Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:

Subscribers log in here

Chronic refractory immune thrombocytopenia (ITP) in adults


Although immune thrombocytopenia (ITP, previously called idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura) is an acute, self-limited disease in the vast majority of children, it often relapses in adults following initial treatment with glucocorticoids, requiring additional treatment. (See "Treatment and prognosis of immune thrombocytopenia (ITP) in adults", section on 'Natural history'.)

Chronic refractory ITP is not common. A review of six case series suggested that less than 10 percent of adult patients initially diagnosed with ITP may eventually be considered to be refractory and require further treatment following failure of splenectomy [1].

The treatment of patients with chronic refractory ITP, defined here as a failure to respond to both splenectomy and rituximab, will be discussed here. Accordingly, the use of splenectomy and rituximab in the treatment of ITP is discussed elsewhere. (See "Treatment and prognosis of immune thrombocytopenia (ITP) in adults", section on 'Splenectomy' and "Treatment and prognosis of immune thrombocytopenia (ITP) in adults", section on 'Rituximab'.)

The clinical manifestations, diagnosis, and treatment of patients presenting with new-onset ITP are discussed separately. (See "Clinical manifestations and diagnosis of immune thrombocytopenia (ITP) in adults" and "Treatment and prognosis of immune thrombocytopenia (ITP) in adults".)

Treatment of the patient with acute, severe bleeding, in preparation for surgery, or settings in which a rapid increase in platelet count is required, is discussed separately. (See "Treatment and prognosis of immune thrombocytopenia (ITP) in adults", section on 'Life-threatening bleeding and surgery'.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Mar 2014. | This topic last updated: Nov 18, 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
  1. George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost 2006; 4:1664.
  2. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009; 113:2386.
  3. Vesely SK, Perdue JJ, Rizvi MA, et al. Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review. Ann Intern Med 2004; 140:112.
  4. European Scientific Working Group on Thrombocytopenias (Accessed on July 11, 2011).
  5. Psaila B, Bussel JB. Refractory immune thrombocytopenic purpura: current strategies for investigation and management. Br J Haematol 2008; 143:16.
  6. Zeng Y, Duan X, Xu J, Ni X. TPO receptor agonist for chronic idiopathic thrombocytopenic purpura. Cochrane Database Syst Rev 2011; :CD008235.
  7. Altomare I, Wasser J, Pullarkat V. Bleeding and mortality outcomes in ITP clinical trials: a review of thrombopoietin mimetics data. Am J Hematol 2012; 87:984.
  8. Toltl LJ, Arnold DM. Pathophysiology and management of chronic immune thrombocytopenia: focusing on what matters. Br J Haematol 2011; 152:52.
  9. George JN, Terrell DR. Novel thrombopoietic agents: a new era for management of patients with thrombocytopenia. Haematologica 2008; 93:1445.
  10. Kuter DJ, Mufti GJ, Bain BJ, et al. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood 2009; 114:3748.
  11. Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine 2004; 25:52.
  12. 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; 135:547.
  13. Molineux G, Newland A. Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: from bench to bedside. Br J Haematol 2010; 150:9.
  14. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006; 355:1672.
  15. 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; 371:395.
  16. 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; 144:409.
  17. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010; 363:1889.
  18. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009; 113:2161.
  19. Khellaf M, Michel M, Quittet P, 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.
  20. Ghanima W, Junker P, Hasselbalch HC, et al. Fibroproliferative activity in patients with immune thrombocytopenia (ITP) treated with thrombopoietic agents. Br J Haematol 2011; 155:248.
  21. Jamali F, Lemery S, Ayalew K, et al. Romiplostim for the treatment of chronic immune (idiopathic) thrombocytopenic purpura. Oncology (Williston Park) 2009; 23:704.
  22. Gernsheimer TB, George JN, Aledort LM, et al. Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP). J Thromb Haemost 2010; 8:1372.
  23. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007; 357:2237.
  24. 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; 373:641.
  25. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 2011; 377:393.
  26. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood 2013; 121:537.
  27. Dmytrijuk A, Robie-Suh K, Rieves D, Pazdur R. Eltrombopag for the treatment of chronic immune (idiopathic) thrombocytopenic purpura. Oncology (Williston Park) 2009; 23:1171.
  28. FDA safety summary available at (Accessed on July 11, 2011).
  29. Tomiyama Y, Miyakawa Y, Okamoto S, et al. A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia. J Thromb Haemost 2012; 10:799.
  30. Sperati CJ, Streiff MB. Acute renal failure in a patient with antiphospholipid syndrome and immune thrombocytopenic purpura treated with eltrombopag. Am J Hematol 2010; 85:724.
  31. Jansen AJ, Swart RM, te Boekhorst PA. Thrombopoietin-receptor agonists for immune thrombocytopenia. N Engl J Med 2011; 365:2240.
  32. Lacey JV, Penner JA. Management of idiopathic thrombocytopenic purpura in the adult. Semin Thromb Hemost 1977; 3:160.
  33. Slichter SJ, Harker LA. Thrombocytopenia: mechanisms and management of defects in platelet production. Clin Haematol 1978; 7:523.
  34. Wandt H, Frank M, Ehninger G, et al. Safety and cost effectiveness of a 10 x 10(9)/L trigger for prophylactic platelet transfusions compared with the traditional 20 x 10(9)/L trigger: a prospective comparative trial in 105 patients with acute myeloid leukemia. Blood 1998; 91:3601.
  35. Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood 2005; 106:2244.
  36. George JN, Kojouri K, Perdue JJ, Vesely SK. Management of patients with chronic, refractory idiopathic thrombocytopenic purpura. Semin Hematol 2000; 37:290.
  37. Provan D, Newland A. Fifty years of idiopathic thrombocytopenic purpura (ITP): management of refractory itp in adults. Br J Haematol 2002; 118:933.
  38. Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clin Proc 2004; 79:504.
  39. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115:168.
  40. 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; 88:3.
  41. McMillan R, Bussel JB, George JN, et al. Self-reported health-related quality of life in adults with chronic immune thrombocytopenic purpura. Am J Hematol 2008; 83:150.
  42. Mathias SD, Gao SK, Miller KL, et al. Impact of chronic Immune Thrombocytopenic Purpura (ITP) on health-related quality of life: a conceptual model starting with the patient perspective. Health Qual Life Outcomes 2008; 6:13.
  43. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001; 97:2549.
  44. Guidry JA, George JN, Vesely SK, et al. Corticosteroid side-effects and risk for bleeding in immune thrombocytopenic purpura: patient and hematologist perspectives. Eur J Haematol 2009; 83:175.
  45. van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002; 13:777.
  46. Zukerman E, Ingelfinger JR. Coping with Prednisone, St Martin's Press, New York 2007.
  47. Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med 1994; 330:1560.
  48. Demiroğlu H, Dündar S. High-dose pulsed dexamethasone for immune thrombocytopenia. N Engl J Med 1997; 337:425.
  49. Borst F, Keuning JJ, van Hulsteijn H, et al. High-dose dexamethasone as a first- and second-line treatment of idiopathic thrombocytopenic purpura in adults. Ann Hematol 2004; 83:764.
  50. Stasi R, Brunetti M, Pagano A, et al. Pulsed intravenous high-dose dexamethasone in adults with chronic idiopathic thrombocytopenic purpura. Blood Cells Mol Dis 2000; 26:582.
  51. Reiner A, Gernsheimer T, Slichter SJ. Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura. Blood 1995; 85:351.
  52. Quiquandon I, Fenaux P, Caulier MT, et al. Re-evaluation of the role of azathioprine in the treatment of adult chronic idiopathic thrombocytopenic purpura: a report on 53 cases. Br J Haematol 1990; 74:223.
  53. Verlin M, Laros RK Jr, Penner JA. Treatment of refractory thrombocytopenic purpura with cyclophosphamine. Am J Hematol 1976; 1:97.
  54. Zaja F, Marin L, Chiozzotto M, et al. Dapsone salvage therapy for adult patients with immune thrombocytopenia relapsed or refractory to steroid and rituximab. Am J Hematol 2012; 87:321.
  55. Rodrigo C, Gooneratne L. Dapsone for primary immune thrombocytopenia in adults and children: an evidence-based review. J Thromb Haemost 2013; 11:1946.
  56. Facon T, Caulier MT, Wattel E, et al. A randomized trial comparing vinblastine in slow infusion and by bolus i.v. injection in idiopathic thrombocytopenic purpura: a report on 42 patients. Br J Haematol 1994; 86:678.
  57. Shvidel L, Sigler E, Shtalrid M, Berrebi A. Vincristine-loaded platelet infusion for treatment of refractory autoimmune hemolytic anemia and chronic immune thrombocytopenia: rethinking old cures. Am J Hematol 2006; 81:423.
  58. George JN, el-Harake MA, Raskob GE. Chronic idiopathic thrombocytopenic purpura. N Engl J Med 1994; 331:1207.
  59. Figueroa M, Gehlsen J, Hammond D, et al. Combination chemotherapy in refractory immune thrombocytopenic purpura. N Engl J Med 1993; 328:1226.
  60. McMillan R. Long-term outcomes after treatment for refractory immune thrombocytopenic purpura. N Engl J Med 2001; 344:1402.
  61. Arnold DM, Nazi I, Santos A, et al. Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura. Blood 2010; 115:29.
  62. Ahn YS, Rocha R, Mylvaganam R, et al. Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women. Ann Intern Med 1989; 111:723.
  63. Maloisel F, Andrès E, Zimmer J, et al. Danazol therapy in patients with chronic idiopathic thrombocytopenic purpura: long-term results. Am J Med 2004; 116:590.
  64. Kappers-Klunne MC, van't Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy. Br J Haematol 2001; 114:121.
  65. Emilia G, Morselli M, Luppi M, et al. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood 2002; 99:1482.
  66. Perrotta S, Amendola G, Locatelli F, et al. Treatment with short-term, high-dose cyclosporin A in children with refractory chronic idiopathic thrombocytopenic purpura. Br J Haematol 2003; 121:143.
  67. Snyder HW Jr, Cochran SK, Balint JP Jr, et al. Experience with protein A-immunoadsorption in treatment-resistant adult immune thrombocytopenic purpura. Blood 1992; 79:2237.
  68. Willis F, Marsh JC, Bevan DH, et al. The effect of treatment with Campath-1H in patients with autoimmune cytopenias. Br J Haematol 2001; 114:891.
  69. Gómez-Almaguer D, Solano-Genesta M, Tarín-Arzaga L, et al. Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias. Blood 2010; 116:4783.
  70. 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; 73:135.
  71. Hou M, Peng J, Shi Y, et al. Mycophenolate mofetil (MMF) for the treatment of steroid-resistant idiopathic thrombocytopenic purpura. Eur J Haematol 2003; 70:353.
  72. Estrada-Gómez R, Vargas-Castro O, Oropeza-Borges M, et al. A single-institution, 20-year prospective experience with an affordable Fc-receptor blockade method to treat patients with chronic, refractory autoimmune thrombocytopenic purpura. Rev Invest Clin 2007; 59:424.
  73. Patel VL, Schwartz J, Bussel JB. The effect of anti-CD40 ligand in immune thrombocytopenic purpura. Br J Haematol 2008; 141:545.
  74. Podolanczuk A, Lazarus AH, Crow AR, et al. Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 2009; 113:3154.
  75. Altaf AM, Sawatzky M, Ellsmere J, et al. Laparoscopic accessory splenectomy: the value of perioperative localization studies. Surg Endosc 2009; 23:2675.
  76. Quah C, Ayiomamitis GD, Shah A, Ammori BJ. Computed tomography to detect accessory spleens before laparoscopic splenectomy: is it necessary? Surg Endosc 2011; 25:261.
  77. Bergeron E, Ratte S, Jeannotte S, Recoskie MJ. The use of a handheld gamma probe for identifying two accessory spleens in difficult locations in the same patient. Ann Nucl Med 2008; 22:331.
  78. Kirshtein B, Lantsberg S, Hatskelzon L, Lantsberg L. Laparoscopic accessory splenectomy using intraoperative gamma probe guidance. J Laparoendosc Adv Surg Tech A 2007; 17:205.
  79. Phom H, Kumar A, Tripathi M, et al. Comparative evaluation of Tc-99m-heat-denatured RBC and Tc-99m-anti-D IgG opsonized RBC spleen planar and SPECT scintigraphy in the detection of accessory spleen in postsplenectomy patients with chronic idiopathic thrombocytopenic purpura. Clin Nucl Med 2004; 29:403.
  80. Facon T, Caulier MT, Fenaux P, et al. Accessory spleen in recurrent chronic immune thrombocytopenic purpura. Am J Hematol 1992; 41:184.
  81. Choi YU, Dominguez EP, Sherman V, Sweeney JF. Laparoscopic accessory splenectomy for recurrent idiopathic thrombocytopenic purpura. JSLS 2008; 12:314.
  82. Woo JH, Park SH, Park YK, et al. Postsplenectomy recurrence of thrombocytopenia with an accessory spleen. Korean J Intern Med 2004; 19:199.
  83. Thanarajasingam G, Vaidya R, Erie A, Wolanskyj AP. Accessory splenectomy for refractory immune thrombocytopenic purpura. Am J Hematol 2011; 86:520.
  84. Gardner FH, Helmer RE 3rd. Aminocaproic acid. Use in control of hemorrhage in patients with amegakaryocytic thrombocytopenia. JAMA 1980; 243:35.
  85. Bartholomew JR, Salgia R, Bell WR. Control of bleeding in patients with immune and nonimmune thrombocytopenia with aminocaproic acid. Arch Intern Med 1989; 149:1959.
  86. Kalmadi S, Tiu R, Lowe C, et al. Epsilon aminocaproic acid reduces transfusion requirements in patients with thrombocytopenic hemorrhage. Cancer 2006; 107:136.
  87. Cines DB, Liebman H, Stasi R. Pathobiology of secondary immune thrombocytopenia. Semin Hematol 2009; 46:S2.
  88. Stasi R. Therapeutic strategies for hepatitis- and other infection-related immune thrombocytopenias. Semin Hematol 2009; 46:S15.
  89. DiMaggio D, Anderson A, Bussel JB. Cytomegalovirus can make immune thrombocytopenic purpura refractory. Br J Haematol 2009; 146:104.
  90. Arnold DM, Bernotas A, Nazi I, et al. Platelet count response to H. pylori treatment in patients with immune thrombocytopenic purpura with and without H. pylori infection: a systematic review. Haematologica 2009; 94:850.
  91. Jackson S, Beck PL, Pineo GF, Poon MC. Helicobacter pylori eradication: novel therapy for immune thrombocytopenic purpura? A review of the literature. Am J Hematol 2005; 78:142.
  92. Rostami N, Keshtkar-Jahromi M, Rahnavardi M, et al. Effect of eradication of Helicobacter pylori on platelet recovery in patients with chronic idiopathic thrombocytopenic purpura: a controlled trial. Am J Hematol 2008; 83:376.
  93. Fujimura K, Kuwana M, Kurata Y, et al. Is eradication therapy useful as the first line of treatment in Helicobacter pylori-positive idiopathic thrombocytopenic purpura? Analysis of 207 eradicated chronic ITP cases in Japan. Int J Hematol 2005; 81:162.
  94. Michel M, Cooper N, Jean C, et al. Does Helicobater pylori initiate or perpetuate immune thrombocytopenic purpura? Blood 2004; 103:890.
  95. Takahashi T, Yujiri T, Shinohara K, et al. Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura. Br J Haematol 2004; 124:91.
  96. Sato R, Murakami K, Watanabe K, et al. Effect of Helicobacter pylori eradication on platelet recovery in patients with chronic idiopathic thrombocytopenic purpura. Arch Intern Med 2004; 164:1904.
  97. Kohda K, Kuga T, Kogawa K, et al. Effect of Helicobacter pylori eradication on platelet recovery in Japanese patients with chronic idiopathic thrombocytopenic purpura and secondary autoimmune thrombocytopenic purpura. Br J Haematol 2002; 118:584.
  98. Stasi R, Rossi Z, Stipa E, et al. Helicobacter pylori eradication in the management of patients with idiopathic thrombocytopenic purpura. Am J Med 2005; 118:414.
  99. Emilia G, Luppi M, Zucchini P, et al. Helicobacter pylori infection and chronic immune thrombocytopenic purpura: long-term results of bacterium eradication and association with bacterium virulence profiles. Blood 2007; 110:3833.
  100. Stasi R, Sarpatwari A, Segal JB, et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review. Blood 2009; 113:1231.
  101. Byrne MF, Kerrigan SW, Corcoran PA, et al. Helicobacter pylori binds von Willebrand factor and interacts with GPIb to induce platelet aggregation. Gastroenterology 2003; 124:1846.
  102. Franceschi F, Christodoulides N, Kroll MH, Genta RM. Helicobacter pylori and idiopathic thrombocytopenic purpura. Ann Intern Med 2004; 140:766.
  103. Asahi A, Nishimoto T, Okazaki Y, et al. Helicobacter pylori eradication shifts monocyte Fcgamma receptor balance toward inhibitory FcgammaRIIB in immune thrombocytopenic purpura patients. J Clin Invest 2008; 118:2939.
  104. Kodama M, Kitadai Y, Ito M, et al. Immune response to CagA protein is associated with improved platelet count after Helicobacter pylori eradication in patients with idiopathic thrombocytopenic purpura. Helicobacter 2007; 12:36.
  105. George JN. Definition, diagnosis and treatment of immune thrombocytopenic purpura. Haematologica 2009; 94:759.
  106. Huhn RD, Fogarty PF, Nakamura R, et al. High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia. Blood 2003; 101:71.
  107. Passweg JR, Rabusin M, Musso M, et al. Haematopoetic stem cell transplantation for refractory autoimmune cytopenia. Br J Haematol 2004; 125:749.