11):477.
124. Orita T, Tsunoda H, Yabuta N, et al. A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor. Blood. 2005;105(2):562-566.
125. Frederickson S, Renshaw MW, Lin B, et al. A rationally designed agonist antibody fragment that functionally mimics thrombopoietin. Proc Natl Acad Sci U S A. 2006;103(39):14307-14312.
126. Nakamura T, Miyakawa Y, Miyamura A, et al. A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis. Blood. 2006;107(11):4300-4307.