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  • 1. MLAB 1415: HematologyMLAB 1415: Hematology Keri Brophy-MartinezKeri Brophy-Martinez Chapter 11: Thalassemia 1
  • 2. OverviewOverview 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. 2
  • 3. ThalassemiaThalassemia 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. 3
  • 4. Genetics of ThalassemiaGenetics of Thalassemia May be either homozygous defect or heterozygous defect. Genetic defects usually falls into one of below categories ◦ Gene deletion ◦ Promoter deletion ◦ Nonsence mutation ◦ Mutated termination ◦ Splice site mutation 4
  • 5. Review of Hgb StructureReview 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 5
  • 6. PathophysiologyPathophysiology  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
  • 7. Pathophysiology con’tPathophysiology 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 7
  • 8. Clinical and Laboratory Findings Associated with ThalassemiaClinical and Laboratory Findings Associated with Thalassemia
  • 9. Clinical FindingsClinical Findings 9
  • 10. Comparison of HemoglobinopathiesComparison of Hemoglobinopathies and Thalassemiasand 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 African Mediterranean Asian 10 Thalassemia: globin chains structurally normal Hemoglobinopathies: globin chain is abnormal
  • 11. BetaBeta ThalassemiaThalassemia 11
  • 12. Classical Syndromes of BetaClassical Syndromes of Beta ThalassemiaThalassemia 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. 12
  • 13. Beta Thalassemia MinorBeta 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. 13
  • 14. Beta Thalassemia MinorBeta 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. 14
  • 15. FIGURE 11-11 Patients withFIGURE 11-11 Patients with ββ-thalassemia minor show minimal morphologic abnormalities to include microcytosis-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 10with target cells. The CBC in this patient showed the following results: Hb 11.1 g/dL; RBC count 5.2 x 101212 /L; MCV 61/L; MCV 61 fL; MCH 20.2 pg; MCHC 33 g/L. (Wright-Giemsa stain; 1000x magnification)fL; MCH 20.2 pg; MCHC 33 g/L. (Wright-Giemsa stain; 1000x magnification)
  • 16. ββ-thal Minor – microcytic, occ-thal Minor – microcytic, occ codocyte, basophilic stipplingcodocyte, basophilic stippling
  • 17. Beta Thalassemia Major/ Cooley’sBeta Thalassemia Major/ Cooley’s anemiaanemia 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 17
  • 18. Clinical Findings:Clinical Findings: ββ-Thalassemia Major-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
  • 19. FIGURE 11-8 Increased erythropoiesis in the bone marrow of patients withFIGURE 11-8 Increased erythropoiesis in the bone marrow of patients with ββ-thalassemia major expands the marrow cavity-thalassemia major expands the marrow cavity producing the typical “hair-on-end” appearance as seen on this radiograph of the skull of a boy withproducing the typical “hair-on-end” appearance as seen on this radiograph of the skull of a boy with ββ-thalassemia.-thalassemia.
  • 20. Laboratory Findings:Laboratory Findings: ββ-Thalassemia Major-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
  • 21. FIGURE 11-9 Peripheral blood smear from a patient withFIGURE 11-9 Peripheral blood smear from a patient with ββ-thalassemia major showing marked anisopoikilocytosis.-thalassemia major showing marked anisopoikilocytosis. Target cells, schistocytes, teardrops, and ovalocytes are the major poikilocytes observed. An NRBC is also present.Target cells, schistocytes, teardrops, and ovalocytes are the major poikilocytes observed. An NRBC is also present. (1000x magnification; Wright-Giemsa stain)(1000x magnification; Wright-Giemsa stain)
  • 22. ββ-Thalassemia Major-Thalassemia Major Treatment ◦ Regular transfusions  Minimize anemia  Reduce excess iron absorption  Suppress ineffective erythropoiesis ◦ Iron-chelating agents ◦ Splenectomy Prognosis ◦ Untreated – die during 1st or 2nd decade ◦ Hypertransfusion with iron chelation  Extend for ≥ 1 decade
  • 23. Hereditary Persistence of FetalHereditary Persistence of Fetal Hemoglobin (HPFH)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 23