Erythropoiesis and haemoglobin production lecture 13 Flashcards
What is the erythron
total mass of circulating red blood cells and the RBC forming tissues from which they are derived
Describe erythroid development
Early stages of differentiation can only be identified by cell markers
Multipotent stem cell, BFU-E, CFU-E➡️ Late differentiation- pro erythroblasts Early erythroblasts Late erythroblasts Reticulocytes ➡️RBCs
Erythroblastic islands- blood cells form in groups around macrophages for cytokine signalling and nuclear phagocytosis
Describe RBC structure
Biconcave full of haemoglobin
Normoblasts extrude nucleus
Autophagy in reticulocytes- no mitochondria
Sensitive to oxidative damage
V flexible due analytic and spectrin proteins attached to the membrane
Describe some pathogenesis from the alteration in RBC structure
Hereditary sphericytosis- mutation in ankyrin
Hereditary elliptocytosis- mutation in spectrin
Both lead to morphological changes and susceptibility to haemolysis
Sphericytosis- immune haemolysis
Fragments- microanguopsthic haemolysis- fibrin mesh grates up RBCs in small vessels
Define erythroposiesis
erythroposiesis is tightly regulated by cytokines which cause diffrentiation of immature cells
INduction of a sequecne of transcriptio nfactors by the cytokines leads to deicsions to diffrentiate into erythroid rather than megakaryocyti lineages and then further diffrentiation to red blood cells.
Describe the important transcription factors involved in erythropoiesis
GATA2, HIF1A, GATA1 And the growth factor EPO
EKLF drives erythrocytes development and inhibits Fli1 which drives megakaryocyte development
Describe haemoglobin
MAde of 4 subunits - 2 alpha and 2 beta
Each contain a haem molecule
Haem is a planar flat molecule with central Fe2+
Foatal development withi yolk sac, goes to dorsal aorta, then to liver and then bone marrow once born
THe formation of haem is a multi-stage process with several enzymatic processes starting with delta levulinic acid - done in liver by taking up iron to make haem.
Inherited defects in the cascade leads to various disease known as prophyias
Describe haemoglobin production in development
Subunits are regulated by GATA1, GATA2 and EKLF
Local control regions and GATA1/2 and EKLF promote and silence the transcpriotn of globin genes for Hb production in sequence through development from embryo to adult
Early haemoglobin has increased oxygen affinity to allow the uptake of oxygen from the placenta
Adult alpha haemoglobin is produced after 6 weeks
Beta haemoglobin not produced until birth
Beta haemoglobin relpaces gamma haemoglibin several weeks after birt
Fetal haemoglobin made of 2x alpha and 2x gamma subunits
Alpha globin gene are located on chromosome 16 whilst beta is chromosome 11.
Describe some Haemoglobinopathies
- Thalassaemias - lack of haemoglobin, inherited disease causing abnoraml production of haemoglboin
- Sickle cell disease - group of diseases assocaited with inheritence of haemoglobin S
Haemoglobin S is a mutation from glutamine to valine in beta globin, leads to abnormallity of beta haemoglobin, Glutamine become valine, when slightly hypoxic the haemoglobins will crystallise making the sickle shapes - making them non felxible and cannot pass through small vessels. Shift in oxygen dissocaition curve, therefore give oxygen off better to surrounding tissues.
Describe erythropoietin
Most important cytokine involved in the terminal differentiation of red cells- affects early erythroid differentiation
CFU-E➡️ProEB
Made in the kidney by oxygen-sensitive cells around the glomerulus
Interacts with the transmembrane tyrosine kinase
EPO receptor- dimerises and phosphorylates JAK2 which lead to proliferation and differentiation
Describe hypoxia inducible factors
HIF involved with hypoxia, inflammation, angiogenesis
Degraded by ubiquitination in normoxia
HIF-2alpha with O2 wil get ubiquitinated and will tag proteins to get degraded
In hypoxic conditions, increased production of HIF-2alpha, hypoxic response element in Epo gene in promotor leading to production of Epo and therefore increased erythropoisesus.
Describe iron and anaemia
Iron is required for production of haem
Absorbed as Fe2+ and used as Fe3+
Regulation by iron storage is by absorption, controlled by hepcidin, in turn contrlled by HIF.
Iron is difficult to obtain but too much iron is toxin leading to liver damage.
In hypoxia, erthropoietin increases and hepcidin decreases, leading to more iron absorbtion for more red blood cells to be made.
Increaed production of Epo so therefore more erythropoiseis so need more iron . Blocking of hepcidin allos ferroportin to start working and the immobilisation of iron from macrophages. Hepcidin stops you from taking iron from macrophages and absorbing iron from the diet, so blocking hepcidin leads to increased RBC produciton.
Describe amaemia
Caused by lack of production of RBC - by marrow failure, ineffective erthropoiesis, reduced erythropoitin, nutritional deficiencies (B12, iron, folic acid)
Increased destruction of RBCs - haemolysis ( immune oxidative damange, red cell membrane disorders
