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For further information, see CMDT Part 13-04: The Thalassemias

Key Features

Essentials of Diagnosis

  • Microcytosis out of proportion to degree of anemia

  • Positive family history or lifelong personal history of microcytic anemia

  • Normal or elevated red blood cell (RBC) count

  • Abnormal RBC morphology with microcytes, hypochromia, acanthocytes, and target cells

  • In beta-thalassemia, elevated levels of hemoglobin A2 and F

General Considerations

  • Hereditary disorders characterized by reduction in synthesis of globin chains (alpha or β), causing reduced hemoglobin synthesis and eventually hypochromic microcytic anemia

  • Normal adult hemoglobin is primarily hemoglobin A, a tetramer of two alpha-chains and two beta-chains (alpha2beta2)

  • Thalassemias are described as

    • Trait, when there are laboratory features without clinical impact

    • Intermedia, when there is a RBC transfusion requirement or other moderate clinical impact

    • Major, when the disorder is life-threatening

  • Alpha-thalassemia syndromes are determined by the number of functional alpha-globin genes

    • Normal (four alpha-globin genes, normal hematocrit)

    • Silent carrier (three alpha-globin genes, normal hematocrit)

    • Alpha-thalassemia minor or trait (two alpha-globin genes, hematocrit 28–40%, mean cell volume [MCV] 60–75 fL)

    • Hemoglobin H disease (one alpha-globin gene, hematocrit 22–32%, MCV 60–70 fL)

    • Hydrops fetalis (0 alpha-globin genes, fatal in utero)

  • Beta-thalassemia: Reduced beta-globin chain synthesis results in relative increase in proportions of hemoglobins A2 and F compared with hemoglobin A, because beta-like globins (delta and gamma) substitute for missing beta-chains

  • With reduced beta-chains

    • Excess alpha-chains precipitate, causing hemolysis

    • Bone marrow becomes hyperplastic, resulting in bony deformities, osteopenia, and pathologic fractures

Demographics

  • Alpha-thalassemia occurs primarily in persons from southeast Asia and China and, less commonly, in blacks and persons of Mediterranean origin

  • Beta-thalassemia affects persons of Mediterranean origin (Italian, Greek) and to lesser extent Asians and blacks

Clinical Findings

Symptoms and Signs

  • Alpha-thalassemia silent carriers: asymptomatic

  • Alpha-thalassemia trait: clinically normal with mild microcytic anemia

  • Hemoglobin H disease

    • Chronic hemolytic anemia of variable severity

    • Pallor

    • Splenomegaly

  • Hydrops fetalis

    • Only hemoglobin species made is called hemoglobin Bart's (γ4)

    • All four alpha-globin genes are deleted, no normal hemoglobin is produced and the affected fetus is stillborn

  • Heterozygotes for beta-thalassemia (thalassemia minor): mild microcytic anemia

  • Homozygotes for mild beta-thalassemia (thalassemia intermedia): chronic hemolytic anemia

  • Homozygotes for major beta-thalassemia (thalassemia major)

    • Severe anemia requiring transfusion

    • Growth failure

    • Bony deformities (abnormal facial structure, pathologic bone fractures)

    • Hepatosplenomegaly and jaundice

Differential Diagnosis

  • Iron deficiency anemia (thalassemia has lower MCV, normal iron studies, more normal RBC count, more abnormal peripheral blood smear at modest levels of anemia, and usually reticulocytosis)

  • Other hemoglobinopathy (eg, sickle thalassemia, hemoglobin C disorders)

  • Sideroblastic anemia

  • Anemia of chronic disease

Diagnosis

Laboratory Tests

Alpha-thalassemia trait

  • Mild or no anemia (hematocrit 28–40%) with strikingly ...

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