Function of eltrombopag-induced platelets compared to platelets from control patients with immune thrombocytopenia

 

 Buy Article Permissions and Reprints

Summary

Data on the in vivo function of platelets induced by the thrombopoietin receptor agonist eltrombopag are scarce. To assess a possible influence of eltrombopag we compared platelet function of eltrombopag-treated immune thrombocytopenia (ITP) patients (group 1; n=10) after treatment response to that from control ITP patients (group 2; n=12). We further analysed platelet function at baseline and after one, three, and four weeks of eltrombopag treatment and estimated daily changes of platelet function during the eltrombopag-induced platelet rise. The formation of platelet-monocyte aggregates (PMA), P-selectin expression [MFI], and platelet adhesion under high shear conditions (surface coverage, SC) in vivo and after in vitro addition of agonists (ADP, TRAP-6, Collagen) were similar between both groups after response to eltrombopag treatment. Only TRAP-6 induced a lower SC in the eltrombopag group (p=0.03). All platelet function parameters except for Collagen-induced P-selectin expression changed significantly during treatment with eltrombopag. PMA, naïve and after addition of ADP or TRAP-6 increased with increasing platelet counts. P-selectin expression decreased, when measured without and upon addition of ADP, increased in the presence of TRAP-6, and remained unchanged after addition of Collagen. SC increased during the eltrombopag-induced platelet rise. All significant changes of platelet function correlated to changes in platelet counts. Two patients developed venous thromboses during eltrombopag treatment, but no association with any distinct single platelet function parameter or combinations thereof was identifiable. Thus, eltrombopag-induced platelets function similar to those from control ITP patients without discernible increased hyper-reactivity.

^* Ingrid Pabinger and Simon Panzer share senior authorship.

• References

• 1 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: 641-648.
  CrossrefPubMedGoogle Scholar
• 2 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: 393-402.
  CrossrefPubMedGoogle Scholar
• 3 Cheng G, Saleh MN, Marcher C. et al. Department of Error. Lancet 2011; 377: 382.
  CrossrefPubMedGoogle Scholar
• 4 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: 395-403.
  CrossrefPubMedGoogle Scholar
• 5 Pecci A, Gresele P, Klersy C. et al. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood 2010; 116: 5832-5837.
  CrossrefPubMedGoogle Scholar
• 6 Imbach P, Crowther M. Thrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med 2011; 365: 734-741.
  CrossrefPubMedGoogle Scholar
• 7 Bussel JB, Cheng G, Saleh MN. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007; 357: 2237-2247.
  CrossrefPubMedGoogle Scholar
• 8 Erhardt JA, Erickson-Miller CL, Aivado M. et al. Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol 2009; 37: 1030-1037.
  CrossrefPubMedGoogle Scholar
• 9 Psaila B, Bussel JB, Linden MD. et al. In vivo effects of eltrombopag on platelet function in immune thrombocytopenia: no evidence of platelet activation. Blood 2012; 119: 4066-4072.
  CrossrefPubMedGoogle Scholar
• 10 Michelson AD, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104: 1533-1537.
  CrossrefPubMedGoogle Scholar
• 11 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: 3-40.
  PubMedGoogle Scholar
• 12 Panzer S, Stegfellner M, Jungbauer L. et al. Combined effects of genetic polymorphisms of P-selectin and P-selectin glycoprotein ligand-1 on the binding of platelets to monocytes. Thromb Res 2010; 125: 475-477.
  CrossrefPubMedGoogle Scholar
• 13 Haselboeck J, Pabinger I, Ay C. et al. Platelet activation and function during eltrombopag treatment in immune thrombocytopenia. Ann Hematol 2012; 91: 109-113.
  CrossrefPubMedGoogle Scholar
• 14 Panzer S, Rieger M, Vormittag R. et al. Platelet function to estimate the bleeding risk in autoimmune thrombocytopenia. Eur J Clin Invest 2007; 37: 814-819.
  CrossrefPubMedGoogle Scholar
• 15 Bussel JB, Cheng G, Saleh MN. et al. Thromboembolic Events observed in Eltrombopag Clinical Trials in Chronic Immune Thrombocytopenic Purpura. Blood (ASH Annual Meeting Abstracts). 2009 114. Abstract 2423.
  PubMedGoogle Scholar
• 16 Zoller B, Li X, Sundquist J. et al. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. Lancet 2012; 379: 244-249.
  CrossrefPubMedGoogle Scholar
• 17 Aledort LM, Hayward CP, Chen MG. et al. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol 2004; 76: 205-213.
  CrossrefPubMedGoogle Scholar
• 18 McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004; 104: 956-960.
  CrossrefPubMedGoogle Scholar
• 19 Norgaard M, Jensen AO, Engebjerg MC. et al. Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Blood 2011; 117: 3514-3520.
  CrossrefPubMedGoogle Scholar
• 20 Panzer S, Hocker L, Rieger M. et al. Agonistinducible platelet activation in chronic idiopathic autoimmune thrombocytopenia. Eur J Haematol 2007; 79: 198-204.
  CrossrefPubMedGoogle Scholar
• 21 Psaila B, Bussel JB, Linden MD. et al. Comparison of Platelet Function and Bleeding in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura (ITP) and Chemotherapy-Induced Thrombocytopenia (CIT). Blood (ASH Annual Meeting Abstracts) 2007; 110: 2094.
  PubMedGoogle Scholar
• 22 Rinder HM, Tracey JB, Recht M. et al. Differences in platelet alpha-granule release between normals and immune thrombocytopenic patients and between young and old platelets. Thromb Haemost 1998; 80: 457-462.
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Shantsila E, Lip GY. The role of monocytes in thrombotic disorders Insights from tissue factor, monocyte-platelet aggregates and novel mechanisms. Thromb Haemost 2009; 102: 916-924.
  Article in Thieme ConnectPubMedGoogle Scholar