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MLAB 1415: Hematology Keri Brophy-Martinez Thalassemia: Part One 1 Overview Diverse group of congenital disorders which manifest as anemia of varying degrees. ◦ Can be either homozygous or heterozygous inheritance Result of quantitative defective production of one or more globin portion(s) of hemoglobin molecule. The decreased globin production causes ◦ Imbalanced globin chain synthesis ◦ Defective hemoglobin production ◦ Damage to the RBC 2 Thalassemia Distribution 3 Thalassemia Results in overall decrease in amount of hemoglobin produced 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. May contribute protection against malaria. 4 Review of Hgb Structure Normal globin genes ◦ Alpha, beta, delta, gamma Form hgb A (97%), hgb A2(2-3%), hgb F (2%) ◦ Epsilon, zeta: in utero ◦ Gamma: 3rd trimester until birth ◦ Adult hemoglobin composed two alpha and two beta chains Thalassemia causes an excess or absence of one of these chains 5 Pathophysiology: Beta Thalassemia α-chain excess unstable 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 6 Pathophysiology: Alpha Thalassemia β-chain excess ◦ Unstable ◦ Combines to form hgb molecules with 4 βchains (Hemoglobin H) Infants: excess gamma chains combine with hgb molecules (Hemoglobin Bart’s) ◦ High oxygen affinity, poor transporter of oxygen 7 Clinical and Laboratory Findings Associated with Thalassemia Clinical Findings 9 Comparison of Hemoglobinopathies and Thalassemias Disease RBC count Hemoglobinopathy Indices RBC Morph Abnormal Hb Ancestry Normocytic Target cells, sickle cells (HbS), Crystals (HbC) HbS,HbC, HbE etc African Mediterranean Middle Eastern Asian Target cells, basophilic stippling HbH Hb Bart’s African Mediterranean Asian Normochromic Thalassemia Microcytic Hypochromic Retic Count Thalassemia: globin chains structurally normal Hemoglobinopathies: globin chain is abnormal 10 Beta Thalassemia 11 Classical Syndromes of Beta 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 transfusiondependent hemolytic anemia. 12 Beta Thalassemia Minor Caused by heterogenous mutations that affect beta globin synthesis. Usually presents as mild, asymptomatic hemolytic anemia Have one normal beta gene and one mutated beta gene. 13 Beta Thalassemia Minor Anemia usually mild Rarely see hepatomegaly or splenomegaly. Have high Hb A2 levels ◦ 3.5-8.0% Normal to slightly elevated Hb F levels. Different variations of this form depending upon which gene has mutated Normally require no treatment. Iron deficiency anemia. Should be ruled out 14 Beta Thalassemia Major/ Cooley’s anemia Severe microcytic, hypochromic anemia. ◦ Severe anemia causes marked bone changes due to expansion of marrow space for increased erythropoiesis. ◦ See characteristic changes in skull, long bones, and hand bones “hair on end” Detected early in childhood- 6 months- 2 yrs. Hb A production is reduced HbA2 and Hg F production increased 15 Clinical Findings: β-Thalassemia Major Infants ◦ Irritability, pallor, failure to thrive ◦ Diarrhea, fever, enlarged abdomen Severe anemia Cardiac failure Bronze pigmentation of skin Bone changes ◦ Bossing of skull, facial deformities, “hair-on-end” appearance of skull Hepatosplenomegaly Laboratory Findings: β-Thalassemia Major Hb can be as low as 2–3 g/dL Microcytic hypochromic ◦ MCV < 67 fL, ↓ MCH and MCHC Peripheral blood smear ◦ Anisocytosis and poikilocytosis ◦ Basophilic stippling, polychromasia ◦ NRBCs ◦ ↑ RDW β-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 Hereditary Persistence of Fetal Hemoglobin (HPFH) Rare condition characterized by continued synthesis of Hemoglobin F in adult life. Do not have usual clinical symptoms of thalassemia. Kleihauer-Betke stain useful tool to identify 19 References • • Harmening, D. M. (2009). Clinical Hematology and Fundamentals of Hemostasis. Philadelphia: F.A Davis. McKenzie, S. B., & Williams, J. L. (2010). Clinical Laboratory Hematology. Upper Saddle River: Pearson Education, Inc.