Key Points

• The RBC mass reflects the oxygen-carrying capacity of the body.

• Oxygen supply depends on RBC mass, lung function, circulatory system, supply of EPO, and bone marrow.

The major role of the red blood cell (RBC, erythrocyte) is to transport oxygen from the lungs to the tissues and organs in the body. This is accomplished by the reversible binding of oxygen to the heme moiety of the hemoglobin molecule. Hemoglobin (Hb) is the most prominent RBC protein. The functional ability of the Hb molecule is determined by primary amino acid structure, pH (Bohr effect), temperature, and intracellular concentration of 2,3-biphosphoglycerate (2,3-BPG). Abnormalities of Hb function most frequently result from mutations (amino acid substitutions) in one or more of the globin genes. These mutations, such as the mutation that causes sickle cell disease, can alter the stability of the Hb molecule or its oxygen-binding properties. Many of these mutations result in tissue hypoxia because the instability of the molecule results in the early death of the RBC in circulation (hemolysis). Other Hb mutations can affect oxygen binding and release or can produce free-globin chains that may bind to the inner RBC membrane, resulting in membrane instability (Heinz bodies). Hemoglobin is also recognized as the major "sink" of nitric oxide (NO) in the blood. This has important implications for the control of vascular tone in the microcirculation.

Under normal conditions, regulation of erythropoiesis can be viewed as a positive control loop. Red cell production is regulated by EPO. Production of EPO occurs primarily in the kidney, although a small amount is produced by the liver; this is a holdover from fetal life, when the liver was the major source of EPO production. EPO stimulates RBC production by binding to specific receptors on the surface of erythroid progenitor cells in the marrow. This activates a number of cell division steps that results in approximately 16 to 32 mature RBCs for each progenitor cell stimulated. These new RBCs leave the bone marrow and circulate for about 120 days as mature cells. The circulating red blood cells make up the RBC mass.

The RBC mass represents the oxygen-carrying capacity of the body. As RBCs traverse the circulation, the cells provide oxygen for all metabolic functions. In the kidney, oxygen availability is sensed by specialized peritubular capillary lining cells. The sensing mechanism is mediated by hypoxia-inducible factor 1a (HIF-1a). The adequacy of the oxygen supply depends not only on RBC mass, but also on normal lung function, a normal circulatory system that allows RBCs to be delivered effectively to all parts of the body, an adequate supply of EPO to stimulate RBC production, and a normally functioning bone marrow. Abnormalities in any of these factors can affect RBC production and result in anemia (too few RBCs) or erythrocytosis (too many RBCs).

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