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Thrombopoietin Receptor Agonists



The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts.  Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, caused by induction of anti-thrombopoietin antibodies.  For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches to activating the thrombopoietin receptor were sought.

Two thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and other thrombocytopenic conditions.  Eltrombopag is a peptide-like, small molecular weight agonist of the thrombopoietin receptor, which is orally available and results in significant increases in platelet counts in normal persons as well as patients with ITP.  Romiplostim, in contrast, is a recombinant polypeptide that binds to and activates the thrombopoietin receptor despite having no amino acid homology to native thrombopoietin.  It also increases platelet counts in normal subjects as well as patients with chronic ITP and has not been associated with induction of anti-thrombopoietin antibodies.





Eltrombopag (el trom' boe pag) is a small molecular weight peptide-like molecule that binds to the transmembrane domain of the thrombopoietin receptor and causes its activation and the proliferation and differentiation of megakaryocytes, with a resultant increase in synthesis and release of platelets.  In multiple clinical trials, eltrombopag was shown to raise the platelet count in patients with idiopathic thrombocytopenic purpura (ITP), aplastic anemia and cirrhosis due to chronic hepatitis C during interferon therapy.  Eltrombopag was approved for use in ITP in the United States in 2008 and indications have subsequently been expanded to other thrombocytopenic conditions.  Eltrombopag is available as tablets of 12.5, 25, 50, 75 and 100 mg under the brand name Promacta.  The typical dose is 25 to 50 mg once daily by mouth.  The most common side effects include nausea, diarrhea, fatigue, muscle aches, headaches and dizziness.  Rare, but potentially serious adverse reactions include vascular occlusions, stroke and myocardial infarction.



In clinical trials in patients with ITP, ALT elevations occurred in 10% to 11% of eltrombopag vs 3% to 7% of placebo treated subjects, but the elevations were usually mild and transient, resolving once eltrombopag was discontinued and sometimes even with continued use.  Instances in which there was recurrence of serum enzyme elevations with restarting eltrombopag have been reported and several patients were said to have developed serious liver disease on treatment, perhaps as a result of portal vein thrombosis.  Because of such reports, eltrombopag has a boxed warning about hepatotoxicity and the possibility of hepatic decompensation when treating patients with chronic hepatitis C, in which situation monitoring of liver tests is recommended.  Despite this, there have been no published reports of idiosyncratic clinically apparent liver injury attributable to eltrombopag therapy in the medical literature and the clinical characteristics, timing on onset, pattern of enzyme elevations and response to withdrawal of therapy of the liver injury attributed to the drug have not been described. 


Likelihood score: E* (suspected, but unproven cause of clinically apparent liver injury).


Mechanism of Injury

A mechanism of injury that might lead to serum enzyme elevations during eltrombopag therapy is not known.  The thrombosis induced by thrombopoietin receptor agonists might cause a hypercoagulable state resulting in portal vein or hepatic vein thrombosis.  Eltrombopag is metabolized in the liver, largely by the cytochrome P450 system (CYP 1A2, 2C8) and by the uridine diphosphate glucuronosyltransferase transport system (UGT1A1 and 1A3) and can have significant drug-drug interactions, particularly with statins.  Eltrombopag should also be taken on an empty stomach at least 1 hour before and 2 hours after a meal.


Outcome and Management

Serum aminotransferase elevations above 3 times the upper limit of normal (if confirmed and persistent) during eltrombopag therapy should lead to dose reduction or temporary cessation.  Enzyme elevations accompanied by jaundice or symptoms should lead to immediate discontinuation.  Eltrombopag has not been implicated in cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome, but has been linked to clinical worsening or decompensation in patients with cirrhosis due to hepatitis C.  For this reason, testing for serum aminotransferase and bilirubin levels is recommended before starting eltrombopag and monitoring for changes if symptoms or signs of liver injury arise.  There is no reason to suspect any degree of cross sensitivity in risk for hepatic injury among the various thrombopoietin receptor agonists or other hematologic growth factors.




Romiplostim (roe" mi ploe' stim) is a recombinant fusion protein consisting of four linear 14 amino acid peptides fused to the Fc fragment of the human IgG1 heavy chain that binds to the thrombopoietin receptor, despite lack of homology with native thrombopoietin.  The fusion polypeptide has a prolonged half-life, but must be administered parenterally.  In several clinical trials, romiplostim was shown to raise platelet counts in patients with chronic ITP without inducing anti-thrombopoietin antibodies.  Romiplostim was approved for use in ITP in the United States in 2008 and indications have subsequently been expanded to other thrombocytopenic conditions.  Romiplostim is available as a solution in vials of 250 and 500 mcg/mL.  The typical initial dose is 1 mcg/kg weekly by subcutaneous injection, which can be increased to a maximum of 10 mcg/kg based upon tolerance and effect.  The most common side effects include nausea, diarrhea, fatigue, muscle aches, headaches and dizziness.  Rare, but potentially serious adverse reactions include vascular occlusions, stroke and myocardial infarction.



In clinical trials in patients with ITP, romiplostim was not linked to ALT elevations or to episodes of clinically apparent liver injury.  Since its approval and more widespread use, romiplostim has not been linked to cases of hepatic injury. 


Likelihood score: E (unlikely cause of clinically apparent liver injury).


Mechanism of Injury

A mechanism of injury by which romiplostim might cause liver injury is not known.  It is a recombinant polypeptide and is likely metabolized by many tissues including the cells on which it acts.  Romiplostim has not been linked to serious drug-drug interactions.


Outcome and Management

Romiplostim has not been implicated in cases of clinically apparent liver injury, liver failure or chronic hepatitis.  Patients who have developed serum enzyme elevations during treatment with eltrombopag have been successfully and safety switched to romiplostim therapy.


Drug Class:  Hematologic Growth Factors


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Thrombopoietin Receptor Agonists


Eltrombopag – Promacta®
Romiplostim – Nplate®


Hematologic Growth Factors



Product labeling at DailyMed, National Library of Medicine, NIH


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Thrombopoietin Receptor Agonists
Eltrombopag 496775-61-2 C25-H22-N4-O4 Image of Nintedanib Chemical Structure
Romiplostim 267639-76-9 Protein Not Available
Thrombopoietin 9014-42-0 Protein Not Available

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Thrombopoietin Receptor Agonists


References updated: 10 February 2018    

Abbreviations:  ITP, idiopathic thrombocytopenic purpura. 

  1. Zimmerman HJ. Hormonal derivatives and related drugs. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp 555-88.  (Review of hepatotoxicity published in 1999; the hematologic growth factors are not specifically mentioned).

  2. Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.  (Textbook on hepatotoxicity; hematologic growth factors are not discussed).

  3. Kaushansky K, Kipps TJ. Hematopoietic agents: growth factors, minerals and vitamins. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1067-99.  (Textbook of pharmacology and therapeutics).

  4. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001; 98: 3241-8. PubMed Citation  (Analysis of 3 subjects who developed thrombocytopenia [<10,000] after 2 to 28 injections of a commercial pegylated recombinant thrombopoietin; identified antibodies to thrombopoietin as the probable cause).

  5. Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: double-blind randomised controlled trial. Lancet 2008; 371: 395-403. PubMed Citation  (Among 125 patients with ITP treated with standard of case or romiplostim for 24 weeks, side effects more common with the drug included dizziness, insomnia, abdominal and muscle pain; no mention of ALT elevations or hepatotoxicity).

  6. 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. PubMed Citation  (Among 142 patients with chronic ITP who were treated with romiplostim for up to 3 years, platelet count responses [>50,000] occurred in 87%, but there were 5 serious thrombotic events including one case of portal vein thrombosis).

  7. Two new drugs for chronic ITP. Med Lett Drugs Ther 2009; 51 (1305): 10-1. PubMed Citation  (Concise review of the mechanism of action, clinical efficacy, safety and costs of romiplostim and eltrombopag after their approval for use in ITP in the US mentions that liver function test abnormalities occurred in 10% of eltrombopag treated vs 8% of placebo treated patients, and that one developed “grade 4 liver function test abnormalities and died”).

  8. Kuter DJ, Rummel M, Boccia R, Macik BG, Pabinger I, Selleslag D, Rodeghiero F, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010; 363: 1889-99. PubMed Citation  (Among 234 adults with ITP treated with standard of care or romiplostim, bleeding episodes as well as need for splenectomy and blood transfusions were lower in romiplostim treated subjects; one patient receiving standard of care died of hepatic failure; no mention of ALT elevations or hepatotoxicity).

  9. Kuter DJ. Biology and chemistry of thrombopoietic agents. Semin Hematol 2010 Jul; 47 (3): 243-8. PubMed Citation  (Review of the structure and mechanism of action of thrombopoietin and the development of two mimetic drugs [eltrombopag and romiplostim] for use in chronic ITP).

  10. Khellaf M, Michel M, Quittet P, Viallard JF, Alexis M, Roudot-Thoraval F, Cheze S, et al. Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program. Blood 2011; 118: 4338-45. PubMed Citation  (Among 72 patients with ITP treated with romiplostim for at least 2 years, long term platelet response occurred in 65% of patients and common side effects were arthralgias, fatigue and nausea; no mention of ALT elevations or hepatotoxicity).

  11. Cooper N, Terrinoni I, Newland A. The efficacy and safety of romiplostim in adult patients with chronic immune thrombocytopenia. Ther Adv Hematol 2012; 3: 291-8. PubMed Citation  (Review of the efficacy and safety of romiplostim in treatment of adults with ITP; no mention of ALT elevations or hepatotoxicity).

  12. Cheng G. Eltrombopag, a thrombopoietin- receptor agonist in the treatment of adult chronic immune thrombocytopenia: a review of the efficacy and safety profile. Ther Adv Hematol 2012; 3: 155-64. PubMed Citation  (Review of the efficacy and safety of eltrombopag based upon 5 prospective trials in ITP, reported serum ALT elevations in 10% of eltrombopag vs 3% of placebo recipients, but elevations were usually asymptomatic and transient, often resolving spontaneously; no episodes of serious clinically apparent liver injury).

  13. Tsukamoto S, Nakaseko C, Takeuchi M, Kumagai K, Komatsu T, Tanaka H, Hara S, et al. Safety and efficacy of romiplostim in patients with eltrombopag-resistant or -intolerant immune thrombocytopenia. Br J Haematol 2013; 163: 286-9. PubMed Citation  (Among 3 patients with ITP who developed ALT elevations during eltrombopag therapy and who were switched to romiplostim, the liver dysfunction resolved in all).

  14. Kuter DJ, Bussel JB, Newland A, Baker RI, Lyons RM, Wasser J, Viallard JF, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol 2013; 161: 411-23. PubMed Citation  (Among 292 patients with ITP treated with romiplostim for up to 5 years, thrombotic events occurred in 6.5% including one case of portal vein thrombosis, whose platelet count was 473,000 three days before the event).

  15. Rodeghiero F, Stasi R, Giagounidis A, Viallard JF, Godeau B, Pabinger I, Cines D, et al. Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials. Eur J Haematol 2013; 91 (5): 423-36. PubMed Citation  (A pooled analysis of long term studies of romiplostim in 653 patients with ITP reported that thrombotic events occurred in 6% on romiplostim and 3.6% on placebo; no mention of ALT elevations or clinically apparent liver injury).

  16. Kuter DJ. Milestones in understanding platelet production: a historical overview. Br J Haematol 2014; 165: 248-58. PubMed Citation  (History of the development of agents to increase platelet counts focusing upon eltrombopag and romiplostim).

  17. Hitchcock IS, Kaushansky K. Thrombopoietin from beginning to end. Br J Haematol 2014; 165: 259-68. PubMed Citation  (History of discovery of thrombopoietin and evolution of knowledge about its mechanism of action and development of drugs that activate its receptor).

  18. Prica A, Sholzberg M, Buckstein R. Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials. Br J Haematol 2014; 167: 626-38. PubMed Citation  (Systematic review identified 5 trials of thrombopoietin receptor agonists in 384 patients with myelodysplastic syndromes; no discussion or mention of ALT elevations or hepatotoxicity in review of safety).

  19. Kim YK, Lee SS, Jeong SH, Ahn JS, Yang DH, Lee JJ, Kim HJ. Efficacy and safety of eltrombopag in adult refractory immune thrombocytopenia. Blood Res 2015; 50: 19-25. PubMed Citation  (Among 18 Korean patients with refractory ITP treated with eltrombopag, ALT elevations occurred in 5 and were greater than 5 times ULN in 2, but none required drug discontinuation or developed clinically apparent liver injury).

  20. Platzbecker U, Wong RS, Verma A, Abboud C, Araujo S, Chiou TJ, Feigert J, et al. Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol 2015: e417-26. PubMed Citation  (Among 98 patients with low platelet counts due to myelodysplastic syndromes treated with eltrombopag vs placebo, ALT elevations occurred in 9% of treated subjects, but only 1 was above 5 times ULN).

  21. Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, Sosothikul D, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial.  Lancet 2015; 386 (10004): 1649-58. PubMed Citation  (Among 92 children with chronic ITP treated with eltrombopag or placebo for 13 weeks, adverse events included AST elevations in 6% vs 0%, but only 1 patient had elevations above 5 times ULN).

  22. Cines DB, Gernsheimer T, Wasser J, Godeau B, Provan D, Lyons R, Altomare I, et al. Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim. Int J Hematol 2015; 102: 259-70. PubMed Citation  (Pooled analysis of 1059 patients in 14 trials of romiplostim  mentions that common side effects were headache and epistaxis and serious adverse events include thromboses and bleeding including 4 cases of portal vein thrombosis; but there were no liver related serious adverse events or deaths).

  23. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to eltrombopag or romiplostim).

  24. Vishnu P, Aboulafia DM. Long-term safety and efficacy of romiplostim for treatment of immune thrombocytopenia. J Blood Med 2016; 7: 99-106. PubMed Citation  (Review of long term safety of romiplostim discusses common symptoms of headache, fatigue, epistaxis and arthralgia, but does not mention ALT elevations or hepatotoxicity).

  25. Zaja F, Barcellini W, Cantoni S, Carpenedo M, Caparrotti G, Carrai V, Di Renzo N, et al. Thrombopoietin receptor agonists for preparing adult patients with immune thrombocytopenia to splenectomy: results of a retrospective, observational GIMEMA study. Am J Hematol 2016; 91: E293-5. PubMed Citation  (Among 31 patients with ITP treated with eltrombopag [n=7] or romiplostim [n=24] in preparation of surgery, platelet counts rose from a mean of 11,000 to 114,000/uL, and 29 underwent splenectomy, one developing portal vein thrombosis and one pulmonary embolus).

  26. Kurokawa T, Murata S, Ohkohchi N. Stable liver function during long-term administration of eltrombopag, a thrombopoietin receptor agonist, in patients with chronic liver disease. Tohoku J Exp Med 2016; 240: 277-9. PubMed Citation  (Among 5 patients with chronic liver disease and thrombocytopenia treated with eltrombopag for 6 months, all had improvements in platelet counts without worsening of ALT or bilirubin levels).

  27. González-López TJ, Fernández-Fuertes F, Hernández-Rivas JA, Sánchez-González B, Martínez-Robles V, Alvarez-Román MT, Pérez-Rus G, et al. Efficacy and safety of eltrombopag in persistent and newly diagnosed ITP in clinical practice. Int J Hematol 2017; 106: 508-16. PubMed Citation  (Among 220 Spanish adults with ITP treated with eltrombopag for up to 15 months, clinical responses occurred in 80% and 10 [5%] had serum enzyme elevations, all of which resolved on dose modification or discontinuation and none were accompanied by symptoms or jaundice).

  28. Hwang YY, Gill H, Chan TSY, Leung GMK, Cheung CYM, Kwong YL. Eltrombopag in the management of aplastic anaemia: real-world experience in a non-trial setting. Hematology 2018 Jan 5:1-6. PubMed Citation  (Among 20 patients with aplastic anemia treated with eltrombopag, 90% had an objective response, but all also had skin discoloration; no mention of ALT elevations or hepatotoxicity).

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Thrombopoietin Receptor Agonists
  1. PubMed logoRecent References on Thrombopoietin Receptor Agonists

  2. Clinical Trials logoTrials on Thrombopoietin Receptor Agonists

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