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).
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.
