Erythropoietin (EPO) Physiology

Structure of erythropoietin (EPO)

  • Glycoprotein hormone
  • 165 amino acids
  • Molecular mass – 30 kDa

Site of production/synthesis of erythropoietin (EPO)

  1. Kidneys (75-90%): Peritubular interstitial cells
  2. Liver (15%; chief source in fetus and neonates): Centrilobular hepatocytes

After birth, erythropoietin is not detectable until 8-12 weeks after birth leading to physiological anaemia of the newborn.

Gene for erythropoietin is on chromosome 7.

Mechanism of action of erythropoietin (EPO)

1. Receptor: Tyrosine-kinase (JAK/STAT pathway)

2. Functions in hematopoiesis:

  • Poerthyroblast production:
    • Proliferation: Stimulates mitosis in committed erythroid progenitor cells; it doesn’t act on pluripotent stem cells
    • Differentiation (major): Prevents DNA breakdown
  • Speeds up RBC maturation: Shortens time between recrutiment of precursor stem cells and release of reticulocytes
  • Hemoglobin synthesis: Erythropoietin stimulates the rate-limiting step in hemoglobin synthesis, i.e. formation of ALA from glycine and succininc acid by ALA synthase

Increase in circulating RBCs triggered by erythropoietin takes 2-3 days to appear, since red cell maturation is a slow process.

erythropoietin mechanism

3. Proposed functions outside bone marrow:

  • Blood vessels: Angiogenesis
  • Brain: Neurotrophic and neuroprotective

Stimulation of erythropoietin (EPO) production

1. Hypoxia sensed by kidney (renal hypoxia): Hypoxia increases the abundance of the α subunit of the hypoxia-inducible factor (HIF-1α) which would otherwise undergo ubiquitin-proteasome degradation under normoxic conditions. Abundance of HIF-1α enchances production of erythropoietin mRNA. This can be due to hypoxemia or renal vasoconstriction.

2. Hormones: Androgens, Thyroxine,  Growth hormone, Prolactin, ACTH, Adrenocortical steroids

3. Hemolysates: Products released following hemolysis of RBCs

Mnemonic: Remember 3 “H” that stimulate erythropoietin production.

Erythropoietin (EPO) metabolism

  • Principal site of inactivation is liver.
  • Half-life in circulation is about 5 hours.

Clinical uses of erythropoietin (EPO)

  1. Anemia of chronic renal failure
  2. Myelodysplastic syndrome
  3. Anemia associated with malignancy
  4. Anemia of chronic disease
  5. AIDS
  6. Anemia of prematurity
  7. Presurgical uses (Jeovah’s witness)

Erythropoietin abuse

In blood doping to increase endurance and physical fitness in sports


  1. Kumar and Clark’s Clinical Medicine By Parveen Kumar, Michael L Clark
  2. Principles of Physiology for the Anaesthetist, Second edition By Peter Kam, Ian Power
  3. Ganong’s review of Medical Physiology, 24th edition
  4. Medical Physiology, 2nd Edition by Walter Boron Emile Boulpaep

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