OVERVIEW: What every practitioner needs to know

Thalassemia may be defined as a heterogeneous group of inherited disorders characterized by reduced or absent globin chain synthesis. It is the deleterious effects of the excessively produced globin subunits that damage the red cell precursors, leading to a microcytic hypochromic anemia of variable severity.

The β-thalassemias are classified into β thalassemia major, intermedia, and minor. Beta-thalassemia major is so severe that dependency on blood transfusions is usually established within the first two years of life.

The four classical alpha thalassemias are usually due to deletion of one, two, three, or all four of the alpha genes.

Are you sure your patient has a thalassemia? What are the typical findings for this disease?


Well over 200 different gene mutations, most commonly point mutations, of the globin genes have been identified as a cause of the β- thalassemia syndromes.

Beta-thalassemia major is a clinically severe disorder due to two identical or dissimilar β-thalassemia mutations, each on chromosome 11. The reduced amount (beta+) or absence (beta 0) of beta globin chains results in an excess of unbound alpha chains. These excess alpha chains precipitate in erythroid precursors in the bone marrow, leading to premature cell death and ineffective erythropoiesis. Anemia stimulates production of erythropoietin with consequent intensive but ineffective expansion of the bone marrow (up to 25 to 30 times normal). Additionally, prolonged and severe anemia with an increased erythropoietic drive results in hepatosplenomegaly and extramedullary hematopoiesis.

Alpha-thalassemias are characterized by a decreased synthesis of alpha globin chains. The alpha-thalassemias are most commonly due to gene deletions. There are four classical alpha-thalassemias: Alpha-thalassemia-2 trait (also known as the silent carrier) is a deletion of one of the four alpha genes; Alpha-thalassemia-1 trait – a deletion of two alpha genes; Hemoglobin H disease – a deletion of three alpha genes; and Hydrops Fetalis with Hemoglobin Barts in which all four alpha genes are deleted.

Deletion of two alpha globin genes can occur in two ways: cis deletion (two gene deletions from the same chromosome 16) and trans deletion (one gene deletion from each of the chromosome 16 homologues). The cis deletion is common in Asia and the Mediterranean basin and is the only type associated with Hemoglobin H disease and hydops fetalis. Two gene deletion is also very common in the black population and is almost always associated with the deletion in the trans position. Therefore, Hemoglobin H disease and Hydrops Fetalis is virtually never seen in the black population.

Hemoglobin A production is about 25%-30% of the total hemoglobin in Hemoglobin H disease. With decreased synthesis of the alpha chains, gamma chains accumulate during gestation, and beta chains accumulate during adult life. The excess beta chains are somewhat more soluble than the excess alpha chains seen in the β- thalassemias, and will form tetramers of β4 called Hemoglobin H. Hemoglobin H does not readily precipitate to form inclusion bodies in developing erythroblasts; hence, the degree of intramedullary erythroid hematopoiesis is less compared with β-thalassemia. Hemoglobin H precipitates slowly from circulating red cells, and these patients will tend to have a moderate hemolytic anemia with relatively little ineffective erythropoiesis.

Hydrops Fetalis with Hemoglobin Barts results from total absence of alpha globin synthesis ( the four gene deletion state) – no physiologically useful hemoglobin is produced beyond the embryonic stage, and thus is incompatible with life. Hemoglobin Barts has an extraordinarily high affinity for oxygen and does not release the oxygen to fetal tissues. Severe asphyxia occurs, causing profound edema (hydrops) and death in utero.


β-thalassemia major. Untreated and undiagnosed infants with β-thalassemia major will typically present within the first two years of life with failure to thrive, pallor, hepatosplenomegaly, and jaundice. In developing countries where patients are untreated or poorly transfused, these children will also develop poor musculature, skeletal changes resulting from expansion of the bone marrow (genu valgum, frontal bossing, prominent malar eminence, hypertrophy of the maxilla) and development of masses from extramedullary hematopoiesis. However, if early regular transfusions are initiated and a hemoglobin of 9.5-10.5 is maintained, growth and development tends to be normal. Iron overload must be well managed with chelation.

Individuals with β-thalassemia intermedia will present later in life because their anemia is less severe. By definition, these individuals do not require erythrocyte transfusions or only occasionally require transfusion. Compensatory extramedullary erythropoiesis is commonly encountered. Clinically, this may manifest as deformities of the bone and face, along with erythropoietic masses that primarily affect the spleen, liver, lymph nodes, chest and spine. In fact, extramedullary erythropoietic masses may cause neurologic problems such as spinal compression with paraplegia. Patients with thalassemia intermedia may also develop gallstones and leg ulcers, and are predisposed to thrombosis, especially if splenectomized. This may include deep venous thrombosis, portal vein thrombosis, stroke, and pulmonary emboli.

Patients with β-thalassemia minor are typically clinically asymptomatic with evidence of a mild hydrochromic, microcytic anemia.

β- thalassemia may also be combined with production of an abnormal hemoglobin. The most common combination worldwide is Hemoglobin E/beta-thalassemia, which is most prevalent in Southeast Asia. Hemoglobin C/beta-thalassemia and Hemoglobin S/beta-thalassemia are also frequently encountered. Hemoglobin S/beta-thalassemia is clinically more similar to sickle cell anemia than thalassemia.

Alpha-thalassemia. Alpha-thalassemia-2 is an asymptomatic silent carrier state. There are no hematologic manifestations. This is very common in African American blacks, having a gene frequency of 15% to 20%. Alpha-thalassemia-1 trait is also clinically asymptomatic but is usually associated with a mild microcytic anemia. Individuals with Hemoglobin H disease, while variable, will usually present with a mild anemia and splenomegaly, but bone changes are uncommon. Infants with Hemoglobin Barts Hydrops Fetalis syndrome are stillborn between 34-40 weeks gestation or are born alive but die within hours. Pallor, edema, and hepatosplenomegaly are noted.

The development of newborn screening programs for hemoglobinopathies in all states of the United States has changed the clinical presentation. Nearly all children with major thalassemia syndromes in the United States are detected through dried blood spot analysis done as part of newborn screening programs introduced primarily to detect sickle cell syndromes.

The relevant results are:

  • 1 and 2-gene deletion alpha-thalassemia – Hemoglobin Barts is detected on screening. It is a tetramer of gamma chains, and is only detectable in the newborn period.

  • 3-gene deletion alpha-thalassemia – Hemoglobin H is a tetramer of Beta chains, which account for 5%-30% of the hemoglobin level in patients with Hemoglobin H disease. Hemoglobin H has a high affinity for oxygen, and is an ineffective carrier of oxygen to tissue under normal physiologic situations.

  • 4-gene deletion alpha thalassemia – this leads to Hydrops Fetalis, as these patients cannot form alpha chains, and therefore are incapable of producing Hemoglobin A, F, or A2. A rare few infants began transfusion in utero and survived to birth.

  • Homozygous β0-thalassemia and thalassemia intermedia – only Hemoglobin F will be detected, since no (or rare) Beta chains can be produced.

  • Beta thalassemia minor – this is usually not detected on the newborn screen, since diagnosis relies on increased Hgb A2 levels, which are minimal in the newborn.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory evaluation typically includes a CBC, reticulocyte count, and hemoglobin electrophoresis.

Individuals with β- thalassemia major may present with hemoglobin levels ranging from 2 to 3gm/dl or even lower; the red cells are microcytic with mean corpuscular volume (MCV)>50<70fl. The red cells show marked anisopoikilocytosis with target cells, hypochromasia, variable basophilic stippling, and numerous nucleated red cells; the reticulocyte count is typically low, reflecting ineffective erythropoiesis.

In homozygous β0-thalassemia, hemoglobin electrophoresis shows no hemoglobin A, and hemoglobin F comprises 92-95% of the total hemoglobin. In β+ homozygous or β+/β0 compound heterozygous thalassemia, hemoglobin A may comprise 10%-30% of the hemoglobin, with hemoglobin F comprising 70%-90% of the total. Beta- thalassemia intermedia is typically characterized by hemoglobin levels of 7-10gm/dl, and microcytosis with an MCV<50<80fl. Hemoglobin values associated with thalassemia trait are typically 9-11gm/dl. The peripheral blood smear often demonstrates microcytosis, hypochromia, targeting, basophilic stippling and elliptocytes; however, in occasional patients the red cells may be nearly normal. Hemoglobin electrophoresis demonstrates an elevated hemoglobin A2 of 3.5%-7%.

If routine laboratory studies fail to establish the diagnosis of thalassemia on presentation, molecular genetic analysis may be used to identify the beta globin gene mutation. Most commonly, polymerase chain reaction (PCR)-based procedures are used, and if mutation analysis fails to identify the mutation, gene sequencing may be used.

Alpha-thalassemias. The silent carrier state shows no hematologic manifestations. In the newborn period, only small amounts of Hemoglobin Barts (up to 3%) may be detected by electrophoresis. Alpha-thalassemia-1 trait is a mild microcytic anemia with approximately 3%-8% of Hemoglobin Barts noted in the newborn period.

Hemoglobin H disease is a moderately severe but variable microcytic, hypochromic anemia. Because Hemoglobin H is unstable and precipitates in circulating red cells, incubation of blood in a supravital oxidizing stain such as brilliant cresyl blue will often demonstrate multiple small inclusions within the red cells. Electrophoresis will demonstrate the fast migrating Hemoglobin H, accounting for 3%-30% of the total hemoglobin.

Severe anemia is present in the infant with Hydrops Fetalis, with hemoglobins ranging from 3-10gm/dl, markedly hypochromic, microcytic red cells, with target cells and numerous nucleated red cells. Hemoglobin electrophoresis reveals predominantly Hemoglobin Barts with a small amount of Hemoglobin H. Hemoglobin A and F are totally absent.

What other disease/condition shares some of these symptoms?

For infants detected with thalassemias via newborn screening testing, a confirmatory hemoglobin electrophoresis should be obtained. This is suggested to avoid errors in labeling or reporting. Newborn screening testing has extremely high sensitivity and specificity, unless the infant has been transfused. Hematologic consultation is suggested.

For infants and older children with thalassemia syndromes, the most common differential diagnosis is among Beta-thalassemia minor, 2-gene deletion Alpha-thalassemia, the anemia of chronic disease, and iron deficiency. Table I lists suggestive differences in the CBC, but iron studies and hemoglobin electrophoresis are the definitive studies. The Mentzer index, which divides the MCV by the RBC number, may be useful in differentiating iron deficiency from Beta-thalassemia minor. Patients with iron deficiency typically have reduced RBC numbers, while patients with thalassemia minor have increased RBC numbers. A Mentzer index <11 suggests thalassemia, >13 suggests iron deficiency, and between11-13 is indeterminate. The Mentzer index does not apply to alpha-thalassemia. Patients with thalassemia typically have normal or increased iron stores because of increased GI absorption of iron. Electrophoresis results are noted in the Laboratory Evaluation section above.

Table I.
Alpha-Thalassemia 2-gene deletion Fe Deficiency Beta-Thalassemia Minor Anemia of Chronic
Hemoglobin 9-10 <10 9-10 <10
MCV ↓↓ ↓ or N
Platelets N N ↑↑
Mentzer Index NA >13 <11 NA

If you are able to confirm that the patient has a thalassemia, what treatment should be initiated?

For β-thalassemia major, early and regular transfusions are initiated and a target hemoglobin of 9.5-10.5 is maintained. Iron overload must be well managed with chelation. Growth and development can be normal with good care and follow-up.

β-thalassemia intermedia will often present later in life with less severe anemia. These individuals generally do not require erythrocyte transfusions or only occasionally require transfusion.

Patients with β-thalassemia minor and the alpha-thalassemias are typically clinically asymptomatic and do not require therapy.

What is the evidence?

Weatherall, DJ, Lichtman, MA, Kipps, T, Kaushansky, K, Beutler, E, Seligsohn, U, Prchal, JT. “Disorders of globin synthesis: the thalassemias”. Williams hematology. 2006. pp. 633-66. (This is a comprehensive general review of each of the thalassemias.)

Steinberg, MH, Embury, SH. “Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene”. Blood. vol. 68. 1986. pp. 985-90. (This is a comprehensive general review of Alpha-thalassemia.)

Galanello, R, Origa, R. “Beta-thalassemia”. Orphanet J Rare Dis. vol. 5. 2010. pp. 11(This is a comprehensive general review of Beta-thalassemia.)

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