The Emergence of Thrombopoietin Receptor Agonists as a Novel Treatment for Immune Thrombocytopenia

Abstract

Primary immune thrombocytopenia (ITP), until recently referred to as idiopathic thrombocytopenic purpura (ITP), is an acquired autoimmune disorder defined by isolated thrombocytopenia (platelet count <100x 10 9 /l) and the exclusion of other causes of thrombocytopenia. 1 The clinical manifestations of ITP are highly variable and range from the completely asymptomatic patient to frank haemorrhage from any site, the most serious of which is intracranial. 2 Several matters in terms of the optimal treatment of adult patients with chronic ITP remain unresolved. There is limited evidence based on randomised trials to guide management decisions and for some patients morbidity from the side effects of therapy may exceed any problems caused by the ITP. 2,3 Currently, treatment is considered appropriate for symptomatic patients and for those at risk of bleeding. [4][5][6][7][8] Once the decision to treat a patient with ITP has been made, provided the patient's situation is not life-threatening, corticosteroids are the standard initial treatment. 4Intravenous immunoglobulins are generally recommended for patients with critical bleeding and for those unresponsive to corticosteroids. 4 The platelet count also can be supported by anti-D immunoglobulin, which is active in 70-75% of Rh-positive patients only in the pre-splenectomy setting. 9 Splenectomy is traditionally considered to be the second-line treatment in adults with ITP in whom achieving a safe platelet count with initial prednisone therapy has failed. For those who are refractory or relapse after splenectomy, there is a long list of available approaches, 5 most of which have modest response rates.Quite recently a new class of drugs, the thrombopoietin receptor (TPO-R) agonists, have shown remarkable efficacy. Recently published guidelines based on the highest level of evidence recommend the use of these agents for the treatment of patients with chronic ITP. 10 Two of these drugs, romiplostim and eltrombopag, have been approved for use in chronic refractory ITP in the US, the EU and in many other countries. This article discusses the rationale for megakaryocyte stimulation in ITP and presents the results of clinical trials with these new agents. Pathophysiology of Immune ThrombocytopeniaFor many years the prevailing view was that ITP resulted solely from excessive platelet clearance and destruction, mediated by autoreactive antibodies directed against platelet glycoproteins. 11 Kinetic studies conducted in the early 1970s using chromium-51 ( 51 Cr)-labelled allogeneic platelets demonstrated shortened platelet survival and increased platelet turnover in ITP patients, 12,13 consistent with this hypothesis. Interestingly, platelet survival was found to be inversely related to the quantity of bound antiplatelet antibodies. 14 However, when autologous indium-111 ( 111 In)-labelled autologous platelets were studied in the 1980s it became evident that there was considerable heterogeneity in platelet turnover between patients. [15][16][17][18][19] Although the platelet lifesp...

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

“…15,16,36,37 Despite the wide spectrum of conditions where eltrombopag has been used, little is known about the mechanisms of action of this drug on human HSCs. The results of our study demonstrated that eltrombopag promoted successful in vitro human cord and peripheral blood-derived HSCs differentiation towards the megakaryocytic lineage, as assessed by the maturation of high ploidy megakaryocytes expressing the lineage-speEx vivo inquiry on Eltrombopag mechanism of action haematologica | 2016; 101 (12) 1485 27,28 stimulated the activation of all the main biochemical pathways downstream of the c-Mpl receptor. This activation resulted in the expansion of fully differentiated megakaryocytes with an enhanced ability to extend long branched proplatelets.…”

“…[23][24][25] After 13 days of culture, 50 and 100 ng/ml of eltrombopag failed to promote megakaryocyte differentiation (data not shown). Conversely, when concentrations of eltrombopag, in the same range as those measured in the serum of healthy subjects during oral eltrombopag administration (C max 7-10 mg/ml), 27,28 were used in culture, megakaryocytes efficiently differentiated from their progenitors. Specifically, starting from 200 to 500 and 2000…”

Review article: THE ROLE OF ELTROMBOPAG AND ROMIPLOSTIM AS THE THROMBOPOIETIN RECEPTOR AGONIST (TPO-RA) IN TREATMENT OF IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP): WHAT IS TPO-RA, WHEN TPO-RA IS USED AND HOW TO TAKE TPO-RA?

“…Eltrombopag is a non-peptide thrombopoietin receptor agonist which is administered orally in tablet. In a preclinic study, eltrombopag stimulates megakaryocytes differentiation and proliferation by stimulation in thrombopoietin receptor and this drug is dose-dependant (Stasi et al, 2011). Mechanism action of eltrombopag to activate thrombopoietin receptor is different with romiplastim.…”

“…In vitro study, antibody that attack platelet glycoprotein (GP) Ib-IX-V might cause thrombocytopenia via megakaryopoiesis inhibition and pro-thrombocytes formation. (Stasi et al, 2011).…”

“…Most ITP treatments are aimed to reduce autoantibody production and or to slow down opsonized platelet, which in the end will be engulfed by macrophage. Based on the pathophysiology mentioned above, some of patients of ITP have platelet production disturbance rather than excessive platelet destruction (Stasi et al, 2011). Therefore, this review article will discuss about ITP management focus on thrombopoietin receptor agonist (TPO-R) which are eltrombopag and romi-plostim, what are they, when they are used and how to take these drugs.…”