What every physician needs to know:

The thalassemias are among the most common genetic diseases worldwide and are attributable to unbalanced production of the hemoglobin molecule, due to either insufficient production of the α- or β-globin chains. The remaining globin chains precipitate in erythroid precursors and in red blood cells, resulting in an anemia from either ineffective production of red blood cells, hemolysis of red blood cells, or a combination of these effects.

In the case of β-thalassemia, which is due to defective production of the β-globin chain of hemoglobin, the free α-globin chains precipitate in erythroid precursors causing anemia primarily due to impaired production of red blood cells.

In α-thalassemia, reduced production of α-globin results in tetramers of β-globin known as hemoglobin H (HbH) that can precipitate within mature red blood cells. This in turn results in an anemia from hemolysis and destruction of these red blood cells, as well as some ineffective production of such red blood cells.

Continue Reading

The thalassemias generally are transmitted as simple Mendelian genetic diseases. If one acquires a single mutation of the globin genes (a heterozygous state) from the parents, then one is a carrier for thalassemia (described as thalassemia trait). Carriers can have abnormal red blood cell indices indicated by a low mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), abnormalities on hemoglobin analyses, and a mild anemia, but are generally clinically asymptomatic.

Patients who acquire two mutations from their parents (homozygous state) can have a severe disease involving an anemia that may require intermittent or chronic transfusions. There can also be significant morbidity from iron overload in the thalassemias both due to chronic transfusions and from increased absorption of iron in the setting of ineffective red blood cell production.

Are you sure your patient has thalassemia? What should you expect to find?

Patients who have thalassemia have an anemia associated with microcytosis (low MCV) and hypochromia (low MCH), although the extent of anemia can be highly variable.


In the case of α-thalassemia, there are normally four α-globin genes present, with two located on each copy of chromosome 16. When one α-globin gene is deleted, there is generally no consequence and it is difficult to distinguish between these individuals and those without such deletions.

Patients may have two α-globin genes deleted on the same chromosome (in cis) or on different chromosome (in trans), in which case such individuals have microcytic red blood cell indices and hypochromia along with a mild anemia. These patients are considered to have α-thalassemia trait. Those with cis deletions of α-globin have a risk of transmitting severe forms of α-thalassemia to their children and therefore genetic counseling can be helpful in such cases.

Those with three α-globin genes deleted have a condition known as HbH disease, which can be very variable in severity, but which often involves a moderate to severe anemia that can require regular transfusion therapy. The extent of the disease depends on the types of mutations present.

Deletion of all four α-globin genes is usually incompatible with a viable birth, and fetuses affected by such a condition have a severe form of hydrops fetalis, known as Barts hydrops. This condition is so-named because the fetal β-like globin chain (γ-globin) forms Hemoglobin Barts when assembled as a tetramer of four γ-globin chains.


Carriers of β-thalassemia mutations (β-thalassemia trait) have microcytosis, hypochromia, a normal or increased number of red blood cells, and often will have an elevation of the minor adult hemoglobin, (HBA2), along with a mild anemia in some cases. In contrast to α-thalassemia mutations, most β-thalassemia mutations are due to point mutations rather than deletions. Patients who acquire two β-thalassemia mutations generally have a severe microcytic and hypochromic anemia. The extent of anemia can vary depending on the nature of the mutations present in the β-globin genes (which determine whether or not any residual β-globin is produced), the extent of fetal (γ) hemoglobin production to compensate for globin chain imbalance, the presence of concomitant α-thalassemia that can reduced globin chain imbalance, and other unknown factors affecting severity.

Often patients with β-thalassemia will require either chronic transfusions to survive (thalassemia major) or may require intermittent transfusions at times of illness (thalassemia intermedia). There is an increased propensity of these patients to become iron overloaded secondary to increased iron absorption and from chronic transfusions; therefore these patients may require regular iron chelation therapy.

They often have moderate to severe boney abnormalities due to excessive expansion of bone marrow in the face of ineffective erythropoiesis. In addition, β-thalassemia mutations can be found in the compound heterozygous state with mutant hemoglobins. When acquired with hemoglobin E, a thalassemia-like mutant hemoglobin, a thalassemia intermedia syndrome can result, although the severity of this disease is very variable.

When β-thalassemia mutations are coinherited with hemoglobin S, a sickle cell disease syndrome can occur although often the clinical severity of these diseases can be different than sickle cell anemia.

Beware of other conditions that can mimic thalassemia:

There can be diagnostic confusion between thalassemia trait and iron deficiency anemia. Both conditions can have a low red blood cell volume (MCV) and a low amount of hemoglobin per red cell (MCH). Patient with thalassemia trait can have a high red blood cell count and mild or no anemia. Patients with iron deficiency can have a normal or low red cell count and generally get anemia as a later manifestation.

Some practitioners use the Mentzer index (Mentzer index = MCV/red blood cell count [RCV]) to discriminate between thalassemia trait and iron deficiency. In general, those with a Mentzer index of less than 13 have thalassemia trait, while those with iron deficiency usually have an index of greater than 13. However, the utility of this measure is questionable and this distinction may not often be accurate. Assessment of iron stores is often necessary to distinguish the two.

Which individuals are most at risk for developing thalassemia:

Since thalassemia is genetically transmitted, patients often have a family history of these diseases and parents of patients will be carriers for these mutations. Patients of Mediterranean, Southeast and South Asian, and Middle Eastern origin are most frequently affected, although these mutations are widespread in many populations around the world.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

A complete blood count is helpful initially to demonstrate the extent of anemia and to also show that the patient has hypochromia and microcytosis.

The red blood cell count can be increased in those with thalassemia trait and can be helpful in distinguishing this from iron deficiency.

A reticulocyte count can be helpful in examining the response to anemia. Impaired red blood cell production (which is most indicative of β-thalassemia) will result in relatively low reticulocyte counts. A disease where destruction of red blood cells predominates will be characterized by increased reticulocyte counts.

A blood smear can be helpful, since morphology will show hypochromic and microcytic red blood cells, variation in red blood cell size (anisocytosis), and certain unique cell shapes such as target cells. Stains of a smear with brilliant cresyl blue can reveal hemoglobin precipitates that occur in HbH disease.

Hemoglobin electrophoresis or high performance liquid chromatography can be useful to examine whether other hemoglobin types may be present (i.e., hemoglobin E or S) and if done quantitatively, will indicate whether hemoglobins A2 and F are elevated, as occurs in β-thalassemia. In HbH disease, HbH can be detected and Hemoglobin Barts can also be detected in newborn infants.

In patients with severe or transfusion dependent thalassemia, measurement of iron burden by ferritin can be helpful, although this is not necessarily the most accurate measurement of iron overload (imaging modalities can be better).

Once thalassemia has been diagnosed and characterized using the laboratory testing described above, genetic testing can often be helpful. Detection of α-thalassemia deletions and β-thalassemia mutations by polymerase chain reaction (PCR) and sequencing are available from a number of clinical laboratories and can be helpful in predicting clinical course or in reducing uncertainty of a diagnosis.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of thalassemia?

In general there are no imaging studies that are useful to make a diagnosis of thalassemia. However, imaging can be useful in examining patients with thalassemia.

Plain films can be useful to assess for bone abnormalities that can occur due to ineffective red blood cell production and consequent expansion of the bone marrow space.

Nuclear medicine techniques can be useful to assess splenic size and function, which could be useful if splenectomy is under consideration.

Computed tomography (CT) and magnetic resonance imaging (MRI) scans can be useful in assessing the extent of extramedullary hematopoiesis that occurs in these patients.

Finally, newer MRI imaging modalities are proving useful for assessing iron burden in patients with thalassemia and the consequent iron overload present.

If you decide the patient has thalassemia, what therapies should you initiate immediately?

Depending on the extent of anemia and effects on growth, transfusion therapy can be utilized in patients with thalassemia. The necessity and frequency of transfusions vary depending upon availability of a safe blood supply, clinical course, and co-morbidities. Often younger children are kept on transfusion regimens to ensure that growth potential is maximized and then it is possible to later liberalize such transfusion regimens.

Thalassemia major patients undergoing chronic transfusions and even thalassemia intermedia patients who may have only rare transfusions have an increased propensity to absorb iron. Therefore, these patients are at risk for becoming iron overloaded.

In order to avoid possible complications of iron overload, including cardiac disease, cirrhosis, pancreatic islet cell failure, testicular failure, and joint disease, regular iron chelation regimens need to be undertaken. Two Food and Drug Administration (FDA) approved iron chelators are currently available.

Deferoxamine is a drug that needs to be delivered either by the subcutaneous route or in an intravenous fashion. In general, it is best delivered by pumps that allow continuous infusion of this medication via a subcutaneous route. Recently deferisirox, an orally bioavailable iron chelator became available.

More definitive therapies?

Beyond regular transfusion therapy and iron chelation to deal with the resulting iron overload, few definitive therapies exist. Bone marrow transplantation is potentially curative, although there are a number of limitations to the widespread use of such therapies. One needs to find an appropriate donor and there are a number of morbidities associated with such therapies. This includes graft-versus-host disease and graft rejection.

There are a number of other therapies that are currently under experimental investigation. This includes approaches to use gene therapy to allow non-mutated forms of the β-globin genes to be introduced into red blood cell progenitors, so that the disease can be ameliorated. While early trials of these therapies are showing some promise, there are many limitations to address before such therapies can become more widely used.

There is also ongoing work to attempt to find ways to induce fetal hemoglobin (γ-globin) to ameliorate the globin chain imbalance found in patients with β-thalassemia.

These therapies are currently either in the early stages of development or in early clinical trials.

What other therapies are helpful for reducing complications?

Patients who will undergo splenectomy should be vaccinated against polysaccharide encapsulated organisms including Streptococcus pneumoniae, Haemophilus
influenzae type b, and Neisseria meningitides. Splenectomized patients have an increased risk of acquiring these infections and so appropriate antibiotic coverage may be necessary should such patients become ill.

Thalassemia patients can also have a number of endocrine complications. In particular, impaired growth and hormone deficiencies can be a major problem. The use of hormone replacement can have a valuable role in treating these patients, but this needs to be done under the guidance of an endocrinologist with appropriate expertise.

The bone disease seen in thalassemia can also be improved with the use of calcium supplementation, vitamin D, and bisphosphonates, although more data is needed on the use of these agents and they should be tailored for the individual patient, depending upon the extent of bone disease present.

What should you tell the patient and the family about prognosis?

With regular transfusion therapies and appropriate iron chelation, patients with thalassemia can live into adulthood. Women with thalassemia can even successfully carry pregnancies to term.

All patients with these diseases need to be followed by multiple specialists including hematologists, cardiologists, endocrinologists, psychologists, and others to properly manage the various problems and issues that arise from living with thalassemia.

"What if" scenarios.

Recent studies of patients with thalassemia intermedia, suggest that a large fraction of patients may be able to survive without major morbidity, even if regular transfusions are stopped. A major issue in children is ensuring that they are able to reach their maximal growth potential and therefore transfusions may have a role to support growth. Subsequently many patients may not require regular transfusions.

Trials of halting transfusions in specific patients with thalassemia may be useful, although these need to be done carefully and with the guidance of a hematologist with expertise in this area. Future clinical studies will likely address in more depth whether there may be benefit to reducing regular transfusions in a subset of patients who currently receive such therapy.



In α-thalassemia there is reduced production of α-globin, which is generally caused by deletions of the α-globin genes. The reduced production of α-globin causes the unpaired β-globin chains to form unstable tetramers known as hemoglobin H (HbH) that can precipitate within mature red blood cells. This in turn results in an anemia from hemolysis and destruction of these red blood cells, as well as some ineffective erythropoiesis from precipitation of HbH in precursors. In order to compensate for this increased destruction of red blood cells, there is an expansion of erythroid precursors within the marrow and in other extramedullary organs, including the spleen.


Beta-thalassemia is due to defective production of the β-globin chain of hemoglobin, which generally results from point mutations affecting either the transcription, splicing, or translation of the adult β-globin gene. As a result of the impaired β-globin production, there are free α-globin chains that precipitate in erythroid precursors. This results in death of these cells from toxicity and the resulting unfolded protein responses, which leads to ineffective erythropoiesis. As a result of this, there is an accumulation of erythroid precursors in the bone marrow, as well as at other sites in the body including the spleen, liver, and other extramedullary organs. The expansion of erythroid precursors within the bone marrow is responsible for the consequent bone disease.

What other clinical manifestations may help me to diagnose thalassemia?

Many patients with thalassemia will have hepatosplenomegaly as a result of extramedullary hematopoiesis, which should be assessed on clinical exam. Furthermore, signs of medullary expansion such as frontal bossing can be helpful in assessing the severity of thalassemia.

It is also important to carefully examine growth charts of children with thalassemia, which may affect a decision to transfuse the patient more frequently to support growth.

What other additional laboratory studies may be ordered?

As noted above, genetic testing to delineate specific mutations may be useful for predicting the clinical course in certain patients. However, limitations exist to make genotype and phenotype correlations. Recent studies suggest that other genetic variation may contribute to the variation in clinical phenotype and therefore in the future, such testing may be of benefit to patients with thalassemia.

What’s the evidence?

Weatherall, DJ, Clegg, JB. “The Thalassaemia Syndromes”. 2001. [This textbook is an excellent and comprehensive resource on the thalassemias that covers both basic science and clinical knowledge from this field.]

Cunningham, MJ, Sankaran, VG, Nathan, DG, Orkin, SH, Orkin, SH, Nathan, DG, Ginsburg, D, Look, AT, Fisher, DE, Lux, SE. “The Thalassemias”. 2009. pp. 1015-1106. [An updated textbook chapter covering the pathophysiology and clinical management of the thalassemia syndromes.]

Sankaran, VG, Nathan, DG. “Thalassemia: an overview of 50 years of clinical research”. Hematol Oncol Clin North Am. vol. 24. 2010. pp. 1005-1020. [A recently written historical overview of clinical research in the thalassemia field.]

Taher, AT, Musallam, KM, Cappellini, MD, Weatherall, DJ. “Optimal management of beta thalassaemia intermedia”. Br J Haematol. vol. 152. 2011. pp. 512-523. [An updated review of the latest clinical management for patients with thalassemia intermedia.]

Rund, D, Rachmilewitz, E. “Beta-thalassemia”. N Engl J Med. vol. 353. 2005. pp. 1135-1146. [An excellent and brief overview reviewing the pathophysiology and management of β-thalassemia.]

Higgs, DR, Weatherall, DJ. “The alpha thalassaemias”. Cell Mol Life Sci. vol. 66. 2009. pp. 1154-1162. [An excellent overview of α-thalassemia.]

Fucharoen, S, Viprakasit, V. “Hb H disease: clinical course and disease modifiers”. Hematology Am Soc Hematol Educ Program. 2009. pp. 26-34. [A recent review covering what is known about HbH disease.]

Sankaran, VG, Nathan, DG. “Reversing the hemoglobin switch”. N Engl J Med. vol. 363. 2010. pp. 2258-2260. [A brief overview on the latest basic science research of how fetal hemoglobin can be therapeutically induced.]