Thrombopoietin: a tool for understanding thrombopoiesis

Abstract

Summary. Although first proposed to be the primary regulator of platelet production 45 years ago, the gene for thrombopoietin was cloned only within the last decade. Since then, our understanding of megakaryocyte and platelet production has increased substantially, and it is now appreciated that in addition to its critical role in regulating thrombopoiesis, the hormone affects multiple aspects of hematopoiesis, including playing a non-redundant role in stem cell survival, self-renewal and expansion. In addition to this greater physiological understanding of thrombopoietin biology, the molecular mechanisms by which the hormone affects cell survival and proliferation are coming under increased scrutiny. At least four signaling pathways have been identified that play important and non-overlapping roles in stem cell and megakaryocyte growth and development, potentially providing new strategies to therapeutically intervene in hematopoiesis. This review will focus on our current understanding of these processes.

Megakaryocyte development and platelet production

“…Mechanisms regulating megakaryocytopoiesis operate at the levels of proliferation, differentiation and platelet release (Gewirtz, 1995;Kaushansky, 2003). In addition to the steady state megakaryocytopoiesis, which supplies 10 11 platelets every day and a new turnover every 8-9 d, MKs also respond to changes in requirements for circulating platelets, increasing more than 10-fold under conditions that demand platelet production (Kaushansky, 2005a).…”

“…TPO shares high homology with erythropoietin (EPO) in its N-terminal half, reflecting a close evolutionary relationship between their receptor signalling pathways. TPO binds to its receptor on MKs and selectively initiates proliferation, maturation and cytoplasmic delivery of platelets into the circulation (Kaushansky, 1997(Kaushansky, , 2003. TPO is produced constitutively by the liver and its circulating levels are regulated by the extent of binding to c-Mpl receptors on circulating platelets and marrow MKs resulting in the elimination of TPO-c-Mpl complexes (Kaushansky, 1997;Scheding et al, 2002).…”

Understanding cyclical thrombocytopenia: A mathematical modeling approach

“…Although the understanding of platelet regulation is rapidly evolving, the molecular basis of this pro cess is not completely elucidated. Substantial progress was achieved by the discovery and the cloning of TPO and its receptor in 1994 (49). This fact allowed the "simulation" of platelet formation in the laboratory for a better visualization and understanding of the process.…”

Prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation: associations with impaired platelet production and increased platelet turnover

“…In contrast, TPO has been identified as a key cytokine for megakaryogenesis and thrombopoiesis. 14 A large increase in circulating TPO is detected in conditions in which bone marrow megakaryocytes are absent or present at low levels, such as aplastic anemia and amegakaryocytic thrombocytopenia. In addition, the detection of autoantibodies reactive with platelet surface GPs, such as GPIIb-IIIa, is a hallmark of immune thrombocytopenia, especially idiopathic thrombocytopenic purpura (ITP).…”