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(Mediterranean Anemia; Thalassemia Major and Minor)

By Evan M. Braunstein, MD, PhD, Assistant Professor of Medicine, Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine

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Patient Education

Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha thalassemia is particularly common among people of African, Mediterranean, or Southeast Asian ancestry. Beta-thalassemia is more common in people of Mediterranean, Middle Eastern, Southeast Asian, or Indian 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 is a hemoglobinopathy that is among the most common inherited disorders of hemoglobin production. It results from unbalanced Hb synthesis caused by decreased production of at least one globin polypeptide chain (beta, alpha, gamma, delta).


Alpha thalassemia results from decreased production of alpha-polypeptide chains due to a deletion of one or more alpha genes. People normally have four alpha alleles (two on each of a pair of chromosomes) because the alpha gene is duplicated. Disease classification is based on the number and location of deletions:

  • Alpha + thalassemia: Loss of a single gene on one chromosome (alpha/--)

  • Alpha 0 thalassemia: Loss of both genes on the same chromosome (--/--)


Beta-thalassemia results from decreased production of beta-polypeptide chains due to either mutations or deletions in the beta globin gene, leading to impaired production of Hb A. Mutations or deletions may result in partial loss (beta + allele) or complete loss (beta 0 allele) of beta globin function. There are two beta globin genes, and patients may have heterozygous, homozygous, or compound heterozygous mutations. In addition, patients may be heterozygous or homozygous for abnormalities in 2 different globin genes (eg, beta and delta).

Beta-delta-thalassemia is a less common form of beta-thalassemia in which production of both the delta chain as well as the beta chain is impaired. These mutations may be heterozygous or homozygous.

Symptoms and Signs

Clinical features of thalassemias are similar but vary in severity depending on the amount of normal Hb present.


Patients with a single alpha + allele are clinically normal (silent carriers).

Heterozygotes with defects in 2 of the 4 genes (either two alpha + alleles or one alpha 0 allele) tend to develop mild to moderate microcytic anemia but no symptoms. These patients have alpha thalassemia trait.

Defects in 3 of the 4 genes (coinheritance of both alpha + and alpha 0) severely impair alpha-chain production, resulting in the formation of tetramers of excess beta-chains (Hb H) or, in infancy, gamma-chains (Bart’s Hb). Patients with Hb H disease often have symptomatic hemolytic anemia and splenomegaly.

Defects in all 4 genes (two alpha 0 alleles) is a lethal condition in utero (hydrops fetalis), because Hb that lacks alpha chains does not transport oxygen.


In beta-thalassemia, clinical phenotypes are classified into 3 groups based on the degree to which beta globin production is impaired:

  • Minor (or trait)

  • Intermedia

  • Major

Beta-thalassemia minor (trait) occurs in heterozygotes, who are usually asymptomatic with mild to moderate microcytic anemia.

Beta-thalassemia intermedia causes a variable clinical picture that is intermediate between thalassemia major or minor.

Beta-thalassemia major (or Cooley anemia) occurs in homozygotes or compound heterozygotes (containing a beta 0 allele) and results from severe beta globin deficiency. These patients develop severe anemia and bone marrow hyperactivity. Beta-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 disease). 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. Iron chelation is usually necessary.


  • Evaluation for hemolytic anemia if suspected

  • Peripheral smear

  • Hemoglobin electrophoresis

  • DNA testing (prenatal diagnosis)

Thalassemia trait is commonly detected when routine peripheral blood smear and complete blood count show microcytic anemia and elevated red cell count. If desired, the diagnosis of beta thalassemia trait can be confirmed with quantitative Hb studies. No intervention is needed.

More severe 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 hemoglobin studies are done. Serum bilirubin, iron, and ferritin levels are increased.

In alpha-thalassemias, the percentages of Hb F and Hb A2 are generally normal, 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.

In beta-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 A2 is diagnostic for beta-thalassemia minor. In beta-thalassemia major, Hb F is usually increased, sometimes to as much as 90%, and Hb A2 is usually elevated to > 3%.

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 beta-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 beta-thalassemia minor or alpha-thalassemia minor. The prognosis of Hb H disease and beta-thalassemia intermedia varies.

Life expectancy is decreased in people with beta-thalassemia major mostly due to complication from chronic transfusions.


  • Often RBC transfusion, with or without iron chelation therapy

  • Splenectomy if splenomegaly is present

  • Allogeneic stem cell transplantation if possible

Alpha-thalassemia trait or beta-thalassemia trait: No treatment.

Hb H disease: splenectomy may be helpful if anemia is severe or splenomegaly is present.

Patients with beta-thalassemia intermedia 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.In beta thalassemia major, give transfusions as needed to maintain the Hb around 9 to 10 g/dL and avoid severe clinical manifestations. To prevent or delay complications due to iron overload, excess (transfusional) iron must be removed (eg, via chronic iron chelation therapy). Chelation therapy is generally initiated when serum ferritin levels are > 1000 ng/mL or after about 1 to 2 yr of scheduled transfusions. Splenectomy may help decrease transfusion requirements for patients with splenomegaly.

Allogeneic stem cell transplantation is the only curative option and should be considered in all patients.

Key Points

  • Thalassemias result from decreased production of at least one globin polypeptide chain (beta, alpha, gamma, delta); 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 frequent transfusions.

  • Diagnose using Hb electrophoresis.

  • Transfuse as needed, but monitor for iron overload and use chelation therapy.

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

  • Allogeneic stem cell transplantation is curative.