Biologic aspects of thrombopoietin and the development of novel thrombopoietic agents for clinical use.

Thrombocytopenia is a frequent finding in several clinical settings, including bone marrow failure associated with various disorders, immune-mediated thrombocytopenia, and chronic liver diseases. Currently, there is an unmet need for thrombopoietic agents to treat this condition. Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the thrombopoietin receptor that is expressed on the surface of megakaryocytes and megakaryocytic precursors. Although clinical trials with first generation thrombopoietic agents were abruptly discontinued after the development of TPO autoantibodies had been observed, non-antigenic second generation thrombopoietic growth factors with unique pharmacological properties have been developed. These include TPO peptide mimetics (AMG 531 and Fab59), TPO non-peptide mimetics (eltrombopag, NIP-004, and AKR-501) and TPO agonist antibodies. All of these bind to and activate the TPO receptor in different ways but all via JAK2/STAT signalling pathways, producing a dose-dependent rise in platelet counts. In view of their use as therapeutic agents, nonpeptide agonists seem to have an advantage over peptide agonists, in that they could be orally bioavailable. The aim of the present review is to illustrate the biology of TPO and its receptor, and to describe the structure and function of the new thrombopoietic agents.