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(Mediterranean Anemia; Thalassemia Major and Minor)


Evan M. Braunstein

, MD, PhD, Johns Hopkins University School of Medicine

Reviewed/Revised Jun 2022 | Modified Sep 2022

Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha-thalassemia is particularly common among people with African, Mediterranean, or Southeast Asian ancestry. Beta-thalassemia is more common among people with 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 hemoglobin analysis. Treatment for severe forms may include transfusion, splenectomy, chelation, and stem cell transplantation.

Pathophysiology of Thalassemias

Thalassemia is a hemoglobinopathy Overview of Hemoglobinopathies Hemoglobinopathies are genetic disorders affecting the structure or production of the hemoglobin molecule. Hemoglobin molecules consist of polypeptide chains whose chemical structure is genetically... read more that is among the most common inherited disorders of hemoglobin production. The normal adult hemoglobin molecule (Hb A) consists of 2 pairs of chains designated alpha and beta. Normal adult blood also contains 2.5% Hb A2 (composed of alpha and delta chains) and < 1.4% hemoglobin F (fetal hemoglobin), which has gamma chains in the place of beta chains. Thalassemia results from unbalanced hemoglobin 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 genes (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 hemoglobin (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 of Thalassemias

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


Patients with a single alpha + allele (alpha/alpha;alpha/--) are clinically normal and are called silent carriers.

Patients who are heterozygous with defects in 2 of the 4 genes such as two alpha + alleles (alpha/--;alpha/--) or one alpha 0 allele (alpha/alpha;--/--) tend to develop mild to moderate microcytic anemia but no symptoms. These patients have alpha-thalassemia trait.

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

Defects in all 4 genes via two alpha 0 alleles (--/--;--/--) is a lethal condition in utero (hydrops fetalis), because hemoglobin that lacks alpha chains cannot 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 patients who are heterozygous (beta/beta + or beta/beta 0), who are usually asymptomatic with mild to moderate microcytic anemia. This phenotype may also occur in mild cases of beta +/beta +.

Beta-thalassemia intermedia is a variable clinical picture that is intermediate between thalassemia major or minor, caused by inheritance of 2 beta thalassemia alleles (beta +/beta 0 or severe cases of beta +/beta +).

Beta-thalassemia major (or Cooley anemia) occurs in patients who are homozygous (beta 0/beta 0) or severe compound heterozygotes (beta 0/beta +) 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 years 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 Sickle Cell Disease Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in people with African ancestry. It is caused by homozygous inheritance of genes for hemoglobin... read more Sickle Cell Disease ). Splenomegaly, often massive, is common. Splenic sequestration may develop, accelerating destruction of transfused normal red blood cells. 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 Overview of Iron Overload Typical adults lose about 1 mg iron (Fe) per day in shed epidermal and gastrointestinal cells; menstruating females lose on average an additional 0.5 to 1 mg/day from menses. This iron loss... read more , iron deposits in heart muscle may cause heart failure. Hepatic siderosis is typical, leading to functional impairment and cirrhosis. Iron chelation is usually necessary.

Diagnosis of Thalassemias

  • 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 hemoglobin studies. No intervention is needed; in women, anemia can be worsened by pregnancy.

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 (measurement of the quantities of different hemoglobin types) 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 genetic tests. The diagnosis often is one of exclusion of other causes of microcytic anemia.

In beta-thalassemia major, anemia is severe, often with hemoglobin 6 g/dL (≤ 60 g/L). The red blood cell count is elevated relative to hemoglobin, and the cells are very microcytic. The blood smear is virtually diagnostic, with many nucleated erythroblasts; target cells; small, pale red blood cells; and punctate and diffuse basophilia.

In quantitative hemoglobin studies, mild elevation of Hb A2 only is diagnostic for beta-thalassemia minor. In beta-thalassemia major, Hb F is also 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 hemoglobin electrophoresis. The specific molecular defect can be characterized but does not alter the clinical approach.

Recombinant DNA approaches of gene mapping (particularly polymerase chain reaction [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.

Imaging tests 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. Chest imaging may reveal evidence of paravertebral extramedullary hematopoiesis.

Prognosis for Thalassemias

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 complications from chronic transfusions.

Treatment of Thalassemias

  • Often red blood cell transfusion, with or without iron chelation therapy

  • Splenectomy if splenomegaly is present

  • Allogeneic stem cell transplantation if possible

  • Luspatercept for treatment of transfusion-dependent beta thalassemia

In patients with alpha-thalassemia trait or beta-thalassemia trait, no treatment is needed.

In 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 red blood cell transfusion Red blood cells (RBCs) Whole blood can provide improved oxygen-carrying capacity, volume expansion, and replacement of clotting factors and was previously recommended for rapid massive blood loss. However, because... read more may be valuable in severely affected patients. In beta thalassemia major, give transfusions as needed to maintain the hemoglobin level around 9 to 10 g/dL (90 to 100 g/L) 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 Treatment Secondary iron overload results from excess absorption of iron, repeated blood transfusions, or excess oral intake, typically in patients with disorders of erythropoiesis. Consequences can include... read more ). Chelation therapy is generally initiated when serum ferritin levels are > 1000 ng/mL (> 1000 mcg/L) or after about 1 to 2 years of scheduled transfusions. Splenectomy may help decrease transfusion requirements for patients with significant splenomegaly.

Luspatercept is an injectable recombinant fusion protein that inhibits signalling of the transforming growth factor beta pathway. In a randomized, placebo-controlled trial in patients with beta-thalassemia, it reduced transfusion requirements by 33% in 21% of patients (compared to 4.5% of controls). Luspatercept is an option for treatment in transfusion-dependent patients (1 Treatment reference Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha-thalassemia is particularly common among people with African, Mediterranean... read more ).

Treatment reference

Key Points

  • Thalassemias result from decreased production of at least one globin polypeptide chain (beta, alpha, gamma, delta); the resultant abnormal red blood cells 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 red blood cells (including transfused ones).

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

  • Diagnose using hemoglobin 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.

More Information

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