Each day the adult human produces approximately 1 × 1011 platelets, a level of production that can increase 10- to 20-fold in times of increased demand and an additional 5- to 10-fold under the stimulation of exogenous thrombopoietin receptor agonists. Production of platelets depends on the proliferation and differentiation of hematopoietic stem and progenitor cells to cells committed to the megakaryocyte lineage; their maturation to large, polyploid megakaryocytes; and their final fragmentation into platelets. The external influences that affect megakaryopoiesis and thrombopoiesis are a supportive marrow stroma consisting of endothelial and other cells, matrix glycosaminoglycans, and a family of protein hormones and cytokines, including thrombopoietin, stem cell factor, and stromal cell–derived factor-1. The role of the cytokines essential for these processes has been defined, the transcription factors critical for megakaryocyte development have been identified, the molecular mechanisms that underlie the two most unusual aspects of thrombopoiesis—endomitosis and proplatelet formation—have been studied, and reagents to specifically modify platelet production have been generated. This chapter focuses on the development of megakaryocytes, their precursors and their progeny, and the hematopoietic growth factors and transcriptionally active molecules that control the survival, proliferation, and differentiation of these cells.
Acronyms and Abbreviations
CAMT, congenital amegakaryocytic thrombocytopenia; FGF, fibroblast growth factor; GP, glycoprotein; HPS, Hermansky-Pudlak syndrome; IFN, interferon; IL, interleukin; ITP, immune thrombocytopenic purpura; MAPK, mitogen-activated protein kinase; MRTFA, myocardin-related transcription factor A; P4P, polyphosphate-4-phosphatase; PI3K, phosphoinositol 3-kinase; SCF, stem cell factor; SDF, stromal cell-derived factor; TGF, transforming growth factor; TRA, thrombopoietin receptor agonist.
KINETICS OF THROMBOPOIESIS
The circulatory lifespan of a platelet is approximately 10 days in humans with normal platelet counts, but is somewhat shorter in patients with moderate (7 days) to severe (5 days) thrombocytopenia, because a higher proportion of the total-body platelet mass is consumed in the day-to-day function of maintaining vascular integrity.1 Based on a “normal” level of 200 × 109/L platelets, a blood volume of 5 L, and a half-life of 10 days, 1 × 1011 platelets per day are produced. If one megakaryocyte produces approximately 1000 platelets, approximately 1 × 108 megakaryocytes are generated in the marrow each day.
Several independent lines of evidence indicate the transit time from megakaryocyte progenitor cell to release of platelets into the circulation ranges from 4–7 days. For example, after platelet apheresis, the platelet count falls, recovers substantially by day 4, and completely recovers by day 7.2 In most physiologic and pathologic states, the platelet count is inversely related to plasma thrombopoietin levels. For example, liver failure is associated with moderate thrombocytopenia as a result of splenomegaly, caused by portal hypertension, and thrombopoietin deficiency. Within the first week after orthotopic liver transplantation, the platelet count rises substantially, with kinetics matching those of thrombopoietin infusion.3,4 These findings indicate that expansion of the megakaryocyte mass takes from 3–4 days after a thrombopoietin ...