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Hemoglobin Abnormalities

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Hemoglobin Variants

Several hundred abnormal forms of hemoglobin (variants) have been identified, but only a few are common and clinically significant.

Common hemoglobin variants

  • Hemoglobin S: this is the primary hemoglobin in people with sickle cell disease (also known as sickle cell anemia). Approximately 1 in 500 African American babies are born with sickle cell disease, and more than 70,000 Americans live with the disorder, according to the Centers for Disease Control and Prevention. Those with Hb S disease have two abnormal beta chains and two normal alpha chains. The presence of hemoglobin S causes the red blood cell to deform and assume a sickle shape when exposed to decreased amounts of oxygen (such as might happen when someone exercises or has infection in the lungs). Sickled red blood cells are rigid and can block small blood vessels, causing pain, impaired circulation, and decreased oxygen delivery, as well as shortened red cell survival. A single beta (βS) copy (known as sickle cell trait, which is present in approximately 8% of African Americans) rarely causes significant symptoms unless it is combined with another hemoglobin mutation, such as that causing Hb C or beta thalassemia.
  • Hemoglobin C: about 2-3% of people of West African descent are heterozygotes for hemoglobin C (have one copy, known as hemoglobin C trait) and are often asymptomatic. Hemoglobin C disease (seen in homozygotes, those with two copies) is rare and relatively mild. It usually causes a minor amount of hemolytic anemia and a mild to moderate enlargement of the spleen.
  • Hemoglobin E: Hemoglobin E is one of the most common beta chain hemoglobin variants in the world. It is very prevalent in Southeast Asia, especially in Cambodia, Laos, and Thailand, and in individuals of Southeast Asian descent. People who are homozygous for Hb E (have two copies of βE) generally have a mild hemolytic anemia, microcytic red blood cells, and a mild enlargement of the spleen. A single copy of the hemoglobin E gene does not cause symptoms unless it is combined with another mutation, such as the one for beta thalassemia trait.

Less common hemoglobin variants
There are many other variants. Some are silent – causing no signs or symptoms – while others affect the functionality and/or stability of the hemoglobin molecule. Examples of other variants include: Hemoglobin D, Hemoglobin G, Hemoglobin J, Hemoglobin M, and Hemoglobin Constant Spring, a mutation in the alpha globin gene that results in an abnormally long alpha (α) chain and an unstable hemoglobin molecule. Additional examples include:

  • Hemoglobin F: Hb F is the primary hemoglobin produced by the fetus, and its role is to transport oxygen efficiently in a low oxygen environment. Production of Hb F decreases sharply after birth and reaches adult levels by 1-2 years of age. Hb F may be elevated in several congenital disorders. Levels can be normal to significantly increased in beta thalassemia and are frequently increased in individuals with sickle cell anemia and in sickle cell-beta thalassemia. Individuals with sickle cell disease and increased Hb F often have a milder disease, as the F hemoglobin inhibits sickling of the red cells. Hb F levels are also increased in a rare condition called hereditary persistence of fetal hemoglobin (HPFH). This is a group of inherited disorders in which Hb F levels are increased without the signs or clinical features of thalassemia. Different ethnic groups have different mutations causing HPFH. Hb F can also be increased in some acquired conditions involving impaired red blood cell production. Leukemias and other myeloproliferative neoplasms often are also associated with mild elevation in Hb F.
  • Hemoglobin H: Hb H is an abnormal hemoglobin that occurs in some cases of alpha thalassemia. It is composed of four beta (β) globin chains and is produced due to a severe shortage of alpha (α) chains. Although each of the beta (β) globin chains is normal, the tetramer of 4 beta chains does not function normally. It has an increased affinity for oxygen, holding onto it instead of releasing it to the tissues and cells. Hemoglobin H is also associated with significant breakdown of red blood cells (hemolysis) as it is unstable and tends to form solid structures within red blood cells.
  • Hemoglobin Barts: Hb Barts develops in fetuses with alpha thalassemia. It is formed of four gamma (γ) protein chains when there is a shortage of alpha chains, in a manner similar to the formation of Hemoglobin H. Hb Barts disappears shortly after birth due to dwindling gamma chain production.

A person can also inherit two different abnormal genes, one from each parent. This is known as being compound heterozygous or doubly heterozygous. Several different clinically significant combinations are listed below.

  • Hemoglobin SC disease: inheritance of one beta S gene and one beta C gene results in Hemoglobin SC disease. These individuals have a mild hemolytic anemia and moderate enlargement of the spleen. Persons with Hb SC disease may develop the same vaso-occulsive (blood vessel-blocking) complications as seen in sickle cell anemia, but most cases are less severe.
  • Sickle Cell – Hemoglobin D disease: individuals with sickle cell – Hb D disease have inherited one copy of hemoglobin S and one of hemoglobin D-Los Angeles (or D-Punjab) genes. These people may have occasional sickle crises and moderate hemolytic anemia. 
  • Hemoglobin E – beta thalassemia: individuals who are doubly heterozygous for hemoglobin E and beta thalassemia have an anemia that can vary in severity, from mild (or asymptomatic) to severe, dependent on the beta thalassemia mutation(s) present.
  • Hemoglobin S – beta thalassemia: sickle cell – beta thalassemia varies in severity, depending on the beta thalassemia mutation inherited. Some mutations result in decreased beta globin production (beta+) while others completely eliminate it (beta0). Sickle cell – beta+ thalassemia tends to be less severe than sickle cell – beta0 thalassemia. People with sickle cell – beta0 thalassemia tend to have more irreversibly sickled cells, more frequent vaso-occlusive problems, and more severe anemia than those with sickle cell – beta+ thalassemia. It is often difficult to distinguish between sickle cell disease and sickle cell – beta0 thalassemia.

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