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 20th week of life in the fetal liver & spleen, continues in the bone marrow till young adulthood & beyond!
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• Mesoblastic stage-in the yolk sacStarts at 2 weeks of intrauterine lifeintravascular• Hepatic stage-2-7 monthsBoth liver and spleen• 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 Appendicular marrow is found, in skeleton: Bones of the Upper & children throughout Lower limbs the: In Adults active Axial skeleton: hemopoietic marrow Cranium Ribs. is found only in: Sternum The axial skeleton Vertebrae The proximal ends Pelvis of the appendicular skeleton.
In the adult, red blood cells, many whiteblood cells, and platelets are formed inthe bone marrow. In the fetus, blood cellsare also formed in the liver andspleen, and in adults suchextramedullary hematopoiesis mayoccur in diseases in which the bonemarrow becomes destroyed or fibrosed
In children, blood cells are activelyproduced in the marrow cavities of all thebones. By age 20, the marrow in the cavities ofthe long bones, except for the upperhumerus and femur, has become inactive .Active cellular marrow is called redmarrow; inactive marrow that is infiltratedwith fat is called yellow marrow.
The bone marrow is actually one of the largest organsin the body, approaching the size and weight of theliver. It is also one of the most active. Normally, 75% of the cells in the marrow belong to thewhite blood cell-producing myeloid series and only25% are maturing red cells, even though there are over500 times as many red cells in the circulation as thereare white cells.This difference in the marrow reflects the fact that theaverage life span of white cells is short, whereas that ofred 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”
Hematopoietic stem cells (HSCs) are bone marrow cellsthat are capable of producing all types of blood cells.They differentiate into one or another type ofcommitted stem cells (progenitor cells). These in turnform the various differentiated types of blood cells. There are separate pools of progenitor cells formegakaryocytes, lymphocytes, erythrocytes, eosinophils, and basophils; neutrophils and monocytes arisefrom a common precursor.
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)
ERYTHROPOIESIS15-20µm- 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 •15-20 microns •Mitosis present •Nucleus with multiple nucleoli •Basophilic cytoplasm with polyribosomes •No hemoglobin
Basophilic normoblast Large nucleus Basophilic cytoplasm Active mitosis Slight reduction in size
Basophilic DividingProerythroblast Polychromatophilic erythroblast Polychromatophilic or (or intermediate) or Erythroblast orpronormoblast Erythroblast or Early Normoblast Normoblast Normoblast Orthochromatic Orthochromatic (Acidophilic) Reticulocyte erythroblast erythroblast (brilliant cresyl Reticulocyte Extruding Or blue dye) 1 Nucleus Late Erythroblast 32
1.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)1. PHSC2. Myeloid stem cells3. Proerythroblast4. Basophilic Erythoroblasts (Early erythroblasts) (early Normoblast)5. Polychromatophil Erythroblasts (Intermediate erythroblast or Normoblast)6. Orhochromatic Erythroblasts (Late Erythroblast or Normoblasts)7. Reticulocytes Young erythrocytes8. Erythrocytes 35
DurationDifferentiation phase: from pronormoblast to reticulocyte phase- 5 daysMaturation phase: from reticulocyte to RBC- 2 days
Factor needed ofErythropoiesis 1. Erythropoietin ( Released in response to Hypoxia) 2. Vitamin B 6 (Pyridoxine) 3. Vitamin B 9 (Folic Acid) 4. Vitamin B 12 (Cobolamin) Essential for DNA synthesis and RBC maturation 5. Vitamin C Helps in iron absorption (Fe+++ Fe++) 6. Proteins Amino Acids for globin synthesis 7. Iron & copper Heme synthesis 8. Intrinsic factor Absorption of Vit B 12 9. Hormones 37
HematopoiesisFactors 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.
HematopoiesisFactors 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.
HematopoiesisFactors 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.
HematopoiesisFactors 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 B12 , 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.
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 erythropoiesis1. Tissue Oxygenation
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
Action of Erythropoietin:1. Formation of Pronormoblast from stem cell2. Speeds up the differentiation through various stages of erythropoiesisMechanism of Action:• Formation of ALA synthetase• Activation of Adenylyl Cyclase• Synthesis of transferrin receptors
Maturation factorsVitamin B12 and Folic acid: Essential for DNA synthesis (Thymidine triphosphate) Abnormal and diminished DNA Failure of division and maturation Macrocytic / Megaloblastic anemia
Pernicious AnemiaIntrinsic factor of Castle- secreted by parital cells of gastric mucosaEssential for absorption of Vitamin B12 by enteric route
Other Factors Cobalt Copper Proteins Vitamin C
Clinical AspectsAnemias: Reduced RBC count / reduced Hb concentrationPolycythemia: Increased RBC count Polycythemia vera Secondary polycythemia- due to hypoxia