HEMA-1-Chapter-3.pdf

CHAPTER 3: ERYTHROCYTE A. ERYTHROPOIESIS - A process by which erythroid precursor cells differentiate to become mature RBC. - The primary regulator of this process is ERYTHROPOIETIN - It normally takes 3-5 days for the production of reticulocytes from pronormoblasts. - The reti...

CHAPTER 3: ERYTHROCYTE A. ERYTHROPOIESIS - A process by which erythroid precursor cells differentiate to become mature RBC. - The primary regulator of this process is ERYTHROPOIETIN - It normally takes 3-5 days for the production of reticulocytes from pronormoblasts. - The reticulocytes remain in the bone marrow for 1-2 days before being released in the circulation. - In the peripheral circulation, the reticulocyte continues to mature for one more day. - Primary stimulus for EPO production and thus erythropoiesis – HYPOXIA STAGE CELL NUCLEUS CYTOPLASM N/C OTHER DESCRIPTION SIZE RATIO (um) PRONORMOBLAST/ 14-20 1-2 nucleoli, fine Deeply 8:1 Globin production RUBRIBLAST chromatin basophilic, non- begins, up to 16 RBCS granular are produced from a single rubriblast BASOPHILIC 12-17 Nucleoli usually not Intensely 6:1 Detectable level of NORMOBLAST/ visible, slightly coarse basophilic Hemoglobin synthesis PRORUBRICYTE chromatin POLYCHROMATOPHILIC 10-15 Nuclear volume Blue-gray to 4:1 Last stage capable of NORMOBLAST/ occupies only half of pink-gray mitosis, 1st stage where RUBRICYTE the cell area, hemoglobin synthesis moderately condensed is visible chromatin, intensely staining chromatin ORTHROCHROMIC 7-12 Small pyknotic (dark Pink 1:2 Nearly complete NORMOBLAST/ structure less and non- production of METARUBRICYTE functional nucleus Hemoglobin, later in this stage the nucleus is ejected RETICULOCYTE/DIFFUSELY 7-10 Non-nucleated Pink to slightly reticulum of RNA are BASOPHILI ERYTHROCYTE pinkish-gray, only visible using contains fine SUPRAVITAL STAIN, basophilic end of hemoglobin reticulum of synthesis RNA ERYTHROCYTE/DISCOCYTE 6-8 Non-nucleated Pink BICONCAVE, appears salmon pink, 1/3 central palor, has a lifespan of 120 days B. GENERAL MORPHOLOGIC CHANGES ASSOCIATED WITH MATURATION NUCLEUS CYTOPLASM 1. Loss of nucleoli 1. Decrease in basophilia 2. Decrease in size of nucleus 2. Increase in the proportion of the cytoplasm 3. Condensation of chromatin 3. Appearance of granules 4. Possible changes in shape 5. possible loss of nucleus C. MORPHOLOGIC CHANGES ASSOCIATED WITH RBC MATURATION 1. ↓ overall size 2. ↓ size of nucleus & N:C ratio 3. Nuclear chromatin pattern 4. Nucleoli disappear 5. Decrease in basophilia D. ERYTHROCYTE NOMENCLATURE NORMOBLASTIC RUBRIBLASTIC ERYTHROBLASTIC Pronormoblast Rubriblast Proerythroblast Basophilic normoblast Prorubricyte Basophilic erythroblast Polychromatic normoblast Rubricyte Polychromatic erythroblast Orthochromatic normoblast Metarubricyte Orthochromatic erythroblast Polychromatophilic erythrocyte Reticulocyte Polychromatophilic erythrocyte Erythrocyte Erythrocyte Erythrocyte E. ERYHTROCYTE METABOLISM 1. Embden-Meyerhof pathway o Major source of red cell energy o Anaerobic glycolytic pathway o 90% glycolysis occurs in this pathway o Results in a net gain of 2 ATP molecules per 1 glucose molecule o ATP controls Na and K and prevent oxidation of membrane lipid o Common enzyme being deficient is PYRUVATE KINASE 2. Hexose Monophosphate pathway o Aerobic glycolysis o 10% glycolysis occurs in this pathway o NADP is reduced to NADPH > NADPH reduces glutathione > reduced glutathione reduces peroxide to water, which prevents denaturation of hemoglobin o Common enzyme being deficient is G6PD (deficiency of this enzyme yields HEINZ BODIES 3. Methemoglobin reductase pathway o NADPH reduces Ferric iron to Ferrous state in the presence of Methemoglobin reductase o Maintains hemoglobin in Ferrous state to be functional (Fe2+) 4. Rapoport-Luebering Pathway o Generates 2,3 diphosphoglycerate (2,3-DPG) which regulates oxygen delivery to tissues by competing with oxygen for hemoglobin o When 2,3-DPG binds hemoglobin, oxygen is released which enhances delivery of oxygen to tissues o ↑ 2,3-DPG = ↓O2 affinity = ↑ O2 delivery F. RBC MEMBRANE o RBC deformability  Has an excess surface-to-volume ratio which enables RBCs to stretch as they pass capillaries and splenic pores  When hemoglobin (viscosity) increases, RBC becomes less deformable o RBC elasticity  Attributed to the membrane composition which is 8% Carbohydrate, 52% Proteins, 40% Lipids  Deficiency in enzymes required for cholesterol exchange between thte plasma and RBC membrane leads to a decrease in tensile strength (acanthocytosis)  When cholesterol increases, the RBCs gains tensile strength but loses elasticity o RBC Membrane proteins  Integral protein: Glycophorin A (contains SIALIC ACID responsible for the negativity of red cell membrane- ZETA POTENTIAL)  Peripheral protein: Spectrin (maintains biconcavity of RBCs) and Actin  Loss of ATP leads to decrease in Spectrin phosphorylation and subsequently a loss in membrane deformability o Osmotic balance and Permeability  RBC membrane is impermeable to Na, K, and Ca  Permeable to water, HCO3, and Cl  Damage to the ATPase cation pumps leads to influx of sodium, as sodium enters the cell water follows causing it to swell and become spheroid G. ERYHTROCYTE DESTRUCTION 1. Macrophage-mediated hemolysis (Extravascular hemolysis) o The spleen generates a stressful environment for the RBCs o Glucose is low that leads to reduced glycolysis and reduced ATP production o The pH is low and leads to oxidation of iron o ATP dependent cellular processes begin to fail and lead to a loss in RBC flexibility o RBCs become trapped in splenic sieve and are phagocytosed by macrophages 2. Mechanical hemolysis (Intravascular hemolysis) o Small portion of RBCs rupture in the blood vessels due to turbulence o Haptoglobin and Hemopexin salvage released hemoglobin so that iron is not loss in the urine o Albumin temporarily holds metheme and passes it eventually to hemopexin H. HEMOGLOBIN METABOLISM 1. Structure  Hemoglobin = 4 globin chains + 4 heme groups (4Fe+4 protoporphyrin)  MW 64,000 Da 2. Synthesis a. Heme o Occurs in the mitochondria and cytoplasm of bone marrow RBC precursors o Begins in the mitochondria with the formation of D-ALA from glycine and succinyl coenzyme A o The pathway continues until, in the final step of production of heme, Fe2 combines with protoporphyrin IX in the presence of Ferrochelatase/Heme synthase to make heme o Heme leaves the mitochondria and is joined to the globin chains in the cytoplasm BIOSYNTHESIS OF HEME Succinyl coenzyme A + Glycine Vit. B6) ↓ D-ALA synthase Delta-aminolevulinic acid ↓ D-ALA dehydrase Porphobilinogen ↓ Uroporphyrinogen III cosynthetase Uroporphyrinogen III ↓ Uroporphyrinogen decarboxylase Coproporphyrinogen III ↓ Coproporphyrinogen oxidase Protoporphyrinogen IX ↓ Protoporphyrinogen oxidase Protoporphyrin IX Fe ++ (Ferrous) ↓ Ferrochelatase HEME MOLECULE b. Globin o Produced on specific ribosomes in the cytoplasm of the RBCs o The globin in each hemoglobin molecule consist of four polypeptide chains which determine the type of hemoglobin formed NORMAL HUMAN HEMOGLOBINS HEMOGLOBIN MOLECULAR STRUCTURE STAGE OF LIFE Gower I 2 Zeta, 2 Epsilon Embryonic Gower II 2 Alpha, 2 Epsilon Embryonic Portland 2 Zeta, 2 Gamma Embryonic Fetal (HbF) 2 Alpha, 2 Gamma Newborn and adult A1 2 Alpha, 2 Beta Newborn and adult A2 2 Alpha, 2 Delta Newborn and adult NORMAL HGB CONCENTRATION IN ADULTS: 92-95% HbA 2-3% HbA2 1-2% HbF 3. Function o Carry oxygen for tissue oxygenation and carry CO2 for excretion in the lungs o 1g Hgb = 1.34 ml of Oxygen o The affinity of hemoglobin depends on the partial pressure of oxygen 4. Oxygen dissociation curve o Describes the relationship between pO2 and the oxygen content of hemoglobin o Hemoglobin has a low affinity for oxygen at low tension and a high affinity for oxygen at high oxygen tension o It has a normal sigmoid shape o BOHR EFFECT: shifts of curve to the left or right occur if there are changes in the blood’s pH Shift to the left Shift to the right RESULT Increased affinity for oxygen leading Decreased affinity for oxygen leading to a decreased oxygen delivery to a increased oxygen delivery FACTORS Alkalinity Acidity ↓ 2-3 DPG ↑ CO2 ↓ PCO2 ↑ 2-3 DPG ↓ temperature ↑ temperature Hb variants with increased affinity for Hb variants with decreased affinity for O2 O2 CONDITIONS Lowered body temperature High fever Blood transfusion with depleted 2-3 Acidosis DPG Conditions that produce hypoxia Alkalosis Methemoglobinemia Increased carboxyhemoglobin