MLAB 1415: Hematology Keri Brophy-Martinez

1. MLAB 1415: HematologyKeri Brophy-Martinez Chapter 11: Thalassemia

2. Overview • 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.

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. • May be either homozygous defect or heterozygous defect.

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 of one of these chains

5. 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

6. Pathophysiologycon’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. Clinical and Laboratory Findings Associated with Thalassemia

8. Clinical Findings

9. Comparison of Hemoglobinopathies and Thalassemias 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 thalassemiaintermedia- Severity lies between the minor and major. • Beta thalassemia major - homozygous disorder resulting in severe transfusion-dependent hemolytic anemia.

12. 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.

13. 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.

14. 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)

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

16. Beta ThalassemiaMajor/ 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

17. 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

18. 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.

19. 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

20. 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)

21. 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

22. 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