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01-12-2014 | Review Article

The pharmacology and clinical application of thrombopoietin receptor agonists

Authors: Caizheng Li, Li Zheng

Published in: International Journal of Hematology | Issue 6/2014

Abstract

The discovery and application of thrombopoietin (TPO) and thrombopoietin receptor (TPOR) agonists have changed the clinical treatment of thrombocytopenia. These compounds exert favorable clinical effects without the adverse events caused by traditional treatments (e.g., corticosteroids, immunoglobulins, monoclonal antibodies and splenectomy). This review provides a synopsis of new agents that boost platelet production, especially the TPOR agonists, and highlights their pharmacological characteristics and clinical applications.

Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood. 2001;97(9):2549–54.PubMedCrossRef

George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88(1):3–40.PubMed

George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost. 2006;4(8):1664–72.PubMedCrossRef

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. Cell. 1994;77(7):1117–24.PubMedCrossRef

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. Nature. 1994;369:533–8.PubMedCrossRef

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;87:567–73.PubMed

Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA. 1994;91:11104–8.PubMedCentralPubMedCrossRef

Peck-Radosavljevic M, Zacherl J, Meng YG, Pidlich J, Lipinski E, Längle F, et al. Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver? J Hepatol. 1997;27:127–31.PubMedCrossRef

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. Blood. 1995;85(2):391–401.PubMed

10.

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;106:345–56.PubMedCrossRef

11.

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. Blood. 1996;87(10):4068–71.PubMed

12.

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(6):2154–61.PubMed

13.

Wolber EM, Jelkmann W. Thrombopoietin: the novel hepatic hormone. News Physiol Sci. 2002;17:6–10.PubMed

14.

Geddis AE, Linden HM, Kaushansky K. Thrombopoietin: a pan-hematopoietic cytokine. Cytokine Growth Factor Rev. 2002;13(1):61–73.PubMedCrossRef

15.

Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100(10):3457–69.PubMedCrossRef

16.

Kaushansky K, Drachman JG. The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production. Oncogene. 2002;21(21):3359–67.PubMedCrossRef

17.

Majka M, Ratajczak J, Villaire G, Kubiczek K, Marquez LA, Janowska-Wieczorek A, et al. Thrombopoietin, but not cytokines binding to gp130 protein-coupled receptors, activates MAPKp42/44, AKT, and STAT proteins in normal human CD34(+) cells, megakaryocytes, and platelets. Exp Hematol. 2002;30(7):751–60.PubMedCrossRef

18.

Schulze H, Ballmaier M, Welte K, Germeshausen M. Thrombopoietin induces the generation of distinct Stat1, Stat3, Stata5a and Stat5b homo- and heterodimeric complexes with different kinetics in human platelets. Exp Hematol. 2000;28(3):294–304.PubMedCrossRef

19.

Ezumi Y, Takayama H, Okuma M. Thrombopoietin, c-Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonist-induced aggregation of platelets in vitro. FEBS Lett. 1995;374(1):48–52.PubMedCrossRef

20.

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):1273–82.PubMed

21.

Drachman JG, Sabath DF, Fox NE, Kaushansky K. Thrombopoietin signal transduction in purified murine megakaryocytes. Blood. 1997;89(2):483–92.PubMed

22.

Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607–16.PubMedCentralPubMedCrossRef

23.

Demetri GD. Targeted approaches for the treatment of thrombocytopenia. Oncologist. 2001;6(5):15–23.PubMedCrossRef

24.

Kuter DJ. Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009;60:193–206.PubMedCrossRef

25.

Basser RL, O’Flaherty E, Green M, Edmonds M, Nichol J, Menchaca DM, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99(7):2599–602.PubMedCrossRef

26.

Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98(12):3241–8.PubMedCrossRef

27.

Peeters K, Stassen JM, Collen D, Van Geet C, Freson K. Emerging treatments for thrombocytopenia: increasing platelet production. Drug Discov Today. 2008;13(17–18):798–806.PubMedCrossRef

28.

Wang T, Wang Z, Yang R. Thrombopoietic growth factors in the treatment of immune thrombocytopenic purpura. Crit Rev Oncol Hematol. 2011;77(3):172–83.PubMedCrossRef

29.

Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76(6):628–38.PubMedCrossRef

30.

Bussel JB, Kuter DJ, Phil D, George JN, McMillan R, Aledort LM, et al. AMG531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355(16):1672–81.PubMedCrossRef

31.

Lam MS. Review article: Second-generation thrombopoietin agents for treatment of chronic idiopathic thrombocytopenic purpura in adults. J Oncol Pharm Pract. 2010;16:89–103.PubMedCrossRef

32.

Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, et al. Phase 1 clinical study of eltrombopag, an oral, non-peptide thrombopoietin receptor agonist. Blood. 2007;109:4739–41.PubMedCrossRef

33.

Nichol JL. AMG 531: an investigational thrombopoiesis-stimulating pepti-body. Pediatr Blood Cancer. 2006;47:723–5.PubMedCrossRef

34.

Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine. 2004;25(2):52–60.PubMedCrossRef

35.

Kim MJ, Park SH, Opella SJ, Marsilje TH, Michellys PY, Seidel HM, et al. NMR structural studies of interactions of a small, nonpeptidyl Tpo mimic with the thrombopoietin receptor extracellular juxtamembrane and transmembrane domains. J Biol Chem. 2007;282:14253–61.PubMedCrossRef

36.

Bussel JB, Pinheiro MP. Eltrombopag. Cancer Treat Res. 2011;157:289–303.PubMedCrossRef

37.

Erickson-Miller CL, DeLorme E, Tian SS, Hopson CB, Stark K, Giampa L, et al. Discovery and characterization of a selective, non-peptidyl thrombopoietin receptor agonist. Exp Hematol. 2005;33:85–93.PubMedCrossRef

38.

Erhardt JA, Erickson-Miller CL, Aivado M, Abboud M, Pillarisetti K, Toomey JR. Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol. 2009;37:1030–7.PubMedCrossRef

39.

Erickson-Miller CL, Delorme E, Tian SS, Hopson CB, Landis AJ, Valoret EI, et al. Preclinical activity of eltrombopag (SB-497115), an oral nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009;27(2):424–30.PubMedCentralPubMedCrossRef

40.

Nplate (romiplostim) [prescribing information]. Thousand Oaks, Calif: Amgen Inc; 2008. http://www.nplate.com/patient/pdf/nplate_pi.pdf. Accessed Aug 17 2009.

41.

Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, et al. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood. 2007;109(11):4739–41.PubMedCrossRef

42.

Gibiansky E, Zhang J, Williams D, Wang Z, Ouellet D. Population pharmacokinetics of eltrombopag in healthy subjects and patients with chronic idiopathic thrombocytopenic purpura. J Clin Pharmacol. 2011;51:842–56.PubMedCrossRef

43.

Hayes S, Ouellet D, Zhang J, Wire MB, Gibiansky E. Population PK/PD modeling of eltrombopag in healthy volunteers and patients with immune thrombocytopenic purpura and optimization of response-guided dosing. J Clin Pharmacol. 2011;51(10):1403–17.PubMedCrossRef

44.

Wire MB, Bruce J, Gauvin J, Pendry CJ, McGuire S, Qian Y, et al. A randomized, open-label, 5-period, balanced crossover study to evaluate the relative bioavailability of eltrombopag powder for oral suspension (PfOS) and tablet formulations and the effect of a high-calcium meal on eltrombopag pharmacokinetics when administered with or 2 h before or after PfOS. Clin Ther. 2012;34(3):699–709.PubMedCrossRef

45.

FDA Label approved on 11/20/2008 for PROMACTA,NDA no.022291 [EB/OL]. http://www.fda.gov/cder/foi/label/2008/022291lbl.pdf.

46.

Deng Y, Madatian A, Wire MB, Bowen C, Park JW, Williams D, et al. Metabolism and disposition of eltrombopag, an oral, non-peptide thrombopoietin receptor agonist, healthy human subjects. Drug Metab Dispos. 2011;39(9):1734–46.PubMedCrossRef

47.

Newland A, Caulier MT, Kappers-Klunne M, Schipperus MR, Lefrere F, Zwaginga JJ, 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;135:547–53.PubMedCrossRef

48.

Shirasugi Y, Ando K, Hashino S, Nagasawa T, Kurata Y, Kishimoto Y, et al. A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura. Int J Hematol. 2009;90(2):157–65.PubMedCrossRef

49.

Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial. Lancet. 2008;371:395–403.PubMedCrossRef

50.

Shirasugi Y, Ando K, Miyazaki K, Tomiyama Y, Okamoto S, Kurokawa M, Kirito K, et al. Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial. Int J Hematol. 2011;94:71–80.PubMedCrossRef

51.

Kumagai Y, Fujita T, Ozaki M, Sahashi K, Ohkura M, Ohtsu T, 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;47:1489–97.PubMedCrossRef

52.

Aledort LM, Hayward CPM, Chen M-G, Nichol JL, Bussel JB. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating anti-thrombopoietin antibodies. Am J Hematol. 2004;76:205–13.PubMedCrossRef

53.

Dower WJ, Cwirla SE, Balasubramanian P, Schatz PJ, Baccanari DP, Barrett RW. Peptide Agonists of the Thrombopoietin Receptor. Stem Cells. 1998;16(Suppl 2):21–9.PubMedCrossRef

54.

Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357:2237–47.PubMedCrossRef

55.

Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, 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;373:641–8.PubMedCrossRef

56.

Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377:393–402.PubMedCrossRef

57.

Saleh MN, Bussel JB, Cheng G, Meddeb B, Mayer B, Bailey C, et al. Long-term treatment of chronic immune thrombocytopenic purpura with oral eltrombopag: results from the extend study. 51st annual meeting of the american-society-of-hematology. Blood. 2010;116(21):37–8.

58.

59.

Kantarjian H, O’Brien S, Ravandi F, Cortes J, Shan J, Bennett JM, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer. 2008;113(6):1351–61.PubMedCentralPubMedCrossRef

60.

Kantarjian HM, Giles FJ, Fenaux P, Becker PS, Boruchov AM, Bowen DT, et al. Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study. J Clin Oncol 2007 ASCO Annual Meeting Proceedings. 25 (18 Suppl) 7032.

61.

Kantarjian HM, Giles FJ, Greenberg PL, Paquette RL, Wang ES, Gabrilove JL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010;116(17):3163–70.PubMedCentralPubMedCrossRef

62.

Sekeres MA, Kantarjian H, Fenaux P, Becker P, Boruchov A, Guerci-Bresler A, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer. 2011;117(5):992–1000.PubMedCrossRef

63.

Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, et al. Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009;114(18):3899–908.PubMedCentralPubMedCrossRef

64.

Erickson-Miller CL, Kirchner J, Aivado M, May R, Payne P, Chadderton A. Reduced proliferation of non-megakaryocytic acute myelogenous leukemia and other leukemia and lymphoma cell lines in response to eltrombopag. Leuk Res. 2010;34(9):1224–31.PubMedCrossRef

65.

Shiffman ML, Ghany MG, Morgan TR, Wright EC, Everson GT, Lindsay KL, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology. 2007;132:103–12.PubMedCrossRef

66.

McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, et al. Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. N Engl J Med. 2007;357:2227–36.PubMedCrossRef

67.

Kawaguchi T, Komori A, Seike M, Fujiyama S, Watanabe H, Tanaka M, et al. Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study. J Gastroenterol. 2012;47(12):1342–51.PubMedCentralPubMedCrossRef

68.

Elting LS, Rubenstein EB, Martin CG, Kurtin D, Rodriguez S, Laiho E, et al. Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia. J Clin Oncol. 2001;19:1137–46.PubMed

69.

Natale R, Charu V, Schuette W, Albert I, Tehenes S, McCoy J, et al. Safety of romiplostim for treatment of chemotherapy-induced thrombocytopenia (CIT) in patients with advanced non-small cell lung cancer (NSCLC). 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology; 2009 Sep 20–24; Berlin, GERMANY. EJC Supplement 2009; 7(2):574–574.

70.

Fanale M, Stiff P, Noonan K, McCoy J, Rutstein M, Moskowitz C. Safety of romiplostim for treatment of severe chemotherapy induced thrombocytopenia (CIT) in patients with lymphoma receiving multi-cycle chemotherapy: results from an open-label dose- and schedule-finding study. 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology; 2009 Sep 20-24; Berlin, GERMANY. EJC Supplement, 2009; 7(2):563–563.

71.

Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C. Mostafa Kamel Y. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010;26(10):2339–46.PubMedCrossRef

72.

Alkaabi JK, Alkindi S, Riyami NA, Zia F, Balla LM, Balla SM. Successful treatment of severe thrombocytopenia with romiplostim in a pregnant patient with systemic lupus erythematosus. Lupus. 2012;21(14):1571–4.PubMedCrossRef

73.

Voican CS, Naveau S, Perlemuter G. Successful antiviral therapy for hepatitis C virus-induced cirrhosis after an increase in the platelet count with romiplostim: two case reports. Eur J Gastroenterol Hepatol. 2012;24(12):1455–8.PubMedCrossRef

74.

Cela I, Miller IJ, Katz RS, Rizman A, Shammo JM. Successful treatment of amegakaryocytic thrombocytopenia with eltrombopag in a patient with systemic lupus erythematosus (SLE). Clin Adv Hematol Oncol. 2010;8(11):806–9.PubMed

75.

Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al. Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia. N Engl J Med. 2012;367(1):11–9.PubMedCentralPubMedCrossRef

76.

Lin B, Renshaw MW, Autote K, Smith LM, Calveley P, Bowdish KS, et al. A step-wise approach significantly enhances protein yield of a rationally-designed agonist antibody fragment in E. coli. Protein Expr Purif. 2008;59(1):55–63.PubMedCrossRef

77.

Frederickson S, Renshaw MW, Lin B, Smith LM, Calveley P, Springhorn JP, et al. A rationally designed agonist antibody fragment that functionally mimics thrombopoietin. Proc Natl Acad Sci USA. 2006;103:14307–12.PubMedCentralPubMedCrossRef

78.

Cerneus D, Brown K, Harris R, End D, Molloy C, Yurkow E, et al. Stimulation of platelet production in healthy volunteers by a novel pegylated peptide-based thrombopoietin (TPO) receptor agonist. 47th Annual Meeting of the American-Society-of-Hematology; 2005 Dec 10-13; Atlanta, GA. Blood. 2005;106(11):363A–4A.

79.

Samtani MN, Perez-Ruixo JJ, Brown KH, Cerneus D, Molloy CJ. Pharmacokinetic and pharmacodynamic modeling of pegylated thrombopoietin mimetic peptide (PEG-TPOm) after single intravenous dose administration in healthy subjects. J Clin Pharmacol. 2009;49:336–50.PubMedCrossRef

80.

Suzuki K, Abe M, Fukushima-Shintani M, Sugasawa K, Hirayama F, Kawasaki T, et al. YM477, a novel orally-active thrombopoietin receptor agonist. 47th Annual Meeting of the American-Society-of-Hematology; 2005 Dec 10–13; Atlanta, GA. Blood. 2005;106(11):647A–647A.

81.

Fukushima-Shintani M, Suzuki K, Iwatsuki Y, Abe M, Sugasawa K, Hirayama F, et al. AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis. Exp Hematol. 2008;36:1337–42.PubMedCrossRef

82.

Desjardins RE, Tempel DL, Lucek R, Kuter DJ. Single and multiple oral doses of AKR-501 (TM477) increase the platelet count in healthy volunteers. 48th Annual Meeting of the American-Society-of-Hematology; 2006 Dec 09–12; Orlando FL. Blood. 2006;108(11):145A–145A.

83.

Bussel JB, Zhang J, Tang S, McIntosh J, Kater DJ. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial on the Efficacy, Safety and Tolerability of E5501 (AKR501) In Subjects with Chronic Immune Thrombocytopenia (ITP). 52nd Annual Meeting of the American-Society-of-Hematology (ASH); 2010 Dec 04-07; Orlando, FL.Blood 2010:116:38–38.

84.

Bussel JB, Zhang J, Tang S, McIntosh J, Kater DJ. Efficacy, Safety and Tolerability of E5501 (AKR501) In a 6-Month Extension Study In Subjects with Chronic Immune Thrombocytopenia (ITP). 52nd Annual Meeting of the American-Society-of-Hematology (ASH); 2010 Dec 04–07; Orlando, FL. Blood 2010; 116(21):1516–1516.

85.

Fox NE, Lim J, Chen R, Geddis AE. F104S c-Mpl responds to a transmembrane domain-binding thrombopoietin receptor agonist: proof of concept that selected receptor mutations in congenital amegakaryocytic thrombocytopenia can be stimulated with alternative thrombopoietic agents. Exp Hematol. 2010;38:384–91.PubMedCentralPubMedCrossRef

86.

Dziewanowska ZE, Matsumoto RM, Zhang JK, Schindler K, Loewen G, Doherty JP, et al. Single and multiple oral doses of LGD-4665, a small molecule thrombopoietin receptor agonist, increase platelet counts in healthy male subjects. 49th Annual Meeting of the American-Society-of-Hematology; 2007 Dec 08–11; Atlanta, GA. Blood 2007; 110(11): 390A.

87.

Kai M, Motoki K, Yoshida H, Emuta C, Chisaka Y, Tsuruhata K, et al. Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor. Nat Biotechnol. 2008;26:209–11.PubMedCrossRef

88.

Sanz MA, Aledort L, Mathias SD, Wang X, Isitt JJ. Analysis of EQ-5D scores from two phase 3 clinical trials of romiplostim in the treatment of immune thrombocytopenia (ITP). Value Health. 2011;14(1):90–6.PubMedCrossRef

89.

Dranitsaris G, Tsang P. Eltrombopag or intravenous immunoglobulin as a bridge to splenectomy in adults with chronic idiopathic thrombocytopenic purpura: a canadian economic analysis (abstracts). Clin Lymphoma Myeloma Leuk. 2010;10(3):E26–E26.CrossRef

90.

Vorobyev PA, Krasnova L, Borisenko O. Clinical and Economic Analysis of Eltrombopag in Chronic Idiopathic Thrombocytopenic Purpura in Context of Russian Health Care System. Value in Health 2011.A416.

91.

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):2161–71.PubMedCrossRef

92.

Nakazato T, Ito C, Mihara A, Aisa Y. Successful treatment of eltrombopag-resistant refractory immune thrombocytopenia with romiplostim. Int J Hematol. 2013;97(2):291–3.PubMedCrossRef

Title: The pharmacology and clinical application of thrombopoietin receptor agonists
Authors: Caizheng Li
Li Zheng
Publication date: 01-12-2014
Publisher: Springer Japan
Published in: International Journal of Hematology / Issue 6/2014
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-014-1660-5

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