Thrombopoietin Receptor Agonists


Thrombopoietin (TPO) regulates thrombopoiesis through activation of TPO receptors on the megakaryocyte cell surface, resulting in increased platelet production. 



The TPO receptor agonists increase platelet production through interactions with the TPO receptor on megakaryocytes. 



TPO receptor agonists, romiplostim and eltrombopag, and others have received regulatory approval for patients with chronic ITP who remain at risk of bleeding following treatment with first-line therapies.



These  agents increase platelet counts, decrease bleeding events and reduce the need for adjunctive or rescue treatments. 



Historically, the treatment of ITP has been to inhibit the production of anti-platelet autoantibodies or opsonization of antibody-coated platelets. 



Impaired platelet production is increasingly recognized as a contributor to thrombocytopenia in patients with ITP.



Thrombopoietin (TPO) is a hormone constitutively produced by the liver which regulates platelet production by binding to and activating TPO receptors on the megakaryocyte cell surface, thereby inducing intracellular signalling cascades that lead to increased platelet production.



Plasma levels of TPO are regulated by binding of TPO to circulating platelets which results in its removal from circulation and subsequent degradation.



 In patients with ITP, TPO plasma levels are inappropriately low as compared with individuals with hypoproliferative thrombocytopenias, an observation which led to the development of recombinant thrombopoietins, the first generation of exogenous thrombopoiesis-stimulating agents.



Romiplostim is a recombinant fusion protein peptibody composed of 2 IgG1 constant regions (Fc fragments) linked to a peptide domain containing 4 binding sites for the TPO receptor.



Romiplostim binds to the TPO receptor and results in activation of intracellular signalling cascades (JAK-STAT and MAP kinase pathways) that lead to increased platelet production.



Following a single intravenous or subcutaneous dose, there is a dose-dependent increase in platelet count within 5 to 8 days which returns to baseline by day 28.



A retrospective analysis showed a significant decrease in corticosteroid use from 35% to 20% after 3 years of treatment with romiplostim.



Patients with ITP who previously completed a romiplostim study were enrolled in an open-label extension study in which romiplostim was administered weekly for a median of 78 weeks, A platelet count of ?50,000/?L was achieved in 94.5% of patients during the study. More than 50% of patients had platelet counts of ?50,000/?L on ?90% of all visits.



In a 52-week open-label study, non-splenectomized patients with ITP were treated with romiplostim or standard of care: platelet response was 2.3 times higher in the romiplostim group than the standard of care group.



Treatment failure occurs  less frequently in romiplostim-treated patients compared to standard of care.



Eltrombopag, Promacta, is an oral, small non-peptide molecule which binds to the TPO receptor via its transmembrane domain and activates the JAK-STAT and MAP kinase intracellular pathways to increase platelet production.



Eltrombopag produces a sustained increase in platelet count after 8 days of repeat dosing which decreases to baseline 12 days following discontinuation with a half-life of approximately 12 hours



Guidelines on ITP treatment suggest initiating treatment with TPO receptor agonists in patients at risk of bleeding who relapse following splenectomy or have a contraindication to splenectomy and previous treatment failure.



Thrombocytopenia usually recurs following drug withdrawal. 



These agents are used indefinitely to maintain a platelet count that is likely to minimize bleeding. 



Romiplostim recommended initial dose of is 1 ?g/kg administered subcutaneously once per week and then titrated to a maximum of 10 ?g/kg to achieve a platelet count ?50,000/?L.



The recommended starting dose of eltrombopag is 50 mg per day administered orally and then adjusted to a maximum of 75 mg per day to maintain platelet count ?50,000/?L 



Remissions of ITP have been reported after TPO receptor agonist discontinuation, but thrombocytopenia usually recurs following drug withdrawal. 



Use of these agents are used indefinitely to maintain a platelet count that is likely to minimize bleeding. 



TPO receptor agonists safe, effective treatment option for patients with chronic ITP who are at risk of bleeding.



TPO receptor agonists are associated with increased platelet counts, decreased bleeding events and reduced need for adjunctive or rescue treatments. 



Some experts favor splenectomy before TPO receptor agonist use in the absence of a contraindication to surgery.




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