title: Advances in megakaryocytopoiesis and thrombopoiesis: from bench to bedside.
abstract: Megakaryocytopoiesis involves the commitment of haematopoietic stem cells, proliferation and terminal differentiation of megakaryocytic progenitors (MK-p) and maturation of megakaryocytes (MKs) to produce functional platelets. This complex process occurs in specialized niches in the bone marrow where MKs align adjacent to vascular endothelial cells, form proplatelet projections and release platelets into the circulation. Thrombopoietin (THPO, TPO) is the primary growth factor for the MK lineage and necessary at all stages of development. THPO is constitutively produced in the liver, and binds to MPL (c-Mpl) receptor on platelets and MKs. This activates a cascade of signalling molecules, which induce transcription factors to drive MK development and thrombopoiesis. Decreased turnover rate and platelet number result in increased levels of free THPO, which induces a concentration-dependent compensatory response of marrow-MKs to enhance platelet production. Newly developed thrombopoietic agents operating via MPL receptor facilitate platelet production in thrombocytopenic states, primarily immune thrombocytopenia. Other drugs are available for attenuating malignant thrombocytosis. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease states, and the innovative drugs and therapeutic modalities to stimulate or decrease thrombopoiesis.
authors.affiliation: The Haematology Institute, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel. vardad@tlvmc.gov.il
authors.forename: Varda R
authors.initials: VR
authors.lastname: Deutsch
authors.forename: Aaron
authors.initials: A
authors.lastname: Tomer
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology; D001853:Bone Marrow / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D060833:Cellular Microenvironment / Q000502:physiology; D002986:Clinical Trials as Topic; D006706:Homeostasis; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D008533:Megakaryocytes / Q000166:cytology*; D018716:Molecular Mimicry; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011961:Receptors, Fc / Q000627:therapeutic use; D053628:Receptors, Thrombopoietin / Q000819:agonists / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000188:drug therapy / Q000209:etiology; D013922:Thrombocytosis / Q000188:drug therapy / Q000209:etiology; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; C082218:MPL protein, human; D013926:Thrombopoietin; D053612:Janus Kinases; C488777:romiplostim