Therapeutic cytokine stimulation of thrombocytopoiesis

Endogenous thrombopoietin (TPO) stimulates platelet production by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. Recombinant human (rHu) TPO or pegylated recombinant human megakaryocyte growth and development factor (PEG-rHu MGDF) produce log-linear responses in experimental animals and humans when administered over the dose range of 0.05-25 micrograms/kg/day with respect to peak peripheral platelet counts (or peripheral platelet mass turnover) and marrow megakaryocyte volume, ploidy, number and mass. Other cytokines stimulating megakaryocytopoiesis in various species using different dosing regimens include Interleukin 1 (IL-1), Interleukin 3 (IL-3), Interleukin 6 (IL-6), Interleukin 11 (IL-11), stem cell factor (SCF), granulocytemacrophage colony stimulating factor, (GM-CSF), fusion proteins, such as promegapoietin, and a peptide agonist of TPO receptor. Whereas neither rHuTPO nor PEG-rHuMGDF induce platelet aggregation in vitro, they transiently enhance aggregatory responsiveness of platelets to physiologic agonists from several different experimental animals both in vitro and ex vivo. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the effect of platelet concentration per se. These findings indicate that appropriate dosing of these agents following marrow suppression prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.