Production of red cells, or erythropoiesis, is a tightly regulated process by which hematopoietic stem cells (HSCs) differentiate into erythroid progenitors and then mature into red cells. Erythropoiesis generates ~2 × 1011 new erythrocytes to replace the 2 × 1011 red cells (approximately 1% of the total red cell mass) removed from the circulation each day. Red cell production increases several-fold after blood loss or hemolysis. When one of the progeny of an HSC becomes committed to the erythroid lineage, this early erythroid progenitor undergoes a series of divisions and concurrent maturation that eventually result in morphologically recognizable erythroblasts. After expulsion of the nucleus, a macrocyte (polychromatophilic when Wright-stained, or a reticulocyte if new methylene blue–stained) leaves the marrow. During the first 24–48 hours in the circulation, reticulocytes lose their residual organelles (mitochondria and ribosomes) through an autophagic process (Chap. 14) and undergo reconditioning of the membrane to become mature red blood cells with a morphology of a biconcave disc. Erythropoiesis is controlled by transcription factors and cytokines, the principal ones being GATA 1 and erythropoietin (EPO), respectively, which influence 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, which determines the level of the transcription factors, hypoxia-inducible factors (HIFs)—HIF-1 and HIF-2—the principal regulators of the response to hypoxia. HIFs modulate erythropoiesis by regulation of EPO production by direct EPO-independent mechanism(s) and by facilitating iron availability.
The survival of red cells in the circulation can be measured in a variety of ways: (1) by labeling with radioactive isotopes, particularly 51Cr, and assessing the disappearance of the radioactive tag from the circulation over time; (2) by labeling the erythrocytes with biotin or a fluorescent dye and measuring this marker over time; (3) by determining the disappearance of transfused antigen-matched allogeneic erythrocytes using immunologic markers; and (4) by measuring the excretion of carbon monoxide (CO), a product of heme catabolism.
Such studies show that normal human red cells have a finite lifespan averaging 120 days, with some component of random destruction. The mitochondrial and ribosomal removal highlighting maturation of the reticulocyte is accompanied by increasing cell density, but after a few days of intravascular lifespan, there is little further increase in density or other changes in the physical property of the red cells. Thus, cell density is not a good marker for aged red cells. This has made study of the senescent changes in the red cell that mark it for destruction difficult. Candidates for such changes include changes in membrane AE-1 (anion exchanger-1; also know as band 3) and exposure of phosphatidylserine on the membrane, which may be of major importance.
Acronyms and Abbreviations
ACEI, angiotensin converting enzyme inhibitors; ADP, adenosine diphosphate; AMP, adenosine monophosphate; ASXL1, a polycomb group protein -epigenetic modifier; BCL11A. a critical switching factor for silencing gamma globin; Bcl-xL...