Red Blood Cell PDF

Lecture 2+3 Red blood cell A cell in the blood of vertebrates that transports oxygen and carbon dioxide to and from the tissues. In mammals, the red blood cell is disk-shaped and biconcave, contains hemoglobin, and lacks a nucleus. Also called erythrocyte(from Greek erythros...

Lecture 2+3 Red blood cell A cell in the blood of vertebrates that transports oxygen and carbon dioxide to and from the tissues. In mammals, the red blood cell is disk-shaped and biconcave, contains hemoglobin, and lacks a nucleus. Also called erythrocyte(from Greek erythros for "red" and cytos for "hollow", nowadays translated as "cell") , red cell; Also called red corpuscle. In 1658, the Dutch Jan Swammerdam was the first to describe red blood cells; he had used a microscope. Red blood cells are the most common type of blood cells and are the vertebrate body's principal means of delivering oxygen to body tissues via the blood. Erythrocytes deliver oxygen via hemoglobin, a complex molecule containing heme groups whose iron molecules temporarily link to oxygen molecules in the lungs or gills and release them throughout the body. Hemoglobin also carries some of the waste product carbon dioxide back from the tissues. (Less than 2% of the total oxygen, and most of the carbon dioxide are also held in solution in the blood plasma). Red blood cells consist of almost 90% hemoglobin; the heme is what gives blood its red color. A related compound, myoglobin, acts to store oxygen in muscle cells. Mammalian erythrocytes Erythrocytes in mammals are un nucleate when mature, meaning that they lose their cell nucleus and thus their DNA. (The erythrocytes of all other vertebrates have nuclei.) Erythrocytes also lose their mitochondria and produce energy, in the form of ATP from glucose, via glycolysis followed by lactic acid production. Red cells lack the insulin receptor thus glucose uptake is not regulated by insulin. Mammalian erythrocytes have a flattened ovate shape, depressed in the center. This shape is optimized for the exchange of oxygen with the surroundings. The cells are flexible so as to fit through tiny capillaries, where they release their oxygen load. The spleen acts as a reservoir of red blood cells, but this effect is somewhat limited in humans. In some other mammals such as dogs and horses, the spleen sequesters large numbers of red blood cells that are dumped into the blood during times of exertion stress, yielding a higher oxygen transport capacity.  Human erythrocytes The diameter of a typical human erythrocyte is 6-8 µm. Adult humans have roughly 2-3 × 1013 red blood cells at any given time (women have about 4-5 million erythrocytes per cubic millimeter of blood and men about 5-6 million). Red blood cells are thus much more common than the other blood particles: about 4-11 thousand white blood cells per cubic millimeter, and about 150-400 thousand platelets per cubic millimeter. The red blood cells store collectively about 3.5 grams of iron; that's more than five times the iron stored by all the other tissues combined. The blood types of humans are due to variations in surface glycoprotein of erythrocytes. Erythrocytes develop in about 7 days and live a total of about 120 days. The aging cells swell up to a sphere-like shape and are engulfed by phagocytes, destroyed and their materials are released into the blood. The main sites of destruction are the liver and the spleen. The heme constituent of hemoglobin is eventually excreted as bilirubin. Normal human red blood cells  Circulation 3×1013 R.B.C. 900g Hb 1×1013 R.B.C./h 1×1013 R.B.C./h 0.3g Hb/h 0.3g Hb/h Bone marrow Iron Tissue Macrophage System Diet Bile pigments in stool& urine Amino Acids Small amount of iron Red Blood Cell Formation and destruction Red blood cell fragility Red blood cells, like other cells shrink in solutions with an osmotic pressure greater than that of normal plasma. In solutions with a lower osmotic presser they swell, becoming spherical rather than disk-shaped, eventually lose their Hb (hemolysis). The Hb of hemolyzed red cells dissolves in the plasma, coloring it red. A 0.9% sodium chloride solution is isotonic with plasma. When osmotic fragility is normal, red cells begin to hemolyzed when suspended in o.5% saline; 50% lyses occurs in 0.40-0.42% saline and lyses is complete in 0.35% saline. In hereditary Spherocytosis, the cells are spherocytic in normal plasma and hemolysis are more readily than normal cells in hypotonic sodium chloride solutions, spherocytes are also removed by the spleen.  Red cells can also be lysed by drugs and infections. The susceptibility of red cells to hemolysis by these agents is increased by deficiency of the enzyme glucose 6-phosphate dehydrogenase (G6PD). Which catalyzes the initial step in the oxidation of glucose via the hexose mono phosphate pathway. This pathway generates (NADPH) and this is essential in some way for maintenance of normal red cell fragility. Hemopoiesis Sites of Blood Cell Formation: In first few weeks of gestation the yolk-sac is the main site of Hemopoiesis. From six weeks until 6-7 months of fetal life the liver and spleen are the main organs involved and they continue to produce blood cells until about two weeks after birth. The bone marrow is the most important site from 6-7 months of fetal life and during normal childhood and adult life the marrow is the only source of new blood cells. In infancy all the bone marrow is Hemopoietic but, during childhood, there is progressive fatty replacement of marrow throughout the long bones so that in adult life Hemopoietic marrow is confined to the central skeleton. Even in these Hemopoietic areas, approximately 50% of the marrow consists of fat. The remaining fatty marrow is capable of reversion to hemopoiesis and in many diseases there is also expansion of Hemopoiesis down the long bones. More over the liver and spleen can resume their fetal Hemopoietic role so called extramedullary hemopoiesis. Sites of hemopoiesis Fetus: 0-2 months Yolk-sac 2-7 months Liver and Spleen 5-9 months Bone Marrow Infants: Bone Marrow (particularly all bones) Adults: Vertebrae, Ribs, Sternum, Skull, Sacrum, Pelvis and proximal ends of femur. Hemopoietic Stem Cells It is now thought that the common (pluripotential) stem cell gives rise after a- number of cell division and differentiation steps to a series of progenitor cells for three main marrow cell lines a- erythroid b- granulocyte and monocyte c- megakaryocyte, as well as to a common lymphoid stem cell. Although the appearance of the pluripotential stem cells is probably similar to that of small or intermediate size lymphocytes, their presence can be shown by culture techniques. Human Hemopoiesis Fig. 2.3 Diagrammatic representation of bone marrow pluripotent stem cell and the cell lines that arise from it. Erythropoiesis The earliest recognizable erythroid cell in the marrow is the pronormoblast which- in the usual Romanowsky stain is a large cell with dark-blue cytoplasm, a central nucleus with nucleoli and slightly clumped chromatin. By a number of cell division, this gives rise to a series of progressively smaller normoblats. They also contain progressively more Hb (which stain pink) in the cytoplasm; the cytoplasm stains paler blue as it losses its RNA and protein synthetic apparatus while the nuclear chromatin becomes more condensed. The nucleus is finally extruded from the late normoblats within the marrow and reticulocyte stage results which still contains some ribosomal RNA and is still able to synthesis Hb. This cell spend 1-2 days before maturing, mainly in the spleen, when RNA is completely lost and a completely pink-staining, mature erythrocyte results which is a non-nucleated biconcave disc. A single pronormoblast usually gives rise to 16 mature red cells. Nucleated red cells (normoblasts) appear in the blood if Erythropoiesis is occurring outside the marrow (extramedullary Erythropoiesis) and also with some marrow disease. Normoblasts are not present in normal human peripheral blood. Pronormoblast Earlynormoblast Intermediatenormoblast Latenormoblasts Reticulocyte Mature R.B.C. Fig 2.4 The red cell series (diagrammatic). There is progressive condensation of the nucleus which is extruded at the late normoblast stage. The cytoplasm contains progressively less RNA and more hemoglobin. Erythropoietin Erythropoietic activity is regulated by the hormone erythropoietin, which is produced by the combination of a renal factor with a plasma protein. The stimulus to erythropoietin production is the O 2 tension in the tissues of the kidney. When anemia occurs, or hemoglobin for some metabolic reasons is unable to give up O2 normally, erythropoietin production increases and stimulates erythropoiesis by: 1- Increase the number of stem cells committed to erythropoiesis. The proportion of erythroid cells in the marrow increases and, in the chronic states, there is anatomical expansion of erythroid tissue down the long bones and sometimes into extramedullary sites. 2- Increasing hemoglobin synthesis in red cell precursors. 3- Decreasing maturation time of red cell precursors. 4- Releasing marrow reticulocytes into peripheral blood at an earlier stage than normal (shift reticulocytes). On the other hand, increased O 2 supply to the tissue due to an increased red cell mass or because Hb is able to release its O 2 more readily than normal reduces the erythropoietin drive. Substances needed for erythropoiesis Because of the great numbers of new red cells that are produced each day, the marrow requires many precursors to synthesis new cells and the large amount of hemoglobin. The following groups of substances are needed: 1-Metals: Iron, manganese, cobalt. 2-Vitamins: Vitamin B12 (B12), Folate, Vitamin C, Vitamin E, Vitamin B6 (Pyridoxine), thiamine, riboflavine and pantothenic acid. 3-Amino acids. 4-Hormones: Erythropoietin, androgen and thyroxin. Well recognized anemias occur with B12 or folate deficiency. Anemias also occur with amino acid (protein), thyroxin or androgen deficiency but these may be adaptations to the lower tissue O2 consumption, rather than a direct effect of the deficiency on erythropoiesis. Anemia also occurs in the deficiency of vitamin C (scurvy), vitamin and riboflavin, but it is not clear whether these are purely due to an effect of these deficiencies on erythropoiesis. B6 responsive anemias also occur but these are not usually due to B6 deficiency. Hemoglobin synthesis The main function of red cell is to curry O2 to the tissues and to return CO2 from the tissues to the lungs. In order to achieve this gaseous exchange, they contain a specialised protein, hemoglobin. Each red cell contains approximately 640 million hemoglobin molecules and each molecule of normal adult hemoglobin (HbA) consists of four polypeptide chains α2ß2, each with it is own hem group. The molecular weight of Hb is 68000. Normal adult blood also contains small quantities of two other hemoglobins, Hb F and Hb A2 which also contain α chains but γ and δ chains respectively instead of β (Table 2.1). in the embryo and fetus, Table 2.1 Normal hemoglobin in adult blood. A F A2 Structure α2ß2 α2γ2 α2δ 2 Normal (%) 96-98 0.5-0.8 1.5-3.2 hemoglobin Gower 1, Gower 2, Portland and fetal dominant at different stages. Hem synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl coenzyme A under the action of the rate-limiting enzyme delta-amino laevulinic acid (ALA) synthetase. Vitamin B6 is a coenzyme for this reaction which is stimulate by erythropoietin and inhibited by hem. Ultimately, protoporphyrin combines with iron to form hem each molecule of which combines with a globin chain each with it is own hem group in a pocket is then formed to make up a hemoglobin molecule. Hemoglobin function The red cells in systemic arterial blood carry oxygen from the lungs to the tissues and return in venous blood with CO2 to the lungs. As the Hb molecule loads and unloads O2 the individual globin chains in the Hb molecule move on each other. When O2 is unloaded, the ß chains are pulled apart, permitting entry of the metabolite 2,3 diphospho-glycerate (2,3-DPG) resulting in a lower affinity of the molecule for O2. This movement is responsible for the sigmoid form of Hb O2 dissociation.  RBC Development watches for trends! Pronormoblast 1-Biggest in lineage. 2-Large central nucleus with one or two nucleoli. 3-Basophilic cytoplasm b/c ribosomes. Look for Golgi ghost  Pronormoblast & Basophilic (early) Normoblast Early Normoblast 1-Smaller than pronormoblast. 2-Checkerboard nucleus (heterochromatic) 3-Intense basophilia (lots of ribosomes!)  Intermediate Normoblast 1-Smaller than early normoblast. 2--Smaller intensely heterochromatic nucleus. 3-Purple/lilac cytoplasm mix of basophilia from ribosomes and growing eosinophilia from hemoglobin. 4- Last mitotic stage. Late Normoblast 1-Smaller than Intermediate nomoblast. 2-Small, compact, intensely staining nucleus that is getting ready to be extruded. 2-Eosinophilic cytoplasm due to abundant hemoglobin.  Reticulocyte 1- Immature RBC that has polyribosomes. 2-Appear as Intermediate normoblast on blood smear. 3-When stained with a special (supravital) stain the RNA of reticulocyte is stain blue and can distingush from mature RBC. RBC Precursors 1-Pronormoblast. 2-Basophilic normoblast (Early). 3-Polychromatophilic (Intermediate) Normoblast. 4-Orthrochromatophilic (Late) Normoblast. 5-Reticulocyte. 6-Mature Red Blood Cell. 5-7 days from Pronormoblast to Reticulocyte