Erythropoiesis (Production of red blood cells)

Erythropoiesis Yolk sac in embryonic life Spleen & liver and lymph nodes in middle trimester of pregnancy, early fetal life Red Bone marrow of all the bones in late fetal life and early childhood until age of 5 years. The marrow of the long bones, except for the proximal portions of humeri and tibiae, becomes fatty, produce no more RBCs after 20 yrs.

Beyond this age , red cells are produced in membranous bones such as sternum, vertebrae, ribs and ilia.

Erythrogenesis in bone marrow

Erythropoiesis Erythrocytes are derived from committed erythroid proginator → series of mitotic divisions and maturation phases. Erythropoietin, (kidneys) → stimulates erythropoiesis → proliferation of the committed stem cells and differentiation of erythrocytes 

Blood cells are derived from pleuripotential hematopoietic stem cell. A small portion remain exactly like the original pleuripotential cells. When these cells become committed to form a particular line of cells ,these are called committed stem cells. A committed stem cell that produces erythrocytes is called a CFU-E.

PHSC & blood cells

Stages of Erythropoiesis Pluripotential hemopoietic stem cell Committed stem cell (CFU-E) Proerythroblast Basophilic erythroblast Poly chromatophilic erythroblast Orthochromatic erythroblast Reticulocyte Erythrocyte

Erythropoiesis

Erythropoiesis Tissue  hypoxia (lack of oxygen) is the main stimulus for erythropoietin production. Nucleated red cell precursors in the bone marrow are collectively called erythroblasts. RBCs that have matured to the non-nucleated stage gain entry to the peripheral blood. Once the cells have lost their nuclei they are called erythrocytes.

Erythropoiesis Young  erythrocytes that  contain  residual  RNA  are  called reticulocytes. Bone marrow erythroblast proliferation and maturation occurs in  an orderly and well defined sequence. gradual decrease in  cell  size, condensation and eventual expulsion of the nucleus an increase in hemoglobin production.  

Erythropoiesis Reticulocytes enter into the peripheral blood → maturation into erythrocytes within 24 hours. 1% reticulocytes in the peripheral smear More in new born babies. Visualized by staining with methylene blue Remnants of the ribosomes on the endoplasmic reticulum may be visualized

Erythropoiesis

Erythrocyte kinetics The normal erythrocyte concentration varies with age, sex, and geographic location. ↑ RBC count at birth which Decreases until the age of 2-3 months -physiologic anemia due to low erythropoietin production. ↑RBC count to adult levels at about 14 years of age. Males have higher RBC counts because testosterone stimulates erythropoietin production. High altitude →↓ partial pressure of O2 → ↑ erythropoietin → ↑ RBC

Hypoxia and erythrogenesis

Requirements for normal erythropoiesis Vitamin B12 is required (Synthesis of DNA, maturation) Folic Acid is required (Synthesis of DNA, maturation) Both are required for Thymidine triphosphate Iron Proper porphyrin synthesis Proper globin chain synthesis Cobalt Copper Zinc

Vit B12 and FA are req for the formation of thymidine triphosphate ,one of the essential building blocks of DNA. Failure of nuclear maturation and cell division . Proerythrocytes fail to proliferate rapidly and produce larger than normal RBCs called macrocytes, shape is oval, large, irregular and fragile. Hb content is normal ,life span short.

MATURATION FAILURE DUE TO POOR ABSORPTION OF B12 pernicious anemia, atrophic gastritis. Parietal cells of gastric glands produce IF IF+ B12 IF binds to specific receptor sites on the brush border membrane of the mucosal cells in the ileum. Lack of IF causes faulty absorption of B 12. Sprue, vit B 12 and folic acid not absorbed.

Factors influencing erythropoiesis Growth inducers (interleukin-3),growth and reprod of all types of comitted stem cells. Differentiation inducers cause one type of comitted stem cell to differentiate. Erythropoietin Hypoxia →↑ Renal erythropoietic factor →↑ Erythropoietin →↑ Growth inducers & differentiation inducers →↑erythrogenesis. Low Oxygen for a long time results in growth induction, differentiation and production of large no. of erythrocytes eg. cardiac failure, high altitude. Testosterone, Cortisol.

Erythropoiesis Normally 1-15% of the RBCs die during maturation. Erythroblasts normally spend 4-7 days proliferating and maturing in the bone marrow. The stages of maturation from the most immature to the most mature are:

Proerythroblast

Basophilic Erythroblast

Polychromatophilic Erythroblast

Orthochromic Erythroblast

Reticulocyte

Mature erythrocyte

Erythropoiesis

Erythropoiesis Normal lifespan 100-120 days Old RBCs are removed by the spleen.

The RBC membrane Semi-permeable lipid bilayer Supported by a protein cytoskeleton (contains both integral and peripheral proteins). Extensive damage cannot be repaired The mature cells lack enzymes and cellular organelles necessary to synthesize new lipid or protein.

Cellular Energetics RBCs generate energy almost exclusively from the anaerobic breakdown of glucose .

Polycythemia An increase in RBC mass is called polycythemia and it may lead to an increase in blood viscosity. Polycythemia Relative polycythemia due to decreased plasma volume e.g. in dehydration. Absolute polycythemia due to actual increase in RBC mass. This may occur in disorders that prevent adequate tissue oxygenation

Polycythemia Secondary polycythemia Polycythemia vera Individuals living at high altitudes have increased RBC levels because of the decreased partial pressure of O2 at high altitudes which leads to decreased O2 saturation. Polycythemia vera Uncontrolled proliferation/production/cancer of RBC

Choose the best response, During the middle trimester of gestation, which is the main organ for production of RBCs a)Bone marrow b)Liver c)Lymph nodes

Each gram of pure hemoglobin combines with a)15 ml of oxygen 2)1 Each gram of pure hemoglobin combines with a)15 ml of oxygen 2)1.34 ml of oxygen 3)20 ml of oxygen 4)2.24 ml of oxygen

Among Plasma proteins 80% of osmotic pressure is exerted by Albumin Globulin fibrinogen

After 20 years of age, red cells are produced in the Marrow of long bones Liver Vertebrae, sternum and ribs

Thank-you Questions ??