Destruction Of Red Blood Cells PDF

# Destruction of Red Cells ## Lifespan of red cell * Life span of red cell is about 100 to 120 days. * Some techniques have been used to measure the life span of red cells. * Most methods employ the use of tracer substances known as labels to find out how long it takes such labels to disappear f...

# Destruction of Red Cells ## Lifespan of red cell * Life span of red cell is about 100 to 120 days. * Some techniques have been used to measure the life span of red cells. * Most methods employ the use of tracer substances known as labels to find out how long it takes such labels to disappear from the blood. ### Label procedure * One method involves labelling the red cells with radioactive Chromium - About 5-10ml of the subjects blood is drawn. * Radioactive Chromate (Na2CrO4) is added to the blood and returning them after washing, resuspension and incubating for 37°c for some minutes) to the circulation of the individual. * The chromate binds to the β chains of HbA, or the γ chains of HbF. * The samples of the blood are taken at intervals and radio activity is counted. * This is continued until little or no radioactivity can be detected in the blood: The radioactive sart is strongly absorbed on the treated red cells. * The red cell survival time is then determined from radioactive counts of blood samples withdrawn at suitable timed intervals of days. * By this means, it has been established that the average lifespan of red cells in human circulation is about 120 days. * β chains of HSA > chromate binds to β chains of HSF. ## Phagocytosis of Red cell by Macrophages * Removal of Senescent RBC (to grow old) from the circulation occurs through phagocytosis (erythrophagocytosis) which takes place mainly in macrophages of the spleen, but also in the liver and a range of bone marrow. * Macrophages recognize wornout cell that display senescence markers. * Following recognition and binding, the RBC are phagocytized, undergo hemolysis and their components are reutilized. ## Aging of RBC * Aging of RBC includes changes in many properties decreasing metabolic activity, morphological alterations, including decreased cell volume, and changes in cell shape, and quantitative and qualitative modulations of the surface. * Decreased metabolic activity is manifested by loss of aspartate amino transferase (ASP) and esterase activities. * In addition, RBC are naturally damaged by oxidation during aging and a number of molecular modifications induced by oxidative stress have been observed in worn out RBC. * Some of these modulations are recognized by macrophages as senescence signals but the relative contribution of these signals to erythro phagocytosis is not known. ## Sites of Phagocytosis * Macrophages are responsible for about 80% phagocytosis of red blood cell while about 10-20% occurs intravascularly. * The macrophages are blood monocytes which leave blood circulation and settle in various tissues throughout the body especially at: * Red pulp of the spleen, the lining of the sinusoids of the bone marrow (littoral cells) * The capillaries of liver (Kupffer cells) * The lymphatic vessels of lymph nodes, the lungs and kidney (mesangial cells), * The brain (microglia), * The subcutaneous tissue of the skin (Langerhans cells) * Osteoclasts found in the bone. * The term reticuloendothelial system was coined as a connective term for all the macrophages in the body at a time when their common origin from monocytes was not known. * The system is now called monocyte-macrophage system (MMS) or mononuclear phagocyte system (MPS). ## Breakdown of Haemoglobin inside the macrophage * When macrophages engulf senescent red blood cell (old), they breakdown their membrane thereby releasing the haemoglobin. * Globin is seperated from haem and is broken down to amino acids, which can be relised. * Haem is oxidised by microsomal haem oxygenase to biliverdin and Fe2+. * This reaction breaks the tetrapyrole ring structure of haem the resulting biliverdin is a straight chain substance. * The Fe2+ is stored as ferritin in the (monocyte-macrophage system) available for haem synthesis next time. * The biliverdin is reduced to bilirubin by biliverdin reductase and extruded into plasma. ## Bilirubin * In the adult, even a marked hemolysis does not produce significant increase of serum bilirubin if the hepatic bilirubin clearance is normal. * In the newborn, however a marked hemolysis will be catastrophic at levels of 3 mg/dl of serum bilirubin the infant will be deeply jaundiced and will develop kernicterus (nuclear jaundice: a grave form of yellow staining and degeneration of intracranial grey matter especially of lenticular nucleus and subthalamic area). * Treatment require blue light which transform bilirubin into colorless product of oxidation which are excreted in the urine. * Secondly, synthetic porphyrins containing tin or zinc instead of iron cause decrease of bilirubin formation by competing for the heme oxygenase activity of macrophages. * This compound have been used in the treatment of hyperbilirubinemia in humans. * Bilirubin is toxic to tissue therefore it is transported in the blood bound to albumin, only. * A minute amount of free form is present in the blood. * If the free form increases bilirubin will invade and damage the tissue. * Free plasma bilirubin can increase in the following pathologic conditions: * Over production * Defective Conjugation in the liver (hepatocyte) * Presence of substances interfering with bilirubin-albumin binding e.g sulphonamides long chain fatty acids from breast milk, salicylates, contrast etc. these agents compete for albumin binding sites. * Bilirubin is fat-soluble and is transported in the blood, bound to albumin which makes it water soluble and prevents excretion by the kidney. * The normal blood concentration of bilirubin is less than 1.5mg/dl. * If the plasma bilirubin rises above 2mg/dl it leads to jaundice. ## Hepatic uptake of Bilirubin * On reaching the liver, bilirubin is taken up by hepatocytes at their Sinusoid Surface. * The albumin - bilirubin bond is broken, albumin remains in the plasma while the free molecule of bilirubin enters the hepatocyte. * This uptake is usually rapid but impairment of uptake will result in unconjugated hyperbilirubinemia occurrence e.g * Male fern oil Jaundice. This oil is used to treat tape worm (Aspidium) * Gilbert's disease: due to failure in liver uptake. ## Conjugation of Bilirubin in the Liver * In the hepatocyte, bilirubin is bound to cytoplasmic proteins: Ligandins and 2 protein (Ligandins are group of enzymes that represent 2% of cytosolic proteins. 2 proteins bind fatty acids. The primary function of these proteins is that of avoiding the reflux of free bilirubin into the blood. Apparently, the time lapse between uptake of bilirubin and conjugation is relatively long. * Note: nuo hyperbilirubinemia and Jaundice is known due to deficiency of ligandins. * One way for cells to neutralize unwanted compounds is to conjugate them with a modified sugar, a glycosyl. * The sugar used for this reaction are xylose, glucose or glucuronic acid (xylose and glucuronic acid are formed from glucose by UDP-glucose dehydrogenase. * Unconjugated bilirubin is lipophilic. * It's conjugated with glucuronic acid to render it hydrophilic. * Thus, it can be eliminated in the bile. * After binding with Ligandins and 2 proteins it's conjugated with glucuronic acid to form the water soluble bilirubin digluconide. * Catalysed by uridine diphosphate glucuronyl transferase, conjugation occurs in the endoplasm. * It is inherited Condition known as Najjar Grigler Syndromes undice with unconjugated bilirubin occurs. * It is believed to be due to failure of hepatic conjugation of bilirubin. ## Excretion of Bilirubin * Conjugated bilirubin (Bilirubin diglucuronide) is actively transported by liver cells into bile canaliculi which form the bile duct to be stored along with other bile components in the gallbladder from where it is released into the duodenum as required by the presence of food in the duodenum. * Dubin Johnson syndrome is a congenital condition due to failure in excretion of conjugated bilirubin. ## Enterohepatic Circulation of Bilirubin * When the conjugated bilirubin reaches the terminal ileum and colon, the bilirubin diglucuronide is hydrolyzed by bacterial β-glucuronidase to urobilinogen. * From here the urobilinogen can take two pathways: it can either be further converted into stercobilinogen, which is then oxidized to stercobilin and passed out in the feces or it is reabsorbed at the small intestine back to the liver and is re-excreted by the liver without further conjugation (enterohepatic circulation). * The rest is excreted, transported in the blood to the kidneys, and passed out in the urine as the oxidised product urobilin, stercobilin and urobilin. * These products are responsible for the coloration of faeces and urine. ## Intravascular Breakdown of Erythrocytes * About 10-20% of normal breakdown of red cells occurs in the blood circulation. * The haemoglobin released into the plasma is bound to a specific plasma protein, haptoglobin, and the complex is taken up by the liver for processing to bilirubin diglucuronide as in extravascular. * If intravascular breakdown of red cells is excessive, the haptoglobin is rapidly used up and haemoglobin appears in urine as haemoglobinuria. ## Red blood cell in Circulation for about 120 days * The red blood cell is removed by macrophages in the spleen, liver and bone marrow. * This process leads to the breakdown of haemoglobin into heme and globin. * Heme is further broken down into biliverdin and Fe2+ which is reused for protein synthesis. * Fe2+ is transported by transferin and stored as ferritin in the liver. * Biliverdin is converted to bilirubin in the liver. * Conjugated bilirubin is excreted in the bile and into the small intestine. * In the small intestine, bacteria convert bilirubin to urobilinogen. * Part of the urobilinogen is reabsorbed by the liver (enterohepatic circulation). * The rest of the urobilinogen is excreted in the feces and urine as stercobilin and urobilin. * The process of red blood cell destruction leads to haemoglobinuria in the urine when the breakdown is excessive. - [Image]: A diagram showing the process of red blood cell destruction and subsequent metabolism of haemoglobin.