RBC Structure andFunction RBC Structure and Function . Production of RBCs: (1) Fetal Life – Liver. (3) Extreme hematologic Stress – Liver and Spleen can revert to making RBC ("Extramedullary Hematopoiesis"). Ex: kid with severe anemia due to thalassemia with hepatosplenomegaly. Bone Marrow (BM) (2) Child/Adult – BM. (Child-lots of the skeleton is involved. Adult-mostly the axial skeleton is involved). . Spleen. BM Environment: cellular proliferation and maturation. . A fine reticular meshwork supports cellular elements as vascular sinuses course through the marrow cavity allowing for the inflow of plasma nutrients but retaining developing cells until they are mature. and mature RBC lives 120 days. reticulocyte (nucleus has been extruded. RBC Development: Stem cell Þ multipotent stem cell Þ BFU-E Þ CFU-E Þ erythroblast Þ Þ RBC RBC Lifespan: From earliest recognizable erythroblast to a mature RBC it takes 3-4 days. but some RNA is left over) for about 1 day. RBCs mature around a central macrophage. . Hemoglobin synthesis: Three components of hemoglobin: (1) globin. (3) iron (protoporphyrin and iron combine to form Heme). as protoporphyrin and iron combine. eventually heme. Synthesis shifts into the cytoplasm but ultimately returns to the mitochondria for final steps in the formation of protoporphyrin IX and. (2) protoporphyrin. In the mitochondria the first step of heme synthesis takes place as glycine and succinyl CoA combine to form delta aminolevulinic acid. Iron enters the developing RBC and ultimately enters the mitochondria to support heme synthesis. "Sideroblastic anemia" = Congenital absence of enzymes along the path of proto-porphyrin synthesis may lead to severe impairment of heme synthesis . Globin chain synthesis: various Hgb's: Hgb A = 2 alpha chains and 2 beta chains Hgb A2 = 2 alpha chains and 2 delta chains Hgb F = 2 alpha chains and 2 gamma chains . can’t reproduce. no nucleus. volume = 90 femtoliters . can’t produce energy (no mitoch). very little cytoplasm. Changes of Hgb throughout life: Birth – most Hgb present is of the fetal variety 4-6 months – gradual decline in synthesis of fetal Hgb with a corresponding increase in Hgb A 6-8 months – approximately 97% of Hgb is Hgb A. 2% is Hgb A-2 and 1% is Hgb F Clinical correlate: beta chain Hgb disorders such as sickle cell disease do not clinically manifest until 46 months of age since fetal Hgb predominates during early infancy Mature RBC = biconcave disk. width = 2 m m. diameter = 8 m m. Ankyrin anchors cytoskeleton to membrane. Membrane antigen structure – there are over 300 RBC membrane Ags. (A. They are Polysaccharides. B. Duffy. etc). Rh. Underneath it is a cytoskeleton of proteins allowing rubbery elasticity with main protein being Spectrin. . Three Constituents of RBCs: RBC membrane + internal metabolic apparatus (ie a bit of cytoplasm) + hemoglobin RBC membrane: Has lipid bilayer membrane with proteins in it. Na/K ATPase channel is abundant on membrane (ATP from pentose phosphate shunt – that’s why G6PD deficient people have problems). net 2 ATPs produced and used to support membrane ion pumps. RBC survival is reduced. When deficiencies of the E-M path exist. leading to hemolysis . Embden-Meyerhof Pathway glycolysis from glucose to lactate. Methemoglobin Reductase Pathway prevents iron of Hgb from being oxidized. . Hgb iron must be in reduced state (Fe+2) in order to transport O 2. The environment is constantly generating oxidant stress and therefore a tendency to oxidize iron to Fe3+. makes NADH which is reducing power. The methemoglobin reductase pathway counteracts this by reducing iron to the +2 state. Patients with methemoglobin reductase deficiency have a substantial quantity of methemoglobin (Hgb with iron in the oxidated state) associated with reduced O 2 carrying capacity. This is an appropriate response to ensure adequate O2 delivery. This pathway is an off-shute of the E-M pathway leading to generation of 2-3 DPG. When venous blood is increasingly deoxygenated. An increased rate of glycolysis leads to an increase in intracellular 2-3 DPG concentration. Luebering-Rapaport Pathway . the rate of glycolysis increases leading to increased 2-3 DPG production and increased O2 release to the tissues. 2-3 DPG is an important regulator of Hgb-O2 release (increased 2-3 DPG giving rise to increased O2 release).3-DPG which shifts saturation curve to the right. . makes 2.modifies affinity of binding of Hgb and O2. medications). If the shunt is defective (as is the case in patients with G6PD deficiency) oxidative insults lead to oxidation of globin chains and denaturation of Hgb leading to precipitates (Heinz bodies) in the RBC. membrane damage and. ultimately. cell death. .This pathway couples oxidative metabolism with NADP and glutathione reductase to provide antioxidant substrate which ultimately combats the effects of oxygen stresses (environmental. Hexose-Monophosphate Shunt (Phosphoglucoate Pathway) . . Ý 2. Ý pH. Ý pCO2. P50 = PO2 at which Hgb is 50% saturated Right shift (O2 released easily) of the curve is caused by: ß O2 affinity. Ý temp Left shift (O2 bound tightly) of the curve is caused by: Ý O2 affinity.3DPG. ß pCO2.3-DPG. ß 2. ß temp Kidneys are sensors (Juxtatubular cells) for O2 delivery Þ Ý EPO . ß pH. Free Hgb is either reabsorbed by renal tubular cells or excreted as free Hgb in the urine . Reticuloendothelial cells participate in the destruction of senescent RBC's. Normally ~10% RBCs lyse while in circulation Þ Hgb gets released into circulation and rapidly disassociates into alpha and beta dimers which are bound by haptoglobin. Globin and heme get recycled. Rate limiting step is conjugation. free Hgb circulates and is filtered by the kidney. Indirect (unconjugated) bilirubin is result if this doesn’t happen. If haptoglobin is depleted. The Hgb/haptoglobin complex is transported to the liver. Destruction of RBCs happens within reticuloendothelial cells – NOT in the circulation. porphyrin is degraded to bilirubin which is conjugated by the liver and excreted in the gut. . As a result. Alterations in regional blood flow as well as a marked increase in cardiac output can compensate for 50% fall in O2 carrying capacity in the anemic patient.. patients with significant anemia frequently have tachycardia and an increased cardiac ejection fraction. blood enters the tissue at a PO2 of 95 and exits at a PO2 of 40.O. blood volume. Regulation of the Erythron: In the basal ideal state. A variety of integrated physiologic components contributes to active O 2 supply to tissues including pulmonary function. Therefore. regional blood flow. 25% of O2 transported by Hgb is release. viscosity). O2 delivery may be altered by: (1) Hgb-O 2 affinity and (2) increase in the number of RBC's. The role of the RBC in the transport of O 2 from the lungs to the tissues is central. Pulmonary function/hemodynamic factors: The lungs and heart manifest a physiologic response in the face of decreased O2 carrying capacity associated with anemia. and hemodynamic factors (C.