Regulation of megakaryocytopoiesis

After 35 years of research, a physiological regulator of platelet productio n has been identified and the recombinant protein is available. With the di scovery of thrombopoietin (TPO), its potential use in a wide variety of cli nical megakaryocytic and platelet disorders has been expected and clinical trials have been undertaken. To date, the reported encouraging pre-clinical studies indicate that, as with erythropoietin or G-CSF, minimal toxicity c an be expected. A potential limiting side-effect of TPO could be the induct ion of thrombosis. Nevertheless, it is too early to know whether this cytok ine will be of major therapeutic importance for patients with life-threaten ing thrombocytopenia, such as patients undergoing bone marrow transplantati on or subjected to a high dose of chemotherapy. Several experimental and cl inical studies are still needed to determine the efficacy of TPO in the pre vention or the amelioration of bleeding, which is the ultimate goal for the appropriate use of cytokines with haemostatic benefit. Basic and clinical studies on regulators of megakaryocytopoiesis have rapidly progressed. Now, there is no doubt that some of these regulators are effective in correctin g haematopoietic disorders of various aetiologies. Studies on negative regu lators not only are important to understand the regulation of megakaryocyto poiesis in normal and pathological states but also have a potential clinica l application. Some of these regulators have been shown to be effective in the treatment of essential thrombocythaemia a nd other myeloproliferative d isorders. Platelet factor 4 (PF4) and some other chemokines are also capabl e of protecting progenitor cells from the cytotoxicity of chemotherapeutic drugs. However, detailed investigations are still required to determine the precise mechanism(s) of action of these regulators and to establish the op timal clinical protocols of negative regulators alone or in association wit h positive regulators for the treatment of various haematological diseases and cancer.