MLAB 1415: Hematology Keri Brophy-Martinez

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MLAB 1415: Hematology Keri Brophy-Martinez Thalassemia: Part One

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

Thalassemia Distribution

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.

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

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

Pathophysiology: Alpha Thalassemia β-chain excess Unstable Combines to form hgb molecules with 4 β- chains (Hemoglobin H) Infants: excess gamma chains combine with hgb molecules (Hemoglobin Bart’s) High oxygen affinity, poor transporter of oxygen

Clinical and Laboratory Findings Associated with Thalassemia

Clinical Findings

Comparison of Hemoglobinopathies and Thalassemias Disease RBC count Indices RBC Morph Abnormal Hb Ancestry Retic Count Hemoglobinopathy Normocytic Normochromic Target cells, sickle cells (HbS), Crystals (HbC) HbS,HbC, HbE etc African Mediterranean Middle Eastern Asian Thalassemia Microcytic Hypochromic Target cells, basophilic stippling HbH Hb Bart’s Thalassemia: globin chains structurally normal Hemoglobinopathies: globin chain is abnormal

Beta Thalassemia

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 transfusion- dependent hemolytic anemia.

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.

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

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

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 Prognosis 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

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.