Thalassemia Symptoms and Causes


Thalassemia is a group of inherited disorders that negatively affect the amount and type of hemoglobin a person produces. Hemoglobin (Hb or Hgb) is found in erythrocytes (RBC). A hemoglobin molecule consists of heme, which is an iron-containing complex, and globin, which are protein chains that surround this heme complex. The types of protein chains in the hemoglobin molecule adversely affect the structure and function of hemoglobin. Different types of hemoglobin are classified according to the different protein chains they contain. Normal hemoglobin types:

  • Hemoglobin A – makes up about 95-98% of Hb in adults. Hb A contains two alpha (α) and two beta (β) protein chains.
  • Hb A 2 – It makes up about 2-3.5% of Hb. It contains two alpha (α) and 2 delta (δ) chains.
  • Hb F – Makes up to 2% of Hb. It contains two alpha (α) and two gamma (γ) protein chains. It is the primary protein produced by the fetus during pregnancy. Levels usually fall within the first year after birth.

Mutations in genes encoding globin chains can cause defects in hemoglobin production. Four genes encode alpha globin and two genes encode beta globin chain.

Hereditary hemoglobin production disorders caused by mutations in these genes are examined in two categories:

  • Thalassemia or decreased normal hemoglobin production (discussed in this article)
  • Abnormal hemoglobin molecule construction (see Different forms of hemoglobin )

Thalassemias are a group of disorders in which mutations in one or more of the globin genes cause a reduction in the amount of a certain globin chain. This situation disrupts the balance between alpha and beta chains (in Hb A), leading to the accumulation of unusual forms of hemoglobin or an increased relative amount of minor hemoglobin components such as Hb A2 or Hb F.


Thalassemias are generally classified according to decreased synthesis of globin chain.

Thalassemia Classifications

Alpha thalassemia  is associated with a deletion or mutation in one or more of the four alpha globin gene copies. The more genes that are negatively affected, the less alpha globin is produced. Four different types of alpha thalassemia:

  • Asymptomatic Carrier Status (1 gene affected) . Although hemoglobin levels and erythrocyte indexes are normal in these carriers, the diseased gene can be passed on to children. Often these individuals are identified only by the presence of a child with an HbH disease or hereditary alpha thalassemia (see below). DNA analysis is the only way to diagnose this condition .
  • Alpha Thalassemia Inheritance (2 negatively affected genes) . In those with alpha thalassemia inheritance, erythrocytes (RBCs) are  microcytic, hypochromic , mild chronic anemia patients with low MCV and generally do not show any other disease symptoms. This type of anemia does not respond to iron supplements. Generally, alpha thalassemia is diagnosed by excluding other causes of microcytic anemia. Although the diagnosis can be confirmed by DNA analysis, it is not a routine practice.
  • Hemoglobin H Disease (3 genes negatively affected) The drastic reduction in the amount of alpha globin chains produced in this disease leads to an increase in beta chains and ultimately to the accumulation of beta tetramers (4 beta chain groups) known as Hemoglobin H. Hb H disease can cause moderate to severe anemia and splenomegaly (enlarged spleen). However, the clinical picture associated with HbH is highly variable. Some individuals are asymptomatic , while others are severely anemic. Hemoglobin H disease is most common in people of South East Asian or Mediterranean origin.
  • Alpha Thalassemia Major (hydrops fetalis, 4 negatively affected genes) . It is the most severe form of alpha thalassemia, and no alpha globin is produced, so no HbA or HbF is produced. Fetuses with alpha thalassemia major are anemic in early pregnancy . The heart and liver of fetuses with hydrops are often enlarged. Diagnosis is usually made in the last months of pregnancy when fetal ultrasonography shows the presence of hydropic fetus. In approximately 80% of the cases, blood poisoning ( toxemia ) will occur in the mother and heavy bleeding ( hemorrhage ) may develop after delivery. Fetuses with alpha thalassemia major are often aborted prematurely, or are stillborn or die soon after birth.

Alpha thalassemia is most common in South East Asian, South China, Middle East, Indian, African and Mediterranean ethnic origins.

Beta thalassemia is associated with mutations in one or both beta globin genes. Although one hundred to 200 mutations have been identified, only about 20 are common. The severity of anemia caused by   beta thalassemia varies depending on which mutation(s) are present, whether they reduce beta globin production (called beta + thalassemia) or completely eliminate it (called beta 0 thalassemia). Different types of beta thalassemia:

  • Beta Thalassemia Inheritance . This person has a normal and a mutated (modified) gene. These individuals will generally have no health problems other than a mild anemia that is microcytic and possibly unresponsive to iron supplements. This gene mutation can be passed on to that person’s child.
  • Thalassemia Intermedia . This patient still produces some beta globin, but has two abnormal genes. The severity of anemia and health problems depend on existing mutations. The sharp dividing line between thalassemia intermedia and intermedia major is related to the degree of anemia, the number and frequency of blood transfusions required for treatment. People with thalassemia intermedia may need blood transfusions occasionally, if not regularly.
  • Thalassemia Major (Cooley Anemia) . It is the most severe form of beta thalassemia. The patient has two abnormal genes that cause a drastic decrease or complete cessation of beta globin production and inhibit the production of significant amounts of Hb A. This disease usually occurs in three-month-old infants and causes life-threatening anemia. This anemia requires lifelong regular blood transfusions and considerable ongoing medical care. Over time, these frequent blood transfusions lead to excessive accumulation of iron in the body. Left untreated, these excessive amounts of iron can build up in the liver, heart, and other organs, leading to premature death from organ failure.

In cases where the beta thalassemia gene and the  different hemoglobin form gene are inherited, other thalassemia forms also occur. The most important forms of thalassemia are:

  • Hb E – beta thalassemia. Hb E is one of the most common forms of hemoglobin found primarily in people of South East Asian descent. If a person has an Hb E gene and a beta thalassemia gene, this combination causes Hb E-beta thalassemia. Hb E beta thalassemia causes moderately severe anemia similar to beta thalassemia intermedia.
  • HbS – beta thalassemia or sickle cell – beta thalassemia. Hb S is one of the best-known forms of hemoglobin. Inheritance of an Hb S gene and a beta thalassemia gene results in Hb S-beta thalassemia. The severity of the disease depends on the amount of beta globin that the beta gene triggers. If no beta globin is produced, the clinical picture is almost completely similar to that of sickle cell anemia .


 Laboratory Tests

Complete blood count : A complete blood count gives a panorama of the cells and fluid in your bloodstream. Among other things, the complete blood count will inform the doctor about the number of erythrocytes and the amount of hemoglobin contained in them. He or she will provide the doctor with assessments of the size and shape of the red blood cells present, and how much hemoglobin ( also called red cell indices ) is in them. These assessments also include mean cell volume (MCV), which is a measurement of red cell size. A low MCV is the first sign of thalassemia.  If iron deficiency has been ruled out when the MCV is low, the person may be a carrier of thalassemia inherited  .

 Blood smear preparation  (also called peripheral smear and formula leukocyte). In this test, a thin layer of blood, which is placed on a slide and stained with a special dye, is examined under a microscope. The number and types of leukocytes, erythrocytes and platelets can be evaluated for whether they are normal and mature. Various disorders negatively affect normal erythrocyte production. In thalassemia, erythrocytes are often microcytic (low MCV) .

Also, red blood cells:  

  • may be hypochromic
  • They can vary in size (anisocytosis) and shape (poikilocytosis).
  • May have a cell nucleus – normal matured erythrocytes do not have a nucleus
  • They may have an uneven distribution of hemoglobin (causing the formation of bull’s-eye-like “target cells” under the microscope).

The higher the percentage of abnormal-looking erythrocytes, the greater the likelihood of the underlying disorder and impaired oxygen carrying capacity.

Iron tests  These tests relate to :  iron ,  ferritin , unsaturated iron binding capacity (UIBC),  total iron binding capacity (TDBK) and  percent transferrin saturation . These tests measure different aspects of the body’s iron stock and use. These tests are ordered to help determine if iron deficiency is causing and/or aggravating anemia. One or more of these tests are ordered to help monitor the degree of iron overload in a thalassemia patient.

Hemoglobinopathy (Hb) assessment . This test measures the type and relative amounts of hemoglobin present in erythrocytes. Hemoglobin A is a normal type of hemoglobin found in adults that contains both alpha and beta globin. Those who inherit beta thalassemia usually also have a large percentage of HbA2 and/or F. HbH can be seen in alpha thalassemia patients with HbH disease. 

 DNA analysis : This test is used to look for deletions and mutations in alpha and beta globin-forming genes. Family background studies may be performed to assess carrier status and to identify the type of mutations present in other family members. Although DNA testing is not routinely performed, this test can be used to diagnose thalassemia and determine carrier status.


Most people with inherited thalassemia do not need any treatment. However, these patients may request genetic counseling because they can pass this inheritance on to their children.

Patients with hemoglobin H or beta thalassemia intermedia will experience anemia of varying severity throughout their lives  . Although they can lead relatively normal lives, they will need regular monitoring and may sometimes require blood transfusions. Although folic acid supplements are often given to help fight anemia, iron supplements are not recommended.

Patients with beta thalassemia major will usually need blood transfusions every 3 or 4 weeks throughout their lives. These blood transfusions provide the body with a sufficient concentration of oxygen and help prevent developmental abnormalities and organ damage. However, frequent blood transfusions increase the amount of iron to toxic levels, leading to accumulations of iron in the liver, heart and other organs. Regular iron chelation therapy is used to help reduce iron in the body  . This treatment includes the administration of a drug that binds to iron and the excretion of the formed compound from the body with urine. Surgical removal of the spleen (splenectomy) may also be required.

Bone marrow transplantation is also used in the treatment of beta thalassemia major.

Fetuses with alpha thalassemia major often miscarry prematurely, are stillborn, or die shortly after birth. Treatment focuses on identifying the condition, terminating the pregnancy, or monitoring the mother for complications. Experimental treatments, such as fetal blood or even bone marrow transplants, have been successful in keeping very few babies alive until term.

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