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Erythropoietin


Erythropoietin
Erythropoiesis is regulated by the hormone erythropoietin. Erythropoietin is a heavily glycosylated polypeptide. Normally, 90% of the hormone is produced in the peritubular interstitial cells of the kidney and 10% in the liver and elsewhere. There are no preformed stores and the stimulus to erythropoietin production is the oxygen (O2) tension in the tissues of the kidney (Fig. 2.5). Hypoxia induces synthesis of hypoxia‐inducible factors (HIF‐1α and β), which stimulate erythropoietin production and also new vessel formation and transferrin receptor synthesis, and reduces hepcidin synthesis, increasing iron absorption. Von Hippel‐Lindau (VHL) protein breaks down HIFs and PHD2 hydroxylates HIF‐1α allowing VHL binding (Fig. 2.5). Abnormalities in these proteins may cause polycythaemia (see Chapter 15).

Erythropoietin production therefore increases in anaemia, and also when haemoglobin for some metabolic or structural reason is unable to give up O heric O2 is low or when defective cardia or pulmonary function or damage to the renal circulation affects O2 delivery to the kidney.
Erythropoietin stimulates erythropoiesis by increasing the number of progenitor cells committed to erythropoiesis. The transcription factor GATA‐2 is involved in initiating erythroid differentiation from pluripotential stem cells. Subsequently the transcription factors GATA‐1 and FOG‐1 are activated by erythropoietin receptor stimulation and are important in enhancing expression of erythroid‐specific genes (e.g. globin, haem biosynthetic and red cell membrane proteins) and also enhancing expression of anti‐apoptotic genes and of the transferrin receptor (CD71). Late BFUE and CFUE, which have erythropoietin receptors, are stimulated to proliferate, differentiate and produce haemoglobin. The proportion of erythroid cells in the marrow increases and, in the chronic state, there is anatomical expansion of erythropoiesis into fatty marrow and sometimes into extramedullary sites. In infants, the marrow cavity may expand into cortical bone resulting in bone deformities with frontal bossing and protrusion of the maxilla (see p. 78).
Conversely, increased O2 supply to the tissues (because of an increased red cell mass or because haemoglobin is able to release its O2 more readily than normal) reduces the erythropoietin drive. Plasma erythropoietin levels can be valuable in clinical diagnosis. They are high in anaemia unless this is due to renal failure and if a tumour secreting erythropoietin is present, but low in severe renal disease or polycythaemia vera (Fig. 2.6).
The amplification and maturation sequence in the development of mature red cells fromthe pronormoblast, Comparison of the DNA and RNA content, and marrow and peripheral blood distribution, of the erythroblast (normoblast), reticulocyte and mature red blood cell (RBC).

Indications For Erythropoietin Therapy
Recombinant erythropoietin is needed for treating anaemia resulting from renal disease or from various other causes. It is given subcutaneously either three times weekly or once every 1–2 weeks or every 4 weeks, depending on the indication and on the preparation used (erythropoietin alpha or beta, darbepoetin alpha (a heavily glycosylated longer‐acting form), or Micera the longest‐ acting preparation). The main indication is end‐stage renal disease (with or without dialysis). The patients often also need oral or intravenous iron. Other uses are listed in Table 2.2. The haemoglobin level and quality of life may be improved. A low serum erythropoietin level prior to treatment is valuable in predicting an effective response. Side‐effects include a rise in blood pressure, thrombosis and local injection site reactions. It has been associated with progression of some tumours which express Epo receptors.
The marrow requires many other precursors for effective erythropoiesis. These include metals such as iron and cobalt, vitamins (especially vitamin B12, folate, vitamin C, vitamin E, vitamin B6, thiamine and riboflavin) and hormones such as androgens and thyroxine. Deficiency in any of these may be associated with anaemia.
The production of erythropoietin by the kidney in response to its oxygen (O2) supply. Erythropoietin stimulates erythropoiesis and so increases O2 delivery. BFUE, erythroid burst‐forming unit; CFUE, erythroid colony‐forming unit. Hypoxia induces hypoxia inducible factors (HIFs) α and β, which stimulate erythropoietin production. Von‐Hippel–Lindau (VHL) protein breaks down HIFs. PHD2 (prolyl hydroxylase) hydroxylates HIF‐1α allowing VHL binding to HIFs. Mutations in VHL, PHD2 or HIF‐1α underlie congenital polycythaemia (see p. 171).