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Production of red cells or erythropoiesis, is a tightly regulated process by which hematopoietic stem cells differentiate into erythroid progenitors and then mature into red cells. Erythropoiesis generates ∼2 × 1011 new erythrocytes to replace the 2 × 1011 red cells (∼1% of the total red cell mass) removed from the circulation each day. Red cell production increases severalfold after blood loss or hemolysis.

When one of the progeny of the multipotential hematopoietic stem becomes committed to the erythroid lineage, this early erythroid progenitor undergoes a series of divisions that eventually result in morphologically recognizable erythroblasts. After expulsion of the nucleus, a polychromatophilic macrocyte (a reticulocyte if stained with new methylene blue) leaves the marrow. During the first 24 hours in the circulation, polychromatophilic macrocytes lose their residual organelles (mitochondria and ribosomes) through the action of degradative enzymes and become indistinguishable from other red cells of any age by light microscopy. Erythropoiesis is controlled by transcription factors and cytokines, the principal ones being GATA 1 and erythropoietin (EPO), which influence the rate of lineage commitment, proliferation, apoptosis, differentiation, and number of divisions from the earliest progenitor to late erythroblasts. The number of red cells produced varies in response to tissue oxygenation that determines the level of the transcription factors, hypoxia-inducible factors (HIF), HIF-1 and HIF-2, the principal regulators of the response to hypoxia. HIFs modulate erythropoiesis by regulation of EPO production and iron metabolism.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: ACEI, angiotensin-converting enzyme inhibitors; AngII, angiotensin II; Bcl-xL, an antiapoptotic factor; BFU–E, burst-forming unit–erythroid; CFU–E, colony-forming unit–erythroid; CIS, a signal transduction protein that downregulates activity of erythropoietin receptor; CPM, counts per minute; EPO, erythropoietin; EPOR, EPO receptor; FOG, “friend of GATA,” a GATA-1 interacting protein; GATA-1 transcription factor; HCP, hematopoietic cell phosphatase; Hct, hematocrit; HIF, hypoxia-inducible transcription factor; ICSH, International Committee on Standardization in Hematology; JAK2, a tyrosine kinase that interacts with erythropoietin receptor; miRNAs, microRNAs are small molecular noncoding RNA molecules; OS-9, osteosarcoma protein 9; PU.1, transcription factor; RACK1, receptor of activated protein kinase C; RAS, the renin–angiotensin system; RCM, red cell mass; RSUME, RWD-containing sumoylation enhancer; SOCS3, a signal transduction protein (also known as CIS3) that downregulates activity of erythropoietin receptor; SSAT, spermidine/spermine-N-acetyltransferase; VHL, von Hippel-Lindau protein.

Erythrocytes evolved largely for the purpose of transporting oxygen to tissues. Thus, the size of the red cell mass and the rate of red cell production must be closely related to supply and demand for oxygen in the tissues. Toward the end of the 19th century, French mountaineers and physiologists established that a low tissue tension of oxygen stimulates red cell production.1 In 1906, Paul Carnot, a professor at the Sorbonne, and Mademoiselle DeFlandre, his associate, suggested that hypoxia generates a humoral factor capable of stimulating red cell production.2 Based on questionable experimental data, influential biochemist Friederich ...

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