Thrombopoietin mimetic agents in the management of immune thrombocytopenic purpura.
Thrombopoietin (TPO) is a potent endogenous cytokine and the principal regulator of platelet production. Advances in the understanding of the structure of TPO enabled development of the first generation of thrombopoietic growth factors, recombinant human thrombopoietin (rhTPO) and pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF). Clinical results showed that these agents were effective in promoting increases in platelet counts in a variety of thrombocytopenic disorders. However, clinical development was halted when studies demonstrated risk for autoantibody formation with cross-reactivity to endogenous TPO. A second generation of thrombopoietic growth factors, including TPO peptide and nonpeptide mimetics and TPO agonist antibodies, utilizing different mechanisms from recombinant growth factors to promote platelet production, are currently in development. The TPO peptide mimetic AMG 531 and the nonpeptide mimetic eltrombopag are in advanced clinical trials and have both resulted in dose-dependent increases in platelets in healthy subjects and in significant increases in platelets in patients with chronic immune thrombocytopenic purpura (ITP). Clinical trials are also being conducted to examine the efficacy and safety of eltrombopag to treat thrombocytopenia in hepatitis C virus (HCV)-infected individuals. These agents appear to be well tolerated and the formation of autoantibodies appears to be limited to first-generation growth factors. Increases in marrow reticulin have been demonstrated with some growth factors, but this appears to be a reversible phenomenon and is not associated with formation of collagen fibrosis. There appears to be no increased incidence of thrombotic events in patients who achieve high platelet counts with growth factor treatments, and although occasional thrombotic events have been reported, their association to the treatment is uncertain. While there is evidence that activation of signaling pathways involved in platelet production may result in reduction in the threshold for platelet activation, this appears to have minimal clinical relevance for the use of thrombopoietin growth factors.
Newland
Adrian
A
Department of Haematology, Centre for Haematology, The Royal London Hospital, London, UK. Adrian.Newland@rcpath.org
D032701:Biomimetics; D016207:Cytokines / Q000187:drug effects; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects; D015394:Molecular Structure; D010976:Platelet Count; D011696:Purpura, Thrombocytopenic / Q000188:drug therapy*; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D034061:Thrombopoiesis / Q000187:drug effects; D013926:Thrombopoietin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin