As is obvious from the hematocrit, most blood cells are RBCs—also called erythrocytes. Mature RBCs are biconcave, flexible discs that lack nuclei but are packed with hemoglobin. Their function is to transport respiratory gases (see Key Concept 48.4). The shape of RBCs gives them a large surface area for gas exchange, and their flexibility enables them to squeeze through narrow capillaries. Men have 4.5–6.0 million red blood cells per microliter of blood, and women have 3.5–5.0 million.

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RBCs, as well as all the other cellular components of blood, are generated by stem cells in the bone marrow, particularly in the ribs, breastbone, pelvis, vertebrae, and the long bones of the limbs. RBC production is controlled by a hormone, erythropoietin (EPO), released by cells in the kidneys in response to insufficient oxygen—hypoxia. Many tissues respond to hypoxia by expressing a transcription factor called hypoxia-inducible factor 1 (HIF-1). When the kidneys become hypoxic and express HIF-1, one of the actions of the transcription factor is to activate the gene encoding erythropoietin. Increased circulating erythropoietin extends the lives of mature RBCs and stimulates production of new RBCs in the bone marrow.

Under normal conditions, your bone marrow produces about 2 million RBCs every second. Developing RBCs divide many times while still in the bone marrow, and during this time they produce hemoglobin. When hemoglobin makes up about 25 percent of the volume of the immature RBC, the nucleus is extruded from the cell and other cell organelles are also lost. This process is almost complete when the newly mature RBC squeezes between the endothelial cells of blood vessels in the bone marrow and enters the circulation. Loss of nuclei from the RBCs occurs in most mammalian species, but the RBCs of a few mammals and of all other vertebrates are nucleated.

Each RBC circulates for about 120 days. As it gets older, its membrane becomes less flexible and more fragile, so older RBCs are more likely to rupture as they bend to fit through narrow capillaries. RBCs are particularly squeezed in the spleen, an organ that sits near the stomach in the upper left side of the abdominal cavity. The spleen has many sinuses (cavities) that serve as reservoirs for RBCs. To get into the sinuses, however, the RBCs must squeeze between spleen cells. When old RBCs are ruptured by this squeezing, their remnants are taken up and degraded by macrophages (a class of white blood cells that ingest debris and foreign materials; see Key Concept 41.3).