MLAB 1415: HematologyMLAB 1415: HematologyKeri Brophy-MartinezKeri Brophy-Martinez

Chapter 11:Thalassemia

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Overview 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.

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Thalassemia 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. 3

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

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Review of Hgb StructureReview of Hgb StructureNormal 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

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PathophysiologyPathophysiologyα-chain excess

unstablePrecipitates within the cell, causes damageMacrophages destroy the damaged RBCs in

the bone marrow, leads to ineffective erythropoiesis

Spleen also removes damaged RBCs, leads to chronic extravascular hemolysis

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Pathophysiology con’tPathophysiology con’tβ-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

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Clinical and Laboratory Findings Associated with ThalassemiaClinical and Laboratory Findings Associated with Thalassemia

Clinical FindingsClinical Findings

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Comparison of Comparison of Hemoglobinopathies and Hemoglobinopathies and ThalassemiasThalassemias

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

AfricanMediterraneanMiddle EasternAsian

Thalassemia Microcytic

Hypochromic

Target cells, basophilic stippling

HbHHb Bart’s

AfricanMediterraneanAsian

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Thalassemia: globin chains structurally normalHemoglobinopathies: globin chain is abnormal

Beta Beta ThalassemiaThalassemia

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Classical Syndromes of Beta Classical Syndromes of Beta ThalassemiaThalassemiaBeta 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 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.

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Beta Thalassemia Minor Beta Thalassemia Minor

Anemia usually mildRarely 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 FIGURE 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 10 1212/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)

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

Beta Thalassemia Major/ Beta Thalassemia Major/ Cooley’s anemia 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 reducedHbA2 and Hg F production increased

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Clinical Findings:Clinical Findings:ββ-Thalassemia Major-Thalassemia MajorInfants

◦Irritability, pallor, failure to thrive◦Diarrhea, fever, enlarged abdomen

Severe anemiaCardiac failureBronze pigmentation of skinBone 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 FIGURE 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 with producing the typical “hair-on-end” appearance as seen on this radiograph of the skull of a boy with ββ-thalassemia.-thalassemia.

Laboratory Findings:Laboratory Findings:ββ-Thalassemia Major-Thalassemia Major

Hb can be as low as 2–3 g/dLMicrocytic hypochromic

◦MCV < 67 fL, ↓ MCH and MCHCPeripheral blood smear

◦Anisocytosis and poikilocytosis◦Basophilic stippling, polychromasia◦NRBCs◦↑ RDW

FIGURE 11-9 Peripheral blood smear from a patient with FIGURE 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)

ββ-Thalassemia Major-Thalassemia MajorTreatment

◦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

Hereditary Persistence of Fetal Hereditary 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

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