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ICD-10 ICD10 F84.0-F84.1
ICD-9 282.4
MedlinePlus 000587
MeSH D013789

Thalassemia (American English) or thalassaemia (British English) is a recessive trait inherited disease of the red blood cells.[1][2] The clinical disorder is also known as Cooley's Anemia. [3]. In thalassemia, the genetic defect results in a reduced rate of synthesis of normal hemoglobin chains. Thalassemia is a type of hemoglobinopathy, a generic term for any structural abnormality of hemoglobin, including thalassemia, sickle cell anemia, Hemoglobin E, and thousands of other hemoglobin changes. The blood cells are vulnerable to mechanical injury and therefore have a shortened survival time. Blood transfusions on a regular basis may be necessary to maintain an acceptable hemoglobin concentration. Allogeneic stem cell transplants can be performed to prevent the complications of chronic transfusion: in particular, iron accumulation. Hemapoetic stem cell transplantation for thalassemia is usually performed after the age of three, when a child's immune system is more fully developed.

The disease is named after its geographical association with the Mediterranean sea : Thalassa is Greek for the sea, Haima is Greek for blood. Thalassemia occurs in all populations and ethnic groups, but its prevalence differs among different populations. Thalassemia may protect the host from malaria infections, explaining its geographic distribution.[4]


The thalassemias are classified according to which chain of the globin molecule is affected: in α thalassemia, the production of α globin is deficient, while in β thalassemia the production of β globin is defective. Thalassemia produces a deficiency of α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin.

α thalassemia

β thalassemia

  • Thalassemia trait
  • Thalassemia intermedia
  • Thalasemmis major
  • Hemoglobin E thalassemia


The estimated prevalence is 16% in people from Cyprus, 3-14% in Thailand, and 3-8% in India, Pakistan, Bangladesh, and China. There are also higher prevalences in descendants of people from Latin America, the Caribbean, and Mediterranean countries (e.g. Spain). A lower prevalence has been reported from black people in Africa (0.9%) and northern Europe (0.1%).(4)

Alpha (α) thalassemias

The alpha thalassemias involve the genes HBA1 (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 141800. World Wide Web URL: and HBA2 (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 141850. World Wide Web URL:, inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. α thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called hemoglobin H) that have abnormal oxygen dissociation curves.

There are four genetic loci for α globin, two of which are maternal in origin and two paternal in origin. The more of these loci that are deleted or affected by mutation, the more severe will be the manifestations of the disease:

  • If all four loci are affected, the fetus cannot live once outside the uterus and may not survive gestation: most such infants are dead at birth with hydrops fetalis, and those who are born alive die shortly after birth. They are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains (hemoglobin Barts). Usually, this involves homozygous inheritance of an alpha thalassemia trait, type 1.
  • If three loci are affected, Hemoglobin H disease results. Two unstable hemoglobins are present in the blood, both hemoglobin Barts (tetrameric γ chains) and hemoglobin H (tetrameric β chains). There is a microcytic hypochromic anemia with target cells and Heinz bodies (precipitated Hb H) on the peripheral blood smear. The disease may first be noticed in childhood or in early adult life, when the anemia and splenomegaly are noted. This is usually due to compound heterozygous inheritance of alpha thalassemia type 1 and type 2 traits.
  • If two of the four α loci are affected, alpha thalassemia trait, type 1 results. Two α loci permit nearly normal erythropoiesis, though there is a mild microcytic hypochromic anemia. There is a high prevalence (about 30%) of deletion of one of the two α loci on chromosomes of people of recent African origin, and so the inheritance of two such chromosomes is not uncommon. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron. Two modes of alpha thalassemia trait, type 1 has been noted. One involves cis deletion of two alpha loci on the same chromosome; another involves trans deletion of allelic genes on homologous chromosomes (no. 16).
  • If one of the four α loci is affected, alpha minor or alpha+ thalassemia trait or alpha thalassemia trait, type 2 results and there is minimal effect. Three α-globin loci are enough to permit normal hemoglobin production, and there is no anemia or hypochromia in these people. They have been called α thalassemia carriers.

Beta (β) thalassemias

Beta thalassemia (Cooley's Anemia) is due to mutations in the HBB gene on chromosome 11 (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 141900. World Wide Web URL:, also inherited in a Mendelian recessive fashion.[5] In β thalassemia, a decrease in beta-globin production occurs, causing a less-than-normal amount of beta-globin chains to be made. This results in a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes producing membrane damage, and at high concentrations tend to form toxic aggregates. The severity of the damage depends on the nature of the mutation. Some mutations (βo) prevent any formation of β chains; others (β+) allow some β chain formation to occur. Recently, reports suggest that up to 5% of patients with beta-thalassemias produce fetal hemoglobin (HbF), and the use of hydroxyurea also has a tendency to increase the production of HbF, by as yet unexplained mechanisms.

Any given individual has two β globin alleles, one from their mother and one from their father:

  • If both have thalassemia mutations, a severe microcytic, hypochromic anemia called β thalassemia major or Cooley's anemia results. Untreated, this results in death before age twenty: treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Cure is possible by bone marrow transplantation.
  • If only one β globin allele bears a mutation, β thalassemia minor results (sometimes referred to as β thalassemia trait). This is a mild anemia with microcytosis. Symptoms include weakness and fatigue - in most cases β thalassemia minor may be asymptomatic and many people may be unaware they have this disorder. Detection usually involves counting the mean corpuscular volume (size of red blood cells) and noticing a slightly decreased mean volume than normal.
  • Thalassemia intermedia is a condition intermediate between the major and minor forms. Sufferers can often manage a normal life but may need occasional transfusions e.g. at times of illness or pregnancy. This really depends on the severity of their anemia.

The actual genetic cause of β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Usually, superscripts 0 and + are added to β to indicate complete absence, and deficient synthesis of β globins respectively.

Mainly there are two forms of genetic defects which produce β thalassemias:

  • Nondeletion forms: These defects generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most commonly, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.
  • Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary persistence of fetal hemoglobin syndromes.

Delta (δ) thalassemia

As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations can occur which affect the ability of this gene to produce delta chains. A mutation that prevents formation of any delta chains is termed a delta0 mutation, whereas one that decreases but does not eliminate production of delta chain is termed a delta+ mutation. When one inherits two delta0 mutations, no hemoglobin A2 (alpha2,delta2) can be formed. Hematologically, however, this is innocuous because only 2-3% of normal adult hemoglobin is hemoglobin A2. The individual will have normal hematological parameters (erythrocyte count, total hemoglobin, mean corpuscular volume, red cell distribution width). Individuals who inherit only one delta thalassemia mutation gene will have a decreased hemoglobin A2, but also no hematological consequences. The importance of recognizing the existence of delta thalassemia is seen best in cases where it may mask the diagnosis of beta thalassemia trait. In beta thalassemia, there is an increase in hemoglobin A2, typically in the range of 4-6% (normal is 2-3%). However, the co-existence of a delta thalassemia mutation will decrease the value of the hemoglobin A2 into the normal range, thereby obscuring the diagnosis of beta thalassemia trait. This can be important in genetic counseling, because a child who is the product of parents each of whom has beta0 thalassemia trait has a one in four chance of having beta thalassemia major.

In combination with other hemoglobinopathies

Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:

  • hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to β thalassemia major or thalassemia intermedia.
  • hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly
  • hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.


Red blood cell indices

Red blood cell indices, and ratios among indices[6], may help distinguish causes of microcytic anemia.[7]

Mean corpuscular volume

The accuracy of the mean corpuscular volume (MCV) < 80 fl for diagnosing thalassemia traits (defined as hemoglobin A2 4.1–9.0%) is:[8]

Mentzer index

The Mentzer index suggest thalassmia if less than 13 and suggests iron deficiency anemia if over 13.[9]

Hemoglobin A2

The accuracy of an elevated hemoglobin A2 at detecting abnormal DNA testing is uncertain. There are several situations in which its value will be normal:[10]

  • Specific mild mutations such as the Beta+ IVS-1 nt6 mutation
  • In delta beta-thalassemia, creation of Hemoglobin A2 is impaired due to delta.[11]
  • The triple alpha globin arrangement.[12]
  • Silent beta thalassemia, which also has mean corpuscular volume. The most common mutation for this is the -101 C to T substitution with the distal CACC box.[13]

Hemoglobin F

Treatment and complications

Anyone with thalassemia should consult a properly qualified hematologist.

Thalassemias may co-exist with vitamin deficiencies such as folic acid (or folate, a B-complex vitamin) and iron deficiency (only in Thalassemia Minor). Thalassemia patients may also demonstrate iron overload due to concomitantly inherited defects in the iron regulatory system.

Thalassemia Major and Intermedia

Thalassemia major patients receive frequent blood transfusions that lead to iron overload. Thalassemia intermedia patients vary in their treatment needs based on the severity of their anemia: some require periodic transfusions, while others have no major anemia. All thalassemia patients are prone to enlargement of the spleen, which ultimately may need to be removed, and gallstones. These complications are mostly prevalent to thalassemia major and intermedia patients.

Iron chelation treatment is necessary to prevent iron overload damage to the internal organs in patients with thalassemia major. Because of recent advances in iron chelation treatments, patients with thalassemia major can live long lives if they have access to proper treatment. Popular chelators include deferoxamine and deferiprone. Of the two, deferoxamine is preferred; it is associated with fewer side-effects.[14]

The most common complaint by patients is that it is difficult to comply with the intravenous chelation treatments because they are painful and inconvenient. The oral chelator deferasirox (marketed as Exjade) was recently approved for use in some countries and may offer some hope with compliance, though as of April 2007, its yearly cost was in excess of $12,000.

Untreated thalassemia major eventually leads to death usually by heart failure, therefore birth screening is very important.

In recent years, stem cell transplantation has shown promise for some patients with thalassemia major. Successful transplants can eliminate the need for transfusions.

Thalassemia Minor

Blood iron levels can determine the level of iron overload in the thalassemia minor patient. Thalassemia minor, although not life threatening on its own, can affect quality of life due to the effects of a mild to moderate anemia. Studies have shown that thalassemia minor often coexists with other diseases such as asthma[15], and even bipolar disorder[16].

Thalassemia prevention and management

α and β thalassemias are often inherited in an autosomal recessive fashion although this is not always the case. Reports of dominantly inherited α and β thalassemias have been reported the first of which was in an Irish family who had a two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait.

There are an estimated 60-80 million people in the world who carry the beta thalassemia trait alone. This is a very rough estimate and the actual number of thalassemia Major patients is unknown due to the prevalence of thalassemia in less developed countries in the Middle East and Asia. Countries such as India, Pakistan and Iran are seeing a large increase of thalassemia patients due to lack of genetic counseling and screening. There is growing concern that thalassemia may become a very serious problem in the next 50 years, one that will burden the world's blood bank supplies and the health system in general. There are an estimated 1,000 people living with Thalassemia Major in the United States and an unknown number of carriers. Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.

As with other genetically acquired disorders, aggressive birth screening and genetic counseling is recommended.

A screening policy exists on both sides of the island of Cyprus to reduce the incidence of thalassemia, which since the program's implementation in the 1970s (which also includes pre-natal screening and abortion) has reduced the number of children born with the hereditary blood disease from 1 out of every 158 births to almost zero.[17]


Being a carrier of the disease may confer some protection against malaria,[4][18] and is quite common among people from Italian or Greek origin, and also in some African and Indian regions. This is probably by making the red blood cells more susceptible to the less lethal species Plasmodium vivax, simultaneously making the host RBC environment unsuitable for the merozoites of the lethal strain Plasmodium falciparum. This is believed to be a selective survival advantage for patients with the various thalassemia traits. In that respect it resembles another genetic disorder, sickle-cell disease.

Epidemiological evidence from Kenya suggests another reason: protection against severe anemia may be an advantage.[18]

People diagnosed with heterozygous (carrier) Beta-Thalassemia have some protection against coronary heart disease.[19]

Notable patients


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