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ERYTHROPOIESIS Dr. Raghuveer Choudhary Associate Prof of Physiology Dr S.N.M.C, Jodhpur


HEMOPOIESIS: INTRO Hemo : Referring to blood cells Poiesis : “The development or production of” The word Hemopoiesis refers to the production & development of all the blood cells: Erythrocytes: Erythropoiesis Leucocytes: Leucopoiesis Thrombocytes : Thrombopoiesis . Begins in the 20 th week of life in the fetal liver & spleen, continues in the bone marrow till young adulthood & beyond!

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It is the process of development, differentiation and maturation of RBCs from primitive stem cells Monophyletic and polyphyletic theory Things to learn:- Site, Stages, Duration, Regulating factors, Clinical abnormalities

Sites of erythropoiesis:

Sites of erythropoiesis Mesoblastic stage- in the yolk sac Starts at 2 weeks of intrauterine life intravascular Hepatic stage- 2-7 months Both liver and spleen Myeloid stage

Myeloid stage:

Myeloid stage Occurs in bone marrow Starts at 5 months of fetal life and takes over completely at birth Red bone marrow of all bones Late adult life, red marrow of flat bones


SITES OF HEMOPOIESIS Active Hemopoietic marrow is found, in children throughout the: Axial skeleton: Cranium Ribs. Sternum Vertebrae Pelvis Appendicular skeleton: Bones of the Upper & Lower limbs In Adults active hemopoietic marrow is found only in: The axial skeleton The proximal ends of the appendicular skeleton.

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In the adult, red blood cells, many white blood cells, and platelets are formed in the bone marrow. In the fetus, blood cells are also formed in the liver and spleen, and in adults such extramedullary hematopoiesis may occur in diseases in which the bone marrow becomes destroyed or fibrosed

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In children , blood cells are actively produced in the marrow cavities of all the bones . By age 20, the marrow in the cavities of the long bones, except for the upper humerus and femur, has become inactive . Active cellular marrow is called red marrow ; inactive marrow that is infiltrated with fat is called yellow marrow.

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The bone marrow is actually one of the largest organs in the body, approaching the size and weight of the liver. It is also one of the most active. Normally, 75% of the cells in the marrow belong to the white blood cell-producing myeloid series and only 25% are maturing red cells, even though there are over 500 times as many red cells in the circulation as there are white cells. This difference in the marrow reflects the fact that the average life span of white cells is short, whereas that of red cells is long.


STEM CELLS These cells have extensive proliferative capacity and also the: Ability to give rise to new stem cells ( Self Renewal) Ability to differentiate into any blood cells lines ( Pluripotency ) They grow and develop in the bone marrow. The bone marrow & spleen form a supporting system, called the “ hemopoietic microenvironment”



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Hematopoietic stem cells (HSCs) are bone marrow cells that are capable of producing all types of blood cells. They differentiate into one or another type of committed stem cells (progenitor cells). These in turn form the various differentiated types of blood cells. There are separate pools of progenitor cells for megakaryocytes , lymphocytes, erythrocytes, eosinophils , and basophils ; neutrophils and monocytes arise from a common precursor.

Stem cells:

Stem cells Totipotential stem cells- convert into any tissue type Pluripotent stem cell- Pluripotent hematopoeitic stem cell Committed stem cells- CFU E, CFU G, CFU M, etc


PROGENITOR CELLS Committed stem cells lose their capacity for self-renewal. They become irreversibly committed. These cells are termed as “ Progenitor cells ” They are regulated by certain hormones or substances so that they can: Proliferate Undergo Maturation.


ERYTHROID PROGENITOR CELLS BFU-E : Burst Forming Unit – Erythrocyte: Give rise each to thousands of nucleated erythroid precursor cells, in vitro. Undergo some changes to become the Colony Forming Units-Erythrocyte ( CFU-E ) Regulator: Burst Promoting Activity ( BPA )

Microenvironment :


Stages of erythropoiesis:

Stages of erythropoiesis Pronormoblast Early normoblast Intermediate normoblast Late normoblast Reticulocyte Erythrocyte

Stages of RBC Maturation:

Figure 19.6 Stages of RBC Maturation

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ERYTHROPOIESIS 15-20µm- basophilic cytoplasm, nucleus with nucleoli. 14-17µm-mitosis, basophilic cytoplasm, nucleoli disappears. 10-15µm-’ POLYCHROMASIA ’ Hb appears, nucleus condenses. 7-10µm- PYKNOTIC Nucleus. Extrusion, Hb is maximum. 7.3µm- Reticulum of basophilic material in the cytoplasm. 7.2µm- Mature red cell with Hb .

Pronormoblast :

Pronormoblast 15-20 microns Mitosis present Nucleus with multiple nucleoli Basophilic cytoplasm with polyribosomes No hemoglobin

Basophilic normoblast:

Basophilic normoblast Large nucleus Basophilic cytoplasm Active mitosis Slight reduction in size

Polychromatophilic normoblast:

Polychromatophilic normoblast Chromatin lumps Hb starts appearing Reduced mitoses

Orthochromatic normoblast:

Orthochromatic normoblast Small and pyknotic nucleus Eosinophilic cytoplasm Mitoses absent

Reticulocyte :

Reticulocyte Reticular nuclear fragments Nucleus extruded Slightly larger than RBCs

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32 Proerythroblast or pronormoblast Basophilic erythroblast or Early Normoblast Polychromatophilic (or intermediate) Erythroblast or Normoblast Dividing Polychromatophilic Erythroblast or Normoblast Orthochromatic (Acidophilic) erythroblast Or Late Erythroblast Orthochromatic erythroblast Extruding Nucleus Reticulocyte Reticulocyte (brilliant cresyl blue dye) 1

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Reticulocytes Young erythrocytes Contain a short network of clumped ribosomes and RER. Enter the blood stream Fully mature with in 2 days as their contents are degraded by intracellular enzymes. Count = 1-2% of red cells Provide an index of rate of RBC formation

Erythrocytes Production (Erythropoiesis):

Erythrocytes Production ( Erythropoiesis ) 34 PHSC Myeloid Stem cells Hemocytoblasts : Cell size large 20-25 mircon Nucelus large Less cytoplasm Mitosis present Proerythroblast : Cell size decrease 15-17 mircon Basophilic 1 Erythroblast: Cell size 12-15 mircon Nucelus Condensed Mitosis present Nucleoli Rudimentary Produces huge number of Ribosomes Hb synthesis starts Polychromatophil 2 Erythroblast: Cell size 10-12 mircon Nucelus Condensed Mitosis Absent Orhochromatic 3 Erythroblast: Cell size 8-10 mircon Nucelus More Condensed Reticulocyte : Young Erythrocytes Cell size 7-8 mircon

Erythrocytes Production (Erythropoiesis):

Erythrocytes Production (Erythropoiesis) PHSC Myeloid stem cells Proerythroblast Basophilic Erythoroblasts (Early erythroblasts) (early Normoblast ) Polychromatophil Erythroblasts (Intermediate erythroblast or Normoblast ) Orhochromatic Erythroblasts (Late Erythroblast or Normoblasts ) Reticulocytes Young erythrocytes Erythrocytes 35

Duration :

Duration Differentiation phase: from pronormoblast to reticulocyte phase- 5 days Maturation phase: from reticulocyte to RBC- 2 days

Factor needed of Erythropoiesis:

Factor needed of Erythropoiesis Erythropoietin ( Released in response to Hypoxia) Vitamin B 6 (Pyridoxine) Vitamin B 9 (Folic Acid) Vitamin B 12 ( Cobolamin ) Essential for DNA synthesis and RBC maturation Vitamin C  Helps in iron absorption (Fe+++  Fe++) Proteins  Amino Acids for globin synthesis Iron & copper  Heme synthesis Intrinsic factor  Absorption of Vit B 12 Hormones 37


Factors affecting erythropoiesis :- C) Hormonal factors: i -Androgens: increase erythropoiesis by stimulating the production of erythropoietin from kidney. ii-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 . Hematopoiesis


Hematopoiesis Factors affecting erythropoiesis:- C) Hormonal factors: iii-Glucocorticoids: 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.


Hematopoiesis Factors affecting erythropoiesis :- C) Hormonal factors: iv-Pituitary gland : Affects erythropoiesis both directly and indirectly through the action of several hormones. v- Haematopoietic growth factors: Are secreted by lymphocytes, monocytes & macrophages to regulate the proliferation and differentiation of proginator stem cells to produce blood cells.


Hematopoiesis Factors affecting erythropoiesis:- D)-State of liver & bone marrow: i-Liver: Healthy liver is essential for normal erythropoiesis because the liver is the main site for storage of vitamin B 12 , folic acid, iron & copper. In chronic liver disease anemia occurs. ii-Bone marrow: When bone marrow is destroyed by ionizing irradiation or drugs, aplastic anemia occurs.

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Erythropoietin (Formation & role) 1 Glycoprotein, Mol wt= 34,000. Erythropoietin, a hormone, produced mainly by the kidneys(90%) and also by liver(10%), stimulates erythropoiesis by acting on committed stem cells to induce proliferation and differentiation of erythrocytes in bone marrow. Site of Action: BONE Marrow

Regulation of erythropoiesis:

Regulation of erythropoiesis 1. Tissue Oxygenation

Erythropoietin :

Erythropoietin Glycoprotein with 165 amino acids, 4 oligosaccharide chains and molecular weight of 34,000 Production- 85% by peritubular capillary bed interstitial cells(Kidney) and 15% by perivenous hepatocytes( Liver) Also seen in brain, salivary glands, uterus, oviducts

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Factors increasing erythropoietin secretion: Hypoxia Androgens Growth Hormone Catecholamines Prostaglandins Factors inhibiting erythropoietin secretion: Estrogen Theophylline

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Action of Erythropoietin: Formation of Pronormoblast from stem cell Speeds up the differentiation through various stages of erythropoiesis Mechanism of Action: Formation of ALA synthetase Activation of Adenylyl Cyclase Synthesis of transferrin receptors

Maturation factors:

Maturation factors Vitamin B12 and Folic acid: Essential for DNA synthesis ( Thymidine triphosphate ) Abnormal and diminished DNA Failure of division and maturation Macrocytic / Megaloblastic anemia

Pernicious Anemia:

Pernicious Anemia Intrinsic factor of Castle- secreted by parital cells of gastric mucosa Essential for absorption of Vitamin B12 by enteric route

Other Factors:

Other Factors Cobalt Copper Proteins Vitamin C

Clinical Aspects:

Clinical Aspects Anemias : Reduced RBC count / reduced Hb concentration Polycythemia: Increased RBC count Polycythemia vera Secondary polycythemia - due to hypoxia

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