Annals of Hematology

, Volume 98, Issue 3, pp 581–588 | Cite as

Platelet aggregation response in immune thrombocytopenia patients treated with romiplostim

  • Hanny Al-SamkariEmail author
  • Elizabeth M. Van Cott
  • David J. Kuter
Original Article


The thrombopoietin receptor agonist romiplostim is used for the long-term treatment of chronic immune thrombocytopenia (ITP). ITP patients have an increased thrombotic risk, which could be exacerbated if romiplostim increased platelet hyperreactivity or caused spontaneous platelet aggregation. To investigate this possibility, this study examined platelet function in romiplostim-treated ITP patients and healthy subjects. Light transmission platelet aggregometry utilizing arachidonic acid, collagen, epinephrine, ristocetin, ADP, and saline (to assess spontaneous aggregation) was performed for each subject. In addition, the ADP AC50 (ADP concentration that induced half-maximal aggregation) was determined for each patient as a sensitive measurement of altered platelet reactivity. Fifteen ITP patients and 7 healthy subjects entered the study. All ITP patients had active disease and were receiving weekly romiplostim as the sole ITP-directed therapy. Platelet aggregation in response to the strong agonists arachidonic acid, collagen, and ristocetin was not significantly different between ITP patients and healthy subjects (P = 0.2442, P = 0.0548, and P = 0.0879, respectively). Platelet aggregation in response to weak agonists was significantly reduced in ITP patients compared with that in healthy subjects: median (range) aggregation to ADP, 45% (15–84%) versus 89% (70–95%) (P = 0.0010), and epinephrine, 21% (1.6–90%) versus 88% (79–94%) (P = 0.0085). The median AC50 of ADP was threefold higher in ITP patients versus that in healthy subjects (6.3 μM vs 2.1 μM) (P = 0.0049). Significant spontaneous aggregation was not observed in any patient. Platelets from romiplostim-treated ITP patients do not show evidence for spontaneous aggregation or hyperreactivity, but instead have a modestly reduced aggregation response to ADP and epinephrine.


Platelet aggregation Immune thrombocytopenia ITP Romiplostim Thrombosis Thrombopoietin receptor agonist Platelet function testing 


Author contributions

H. Al-Samkari analyzed data, created tables and figures, and wrote and revised the manuscript; E. Van Cott analyzed data, wrote a portion of the “Materials and methods” section of the manuscript, and critically revised the manuscript; D. Kuter designed the study, collected and analyzed data, created tables and figures, critically revised the manuscript, and supervised the study.


This study was funded by an unrestricted grant from Amgen, Inc. for performance of platelet aggregation studies (contract number 200712852).

Compliance with ethical standards

Conflict of interest

H. Al-Samkari has a consultancy with Agios. E. Van Cott declares she has no conflict of interest. D. Kuter has received research funding from the following: Protalex, Bristol-Myers Squibb, Rigel, Bioverativ, Agios, Syntimmune, Principia, Alnylam; consultancy with the following: ONO, Pfizer, 3SBios, Eisai, GlaxoSmithKline, Genzyme, Shire, Amgen, Shionogi, Rigel, Syntimmune, MedImmune, Novartis, Bioverativ, Argenx, Zafgen; and does paid expert testimony for Amgen and CRICO.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

277_2018_3556_MOESM1_ESM.docx (18 kb)
ESM 1 (DOCX 18 kb)


  1. 1.
    Kuter DJ, Rummel M, Boccia R, Macik BG, Pabinger I, Selleslag D, Rodeghiero F, Chong BH, Wang X, Berger DP (2010) Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 363(20):1889–1899. CrossRefGoogle Scholar
  2. 2.
    Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB (2011) Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 377(9763):393–402. CrossRefGoogle Scholar
  3. 3.
    Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, Parikh AR, Broder K, Calvo KR, Wu CO, Young NS, Dunbar CE (2014) Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood 123(12):1818–1825. CrossRefGoogle Scholar
  4. 4.
    Afdhal N, Duggal A, Ochiai T, Motomiya T, Kano T, Nagata T, Peck-Radosavlejic M (2017) Platelet response to lusutrombopag, a thrombopoietin receptor agonist, in patients with chronic liver disease and thrombocytopenia undergoing non-emergency invasive procedures: results form a phase 3 randomized, double-blind, placebo-controlled study. Blood 130:291 (Abstract)Google Scholar
  5. 5.
    Terrault N, Kuter DJ, Isumi N, Kayali Z, Mitrut P, Tak WY, Bibbiani F (2017) Superiority of avatrombopag to placebo in increasing platelet counts in patients with chronic liver disease-associated thrombocytopenia undergoing scheduled procedures: results from 2, phase 3 randomized studies. Blood 130:18 (Abstract)Google Scholar
  6. 6.
    Afdhal NH, Dusheiko GM, Giannini EG, Chen PJ, Han KH, Mohsin A, Rodriguez-Torres M, Rugina S, Bakulin I, Lawitz E, Shiffman ML, Tayyab GU, Poordad F, Kamel YM, Brainsky A, Geib J, Vasey SY, Patwardhan R, Campbell FM, Theodore D (2014) Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy. Gastroenterology 146(2):442–452 e441. CrossRefGoogle Scholar
  7. 7.
    Al-Samkari H, Marshall AL, Goodarzi K, Kuter DJ (2018) The use of romiplostim in treating chemotherapy-induced thrombocytopenia in patients with solid tumors. Haematologica 103(4):e169–e172. CrossRefGoogle Scholar
  8. 8.
    Al-Samkari H, Marshall AL, Goodarzi K, Kuter DJ (2018) Romiplostim for the management of perioperative thrombocytopenia. Br J Haematol 182(1):106–113. CrossRefGoogle Scholar
  9. 9.
    Al-Samkari H, Kuter DJ (2018) Relative potency of the thrombopoietin receptor agonists eltrombopag, avatrombopag and romiplostim in a patient with chronic immune thrombocytopenia. Br J Haematol 183:168. CrossRefGoogle Scholar
  10. 10.
    Al-Samkari H, Kuter DJ (2018) Thrombopoietin level predicts response to treatment with eltrombopag and romiplostim in immune thrombocytopenia. Am J Hematol 93(12):1501–1508. CrossRefGoogle Scholar
  11. 11.
    Kuter DJ (2011) Romiplostim. Cancer Treat Res 157:267–288. CrossRefGoogle Scholar
  12. 12.
    Debili N, Wendling F, Cosman D, Titeux M, Florindo C, Dusanter-Fourt I, Schooley K, Methia N, Charon M, Nador R et al (1995) The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood 85(2):391–401Google Scholar
  13. 13.
    Peng J, Friese P, Wolf RF, Harrison P, Downs T, Lok S, Dale GL, Burstein SA (1996) Relative reactivity of platelets from thrombopoietin- and interleukin-6-treated dogs. Blood 87(10):4158–4163Google Scholar
  14. 14.
    Harker LA, Hunt P, Marzec UM, Kelly AB, Tomer A, Hanson SR, Stead RB (1996) Regulation of platelet production and function by megakaryocyte growth and development factor in nonhuman primates. Blood 87(5):1833–1844Google Scholar
  15. 15.
    Harker LA, Marzec UM, Hunt P, Kelly AB, Tomer A, Cheung E, Hanson SR, Stead RB (1996) Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. Blood 88(2):511–521Google Scholar
  16. 16.
    Sarpatwari A, Bennett D, Logie JW, Shukla A, Beach KJ, Newland AC, Sanderson S, Provan D (2010) Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica 95(7):1167–1175. CrossRefGoogle Scholar
  17. 17.
    Severinsen MT, Engebjerg MC, Farkas DK, Jensen AO, Norgaard M, Zhao S, Sorensen HT (2011) Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol 152(3):360–362. CrossRefGoogle Scholar
  18. 18.
    Langeberg WJ, Schoonen WM, Eisen M, Gamelin L, Stryker S (2016) Thromboembolism in patients with immune thrombocytopenia (ITP): a meta-analysis of observational studies. Int J Hematol 103(6):655–664. CrossRefGoogle Scholar
  19. 19.
    Fontana V, Jy W, Ahn ER, Dudkiewicz P, Horstman LL, Duncan R, Ahn YS (2008) Increased procoagulant cell-derived microparticles (C-MP) in splenectomized patients with ITP. Thromb Res 122(5):599–603. CrossRefGoogle Scholar
  20. 20.
    Middelburg RA, Carbaat-Ham JC, Hesam H, Ragusi MA, Zwaginga JJ (2016) Platelet function in adult ITP patients can be either increased or decreased, compared to healthy controls, and is associated with bleeding risk. Hematology 21(9):549–551. CrossRefGoogle Scholar
  21. 21.
    Frelinger AL 3rd, Grace RF, Gerrits AJ, Berny-Lang MA, Brown T, Carmichael SL, Neufeld EJ, Michelson AD (2015) Platelet function tests, independent of platelet count, are associated with bleeding severity in ITP. Blood 126(7):873–879. CrossRefGoogle Scholar
  22. 22.
    Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL (2009) Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 113(10):2161–2171CrossRefGoogle Scholar
  23. 23.
    Cines DB, Gernsheimer T, Wasser J, Godeau B, Provan D, Lyons R, Altomare I, Wang X, Lopez A (2015) Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim. Int J Hematol 102(3):259–270. CrossRefGoogle Scholar
  24. 24.
    Afdhal NH, Giannini EG, Tayyab G, Mohsin A, Lee JW, Andriulli A, Jeffers L, McHutchison J, Chen PJ, Han KH, Campbell F, Hyde D, Brainsky A, Theodore D, Group ES (2012) Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 367(8):716–724. CrossRefGoogle Scholar
  25. 25.
    Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, American Society of H (2011) The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 117(16):4190–4207. CrossRefGoogle Scholar
  26. 26.
    Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kuhne T, Ruggeri M, George JN (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113(11):2386–2393. CrossRefGoogle Scholar
  27. 27.
    Panzer S, Hocker L, Rieger M, Vormittag R, Koren D, Dunkler D, Pabinger I (2007) Agonist-inducible platelet activation in chronic idiopathic autoimmune thrombocytopenia. Eur J Haematol 79(3):198–204. CrossRefGoogle Scholar
  28. 28.
    Yanabu M, Suzuki M, Soga T, Sone N, Nagata H, Nomura S, Kokawa T, Yasunaga K (1991) Influences of antiplatelet autoantibodies on platelet function in immune thrombocytopenic purpura. Eur J Haematol 46(2):101–106CrossRefGoogle Scholar
  29. 29.
    Cattaneo M, Cerletti C, Harrison P, Hayward CP, Kenny D, Nugent D, Nurden P, Rao AK, Schmaier AH, Watson SP, Lussana F, Pugliano MT, Michelson AD (2013) Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the Platelet Physiology Subcommittee of SSC/ISTH. J Thromb Haemost 11:1183–1189. CrossRefGoogle Scholar
  30. 30.
    Clancy R, Jenkins E, Firkin B (1972) Qualitative platelet abnormalities in idiopathic thrombocytopenic purpura. N Engl J Med 286(12):622–626. CrossRefGoogle Scholar
  31. 31.
    Olsson A, Andersson PO, Tengborn L, Wadenvik H (2002) Serum from patients with chronic idiopathic thrombocytopenic purpura frequently affect the platelet function. Thromb Res 107(3–4):135–139CrossRefGoogle Scholar
  32. 32.
    Heyns AD, Fraser J, Retief FP (1978) Platelet aggregation in chronic idiopathic thrombocytopenic purpura. J Clin Pathol 31(12):1239–1243CrossRefGoogle Scholar
  33. 33.
    Erhardt JA, Erickson-Miller CL, Aivado M, Abboud M, Pillarisetti K, Toomey JR (2009) Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol 37(9):1030–1037. CrossRefGoogle Scholar
  34. 34.
    Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, Erickson-Miller CL (2007) Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood 109(11):4739–4741. CrossRefGoogle Scholar
  35. 35.
    Psaila B, Bussel JB, Linden MD, Babula B, Li Y, Barnard MR, Tate C, Mathur K, Frelinger AL, Michelson AD (2012) In vivo effects of eltrombopag on platelet function in immune thrombocytopenia: no evidence of platelet activation. Blood 119(17):4066–4072. CrossRefGoogle Scholar
  36. 36.
    Suntsova EV, Demina IM, Ignatova AA, Ershov NM, Trubina NM, Dobrynina J, Serkova IV, Supik ZS, Orekhova EV, Hachatryan LA, Kotskaya NN, Pshonkin AV, Maschan AA, Novichkova GA, Panteleev MA (2017) Bleeding tendency and platelet function during treatment with romiplostim in children with severe immune thrombocytopenic purpura. Int J Hematol 105(6):841–848. CrossRefGoogle Scholar
  37. 37.
    U.S. FDA (2017) Nplate (romiplostim) [prescribing information]. Amgen, Thousand OaksGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Hematology, Massachusetts General Hospital, Zero Emerson PlaceHarvard Medical SchoolBostonUSA
  2. 2.Department of Pathology, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations