When you have abnormal results on a complete blood count (CBC) and/or blood smear that suggest an abnormal form of hemoglobin (hemoglobinopathy); when you have symptoms of hemolytic anemia such as weakness and fatigue and your healthcare practitioner suspects that you have a hemoglobinopathy; when you have a family history of hemoglobinopathy; as part of newborn screening
A blood sample drawn from a vein; sometime a blood sample is collected by pricking a finger (fingerstick) or the heel (heelstick) of an infant and a few drops of blood are collected in a small tube.
A hemoglobinopathy is an inherited blood disorder in which there is an abnormal form of hemoglobin (variant) or decreased production of hemoglobin (thalassemia). A hemoglobinopathy evaluation is a group of tests that determines the presence and relative amounts of abnormal forms of hemoglobin in order to screen for and/or diagnose a hemoglobin disorder.
Hemoglobin (Hb) is the protein in red blood cells (RBCs) that binds to oxygen in the lungs and allows RBCs to carry the oxygen throughout the body, delivering it to the body's cells and tissues. Hemoglobin consists of one portion called heme, which is the molecule with iron at the center, and another portion made up of four globin (protein) chains. Depending on their structure, the globin chains, depending on their structure, have different designations: alpha, beta, gamma, and delta. The types of globin chains that are present are important in the function of hemoglobin and its ability to transport oxygen.
Normal hemoglobin types include:
- Hemoglobin A: makes up about 95%-98% of Hb found in adults; it contains two alpha and two beta protein chains.
- Hemoglobin A2: makes up about 2%-3% of Hb in adults; it has two alpha and two delta protein chains.
- Hemoglobin F (fetal hemoglobin): makes up to 1%-2% of Hb found in adults; it has two alpha and two gamma protein chains. This is the primary hemoglobin produced by the fetus during pregnancy; its production usually falls shortly after birth and reaches adult levels by 1-2 years.
Hemoglobinopathies occur when changes (variants) in the genes that provide information for making the globin chains cause changes in the proteins. These genetic variants may result in a reduced production of one of the normal globin chains or in the production of structurally altered globin chains. Approximately 7% of the world's population carry at least one copy of a genetic variant in one of the hemoglobin chains (carrier), and the rate can vary dramatically based on ethnicity. Genetic variants may affect the structure of the hemoglobin, its behavior, its production rate, and/or its stability. The presence of abnormal hemoglobin within RBCs can alter the appearance (size and shape) and function of the red blood cells.
Red blood cells containing abnormal hemoglobin (hemoglobin variants) may not carry oxygen efficiently and may be broken down by the body sooner than usual (a shortened survival), resulting in hemolytic anemia.
While there are more than 1,000 hemoglobinopathies currently described and novel forms are still being discovered, some of the most common hemoglobin variants include:
- Hemoglobin S, the primary hemoglobin in people with sickle cell disease that causes the RBC to become misshapen (sickle), decreasing the cell's survival
- Hemoglobin C, which can cause a minor amount of hemolytic anemia
- Hemoglobin E, which may cause no symptoms or generally mild symptoms
Thalassemia is a condition in which a gene variant results in reduced production of one of the globin chains. This can upset the balance of alpha to beta chains, leading to decrease in hemoglobin A, causing abnormal forms of hemoglobin to form (alpha thalassemia) or causing an increase of minor hemoglobin components, such as Hb A2 or Hb F (beta thalassemia).
Hemoglobinopathies can be thought of as an alteration of quality of the hemoglobin molecule (how well it functions), while thalassemias are an alteration of quantity.
A hemoglobinopathy evaluation typically involves tests that determine the types and amounts of hemoglobin. Information from these tests, along with results from routine tests such as a complete blood count (CBC) and blood smear, aid in establishing a diagnosis.
How is the test used?
A hemoglobinopathy evaluation is used to detect abnormal forms and/or relative amounts of hemoglobin, the protein found in all red blood cells that transports oxygen. Testing may be used for:
- All states require that newborns be screened for sickle cell disease, S/C Disease and S,Beta-Thalassemia; however, only 87% of states screen for other hemoglobinopathy types.
- Prenatal screening is often performed on high-risk parents with an ethnic background associated with a higher prevalence of hemoglobin disorders and those with affected family members. Screening may also be done in conjunction with genetic counseling prior to pregnancy to determine whether the parents are carriers.
- To identify variants in asymptomatic parents who have an affected child
Several different laboratory methods are available to evaluate the types of hemoglobin that a person has. Some of these include:
- Hemoglobin solubility test: used to test specifically for hemoglobin S, the main hemoglobin in sickle cell disease
- Hemoglobin gel electrophoresis (Hb ELP)
- Hemoglobin isoelectric focusing (Hb IEF)
- Hemoglobin by high performance liquid chromatography (HPLC)
- Hemoglobin by capillary zone electrophoresis (CZE)
- Hemoglobin by mass spectrometry
These methods evaluate the different types of hemoglobin based on the physical and chemical properties of the different hemoglobin molecules.
Most of the common hemoglobin variants or thalassemias can be identified using one of these tests or a combination. The relative amounts of any variant hemoglobin detected can aid in a diagnosis. However, a single test is usually not sufficient to establish a diagnosis of hemoglobinopathy. Rather, the results of several different tests are considered. Examples of other laboratory tests that may be performed include:
- Blood smear
- Reticulocyte count
- Iron studies such as serum iron, TIBC, transferrin
- Genetic testing: may be used to detect variants in the genes that code for the protein chains (alpha and beta globulin) that comprise hemoglobin. This is not a routine test but can be used to confirm whether you have a genetic variant and whether there is one or two copies of the variant (heterozygous or homozygous).
When is it ordered?
Testing for specific hemoglobinopathies is required as part of state-mandated newborn screening. In addition, it is often used for prenatal screening when a parent is at high risk or when parents have a child who has a hemoglobinopathy.
Testing may be ordered when a healthcare practitioner suspects that your signs and symptoms are the result of abnormal hemoglobin production. Abnormal forms of hemoglobin often lead to hemolytic anemia, resulting in signs and symptoms such as:
- Weakness, fatigue
- Lack of energy
- Pale skin
Some severe forms of hemoglobinopathies (e.g., sickle cell disease) may result in serious signs and symptoms, such as episodes of severe pain, shortness of breath, enlarged spleen, and growth problems in children.
What does the test result mean?
Care must be taken when interpreting the results of a hemoglobinopathy evaluation. Typically, the laboratory report includes an interpretation by a pathologist with experience in the field of hematology (hematopathologist).
Results of the evaluation usually report the types of hemoglobin present and the relative amounts. For adults, percentages of normal hemoglobin include:
- Hemoglobin A1(HB A1): about 95%-98%
- Hemoglobin A2 (Hb A2): about 2%-3%
- Hemoglobin F (Hb F): 2% or less
Some of the most common abnormal forms of hemoglobin that may be detected and measured with this testing include:
- Hemoglobin S (Hb S, sickle cell disease or trait)
- Hemoglobin C (Hb C)
- Hemoglobin E (Hb E)
Some less common forms include:
- Hemoglobin F (Hb F): Hb F may be elevated in several disorders, such as beta thalassemia and sickle cell anemia.
- Hemoglobin H (Hb H)
- Hemoglobin Barts
Other types that may be identified include:
- Hemoglobin D
- Hemoglobin G
- Hemoglobin J
- Hemoglobin M
- Hemoglobin Constant Spring
Less common forms often are named after the location of the family or families in whom the genetic variant was first identified (i.e.. Hemoglobin Constant Spring).
Testing may help identify thalassemia by detecting abnormal hemoglobin (e.g., hemoglobin H in alpha thalassemia) or an increase of minor hemoglobin components, such as Hb A2 or Hb F (beta thalassemia).
Two different abnormal genes can be inherited, one from each parent, that may result in a combination of abnormal hemoglobins detected by testing. This is known as being compound heterozygous or doubly heterozygous. Clinically significant combinations — those that result in significant signs and symptoms — include hemoglobin SC disease (symptoms can mimic sickle cell disease), hemoglobin E – beta thalassemia, and hemoglobin S – beta thalassemia.
The following table provides some examples of results that may be seen with a hemoglobinopathy evaluation:
Results Seen Condition Genes Slightly decreased Hb A
Moderate amount Hb S (about 40%)
Sickle cell trait One gene copy for Hb S (heterozygous) Majority Hb S
Increased Hb F (up to 10%)
No Hb A
Sickle cell disease Two gene copies for Hb S (homozygous) Majority Hb C
No Hb A
Hemoglobin C disease Two gene copies for Hb C (homozygous) Majority Hb A
Some Hb H
Hemoglobin H disease (alpha thalassemia) Three out of four alpha genes are mutated (deleted) Majority Hb F
Little or no Hb A
Beta thalassemia major Both beta genes are mutated Majority Hb A
Slightly Increased Hb A2 (4-8%)
Hb F may be slightly increased
Beta thalassemia minor One beta gene is mutated, causing slight decrease in beta globin chain
Why is every newborn screened for hemoglobinopathies?
Newborn screening helps to identify potentially treatable or manageable congenital disorders within days of birth. Potentially life-threatening health problems and serious lifelong disabilities can be avoided or minimized if a condition is quickly identified and treated. Also, since newborn screening programs have mandated testing for certain hemoglobin variants (i.e., Hb S, SC and beta-thalassemia), they have uncovered thousands of children who are carriers. (This is due to new technology, not to an increased prevalence of the gene variants.) Information on carrier status may be important in their future if and when they begin to plan a family.
Is there anything else I should know?
Blood transfusions can interfere with hemoglobinopathy evaluation because any of the methods will detect both the blood donor and your hemoglobin forms, potentially hindering the results. You should wait several months after a transfusion before having this testing done. However, in people with sickle cell disease, the testing may be performed after a transfusion to determine if enough normal hemoglobin has been given to reduce the risk of damage from sickling of red blood cells and prevent sickle cell crisis.
How long will it take to get results?
It depends on the method of testing and the laboratory performing the evaluation. This testing requires specialized equipment and interpretation, thus not every laboratory performs this test. Your sample may be sent to a reference laboratory, so it may take several days before results are available.
What is the treatment for hemoglobinopathy?
Treatment for certain types of hemoglobin disorders may involve supportive care, for example during a sickle cell crisis. The aim is to relieve pain and minimize complications. Sometimes blood transfusions are needed if there is severe anemia. There are some other less common treatments that are available. For more information on these, see the articles on Hemoglobin Abnormalities and Thalassemia as well as the links listed in the Related Content section.