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HEMATOPOIESIS AND THE PHYSIOLOGIC BASIS OF RED CELL PRODUCTION

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Hematopoiesis is the process by which the formed elements of blood are produced. The process is regulated through a series of steps beginning with the hematopoietic stem cell. Stem cells are capable of producing red cells, all classes of granulocytes, monocytes, platelets, and the cells of the immune system. The precise molecular mechanism—either intrinsic to the stem cell itself or through the action of extrinsic factors—by which the stem cell becomes committed to a given lineage is not fully defined. However, experiments in mice suggest that erythroid cells come from a common erythroid/megakaryocyte progenitor that does not develop in the absence of expression of the GATA-1 and FOG-1 (friend of GATA-1) transcription factors (Chap. 1). Following lineage commitment, hematopoietic progenitor and precursor cells come increasingly under the regulatory influence of growth factors and hormones. For red cell production, erythropoietin (EPO) is the primary regulatory hormone. EPO is required for the maintenance of committed erythroid progenitor cells that, in the absence of the hormone, undergo programmed cell death (apoptosis). The regulated process of red cell production is erythropoiesis, and its key elements are illustrated in Fig. 2-1.

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FIGURE 2-1

The physiologic regulation of red cell production by tissue oxygen tension. Hb, hemoglobin.

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In the bone marrow, the first morphologically recognizable erythroid precursor is the pronormoblast. This cell can undergo four to five cell divisions, which result in the production of 16–32 mature red cells. With increased EPO production, or the administration of EPO as a drug, early progenitor cell numbers are amplified and, in turn, give rise to increased numbers of erythrocytes. The regulation of EPO production itself is linked to tissue oxygenation.

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In mammals, O2 is transported to tissues bound to the hemoglobin contained within circulating red cells. The mature red cell is 8 μm in diameter, anucleate, discoid in shape, and extremely pliable in order to traverse the microcirculation successfully; its membrane integrity is maintained by the intracellular generation of ATP. Normal red cell production results in the daily replacement of 0.8–1% of all circulating red cells in the body, since the average red cell lives 100–120 days. The organ responsible for red cell production is called the erythron. The erythron is a dynamic organ made up of a rapidly proliferating pool of marrow erythroid precursor cells and a large mass of mature circulating red blood cells. The size of the red cell mass reflects the balance of red cell production and destruction. The physiologic basis of red cell production and destruction provides an understanding of the mechanisms that can lead to anemia.

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The physiologic regulator of red cell production, the glycoprotein hormone EPO, is produced and released by peritubular capillary lining cells within the kidney. These cells ...

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