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(Mediterranean Anemia; Thalassemia Major and Minor)

by Alan E. Lichtin, MD

Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective Hb synthesis. They are particularly common in people of Mediterranean, African, and Southeast Asian ancestry. Symptoms and signs result from anemia, hemolysis, splenomegaly, bone marrow hyperplasia, and, if there have been multiple transfusions, iron overload. Diagnosis is based on genetic tests and quantitative Hb analysis. Treatment for severe forms may include transfusion, splenectomy, chelation, and stem cell transplantation.


Thalassemia (a hemoglobinopathy—see Hemoglobinopathies) is among the most common inherited disorders of Hb production. It results from unbalanced Hb synthesis caused by decreased production of at least one globin polypeptide chain (β, α, γ, δ).

β-Thalassemia results from decreased production of β-polypeptide chains. Inheritance is autosomal: Heterozygotes are carriers and have asymptomatic mild to moderate microcytic anemia (thalassemia minor); homozygotes (β-thalassemia major, or Cooley anemia) develop severe anemia and bone marrow hyperactivity. β-δ-Thalassemia is a less common form of β-thalassemia in which δ-chain as well as β-chain production is impaired and which also has heterozygous and homozygous states.

α-Thalassemia, which results from decreased production of α-polypeptide chains, has a more complex inheritance pattern, because genetic control of α-chain synthesis involves 2 pairs of genes (4 genes). Heterozygotes for a single gene defect (α-thalassemia-2 [silent]) are usually clinically normal. Heterozygotes with defects in 2 of the 4 genes (α-thalassemia-1 [trait]) tend to develop mild to moderate microcytic anemia but no symptoms. Defects in 3 of the 4 genes more severely impairs α-chain production, resulting in the formation of tetramers of excess β chains (Hb H) or, in infancy, γ chains (Bart’s Hb). Defects in all 4 genes are a lethal condition in utero, because Hb that lacks α chains does not transport O 2 . In blacks, the gene frequency for α-thalassemia is about 25%; only 10% have defects in more than 2 genes.

Symptoms and Signs

Clinical features of thalassemias are similar but vary in severity. β-Thalassemia major manifests by age 1 to 2 yr with symptoms of severe anemia and transfusional and absorptive iron overload. Patients are jaundiced, and leg ulcers and cholelithiasis occur (as in sickle cell anemia). Splenomegaly, often massive, is common. Splenic sequestration may develop, accelerating destruction of transfused normal RBCs. Bone marrow hyperactivity causes thickening of the cranial bones and malar eminences. Long bone involvement predisposes to pathologic fractures and impairs growth, possibly delaying or preventing puberty.

With iron overload, iron deposits in heart muscle may cause heart failure. Hepatic siderosis is typical, leading to functional impairment and cirrhosis.

Patients with Hb H disease often have symptomatic hemolytic anemia and splenomegaly.


  • Evaluation for hemolytic anemia if suspected

  • Peripheral smear

  • Electrophoresis

  • DNA testing (prenatal diagnosis)

Thalassemias are suspected in patients with a family history, suggestive symptoms or signs, or microcytic hemolytic anemia. If thalassemias are suspected, laboratory tests for microcytic and hemolytic anemias and quantitative Hb studies are done. Serum bilirubin, iron, and ferritin levels are increased.

In β-thalassemia major, anemia is severe, often with Hb 6 g/dL. RBC count is elevated relative to Hb because the cells are very microcytic. The blood smear is virtually diagnostic, with many nucleated erythroblasts; target cells; small, pale RBCs; and punctate and diffuse basophilia.

In quantitative Hb studies, elevation of Hb A 2 is diagnostic for β-thalassemia minor. In β-thalassemia major, Hb F is usually increased, sometimes to as much as 90%, and Hb A 2 is usually elevated to > 3%. The percentages of Hb F and Hb A 2 are generally normal in α-thalassemias, and the diagnosis of single or double gene defect thalassemias may be carried out with newer genetic tests and often is one of exclusion of other causes of microcytic anemia. Hb H disease can be diagnosed by demonstrating the fast-migrating Hb H or Bart’s fractions on Hb electrophoresis. The specific molecular defect can be characterized but does not alter the clinical approach. Recombinant DNA approaches of gene mapping (particularly the PCR) have become standard for prenatal diagnosis and genetic counseling.

If bone marrow examination is done for anemia (eg, to exclude other causes), it shows marked erythroid hyperplasia. X-rays done for other reasons in patients with β-thalassemia major show changes due to chronic bone marrow hyperactivity. The skull may show cortical thinning, widened diploic space, a sun-ray appearance of the trabeculae, and a granular or ground-glass appearance. The long bones may show cortical thinning, marrow space widening, and areas of osteoporosis. The vertebral bodies may have a granular or ground-glass appearance. The phalanges may appear rectangular or biconvex.


Life expectancy is normal for people with β-thalassemia minor or α-thalassemia minor. The outlook for people with Hb H disease varies. Life expectancy is decreased in people with β-thalassemia major; only some live to puberty or beyond.


  • Sometimes splenectomy

  • Sometimes RBC transfusion and chelation therapy

  • Rarely allogeneic stem cell transplantation

People with α- and β-thalassemia minor require no treatment. Splenectomy may be helpful if Hb H disease causes severe anemia or splenomegaly.

Children with β-thalassemia major should receive as few transfusions as possible to avoid iron overload. However, suppression of abnormal hematopoiesis by periodic RBC transfusion may be valuable in severely affected patients. To prevent or delay iron overload, excess (transfusional) iron must be removed (eg, via chronic iron-chelation therapy). Splenectomy may help decrease transfusion requirements for patients with splenomegaly. Allogeneic stem cell transplantation has been successful, but the requirement for a histocompatible match, mortality and morbidity of the procedure, and lifelong requirement for immunosuppression have limited its usefulness.

Key Points

  • Thalassemias result from decreased production of at least one globin polypeptide chain (β, α, γ, δ); the resultant abnormal RBCs are microcytic, often abnormally shaped, and prone to hemolysis (causing anemia).

  • Splenomegaly, often massive, is common and can result in splenic sequestration that accelerates destruction of RBCs (including transfused ones).

  • Iron overload is common because of increased absorption (due to defective erythropoiesis) and often frequent transfusions.

  • Diagnose using Hb electrophoresis.

  • Treat with as few transfusions as possible, monitor for iron overload and use chelation if needed.

  • Splenectomy may help decrease transfusion requirements for patients with splenomegaly.

  • Allogeneic stem cell transplantation is effective but requires a histocompatible match and has significant risks; it should be done only when prognosis would otherwise be poor.

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