Sickle cell disease diagnosis

A series of blood tests often gives enough information to diagnose sickle cell disease (SCD), an inherited disorder that causes problems with blood circulation and oxygen delivery to body tissues.

In SCD, mutations in the HBB gene lead to the production of abnormal forms of hemoglobin, a protein that helps red blood cells carry oxygen throughout the body. The abnormal protein can cause red blood cells to sickle, or take on a crescent shape, and stick together, causing problems with blood flow and disrupting oxygen delivery to tissues and organs.

Many countries, including the U.S., have broad sickle cell testing programs for infants. This helps with early diagnosis of sickle cell, allowing patients to start appropriate treatment early and helping reduce the risk of complications.

In addition to helping with SCD diagnosis, these testing programs can identify sickle cell trait (SCT), which occurs when someone has one mutated HBB copy and one normal gene copy. Knowing someone is a carrier of an SCD-causing mutation may affect family planning decisions for some people.

How sickle cell disease is diagnosed

Blood tests alone can often diagnose sickle cell. However, several types of tests may be needed to confirm the diagnosis, determine whether someone has SCD or SCT, identify the specific types of hemoglobin present, and determine the disease type. Blood tests for sickle cell may include:

• Complete blood count: assesses blood cell counts and hemoglobin levels
• Peripheral blood smear: assesses the presence of sickled cells in the blood when examined under a microscope
• Solubility test: quickly identifies the most common abnormal hemoglobin variant associated with SCD, called hemoglobin S (HbS)
• Hemoglobin electrophoresis: identifies HbS and other forms of hemoglobin in the blood
• Hemoglobin high-performance liquid chromatography: measures the levels and assesses the relative proportion of HbS and other types of hemoglobin in the blood
• Sickle cell genetic testing: confirms the presence of HBB mutations

A complete blood count, peripheral blood smear, and solubility test may be used as initial sickle cell screening tests. If results are abnormal, additional confirmatory tests may be done to confirm the diagnosis, determine whether a person has SCD or SCT, and identify the specific SCD type.

These confirmatory tests include hemoglobin electrophoresis and/or high-performance liquid chromatography, which can identify HbS and other abnormal hemoglobin variants, and may be used in newborn sickle cell screening or follow-up testing. Despite being able to detect HbS, a solubility test cannot distinguish SCD from SCT, so it is not used for newborn screening.

Genetic testing, a more recent addition to the diagnostic process, may confirm the diagnosis and give doctors more information about disease type, possible severity, treatment options, and family planning.

Newborn screening and early diagnosis

Newborn screening for sickle cell disease is a standard practice in many countries. In the U.S., the newborn screening program expanded after a landmark study suggested that identifying sickle cell at birth and starting treatment early could help prevent infections and save lives, particularly in more severe types of the disease.

The standard sickle cell diagnostic process for infants involves collecting a small blood sample from the heel and sending it to a laboratory for analysis.

If screening indicates that sickle cell may be present, a healthcare provider may contact families about follow-up testing, including more blood tests and genetic tests. Depending on the results, they may confirm a diagnosis of SCD or SCT, or determine that the initial test results were a false positive.

Doctors can also diagnose sickle cell before birth through prenatal testing. There are two main methods for this:

• Chorionic villus sampling: uses a small sample from specific cells in the placenta, usually around 10 to 13 weeks of pregnancy
• Amniocentesis: uses some of the fluid that surrounds a developing fetus (amniotic fluid), usually around 15 to 20 weeks of pregnancy

Both sampling techniques allow a lab to genetically test the fetus for mutations that can cause SCD.

Diagnosing sickle cell in children and adults

Because of widespread newborn screening, sickle cell diagnosis in adults or older children is less common in many regions. However, it can still happen, especially for people born in areas or time periods without a well-established screening process. These individuals often have a history of unexplained symptoms and difficulty getting appropriate care.

Situations that may lead to testing and diagnosis later in life include:

• having chronic anemia, a symptom of SCD that occurs when red blood cell counts and/or hemoglobin levels drop too low, reducing oxygen delivery to tissues and organs
• experiencing recurrent episodes of acute pain, which could be vaso-occlusive crises caused by blood flow blockage in a specific part of the body
• showing signs of abnormalities on routine clinical tests, such as eye exams or standard blood tests, that could suggest the presence of SCD

Genetic tests and other blood tests can be done at any age.

Understanding test results

Doctors can help interpret sickle cell test results and identify next steps for patients and families. For people with suspected SCD or SCT, screening results may show different hemoglobin patterns, including:

• low levels of healthy hemoglobin
• the presence of HbS

More detailed testing can then confirm the presence of HbS or other abnormal hemoglobin variants, which helps determine the disease type. Different types of SCD involve different combinations of these hemoglobin variants.

If a child has healthy hemoglobin, as well as HbS, they may have SCT but not SCD.

What happens after a diagnosis

After diagnosis, next steps may include:

• being referred to a hematologist (blood specialist) or specialized sickle cell clinic
• starting treatment with preventive antibiotics or therapies that reduce the risk of pain crises
• undergoing screening to estimate the risk of stroke, a common sickle cell complication among children
• receiving genetic counseling
• learning about warning signs for complications and developing an emergency plan

A comprehensive care plan for sickle cell will include regular monitoring, mental healthcare, social support, and educational support, with involvement from specialists and primary care providers.

To help estimate the risk of a stroke, many children with SCD have transcranial Doppler ultrasounds, a type of noninvasive diagnostic test that can help detect problems with blood flow in the brain. If stroke risk is high, doctors may recommend preventive treatments.

Besides everyday care, patients and caregivers should be aware of which symptoms require immediate medical attention and what to do if an emergency arises.

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