Thrombopoietin: Understanding and Manipulating Platelet Production

Until recently, platelet production was the least understood aspect of blood cell development. This gap in our understanding resulted from the scarcity of megakaryocytes, the marrow precursor of blood platelets, and from confusion surrounding the cytokines and hormones that support their development. The recent cloning and characterization of thrombopoietin (TPO) has profoundly changed our understanding of platelet production. Using in vitro assay systems, several groups have shown that TPO supports the proliferation of megakaryocytic progenitor cells and their differentiation into mature platelet-producing cells. Moreover, and somewhat surprisingly, TPO also acts in synergy with other pluripotent cytokines on the hematopoietic stem cell to augment development of erythroid and myeloid progenitors. These in vitro effects correlate well with the in vivo biology of the hormone. When administered to normal animals, TPO expands the numbers of hematopoietic progenitors of all lineages and greatly accelerates platelet production. Moreover, when TPO or its receptor is genetically eliminated, progenitor cell levels of all lineages are reduced, and platelet production is profoundly impaired. In animals administered cytoreductive therapy, the use of TPO is associated with accelerated hematopoietic recovery, not only of megakaryocytes and platelets, but also of erythrocytes and leukocytes. It, thus, is hoped that TPO may play an important role in reducing the myelosuppressive complications of naturally occurring and iatrogenic states of marrow failure.