CV-1-Erythropoyesis-Oct_2_2023 (1).pptx

CV-1: Erythropoiesis Guyton & Hall Medical Physiology, 13th Edition, Ch 33: Red blood cells, anemia, and polycythemia, 445-449, 451 Pedro Del Corral, Ph.D. M.D. Associate Professor Department of Physiology & Pathology Burrell College of Osteopathic Medicine October 2nd 2023 1 Objectives • Descri...

CV-1: Erythropoiesis Guyton & Hall Medical Physiology, 13th Edition, Ch 33: Red blood cells, anemia, and polycythemia, 445-449, 451 Pedro Del Corral, Ph.D. M.D. Associate Professor Department of Physiology & Pathology Burrell College of Osteopathic Medicine October 2nd 2023 1 Objectives • Describe the tissues involved in erythropoiesis • Describe the development steps of erythropoiesis • Explain the signals involved in erythropoiesis • Describe the function and mechanism action of erythropoietin • Describe the role of nutrients in erythropoiesis 2 Red Blood cells (RBC) • AKA erythrocytes • Functions • Hemoglobin transport • Oxygen carrier • Carry Carbonic anhydrase • Shape, size, concentration • • • • • Biconcave disks ~7.8 micrometer (diameter) Shape can change in distal vasculature Size: 90-95 cubic micrometers (MCV) Concentration • 5,200,000 per mm3 (men) • 4,700,000 per mm3 (women) 3 Production of red blood cells • Embryonic life • Primitive nucleated RBC produced in yolk sac • 2nd trimester • Liver • Spleen & lymph nodes • Last month of pregnancy & thereafter • Bone marrow • Essentially all bones  Up until age 5 • At ~ age 20: Marrow of long bones become fatty and stops producing RBC • Except for proximal humeri & tibiae • Thereafter  most RBC continue to be produced in marrow of membranous bones • Vertebrae, sternum, ribs, ilia 4 Relative rates of RBC production in the bone marrow of different bones at different ages Figure 33.1 Relative rates of RBC production in bone marrow of different bones at different ages Genesis of red blood cells 5 Genesis of red blood cells: Fig 33-2. Formation of multiple different blood cells from the original pluripotent hematopoietic stem cells in the bone marrow • Pluripotent hematopoietic stem cells • Reproduce, remain/ differentiate • Effects of age • Intermediate cells • Committed 6 Genesis of blood cells • Growth & reproduction • Controlled by different proteins growth inducers • Interleukin-3 stimulates virtually all committed cells • Other factors  more specific • Differentiation • Differentiation inducers • One or more steps  towards final mature cell type • Both of above inducers are under regulatory control, external to marrow • Infection (i.e., WBC) • Chronic hypoxia (i.e., examples) Stages of differentiation 7 Stages of differentiation of RBC Stimulation  CFU-E Stain with basic dyes, spherical nucleus (not fractured) with thin rim of sky blue cytoplasm, little hemoglobin Nucleus condenses, more hemoglobin ER is reabsorbed ↓basophilic material Fractured & spherical nucleus, thin rim of sky blue cytoplasm Poly-chromatic, fractured spherical nucleus Dark, small, spherical nucleus, blue-gray cytoplasm No nucleus, blue-grey cytoplasm Diapedesis capillaries 1-2 days, no basophilic material No nucleus, red cytoplasm • Figure 33-3 Genesis of normal RBC 8 Stages of differentiation of RBC • When proerythroblast loses its nucleolus & become smaller • Basophilic erythroblasts • (accumulation of ribosomes) • Basophilic erythroblasts  darkly staining nucleus and its cytoplasm stains a grayish-green color due to the accumulation of hemoglobin. • Polychromatic erythroblast • Polychromatic erythroblast  the nucleus becomes smaller and darker and the cytoplasm becomes pinker. • Orthochromatic erythroblast • Orthochromatic erythroblast  As it divides, the portion that contains the cytoplasm and organelles becomes: • The reticulocyte • The nucleus was lost (phagocytised) • The reticulocyte contains cytoplasm, cytoplasmic organelles, and many ribosomes. • Released from the bone marrow and develops into a mature erythrocyte after spending 1 to 2 days in the peripheral blood. http://medcell.med.yale.edu/systems_cell_biology/haematopoiesis_lab.php Regulation of RBC production 9 Erythropoietin regulates RBC production • Normally kept within narrow limits • Why? • Tissue oxygenation is the most essential regulator of RBC production • Diseases that ↓ O2 in tissue • Environment • Erythropoietin stimulates RBC production & its formation ↑ in response to hypoxia • Glycoprotein, MW 34,000 • Stimulated by hypoxia. • Hypoxia in the absence of erythropoietin • ↓ RBC production 10 Figure 33-4. Function of the erythropoietin mechanism to increase production of RBC when tissue oxygenation decreases. 11 Erythropoietin is formed mainly in the kidneys • ~90% in kidneys & ~10 in liver • Kidney • Fribroblast like interstitial cells surrounding the tubules in cortex & medullae • Renal tissue hypoxia  hypoxia inducible factor-1 (HIF-1) • Transcription factor for hypoxia related genes • Including erythropoietin • HIF-1 binds to hypoxia response element in erythropoietin gene • ↑ Transcription of m-RNA  erythropoietin • Non-Renal hypoxia  signals stimulate renal erythropoietin synthesis • Catecholamines, prostaglandins, sex steroids • Effects of renal disease or nephrectomy? • Long/short acting preparations 12 Effects of Erythropoietin on bone marrow • Upon hypoxia, erythropoietin release peaks at 24h • New RBC detectable in blood ~ 5 days later • Erythropoietin stimulates production of proerythroblasts from hematopoietic stem cells • It also stimulates the immature cells to pass through the different erythroblastic stages more rapidly than they normally do • The process continues until tissue hypoxia stimulation ceases or Enough RBCs have entered the circulation to offset tissue hypoxia • Erythopoietin will remain at the level needed to maintain the required # of RBC Maturation of the RBC 13 Role of Folic acid & Vitamin B12 on RBC maturation • The RBC need to be synthesize rapidly and in order to do that nutritional requirements must be met • Particularly for RBC maturation • The maturation of RBC requires Vitamin B-12 (cyanocobalamin) and folic acid • Essential for synthesis of DNA • Essential for synthesis of thymidine triphosphate • Low/lack of these nutrients leads to abnormal/diminished DNA • Failure of nuclear maturation & cell division • Slower proliferation • Affects the morphology of the RBC (MCV) • Function properly but last only 1/3 of the their normal life span • Fragile cells 14 Macrocytic megaloblastic anemia 15 Maturation Failure & RBC lifespan • Maturation failure can be cause by poor absorption of Vitamin B12 from the GI tract • Pernicious anemia • Atrophic gastritis  ↓ intrinsic factor: • Binds B-12 (preventing its digestion) • Binds its receptors in the brush border membrane of the mucosal cells in the ileum • B-12 transported via pinocytosis into the blood  stored in liver & released as needed • Normally ~ 3y supply • Maturation failure caused by folic acid deficiency • Green vegetables, fruits, meats • Effects of cooking • Effects of Celiac sprue • The RBC life span is ~ 120 days before being destroy • Become fragile (short life, one-half to one-third normal) • Self destroy as they moved through the red pulp Assessment of erythropoiesis 16 Assessment of erythropoiesis • Ineffective erythropoiesis • ~ 10-15% is ineffective because of cell death within the marrow • Further increased in chronic anemias • ↑LDH & unconjugated bilirubin • Assessment of erythropoiesis • Marrow, Hb, and reticulocyte count • Marrow cellularity, myeloid: erythroid ratio • Reticulocyte count • Expect ↑ in proportion to anemia when erythropoiesis is effective 17