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Fate of Rbc's HEMOGLOBIN AND HEMOGLOBINOPATHIES LECTURE 01 FATE OF RBCS AND JAUNDICE LECTURE 02 & 03 HEMOGLOBIN FIRST YEAR MBBS 2020 Features of a Mature RBC • Biconcave disc • Mean Diameter 7.8 um • Can deform easily. • Bag of fluid with dissolved substances and hemoglobin • No sub cellular particles • Metabolism – Anaerobic respiration- Glycolysis – Pentose phosphate pathway. RBC Count • Remains remarkably constant although there are some variations. • MALE : 5.2 ± 0.3 x 106 /uL. • FEMALE : 4.7 ± 0.3 x 106 /uL. • Life span : 120 Days HEMOGLOBIN HEME-CONTAINING PROTEINS Hemoglobin Myoglobin Cytochromes Catalase Some peroxidases HEMOGLOBIN • Metallo-conjugate protein • Molecular weight is 64,500 • One hemoglobin molecule is composed of four heme groups (subunits) attached with globin (having four polypeptide chains) • One hemoglobin molecule binds with it four oxygen molecules (eight oxygen atoms) • 1 gm hemoglobin carries 1.34 ml of oxygen • Heme synthesis occurs in the mitochondria of bone marrow erythroblasts HEMOGLOBIN FORMATION 2 succinyl-CoA + 2 glycine Pyrrole 4 pyrrole Protoporphyrin IX Protoporphyrin IX + Fe++ Heme Heme + Polypeptide Hemoglobin chain (α β) 2 α chains + 2 β chains Hemoglobin A Types of Hemoglobin • Variations in Hb subunit chains – W.r.t amino acid composition of polypeptide portion – Alpha, beta, gamma, delta Type of Hb Chain Fraction of total composition Hb HbA α2 β2 90% HbF α2 γ2 < 2% HbA2 α2 δ2 2-5 % HbA1C α2 β2 - Glucose 3-9% Embryonic Hemoglobins • Gower 1 Two zeta & two epsilon chains • Gower 2 Two alpha & two epsilon chains • Portland Two zeta & two gamma chains Embryonic/Minor Hemoglobins Organization of Hemoglobin Genes Developmental changes in Hb Hemoglobin F • Blood of the human fetus normally contains fetal hemoglobin • Its structure is similar to that of hemoglobin A except that the β chains are replaced by γ chains • hemoglobin F is α2γ2. The γ chains have 37 amino acid residues that differ from those in the β chain. • Fetal hemoglobin is normally replaced by adult hemoglobin soon after birth Hemoglobin F • In certain individuals, it fails to disappear and persists throughout life. • In the fetal body, its O2 content at a given PO 2 is greater than that of adult hemoglobin because it binds 2,3-BPG less avidly. • Hemoglobin F is therefore critical to facilitate movement of O2 from the maternal to the fetal circulation, particularly at later stages of gestation where oxygen demand increases . • In young embryos there are, in addition, ζ and ε chains, forming Gower 1 hemoglobin (ζ2ε2) and Gower 2 hemoglobin (α2ε2). • Switching from one form of hemoglobin to another during development seems to be regulated largely by oxygen availability, with relative hypoxia favoring the production of hemoglobin F both via direct effects on globin gene expression, as well as upregulated production of erythropoietin. Fetal Hb Abnormalities of hemoglobin formation Hb Type Chain Position Replacement Hemoglobinopathies Qualitative defects Glutamic acid by valine HbS Beta 6 Glutamic acid by lysine HbC Beta 6 Glutamic acid by lysine HbE Beta 26 Hb Bart’s Four gamma chains Hb H Four beta chains Thalassemia Quantative defects Beta thalassemia beta chain Inadequate synthesis of beta chains Alpha thalassemia alpha chain Inadequate synthesis of alpha chains Sickle cell anemia Sickle-Cell Anemia: A Base-Pair Substitution 1 Normal amino acid sequence at the start of the hemoglobin beta chain. 2 One amino acid substitution results in the abnormal beta chain of sickle hemoglobin (HbS). The sixth amino acid in such chains is valine, not glutamic acid. 3 Glutamic acid carries an overall negative charge; valine carries no charge. This difference causes the protein to behave differently. At low oxygen levels, HbS molecules stick together and form rod-shaped clumps that distort normally round red blood cells into sickle shapes. (A sickle is a farm tool with a crescent-shaped blade.) Signs and symptoms Sickle Cell Anemia & trait • Patients with heterozygous genotype (Hgb AS) have sickle cell trait • Patients with homozygous genotype (Hgb S) have sickle cell disease • Sickle Cell Trait (Hgb AS) • Signs & Symptoms • Clinically normal • Acute vasoocclusion occurs only under extreme conditions (vigorous exertion at high altitude) • Painless hematuria sometimes present in adolescent males • Diagnostic testing – CBC and PBS normal – Hemoglobin electrophoresis shows that Hgb S comprises ~40% of hemoglobin and Hgb A 60% • Treatment – No treatment necessary – Genetic counseling appropriate Sickle Cell Anemia (Hgb SS) • Signs and Symptoms – Vary significantly – some pt are virtually asymptomatic while others suffer repeated crises requiring hospitalization – • Chronic hemolytic anemia produces • Jaundice • Pigment (calcium bilirubinate) gallstones • Splenomegaly (early childhood only) • Splenic Infarct and atrophy in adulthood or Splenectomy • Poorly healing ulcers over the lower tibia Types of sickle cell disease 1. Sickle cell anemia: Homozygous state for HbS (βS- βS) 2. Sickle cell trait : Heterozygous carrier state for HbS (βS -β) 3. If one parent has sickle cell anemia and other is normal , all children will have sickle cell trait. 4. If one parent has sickle cell anemia and other has sickle cell trait there is 50% chance of either with each pregnancy. 5. If both parents have sickle cell trait? AA-normal AS-sickle cell trait SS-sickle cell Anemia • Sickle cell – β thalassemia : Double heterozygote in which sickle cell gene is inherited from one parent and beta thalssemia gene from other parent . gene type (βsβo-βsβ+) • 4. Combination of Hbs with other abnormal hemoglobin (HbSD, HbSC, HbSO(arab disease),HbSE). Thalassemias Thalassemias • In normal hemoglobin, number of α and β polypeptide chains is equal. • In thalassemia, the production of these chains become imbalanced because of defective synthesis of globin genes. • This causes the precipitation of the polypeptide chains in the immature RBCs, leading to disturbance in erythropoiesis. • The precipitation also occurs in mature red cells, resulting in hemolysis. Thalassemias • α­thalassemia occurs in fetal life or infancy. In this α­chains are less, absent or abnormal. • In adults, β­chains are in excess and in children, γ­chains are in excess.This leads to defective erythropoiesis and hemolysis.The infants may be stillborn or may die immediately after birth. β-Thalassemia In β­thalassemia, β­chains are less in number, absent or abnormal with an excess of α­chains. The α­chains precipitate causing defective erythropoiesis and hemolysis BETA-THALASSAEMIA • Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. • The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. 1.5% of the global population (80 to 90 million people) are carriers of beta thalassemia, with about 60,000 symptomatic individuals born annually, the great majority in the developing world. Structure Of Haemoglobin SITES OF GOBIN CHAIN SYNTHESIS Globin chain synthesis Point Mutation : Substitution of a single DNA nucleotide base for another – can change the genetic code. Deletion : Absence of one or more nucleotiodes. Insertion : Addition of one or more nucleotides. 3 bases = 1 codon 1 codon= 1 Amino Acid Frame Shift, Sense, Nonsense. Disorders of Haemoglobin Qualitative Haemoglobinopathies Quantitative – Thalassaemias Functionally 1. No problem Goes undetected 2. Solubility Gel.Crystalize, Haemolysis 3. O2 Affinity Cyanosis 4. O2 Affinity Polycythaemia 5. Stability Hemolysis 6. Production Anaemia Thalassaemias - classification Genetic • α –Thalassaemia (deletions) • β –Thalassaemia (mutations) – β 0 - Thalassaemia – β+ Thalassaemia BETA THALASEMIA ;Clinical Features Anaemia Hepato Splenomegaly Skeletal Changes Iron Overload Growth Retardation Clinical Classification Thal Minor –trait, asymptomatic Thal Major –transfusion dependent Thal Intermedia – transfusion not required Hydrops Fetalis –death in utero, α –Thalassaemia α-Thalassemia Lab Diagnosis Blood CP Hb Electrophoresis Alpha/Beta Chain Analysis DNA Analysis Prenatal Diagnosis Prevention Glycosylated /Glycated Hemoglobin (HbA 1C) • Glucose is attached with terminal valine of each beta chain • Normally upto 6% . Increases in diabetics Hemoglobin Levels • Hemoglobin levels are measured – In grams (gm) per deciliter (dl) of blood. NORMAL RANGES : • Adult women: 12-16 gm/dl • Adult males: 14-18 gm/dl • 1 G Hb – 1.34 ml of Oxygen Characteristics of Hb-O2 Bond • Combination of Hb with Oxygen is Loose – Do not combine with positive bond of Iron – Loose bond – Binding reversible – Molecular Oxygen binds and releases • Heme Heme Interaction – Cooperative bonding – Affinity for last oxygen - 300 times more The affinity of hemoglobin for O2 is affected by 1. pH 2. Temperature 3. Concentration of 2,3-Bisphosphoglycerate (2,3-BPG). + • 2,3-BPG and H compete with O2 for binding to deoxygenated hemoglobin Decrease the affinity of hemoglobin for O2 Binding of Oxygen with Hb Binding of Oxygen with Hb Oxygen dissociation curve Functions of Hemoglobin • Transport of Oxygen • Transport of Carbon dioxide – Carbaminohemoglobin (CO2Hgb). • Buffer function + – Carbonic acid H and CO2 – Hb combine with H+ • Binding with Nitric oxide (NO) – NO binds with Sulphur atom SNO – NO relaxes and dilates arterioles • Bile pigments
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