A Textbook of Clinical Pharmacology and Therapeutics

produced by interstitial cells of the renal cortex adjacent to the
proximal tubules and 10% by the liver. Biosynthesis is stimu-
lated by anaemia/tissue hypoxia which increases levels of the
active form of a transcription factor called ‘hypoxia-inducible
factor-1’ (HIF), which enhances transcription of the erythro-
poietin gene. Endogenous erythropoietin homeostasis is fur-
ther controlled by a negative feedback loop that maintains
red-cell mass at an optimal level for oxygen transport.

Uses

Epoetin, the recombinant form of erythropoietinanddarbe-
poetin(an analogue with a longer plasma half-life) are used to
stimulate red cell growth. These agents are given by subcuta-
neous injection. Haemoglobin is monitored to titrate dosing.
Iron supplementation should be used routinely. Recent studies
in cancer patients showed that when compared to placebo, ery-
thropoietic agents used to treat patients with weaknesss,
malaise and fatigue, but whose Hb was not 12 g/dL and who
were not currently receiving cytotoxic chemotherapy, reduced
patient survival. This suggests the need to more critically evalu-
ate and use erythropoietic agents in such patients and in cancer
patients generally, as many tumours express erythropoietin
receptors.

Erythropoietinis used in:

• anaemia of chronic renal failure;


• anaemia of drug-induced bone marrow suppression (e.g.
  cancer chemotherapy or ZDV therapy);


• anaemia with myeloma;


• anaemia of rheumatoid arthritis;


• autologous blood harvesting for transfusion during
  elective surgery;


• prevention of anaemia in premature babies of low birth
  weight.

Mechanism of action

Erythropoietinbinds to a membrane receptor on erythroid

cell precursors. Signal transduction is through a tyrosine

kinase, that increases transcription of the genes for key haem

biosynthetic enzymes. Thus, erythropoietinincreases haem

biosynthesis and causes differentiation of erythroid precur-

sors into mature erythroid cells.

Pharmacokinetics

Elimination occurs by catabolism in the erythroid cells in the

marrow following internalization, by hepatic metabolism and

to a lesser extent urinary excretion.

HAEMATOPOIETICGROWTHFACTORS 393

Stem cell factor

Pluripotent stem cell

Myeloid stem cell

Uncommitted myeloid precursor

Granulocyte

macrophage precursors

Monocyte

precursors

Granulocyte

precursors

Eosinophils Basophils

Granulocyte

Monocytes precursors

Macrophages Neutrophils

G-CSF

GM-CSF

MCSF

GM-CSF

Platelets

Erythrocytes Megakaryocytes

Tpo

Megakaryocyte

precursors

Erythroid

precursors

Lymphoid

stem cell

Lymphocytes

(for influence of

interleukins see

Figure 50.1)

B cell

T cell

MCSF

GM-CSF

Eosinophil

precursors

Basophils

precursors

EPO

SCF

IL-1

IL-3

IL-6

Figure 49.3:Haematopoiesis and haematopoietic growth factors. EPO, erythropoietin; IL, interleukin; G-CSF, granulocyte colony-
stimulating factor; MCSF, macrophage colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor;
SCF, stem-cell factor; Tpo, thrombopoietin.