Erythropoietin

[Ref: WG21: 463-464; PK1:p307-308; KB2:p208]

Function

Increase RBC production
* Increase in circulating RBC appears 2-3 days later

Mechanism of action

1. Increasing RBC precursors by

• Proliferation
  * Increasing number of erythropoietin-sensitive committed stem cells (????BFU-E cells)
• Differentiation
  * Preventing DNA breakdown so more proerythroblasts are formed

2. Shorten the time between recruitment of precursor stem cells and release of reticulocytes

Receptor

Has tyrosine kinase activity

Belongs to cytokine superfamily

Metabolism

• Inactivated in liver (mainly)
• Halflife in circulation: 5 hours
  * [PK1:p307] 3-8 hours
  * [PK1:p236] 6-9 hours
• Renal excretion also contributes

Source of erythropoietin

• 85% produced in kidney
  * From interstitial cells in the peritubular capillary
  * [PK1:p307] 75-90%
• 15% produced in liver
  * By perivenous hepatocytes
  * (???? same as centrilobular hepatocytes [PK1:p307])

Others

• Also produced in brain, uterus, oviducts
• In brain, it protects excitotoxic damage triggered by hypoxia

Adult vs foetus/neonate

During foetal and neonatal life

Liver is

• Major site of erythropoietin production
• Also major site of erythropoiesis

Subsequently,

• Kidney takes over most of the erythropoietin production
• Bone marrow takes over erythropoiesis

NB:

• After birth, erythropoietin is not detectable until 8-12 weeks after birth
  --> Hb level drop
  * i.e. Physiological anaemia of the newborn

Stimulation for release

• Hypoxia (main)
• Anaemia
• Androgens

Others

[WG21:p464]

• Cobalt salts

[PK1:p308]

• Thyroid hormone
• GH

NB:

• At high altitude, erythropoietin release is stimulated by hypoxia, but also facilitated by alkalosis that develops at altitude
• Secretion facilitated by catecholamine via beta-adrenergic mechanism

Recombinant erythropoietin

Epoetin alfa

• Produced in mammalian cell cultures (not in bacteria)
  --> Thus the expensive price
• Erythropoietin produced in bacterial cultures is unglycosylated and lack biological activity
• 95% of transfusion-dependent dialysis patients respond to treatment

Other notes

• Structure - Glycoprotein, with 165 amino acid residues and 4 oligosaccharide chains
• Coded on chromosome 7