Regulations of Erythropoiesis

❖Factors affect and regulate Erythropoiesis:

I. Oxygen supply of tissues: “Tissue hypoxia”: is the most
important regulator factors
II. Available of BFU-E and CFU-E stem cell
III. Hormonal factors:
• Erythropoietin (Epo)
• Growth hormone
• Steroid hormone
• Thyroid hormone
• Androgens
IV. Dietary factors:
• Proteins (amino acids)
• Iron
• Vitamins:
-Vitamin B
12 & Folic Acid
V. Growth Factors:
• Insulin
• IL-1, IL-4, IL-6, IL-7, IL-11,
IL-12, GM-SCF
• Macrophage inflammatory
protein (MIP) and steel
factor (SF)
• Stem Cell Factor (SCF) very
important for growth and
differentiation of BFU-E
VI. State of liver & bone marrow
Regulations of Erythropoiesis conti .
I. Tissue Hypoxia:
▪ Erythropoiesis begins when there is reduction in Hb concentration in
circulating blood
▪ The reduction in Hb will lead to changes in tissue O2 tension within
the kidney. → i.e. Decreased oxygen supply (hypoxia) to kidney
tissues or any body tissues stimulates secretion of Epo hormone
• Hypoxia stimulates kidney to release renal erythropoietic factor
(REF) and also stimulates liver to produce a special type of globulin.
• Both REF & globulin unite in plasma lead to stimulate
formation of Epo in the kidney and liver.
• Then Epo stimulates CFU-S in BM to differentiate and
produce BFU-E and CFU-E.
• Epo accelerates nearly all stages of RBCs formation, i.e. it
stimulates proliferation & differentiation of committed
progenitor stem cells to increase number of mature RBCs
II. Hormonal factors:
1- Erythropoietin (Epo):
▪ The gene for Epo is located on chromosome 7
▪ its the first human hematopoietic growth factor to be identified
▪ Normally, Epo is produced daily at a constant volume to face
request caused by destruction of the 1% of circulating RBC’s
▪ It is a heat stable glycoprotein, with MW= 46,000Kds,
▪ It is production from kidneys 90% and from liver 10%
▪ It is the most important growth factor in erythropoiesis
▪ Epo can cross the placental barrier of the fetus
▪ Blood levels of Epo are inversely related to tissue oxygenation
▪ There is normally an inverse relationship between
haemoglobin concentration and erythropoietin level.
▪ Epo can be measured in plasma & urine
▪ Normal concentration of Epo up to 20 mU/mL
▪ The level of Epo can increase up to 20,000 mU/mL in
response to anemia or arterial hypoxemia
▪ High level of Epo found in many
• Pathological conditions such as: Anemia, Lung diseases,
Hemorrhage, Heart failure and
• physiological in High altitude
▪ Hypoxia induce ( increase in production of Epo ) by
messages transmitted to BM from oxygen sensor in the kidney
▪ Erythropoietin Receptors:
• Epo binds to specific receptors on surface of CFU-S
and BFU-E & CFU-E to increase their number and
stimulate proliferate and differentiation
• They are found with highest number on CFU-E &
pronormoblasts.
• The number of Epo receptors per cell gradually decreases
during erythroid cell differentiation
• Reticulocytes and mature erythrocytes do not contain
Epo receptors
❖Mechanism production of Epo
Epo Regulation of Erythropoiesis
III. Hormonal factors:
2-Androgens:
▪ increase erythropoiesis by stimulating the production of
erythropoietin from kidney.
3-Thyroid hormones:
▪ Stimulate the metabolism of all body cells including the bone
marrow cells, thus, increasing erythropoiesis.
▪ Hypothyroidism is associated with anemia while
▪ Hyperthyroidism is associated with polycythaemia.
4-Steroid hormones:
▪ Stimulate the general metabolism and also stimulate the bone
marrow to produce more RBCs.
▪ In Addison’s disease (hypofunction of adrenal cortex) anemia
present, while in Cushing’s disease (hyperfunction of adrenal
cortex) polycythaemia present.
III. Dietary factors:
1. Proteins: a high biological value are needed in the formation of
globin chains which it enters in hemoglobin formation in RBCs.
2. Metal ions:
A. Iron Fe+2:
▪ Essential for hemoglobin formation in erythroblast cell because
it enters in the formation of the heme part in Hb
▪ Iron in food mostly found in oxidized form (Ferric = Fe+3 )
▪ Fe+3 in stomach is reduced to Ferrous (Fe 2 +) by gastric acid
& Vitamin C then absorbed in reduced form (Fe+2)
▪ Rate of iron absorption depend on the amount of iron stored
▪ Fe+2 Stored in two forms in the cells:
1. Ferritin (apoferritin + iron) in the liver, spleen and BM
2. Hemosiderin insoluble complex molecule
▪ Daily loss of iron is 0.6 mg in male & 1.3mg /day in females.
▪ Total Iron in the body = 4-5g
▪ It is deficiency intake causes iron deficiency anemia
B. Copper Cu:
▪ It is carried & transported by plasma protein ceruloplasmin.
▪ It catalyses the oxidation of Fe++ to Fe+++, a reaction that must occur before
transferrin can combine and transport iron
C. Cobalt Co:
▪ It stimulates Epo release from kidney.
▪ So, excess Co may produce polycythaemia.
3-Vitamins B12 (Cyanocobalamine) & Folic Acid:
▪ Vit-B12: needs the intrinsic factor (IF) from the gastric juice for absorption from
small intestine.
▪ Deficiency of B12 & Folic Acid resulting in:
1- failure of nuclear maturation & division.
2- abnormally large & oval shape RBC.
3- short life span.
4- reduce RBC count & Hb level.
5- macrocytic cell result in anemia.
▪ Deficiency of B12 & Folic Acid causes megaloblastic anemia
or impaired absorption cause pernicious anemia due to IF missing
▪ It’s stimulates Erythropoiesis
▪ It’s found in meat & diary products
V. Growth Factors:
▪ Cytokines secreted by various cells have been found to
stimulate erythropoiesis they include:
• Insulin
• IL-1, IL-4, IL-6, IL-7, IL-11, IL-12,
• Macrophage inflammatory protein (MIP) and steel factor
(SF)
• Stem Cell Factor (SCF) very important for growth and
differentiation of BFU-E
▪ Needs transcription factors
Abnormalities in Erythropoiesis
Abnormal production, maturation and survival of RBCs during
erythropoiesis i.e. Quantitative and/or qualitative abnormalities
❖ Disorders of erythropoiesis may occur as a result of:
1. lack or absence of pluripotent hemopoietic stem cells as seen
(aplastic anemia, or replacement with leukemia, carcinoma)
2. Viral infection or chronic reduction of only the erythrocytic
precursor cells (isolated aplastic anemia) due to autoantibodies
against erythropoietin or against of the precursor RBC cells;
3. Erythropoietin deficiency in renal failure (renal anemia);
4. Chronic inflammation or tumors that can activate
erythropoiesis-inhibiting interleukins (secondary anemia);
5. Abnormal cell differentiation result from defective DNA
synthesis (megaloblastic anemias), which mainly be due to a
deficiency in folic acid or vitamin B12
6. abnormal Hb synthesis due to
▪ deficiency iron intake and metabolism.
▪ Defect globin synthesis
A. Quantitative Abnormalities in production of RBCs:
1. Anemias: reduction the number of RBC below the normal level,
decrease the quantity of Hb, and the volume of packed RBC
2. Polycythemias: excess RBCs production lead to increase blood
viscosity
❖Anemia: Causes
1. Impaired RBC production :
2. Haemolytic anemia → excessive RBC destruction:
3. Blood Loss
I. Impaired RBC production:
1. Inadequate supply of nutrients essential for erythropoiesis.
▪ iron deficiency
▪ vitamin B-12 deficiency
▪ folic acid deficiency
▪ Copper deficiency &Vitamin C deficiency
▪ protein-calori malnutrition
▪ protein depletion
▪ other less common deficiencies
2. Depression of erythropoeitic activity
▪ In endocrine failure (thyroid, androgen, pituitary)
▪ In kidney disease (low production Epo)
3. Anaemias associated with chronic disorders.
▪ infection
▪ connective tissue disorders
▪ inflammatory disorders
▪ disseminated malignancy
▪ renal disease
4. Aplastic anaemia:
5. Anaemia due to replacement of the bone marrow by
▪ leukemia
▪ lymphoma
▪ myeloproliferative disorder
• polycythemia
• essential thrombocythemia
• chronic myeloid leukemia
• myelofibrosis
▪ Myeloma
▪ Myelodysplastic disorders
6. Anaemia due to inherited disorders
▪ Thalassaemia
▪ Sickle anemia
▪ Variants of Hemoglobin
B. Qualitative Abnormalities in morphology of RBCs
production:
▪ RBC production may be: normal or abnormal in shape
▪ Normally, mature erythrocytes (discocytes) are smooth, round,
biconcave (disc shaped), lack a nucleus and elasticity and
flexibility wall.
▪ Many Pathological conditions that may be lead to abnormalities in
RBC production→
▪ RBCs variations from normal production can be classified as:
1. Variation in size (anisocytosis).
2. Variation in shape (poikilocytosis).
3. Hemoglobin content: alteration in color of central hole of
RBC due to Hb concentrations change (normal - normochromic,
increased hole- hyperchromic, decreased hole- hypochromic)
4. Alterations in the erythrocyte distribution on a peripheral
blood smear
1. Variations in Erythrocyte Size: is called anisocytosis
❖ Normal RBC has average diameter of 7.2
mm with a usual variation of 6.8- 7.8 mm.
❖ Rang size limits are generally considered to
be 6.2-8.2 mm.
❖ Normal RBC size is referred to as normocytic.
❖ RBC may be production either
▪ larger than normal is called macrocytic
• RBCs are exceed size than 8.2-mm diameter limit, whereas
▪ Smaller than normal is called microcytic
• RBCs are smaller than the average
6.2-mm diameter.
❖ Variation in cell size is called anisocytosis
2. Variations in Erythrocyte Shape: called poikilocytosis
❖ The general term for mature erythrocytes that have a shape
other than the normal round, biconcave appearance on a stained
blood smear, or variations, is poikilocytosis
❖ Poikilocytes: Specific names have
been given to many of these shapes
2. Variations in Erythrocyte Shape: called poikilocytosis
1. A: normal RBCs (discocytes);
2. B: acanthocytes;
3. C: blister cells;
4. D: burr cells;
5. E: poikilocytes;
6. F: crenated RBCs (echinocytes);
7. G: elliptocytes;
8. H: helmet cells ;
9. I: leptocytes;
10. J: oval macrocytes( megalocytes)
11. K: schistocytes (schizocytes);
12. L: sickle cells(drepanocytes);
13. M: spherocytes;
14. N: stomatocytes;
15. O: target cells (codocytes);
16. P: teardrops (dacryocytes).
Structure and Catabolism of Erythrocytes
Normal Erythrocytes Survival and Life
❖ Mature RBCs have a lifespan of 100-120 days and
❖ senescent RBCs are removed by the spleen.
❖ Important things for RBC survive for 120-day life
cycle, the
following conditions are necessary:
1. RBC membrane must be deformable and
2. must maintain osmotic balance and permeability.
3. Hemoglobin structure and function must be normal
and adequate.
Characteristics of Mature Erythrocytes
❖ Size: mature RBC is approximately 7.2 m in diameter
❖ Shape: Stained RBCs, appear as non-nucleated reddish to pinkish
cytoplasm and biconcave discs
❖ Biconcave shape provides a surface area >50 % greater than that of
a sphere of the same volume, thereby providing an efficient transport
vehicle for oxygen exchange.
❖ Able to squeeze there self through some tight spots in
microcirculation vines. For that RBCs must be easily & reversibly
deformable through capillaries of less than half their diameter
❖ Why RBCs are not true cells? because they:
▪ Contain no nucleus or nucleic acids, and thus, can not division
and con not maintained their compositions.
▪ Contain no cell organelles (as mitochondria, Golgi, ER or
lysosomes) and thus possess no synthetic activities (no protein
biosynthesis, no lipid synthesis & no carbohydrate synthesis).
❖Why RBC have a specialized membrane ?because:
▪ provide both character of fluidity & flexibility
• RBC flexibility is provided by specific membrane proteins
attached to an underlying cytoskeleton that is adaptable to
shape change, elongation & deformation)
▪ Provide biconcave shape to increased aria of O2 and CO2 transport
▪ Contains specific proteins that safe there survival for 120 days
▪ Separate the intracellular fluid environment of the cytoplasm of
cell from the extracellular fluid environment around cell
▪ Selectively pass nutrients and ions into and out of cell
▪ Composed of lipids and proteins to form the cytoskeleton of the
cell, which regulate membrane shape and deformability
▪ Keep electrolytes concentration in balancing inside and outside cell
such as potassium, magnesium, and zinc concentrations in red cells
much higher than in the plasma.
❖ Mature RBCs lack enzymes and cellular organelles necessary
to synthesize new lipid or protein, so extensive damage cannot
be repaired and the cell will be culled in the spleen.
❖ RBCs membrane comprises:
I. 40% is a lipid bilayer (semi-permeable) supported by a protein
cytoskeleton (contains both integral and peripheral proteins),
which determine the membrane fluidity.
▪ Gets lipids from circulating LDL
II. 52% is proteins (which is responsible for flexibility) that are
either peripheral or integral penetrating the lipid bilayer
▪ Mature RBC does not synthesize new proteins
III. 8% is carbohydrates that occur only on the external surface.
Metabolism of Mature Erythrocytes RBC Energetics:
❖ RBC contain enzymes of anaerobic glycolytic pathways to
produce energy that is required to:
1. preserve the membrane integrity
2. various enzymatic reactions
3. Maintain reduced proteins as hemoglobin in its reduced state for
proper functioning
4. cell metabolism
5. prevent oxidation of iron atom in heme ring and the sulfhydryl
groups on the globin molecule
• Oxidation of the normal ferrous state (Fe+2) to ferric state
(Fe+3) results in methemoglobin (metHb) which does not
deliver O2
• Normally 1-3% of Fe+2 in Hb is oxidized to methemoglobin
• Oxidation of sulfhydryl groups causes hemoglobin
precipitation on cell membrane (Heinz body formation)
❖ RBCs contain no mitochondria, so there is
▪ no respiratory chain,
▪ no citric acid cycle, and
▪ no oxidation of fatty acids or ketone bodies.
❖ Sources of Energy in the form of ATP is obtained by
glycolysis process only from:
I. The Embden-Meyerhof Pathway (EMP):
• anaerobic process for energy generation from glucose
catabolism to lactate
• 90%-95% of glucose is metabolized by the EMP
II. Pentose phosphate pathway(PPP):
• 1% of glucose used in this pathway
❖ Glucose transport through RBC membrane in order to metabolism:
▪ by a facilitated diffusion using glucose transporters (GLUT-1)
• Glucose transporters (GLUT-1) are independent on insulin i.e.
insulin does not promote glucose transport to RBCS
Catabolism and Destruction of Erythrocytes
❖ At the end of 120 days the erythrocytes are recognized as
abnormal cell that make it susceptible to destruction by
macrophage
❖ Older erythrocyte have decreased and changes in the contents
of the following:
▪ glycolytic enzyme activity
▪ sialic acid and lipids property
which leads to:
▪ loss of deformability and membrane integrity
▪ Increase rigidity and fragility, and
▪ their hemoglobin begins to degenerate
❖ For this reason the erythrocyte is no longer able to move
through the microcirculation and removed by macrophages in
endothelial system (spleen)
Sits and methods of RBCs Fate:
❖ Spleen is the place where RBCs are tested for viability and integrity
❖ Spleen is the most active site for phagocytosis of aged cells by
macrophage. How?
▪ By blood flow through the splenic venous sinusoids, where
erythrocyte flexibility is tested
▪ The aged and abnormal of erythrocyte shape will be remove and
destruction by phagocytic cell found in microvesseles of spleen
and this process is called extravascular destruction
▪ Intact erythrocytes return to the circulation of blood via the small
splenic venous sinusoids
▪ There are tow methods for destruction of aged and abnormal
RBC:
1. extravascular destruction (90% in spleen)
2. intravascular destruction (10% in lumen of blood vessels)