Thalassemia PDF - Hong Kong Metropolitan University

HONG KONG METROPOLITAN UNIVERSITY MLS 3009SEF Haematology & Transfusion Science I H.LEE Thalassemia 3-2-2025 3/2/2025 Henry Lee Thalassemia 1  Haemoglobinopathy What are t...

HONG KONG METROPOLITAN UNIVERSITY MLS 3009SEF Haematology & Transfusion Science I H.LEE Thalassemia 3-2-2025 3/2/2025 Henry Lee Thalassemia 1  Haemoglobinopathy What are they? – Disorders where the production of normal adult hemoglobin is partly or completely suppressed or replaced by a variant hemoglobin. 3/2/2025 Henry Lee Thalassemia 2  Thalassemia Distribution 3/2/2025 Henry Lee Thalassemia 3 3  Thalassemia Individual -like and -like globin chains are encoded by two distinct gene clusters: 1. the -globin gene cluster on the short arm of chromosome 16 and 2. the -globin gene cluster on the short arm of chromosome 11. 3/2/2025 Henry Lee Thalassemia 4  Thalassemia Thalassemia causes an excess or absence of one of these chains, either Alpha (α) OR Beta (β) Results in an overall decrease in the amount of hemoglobin produced, can cause unusual hemoglobins to form, and may induce hemolysis. Two major types of thalassemia: – Alpha (α) - Caused by defect in rate of synthesis of alpha chains. -- Beta (β) - Caused by defect in rate of synthesis in beta chains. 3/2/2025 Henry Lee Thalassemia 5  Thalassemia The -globin gene cluster comprises three functional globin genes, the embryonic  gene (HBZ), and two fetal/adult  (1 and 2) genes. The -globin gene cluster contains five functional genes, the embryonic  gene, two fetal G and A genes, and adult  and  genes. 3/2/2025 Henry Lee Thalassemia 6 https://sickle.bwh.harvard.edu/ 3/2/2025 Henry Lee Thalassemia 7  SpringerLink.com 3/2/2025 Henry Lee Thalassemia 8  Review of Hgb Structure These genes are arranged along each chromosome, and are differentially expressed at each stage of development to produce different Hb tetramers. 1. The embryonic Hb includes Hb Portland (22), Hb Gower-1 (22), and Hb Gower-2 (22), 2. the fetal Hb consists of 22, 3. In adults, Hb A (22) accounts for 95% of the total Hb, while Hb A2 (22) constitutes the remaining 5% 3/2/2025 Henry Lee Thalassemia 9  Normal Gene Structure Alpha chain genotype Beta chain genotype 2 alpha genes on each 1 beta gene on each chromosome 16 chromosome 11 =4 alpha genes total =2 beta genes total 3/2/2025 Henry Lee Thalassemia 10  Thalassemia Lab Studies – CBC HGB, HCT, MCV, MCH,MCHC DECREASED – Blood Smear Varying degrees of microcytosis, hypochromia, target cells, anisocytosis , poikilocytosis, nRBCs – Retic Count INCREASED – Chemistry Ferritin, serum iron (normal to increased) Bilirubin INCREASED 3/2/2025 Henry Lee Thalassemia 11  Thalassemia Hemoglobin Electrophoresis – Important role in diagnosing and differentiating various forms of thalassemias. – Can differentiate among Hb A, Hb A2, and Hb F, as well as detect presence of abnormal hemoglobins such as Hemoglobin Lepore, Hemoglobin Bart's, or Hemoglobin Constant Spring. – Also aids in detecting combinations of thalassemia and hemoglobinopathies. 3/2/2025 Henry Lee Thalassemia 12  Lapedia.net 3/2/2025 Henry Lee Thalassemia 13  𝛃 Thalassemia Beta-thalassemia results from decreased production of beta-polypeptide chains due to either mutations or deletions in the beta globin gene, leading to impaired production of hemoglobin (Hb) 3/2/2025 Henry Lee Thalassemia 14  𝛃 Thalassemia – 𝛃- chain reduction (mainly 𝛃- gene mutation) – - chain in excess – compensatory increase in γ and δ chain synthesis resulting in increased levels of Hb F and A2 – - chain in excess, unstable and precipitates within the cell, causes damage – Macrophages destroy the damaged RBCs in the bone marrow, leads to ineffective erythropoiesis – Spleen also removes damaged RBCs, leads to chronic extravascular hemolysis 3/2/2025 Henry Lee Thalassemia 15  Beta Thalassemia According to the degree of quantitative reduction in the production of -globin, - thalassemia alleles are classified into three categories: 1) the absence of -globin (0 ); 2) -globin is produced but reduced (+ ); 3) -globin production is minimally reduced (++, also known as silent) 3/2/2025 Henry Lee Thalassemia 16  𝛃 Thalassemia Beta thalassemia minima/ Silent carrier state – the mildest form of beta thalassemia. Beta thalassemia minor - heterozygous disorder resulting in mild hypochromic, microcytic hemolytic anemia. Beta thalassemia intermedia - Severity lies between the minor and major. Beta thalassemia major - homozygous disorder resulting in severe transfusion-dependent hemolytic anemia 3/2/2025 Henry Lee Thalassemia 17  Beta Thalassemia Minor Also call carrier or trait heterozygous disorder of 0 or + one normal beta gene and one mutated beta gene. Hb A still the major haemoglobin mild hypochromic, microcytic anemia Rarely see hepatomegaly or splenomegaly Normally require no treatment. 3/2/2025 Henry Lee Thalassemia 18  Beta Thalassemia Intermedia Beta thalassemia intermedia heterozygous disorder of 0 or + or homozygous disorder of + Severity lies between the minor and major, distinguished clinically by transfusion dependence 3/2/2025 Henry Lee Thalassemia 19  Beta Thalassemia Major Beta thalassemia major - homozygous disorder of 0 or heterozygous of 0 or + - resulting in severe transfusion-dependent hemolytic anemia caused by ineffective erythropoiesis which also caused marked expansion of marrow space and skeletal changes. 3/2/2025 Henry Lee Thalassemia 20 Middle East Medical Portal 3/2/2025 Henry Lee Thalassemia 21  Beta Thalassemia Major Detected early in childhood- 6 months- 2 yrs Hb A production is reduced HbA2 and Hb F production increased Significant physical findings 3/2/2025 Henry Lee Thalassemia 22  Beta Thalassemia Major Beta thalassemia major - Hypochromic, microcytic anaemia - Anisocytosis and poikilocytosis - Schistocytes, ovalocytes and target cells - Basophilic stippling from alpha chain precipitation - Reticulocytes and nRBC presence 3/2/2025 Henry Lee Thalassemia 23 3/2/2025 Henry Lee Thalassemia 24  Beta Thalassemia Major Hb can be as low as 2–4 g/dL Microcytic hypochromic – MCV < 67 fL, – ↓ MCH and MCHC Retic count- mild-moderate increase Peripheral blood smear – Anisocytosis and poikilocytosis – Basophilic stippling, polychromasia – NRBCs – ↑ RDW Iron & Indirect bilirubin- increased 3/2/2025 Henry Lee Thalassemia 25  Beta Thalassemia Major Treatment – Regular transfusions Minimize anemia Suppress ineffective erythropoiesis – Iron-chelating agents Reduce excess iron absorption – Splenectomy Prognosis – Untreated – die during 1st or 2nd decade – Hypertransfusion with iron chelation Extend for ≥ 1 decade 3/2/2025 Henry Lee Thalassemia 26  Alpha Thalassemia The -globin gene cluster comprises three functional globin genes, the embryonic  gene (HBZ), and two fetal/adult  (1 and 2) genes. 3/2/2025 Henry Lee Thalassemia 27  Alpha Thalassemia Normally four alpha globulin genes (two from each parent) At birth there are excess -chain, and later - chain. alpha thalassemia is usually due to delection of the -gene Bart's Hydrops Fetalis Syndrome 3/2/2025 Henry Lee Thalassemia 28  Alpha Thalassemia -thalassemia is classified into 1) 0 -thalassemia, in which both -globin genes are deleted (--/), and 2) + -thalassemia, in which one of two - globin genes is deleted (-/) 3/2/2025 Henry Lee Thalassemia 29  Alpha Thalassemia Classification of -thalassemia 1) Silent carrier state 2) + -thalassemia minor 3) Haemoglobin H Disease 4) Bart’s Hydrops Fetalis Syndrome 3/2/2025 Henry Lee Thalassemia 30  Alpha Thalassemia The normal haploid genotype is  /  If one gene is deleted, the haploid phenotype is  thal 2 If both genes are deleted, the haploid phenotype is  thal 1 Since one gets two genes from each parent, there are four types of  thalassemia:  /  thal 2 = silent carrier  /  thal 1, or  thal 2/  thal 2 =  thal trait with mild anemia 3/2/2025 Henry Lee Thalassemia 31  Alpha Thalassemia  thal 1/  thal 2 = hemoglobin H disease (4= Hb H) Hb H has a higher affinity for O2 and precipitates in older cells. Anemia may be chronic to moderate to severe.  thal 1/  thal 2 = hydrops fetalis which is fatal with stillbirth or death within hours of birth. Haemoglobin Barts has high affinity for O2 that no O2 is delivered to the tissues. 3/2/2025 Henry Lee Thalassemia 32 ScienceDirect.com 3/2/2025 Henry Lee Thalassemia 33  HbH Disease Only one alpha gene out of four is functional Results in accumulation of excess unpaired gamma or beta chains. – The excess chains pair up to form tetrads Beta: hemoglobin H (adults) Gamma: hemoglobin Bart’s (infants) Hgb H precipitates within RBCs triggers hemolysis High affinity for oxygen which reduces oxygen delivery to the tissues 3/2/2025 Henry Lee Thalassemia 34  HbH Disease RBCs are microcytic, hypochromic with marked poikilocytosis. Numerous target cells. 3/2/2025 Henry Lee Thalassemia 35  Brilliant Cresyl Blue Stain Incubation with brilliant cresyl blue stain causes Hemoglobin H to precipitate. Results in characteristic appearance of multiple discrete inclusions -golf ball appearance of RBCs. Inclusions smaller than Heinz bodies and are evenly distributed throughout cell. 3/2/2025 Henry Lee Thalassemia 36 36  HbH LabMedica 3/2/2025 Henry Lee Thalassemia 37  Bart's Hydrops Fetalis Have no functioning alpha chain genes Predominant hemoglobin is Hemoglobin Bart, along with Hemoglobin Portland and traces of Hemoglobin H. Hemoglobin Bart's has high oxygen affinity so cannot carry oxygen to tissues. Baby born with Hydrops Fetalis, which is edema and ascites caused by accumulation of serous fluid in fetal tissues as result of severe anemia. Hepatosplenomegaly and cardiomegaly are present 3/2/2025 Henry Lee Thalassemia 38  -thalassemia In o-thalassemia, the two most common deletion forms are (/--SEA, South Asia) and (/--MED, Mediterranean). Unequal recombination between two homologous segments that are 3.7 kb apart results in the formation of a chromosome with one -globin gene (/-3.7), and similarly, the other mispaired homologous segment, 4.2 kb apart, produces the /-4.2 allele. 3/2/2025 Henry Lee Thalassemia 39  Science Direct.com 3/2/2025 Henry Lee Thalassemia 40  Thalassemia Delta/beta () thalassemia results from a deletion in both  and  genes. Increase in -chain synthesis resulting in increasing amount of HbF - thalassemia heterozygotes clinically show characteristics of thalassemia minor - thalassemia homozygotes clinically show characteristics of thalassemia intermedia with mild hypochromic, microcytic anaemia 3/2/2025 Henry Lee Thalassemia 41  Hereditary Persistence of Fetal Haemoglobin (HPFH) Hereditary persistence of HbF (HPHF) is a benign condition in which significant fetal hemoglobin production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced. The percentage of incorrect expression might be as low as 10%–15% or as high as 100% of the total hemoglobin, usually higher in homozygotes than in heterozygotes. HPHF is usually caused by mutations in the β- or α-globin gene cluster or the γ promoter gene region. 3/2/2025 Henry Lee Thalassemia 42