MLAB 1415: Hematology Keri Brophy-Martinez Chapter 11: Thalassemia

Overview Distribution is worldwide. Diverse group of congenital disorders which manifest as anemia of varying degrees. 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 Distribution is worldwide.

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. May be either homozygous defect or heterozygous defect.

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 of one of these chains

Pathophysiology 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 con’t 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 unless patient in under stress such as pregnancy, infection, or folic acid deficiency. 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%) and normal to slightly elevated Hb F levels. Are different variations of this form depending upon which gene has mutated. Normally require no treatment.  Make sure are not diagnosed with iron deficiency anemia.

FIGURE 11-11 Patients with β-thalassemia minor show minimal morphologic abnormalities to include microcytosis with target cells. The CBC in this patient showed the following results: Hb 11.1 g/dL; RBC count 5.2 x 1012/L; MCV 61 fL; MCH 20.2 pg; MCHC 33 g/L. (Wright-Giemsa stain; 1000x magnification)

β-thal Minor – microcytic, occ codocyte, basophilic stippling

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 Detected early in childhood 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

FIGURE 11-8 Increased erythropoiesis in the bone marrow of patients with β-thalassemia major expands the marrow cavity producing the typical “hair-on-end” appearance as seen on this radiograph of the skull of a boy with β-thalassemia.

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

FIGURE 11-9 Peripheral blood smear from a patient with β-thalassemia major showing marked anisopoikilocytosis. Target cells, schistocytes, teardrops, and ovalocytes are the major poikilocytes observed. An NRBC is also present. (1000x magnification; Wright-Giemsa stain)

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