Thrombopoietin as a Drug: Biologic Expectations, Clinical Realities, and Future Directions

Open Access
Publisher Website
Google Scholar
Abstract
After the cloning of thrombopoietin (c-mpl ligand, Tpo) in 1994, 2 recombinant thrombopoietic growth factors, full-length glycosylated recombinant human Tpo (reHuTPO) and polyethylene glycol conjugated megakaryocyte growth and development factor (PEG-reHuMGDF), have been studied in humans in a variety of clin- ical settings. Both thrombopoietins are generally well tolerated if ad- ministered intravenously (IV). The c-mpl ligands produce a dose-re- lated enhancement of platelet levels, reduce nonmyeloablative chemotherapy-induced mild thrombocytopenia, and mobilize hematopoietic progenitors. On September 11, 1998, the development of PEG-reHuMGDF was suspended in the U.S., due to formation of the neutralizing anti-Tpo antibody. Those neutralizing antibodies lead to thrombocytopenia and pancytopenia in some patients receiv- ing subcutaneous (SC) PEG-reHuMGDF. Japanese investigators in- dicate that the probability of antibody formation against PEG- reHuMGDF is low when the drug is administered IV instead of SC. reHuTPO has a more favorable safety profile from the point of anti- body production. The c-mpl ligands can improve apheresis yields when administered to normal platelet donors. Preliminary data about the use of PEG-reHuMGDF in myelodysplasia, aplastic anemia, and immune thrombocytopenic purpura are promising. Tpo is usually not effective in myeloablative thrombocytopenia when bone marrow hematopoietic progenitors are not present. The major obstacle for the thrombopoietins is their delayed action for managing clinical thrombocytopenia. This review will focus on the biologic basis, cur- rent clinical experience, and future directions for the use of throm- bopoietic molecules as drugs. The identification of a safe, effective, and potent pharmacologic platelet growth factor could significantly improve the management of thrombocytopenia-induced bleeding.