Erythropoiesis and oxygen transport

The rate of erythropoiesis is primarily controlled by the positive growth effect of the glycoprotein hormone erythropoietin (EPO) on erythroid progenitors in the bone marrow. EPO is produced in fetuses primarily by hepatocytes, but after birth, it is primarily produced by peritubular fibroblasts in the renal cortex. EPO production is stimulated by tissue hypoxia. The key regulator of EPO synthesis is hypoxia-inducible factor 1 (HIF-1) , a transcription factor that binds to hypoxia response elements not only in the EPO gene but also in genes involved in glucose metabolism, including glucose transporters and glycolytic enzymes. Plasma EPO levels rapidly increase within 1 hour after initiation of hypoxia and peak within 1 to 2 days. Under normal circumstances, increased EPO leads to a hypercellular marrow with erythroid predominance (erythroid hyperplasia).

Marrow stem cells under the influence of hematopoietic growth factors give rise to the earliest committed erythroid progenitors, erythroid burst-forming unit (BFU-E) cells and erythroid colony-forming unit (CFU-E) cells. BFU-E give rise to CFU-E. CFU-E express the highest density of cell surface EPO receptors and thus is highly sensitive to the positive influence of EPO. EPO binding to a dimerized pair of EPO receptor molecules induces a variety of cytoplasmic signal transduction pathways that ultimately lead to the prevention of apoptosis of CFU-E cells. Under normal conditions, relatively few CFU-E cells survive to form mature red blood cells (RBCs). In contrast, under hypoxic conditions, increased EPO enhances CFU-E survival, leading to an increased number of surviving CFU-E cells. Each CFU-E is capable of giving rise to 8 to 64 immature RBCs. EPO further contributes to erythropoiesis by directly stimulating proliferation and maturation of more differentiated proerythroblasts and normoblasts. After enucleation, mature RBCs are released into the circulation.

A burst in EPO-induced erythropoiesis is followed 3 to 4 days later by an increased number of reticulocytes , young RBCs with a high content of rough endoplasmic reticulum, in peripheral blood. Given the normal RBC half-life of 120 days, approximately 1% of RBCs are normally replaced each day with reticulocytes. Thus, under normal circumstances, reticulocytes account for approximately 1% of all RBCs in blood. In patients with anemia and a normal functional marrow reserve, hypoxia induces EPO production with consequent erythroid hyperplasia in the marrow; reticulocytosis in the blood; and eventual normalization of the RBC count, hemoglobin, and hematocrit.