Lec 1 Physiology of red blood cells I.pdf

Physiology of red blood cells I Ana Alfonso Piérola Clínica Universidad de Navarra Red blood cells Class 1. Red blood cell physiology A. Erythropoiesis • EPO • Iron metabolism • B12 and folic B. Degradation of erythrocytes C. Red blood cell in a CBC: erythrocyte number, Hb concentration, MCV. D. M...

Physiology of red blood cells I Ana Alfonso Piérola Clínica Universidad de Navarra Red blood cells Class 1. Red blood cell physiology A. Erythropoiesis • EPO • Iron metabolism • B12 and folic B. Degradation of erythrocytes C. Red blood cell in a CBC: erythrocyte number, Hb concentration, MCV. D. Main types of anemia Class 2. Blood groups A. ABO system. B. Rh system. Ana Alfonso Piérola – Hematology Department [email protected] The blood The blood • Red, liquid tissue. • Salty taste (NaCl) and metallic odor Characteristics and taste (Fe from Hb) • Composition • Plasma • Cells: red blood cells, leukocytes and platelets • It represents 7-8% of body weight • Blood volume (volemia): around 4.5-6 liters Blood – Formed elements HEMATOPOIESIS Hematopoiesis is the process of formation, development and maturation of the blood's formed elements (erythrocytes, leukocytes and platelets) from a common and undifferentiated cellular precursor known as pluripotential hematopoietic stem cell. The stem cells found in the bone marrow in adults are responsible for forming all the cells and cell derivatives that circulate in the blood. STEM CELLS Stem cells • Proliferation capacity • Differentiation capacity • Self-renewal capacity • They belong to a tissue • Specific markers • Specific function • They do not reproduce Differentiated cells ERYTHROPOIESIS Erythropoiesis ERYTHROPOIESIS ERYTHROPOIESIS • The pluripotential hematopoietic precursor cell (HSC) gives rise to all hematopoietic cells. • HSC after GM-CSF + IL-3 stimulation, differentiate to BFU-E (burst forming unit-erythroid): capacity to form a large colony with hundreds of red cells in culture medium. • From it arises a cell that in culture produces erythrocyte colonies and is therefore called CFU-E (erythrocyte colony forming unit): express a large number of receptors for erythropoietin and transferrin. • The first cell that can be morphologically identified from the red series is the proerythroblast and from there through the stage of basophilic, polychromatophilic and orthochromatic erythroblast gives rise to reticulocytes (which no longer have a nucleus and do not divide. • The reticulocyte stage cells leave the bone marrow by diapedesis. In peripheral blood there is normally 1% reticulocytes • Red blood cells are the last stage of maduration. Morphologic changes in Erythropoiesis ERYTHROPOIESIS Basofilic Erythroblast Proerythroblast Orthochromatic Erythroblast Polychromatophilic Erythroblast Reticulocytes - RBC Regulatory factors - ERYTHROPOIETIN Erythropoietin is a protein produced in kidney in response to hypoxia • ↓O2  ↑hypoxia inducible factor 1 and 2 (HIF-1 and HIF-2)  ↑EPO • EPO circulates in the blood and binds to its receptor on the surface of target cells: CFU-E • EPO is necessary for the survival of these progenitors and induces the proliferation and differentiation of CFU-E into proerythroblasts. • High levels of EPO accelerate the medullary transit of erythroblasts and the release of reticulocytes into the peripheral blood. • As the concentration of O2 reaching the kidney normalizes, the stimulus for EPO production ceases. Iron metabolism Absorption Ferrous iron Ferric iron • Iron is absorbed in the duodenum • Iron need to be reduced from ferric iron to ferrous iron to be absorbed Duodenum • DMT1 transport ferrous iron inside the enterocyte • Ferroportin transport ferrous iron to Daily iron requirements: 1-2 mg blood • Hepfaestin + ceruloplastin are responsible to convert ferrous iron to ferric iron Iron metabolism Transport • Plasma transport is carried out by transferrin which has two molecules of ferric iron • Target tissues: Transferrin receptor recognized transferrin loaded with iron • It binds and internalizes into lysosomal vesicles where iron dissociates from transferrin • Once inside erythroblasts is incorporated into the HB being synthesized • Iron, transferrin and its receptor are reused Iron metabolism Elimination and storage • Elimination: Iron does not have a regulated elimination system: it is simply lost through the shedding of iron-containing cells (1-2 mg/day). In the case of women, through monthly period. • Storage: (macrophages of the spleen, liver and bone marrow) • Ferritin is a water-soluble complex of iron and apoferritin. It constitutes an accessible iron reserve that can be used in case of need for the synthesis of the heme group. • Hemosiderin is a protein very similar to ferritin, but its iron content is much higher. It consists of heterogeneous aggregates of iron, lysosomal components, and other products of intracellular digestion. It is the main form of iron deposition in the body, although hemosiderin iron is more difficult to mobilize for metabolic use. Iron metabolism Regulation of iron metabolism • Hepcidin: regulates iron metabolism • Liver synthesized • It binds to ferroportin and induce its degradation, increasing iron accumulation in macrophages and reduced iron absorption in enterocytes preventing iron from reaching the blood • Hepcidin inducers: inflammation (tumors, infections, hepatopathies...), elevated plasma iron. • Hepcidin inhibitors: EPO and pregnancy B12 and folic acid • Required for DNA synthesis 5-methyl-TFH Homocysteine Methyl-B12 Methionine B12 Deoxyuridine TFH Dihydrofolate reductase Deoxyuridylate 5,10-methylene-TFH Thymidylate synthetase Dihydrofolate Deoxythymidylate ADN Erythrocyte destruction Erythrocyte destruction Erythrocyte half-life: 120 days. Extravascular hemolysis (spleen) Intravascular hemolysis Erythrocyte destruction Extravascular hemolysis (spleen) RBC are phagocytosed by macrophages • Globin is processed • Iron is recycled • the rest (protoporphyrin) • Macrophages: indirect bilirubin (liposoluble). Indirect bilirubin binds albumin and is transported through plasma bound to the liver. • Liver: it is transformed into direct bilirubin (water-soluble) and is eliminated by bile. • GI: metabolized to urobilinogen, stercobilinogen and storcobilin which stains the feces. A fraction of urobilinogen is reabsorbed and eliminated again by bile (enterohepatic circulation). • Kidney A part of the urobilinogen is eliminated in the urine in the form of urobilin which gives the typical yellow color of urine. Pathological hemolysis: increase in indirect bilirubin, but direct bilirubin remains at normal levels because the liver eliminates it correctly in the feces in the form of stercobilin. The presence of an excess of bilirubin is manifested as yellowish coloration of skin and mucous membranes and is called jaundice. Erythrocyte destruction Intravascular hemolysis • Hb is toxic to the kidney so in the blood it binds to haptoglobin and the heme group to hemopexin, and thus prevents it from leaking into the kidney which could be seriously damaged • If hemoglobin exceeds the capacity of haptoglobin and the capacity of the renal tubule cells to reabsorb it, Hb appears in the urine staining it red: hemoglobinuria. It is indicative of severe intravascular hemolysis Anemia ANEMIA DEFINITION: decrease in the concentration of hemoglobin in the blood, which may be due to the fact that there are too few erythrocytes or too little hemoglobin in them. SIGNS / SYMPTOMS: they depend on the speed of onset: asthenia, hypotension, dizziness ... CLASSIFICATION: • Morphological: the mean corpuscular volume. • Microcytic. The most frequent is iron deficiency anemia. • Normocytic. The anemia of chronic diseases. • Macrocytic. The most typical is anemia due to B12 or folic acid deficiency. Pathophysiological: According to the capacity of generation of red blood cells by the bone marrow, measured by the number of reticulocytes. ANEMIA KINETIC CLASSIFICATION OF ANEMIAS - RETICULOCYTES HYPORREGENERATIVE ANEMIAS (or aregenerative or central) LOW RETICULOCYTES Nutrient deficit • • • Iron deficiency Vitamin B12 deficiency Folic acid deficiency Bone marrow disease • • • Aplastic anemia Myelodysplastic syndromes Tumor, infection Decreased erythropoietin production • Advanced chronic kidney failure Hereditary hemolytic anemias • • • Hereditary spherocytosis Sickle cell anemia Thalassemia Acquired hemolytic anemiasas • • • Autoimmune Microangiopathy Malaria Obvious bleeding • • • • Injuries, accidents, surgery Digestive bleeding (hematemesis, melena) Metrorrhagia Hematuria Hidden bleeding • Minor digestive bleeding Iatrogenic • • Repeated venipuncture Hemodialysis • Excessive blood donations REGENERATIVE (or peripheral) ANEMIAS HIGH RETICULOCYTES Increased destruction Blood loss Physiology of red blood cells I Ana Alfonso Piérola Clínica Universidad de Navarra