Sickle Cell Tests

Sickle cell tests may be used to screen for or help diagnose sickle cell anemia (also called sickle cell disease) or to identify individuals who are genetic carriers and have sickle cell trait. Testing may be used for:

• Newborn screening—All states require that newborns be screened for sickle cell anemia, as well as some other hemoglobin disorders.
• Carrier screening—It is recommended that all pregnant women or those considering pregnancy receive information regarding carrier screening for hemoglobin disorders, including sickle cell disease. Carrier screening lets prospective parents know whether they each are carriers and are at risk of passing on two defective gene copies, one from each them, to any children who then would be affected by the disease.
• General screening—to identify sickle cell trait in asymptomatic parents who have an affected child or in other family members of an individual who has sickle cell trait or sickle cell disease. Screening may also be done for those who were not screened at birth because universal newborn testing was not yet implemented.
• Diagnosis—to detect and/or identify sickle cell disease in those with a positive screening test or symptoms of unexplained anemia or abnormal results on a complete blood count (CBC)

Several types of sickle cell tests are available and multiple tests may be required. The types of test used depend on the purpose of testing.

• Hemoglobin S solubility test and sodium metabisulfite test— these tests may be used for screening individuals 6 months old or older. They are not diagnostic and are not used for newborn screening. The tests detect the presence of hemoglobin S but do not distinguish between sickle cell disease and trait.
• Hemoglobinopathy (Hb) evaluation—several kinds of tests are available for evaluating the type and relative amounts of various normal and abnormal hemoglobins. These methods typically separate the different types of hemoglobin that are present so that they can be identified and measured. They may be used for screening, diagnosis and/or monitoring. Examples include:
  • Hemoglobin electrophoresis
  • Hemoglobin fractionation by HPLC
  • Isoelectric focusing
  • Mass spectrometry
  • Capillary zone–In people diagnosed with sickle cell disease, these tests may be used to measure the relative amount of Hb S and follow it over the course of treatment. For example, testing may be done after a blood transfusion or erythrocytapheresis/red cell exchange to ensure that the hemoglobin S level has been reduced. In addition, treatment with the drug hydroxyurea should result in a decrease in Hb S and an increase in fetal hemoglobin (Hb F), and so these tests can be used to monitor how well someone is responding to therapy.
• Genetic testing (DNA analysis)—this tests for mutations in the genes that produce hemoglobin components. It can determine whether someone has one or two gene copies (alleles) of the Hb S mutation or has two different mutations in hemoglobin genes (e.g., Hb S and Hb C). Genetic testing can be used for carrier testing and for diagnosis. For pregnant women, amniotic fluid may be tested at 14 to 16 weeks to provide a diagnosis.  It can also be performed earlier with chorionic villus sampling. Sometimes, testing may be done by analyzing cell-free fetal DNA in the mother’s blood. (To learn more about this type of test, see the article on Non-invasive Prenatal Screening.) Occasionally, a specialized testing called DNA sequencing may be done to help identify less common hemoglobin disorders. Genetic counseling and education should be provided so that patients understand test results, implications of the results, and their risk of passing genetic disorders to any children.

Other tests that may be used to help evaluate someone who is suspected of having or who is known to have sickle cell trait or disease include:

• Complete blood count (CBC)—among other things, the CBC indicates the number of red blood cells as well as the amount of hemoglobin and will evaluate the size and shape of the RBCs present. This test is used to detect anemia.
• Blood smear (also called peripheral smear and manual differential)—a trained laboratorian looks at a thin, stained layer of blood on a slide under a microscope. The number and type of red blood cells are evaluated to see if they are normal. Sickle-shaped RBCs may be seen on the blood smear.
• Iron studies—these tests measure different aspects of the body’s iron storage and usage. They are ordered to help determine whether someone has an iron deficiency anemia or an excess amount of iron (iron overload). People with sickle cell anemia who receive multiple blood transfusions may experience iron overload.

Sickle cell tests are routinely ordered soon after birth to screen newborns for sickle cell anemia.

Testing may be done when those who were born before newborn screening was mandated want to know if they have sickle cell disease or are carrying the sickle cell trait, especially if they are in a high-risk group. In African Americans, sickle cell disease occurs in one out of every 365 births.

Carrier screening may be offered when a woman is pregnant or considering pregnancy. If a woman is found to be a carrier for sickle cell, testing should be offered to her partner.  Sickle cell tests may also be ordered when a person has abnormal results on a complete blood count (CBC) and blood smear and/or has signs and symptoms that suggest the presence of sickle cell anemia.

Examples of signs, symptoms and complications of sickle cell anemia include:

• Pain due to sickle cell crisis—the most common symptoms of sickle cell disease are episodes of pain that can last for extended periods of time. The pain can occur throughout the body and often involves the bones, joints, lungs, and stomach.
• Anemia—sickle cell disease is a hemolytic anemia, meaning that the abnormal, sickled RBCs break down (hemolyze) more quickly than normal red blood cells and cannot be replaced by the body as quickly as needed. This leads to a decreased number of RBCs and reduced ability of the RBCs to transport oxygen throughout the body.
• Increased number and frequency of infections, especially pneumonia, which is the leading cause of death in children with sickle cell disease.
• Coughing, chest pain, and fever suspected to be caused by a serious complication of sickle cell disease called acute chest syndrome.

To learn more about signs and symptoms, see the links in Related Content below.

Newborn screening
In newborns who carry the sickle cell gene copy, most of the hemoglobin is fetal hemoglobin F, but a small amount of hemoglobin S will also be present. If a newborn has sickle cell trait, there may be a small amount of hemoglobin A and hemoglobin S. A full diagnostic evaluation should be done following positive screening results.

Hemoglobin S solubility test and sodium metabisulfite screening
Some hemoglobin S will be present in those who carry one sickle cell gene (sickle cell trait) and much more will be present in those who have sickle cell disease.

Diagnostic testing
Adults with sickle cell trait will produce mostly normal hemoglobin A, while those with sickle cell disease (anemia) will produce mostly Hb S with no Hb A. People who have two gene copies for two different hemoglobin variants will usually produce varying amounts of both types. For example, they may produce both Hb S and Hb C but no Hb A.

Genetic testing
If two copies of the Hb S gene mutation are detected, then the person has sickle cell disease. If the person has one gene that codes for Hb S and one normal gene, then the person has sickle cell trait. If the person has one Hb S copy and a Hb C or beta thalassemia mutation, then the person is likely to experience some symptoms and complications associated with sickle cell disease. If the person has one Hb S gene copy and another, more rare hemoglobin variant, then the person may or may not have any symptoms or complications. See the article on Hemoglobin Abnormalities for more on this.

Some examples of results that may be seen with sickle cell testing are listed in the following table.

Sickle cell anemia symptoms and the complications experienced will vary greatly from person to person, even within the same family.

Recent blood transfusions, typically within the last three months of the date of testing, may cause a false-negative test result with some of the tests (e.g., Hb S solubility tests) because transfusion of normal RBCs reduce the relative amount of hemoglobin S present in an affected person’s system.

People with sickle cell trait are generally healthy, but those who exercise heavily, such as athletes and those who are exposed to dehydration or altitude extremes, may sometimes experience sickle cell anemia symptoms. Sickle cell carriers produce both Hb A and some Hb S. When they are subjected to significant stresses that reduce the amount of oxygen in the body, the RBCs that contain Hb S can sickle.

Anyone can inherit Hb S gene mutations, but sickle cell disease is more prevalent among those of African ancestry and those who can trace their roots to the Mediterranean area, South and Central America, the Middle East, India, and the Caribbean.

It mirrors the areas of the world where malaria is found. Historically, sickle cell offered some protection and survival advantage against malaria. Since people from these areas have moved throughout the world, sickle cell gene mutations have become more widespread. A 2013 study noted that the rates of sickle cell anemia are increasing worldwide and are projected to affect more than 400,000 newborns by 2050, with India and sub-Saharan Africa showing the sharpest increases.

Newborn screening identifies most cases of sickle cell trait and sickle cell anemia. However, this screening was not universally performed in the U.S. until relatively recently. Many adults, and especially athletes born in other countries, may not have been tested to determine their sickle cell status. Since there is some risk of “exertional sickling” during intense training, the National Collegiate Athletic Association (NCAA) advocates testing college athletes who have not documented their sickle cell status.

Your healthcare practitioner may request that DNA sequencing be done to help determine the types of abnormal hemoglobin that may be present. It is not routine testing but may be necessary if it is suspected that you have a less common form of hemoglobin (variant), such as hemoglobin F. Rather than testing for one specific gene mutation, DNA sequencing determines the order of DNA building blocks (nucleotides) in a person’s genetic code. This method may be used to help identify hemoglobin disorders caused by less common mutations.