Erythropoiesis and Anemia PDF

Anaemia 1  Erythropoiesis About 1012 new erythrocytes – made each day. Pronormoblast – earliest erythrocyte precursor in the BM Pronormoblast gives rise to a series of progressively smaller normoblasts by a no. of cell divisions. Usually gives ris...

Anaemia 1  Erythropoiesis About 1012 new erythrocytes – made each day. Pronormoblast – earliest erythrocyte precursor in the BM Pronormoblast gives rise to a series of progressively smaller normoblasts by a no. of cell divisions. Usually gives rise to 16 mature red cells. Nucleated RBCs (NRBCs) – not usually present in the peripheral blood. Presence of NRBCs in the peripheral blood: Extramedullary erythropoiesis Marrow diseases 2 3 4 5 6  Haemoglobin Main function of red cells: carry O2 to the tissues & return CO2 fr the tissues to the lungs. Achieved by: Hb Hb – a specialized protein. Each red cells contains approximately 640 million Hb molecules. Each molecule of normal adult Hb A (HbA) – consists of 4 polypeptide chains α2β2, each with its own haem group. MW: 68000 2 other haemoglobins in normal adult blood: Hb F and Hb A2. 7 8 9 10 11  Hb function Red cells in the systemic arterial blood carry 02 fr the lungs to the tissues & return in venous blood with CO2 to the lungs. The individual globin chains in the Hb molecule move on each other as the Hb molecule loads and unloads O2. When O2 is unloaded, the β chains are pulled apart, permitting entry of the metabolite 2,3- diphosphoglycerate (2,3-DPG) resulting in a lower affinity of the molecule for O2. This movement – responsible for the sigmoid form of the Hb O2 dissociation curve. The P50 of normal blood is 26.6 mmHg. With increased affinity for O2, the curve shifts to the left (the P50 falls) and with decreased affinity for O2, the curve shifts to the right (P50 rises). 12  Normal position of the curve: depends on the concentration of 2,3-DPG, H+ions and CO2 in the red cell & on the structure of Hb molecule. High conc of 2,3 –DPG, H+ or CO2 and the presence of certain haemoglobins (e.g. sickle cell Hb, HbS) – shifts the curve to the right (i.e. O2 is given up more easily) Fetal Hb (HbF) - unable to bind to 2,3-DPG & certain rare abnormal Haemoglobins associated with polycythaemia shifts the curve to the left because they give up O2 less readily than normal. 13 14  Red Cell Metabolism 1. EMBDEN-MEYERHOF PATHWAY 2. HEXOSE MONOPHOSPHATE (PENTOSE PHOSPHATE) PATHWAY 15  Embden-Meyerhof Pathway Glucose which enters the red cell from plasma – metabolised to lactate. For each molecule of glucose used, 2 molecules of ATP are generated. ATP: source of energy for maintenance of red cell volume, shape & flexibility Red cell has an osmotic pressure 5 times that of plasma & an inherent weakness of the membrane results in the continuous Na+ and K+ movement. A membrane ATPase sodium pump is needed & this uses 1 molecule of ATP to move 3 Na+ out & 2 K+ into the cell. NADH is also generated – needed by methaemoglobin reductase to reduce functionally dead methaemoglobin (oxidised haemoglobin) containing ferric iron. 16  The Luebering-Rapoport shunt (the sidearm of this pathway) generates 1,2-DPG which forms a 1:1 complex with Hb, which is important for regulation of haemoglobin’s oxygen affinity. 17 18  Hexose Monophosphate (pentose phosphate) pathway 10% of glycolysis occurs through this pathway. Glucose-6-phosphate is converted to 6-phosphogluconate & to ribulose-5- phosphate. NADPH is generated & is linked to glutathione which maintains sulphydril (SH) groups intact in the cell, including the red cell membrane. NADPH – also used by methaemoglobin reductase to maintain haemoglobin iron in the functionally active Fe2+ state. 19 20  The red cell Must be able to pass through the microcirculation (minimum diameter of 3.5 um), to maintain Hb in a reduced (ferrous) state to maintain osmotic equilibrium despite the high concentration of protein (Hb) in the cell. Total journey throughout its 120 days lifespan: 480km (300 miles). Flexible biconcave disc Able to generate energy as ATP via the anaerobic glycolytic pathway (Embden-Meyerhof) pathway & generate reducing power as NADH Generate reducing power as NADPH via hexose monophosphate shunt. 21 Anaemia 22  Anaemia Defn: reduction in the Hb concentration of the blood below normal for age and sex. Normal values vary btw different laboratories. Typical values: