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]
[PK1:p308]
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