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

2. 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.

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. 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

7. Clinical and Laboratory Findings Associated with Thalassemia

8. Clinical Findings

9. 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

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 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 ( %) 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 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 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

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 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 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 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

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