Sickle cell disease is most commonly diagnosed through newborn screening, a blood test performed within the first few days of life. In countries with universal screening programs, a small blood sample from a baby’s heel is analyzed to identify abnormal types of hemoglobin. For older children and adults who weren’t screened at birth, diagnosis relies on the same core lab tests, often prompted by symptoms like unexplained anemia or episodes of pain.
Newborn Screening
The standard approach is a heel prick blood sample collected between 24 and 72 hours after birth. The blood is placed on filter paper and sent to a lab for analysis, typically using a technique called high-performance liquid chromatography (HPLC). This method separates the different types of hemoglobin in the sample and measures how much of each is present. It can identify sickle hemoglobin (HbS) along with other variants like HbC, HbD, and HbE in a single test.
In a healthy newborn, the dominant hemoglobin is fetal hemoglobin (HbF), with smaller amounts of normal adult hemoglobin (HbA). The lab looks at the pattern of hemoglobin types to flag potential problems. A result showing fetal hemoglobin and sickle hemoglobin but no normal adult hemoglobin (an “FS” pattern) points toward sickle cell disease. A result showing fetal hemoglobin, then adult hemoglobin, then sickle hemoglobin (“FAS” pattern) suggests the baby carries the sickle cell trait but doesn’t have the disease. Any positive result is confirmed through repeat testing.
Confirmatory Testing After a Positive Screen
A newborn screen is just the first step. Because the initial sample is small and the baby’s blood is still dominated by fetal hemoglobin, confirmatory tests are needed to pin down the exact diagnosis. This usually happens through hemoglobin electrophoresis or a repeat HPLC analysis performed after the baby is a few months old, when fetal hemoglobin levels have dropped enough to reveal the full picture.
One important limitation: a common quick test called the sickle solubility test (sometimes called Sickledex) cannot be used in newborns. High levels of fetal hemoglobin dilute the sickle hemoglobin and produce false negatives. This effect can persist for up to six months, which is why solubility testing is reserved for older children and adults.
How Lab Results Distinguish Disease From Trait
The key to diagnosis is the ratio and types of hemoglobin in the blood. In sickle cell disease (HbSS), the most common form, hemoglobin electrophoresis typically shows about 80% sickle hemoglobin, 1% to 20% fetal hemoglobin, 2% to 4.5% HbA2 (a minor normal variant), and no normal adult hemoglobin at all. Someone with sickle cell trait, by contrast, has both normal hemoglobin and sickle hemoglobin, with the normal type predominating.
Sickle cell disease isn’t just one condition, though. Several genotypes cause it, and each looks slightly different on lab tests:
- HbSS (sickle cell anemia): The most severe form. No normal adult hemoglobin is present. About 80% sickle hemoglobin with variable fetal hemoglobin.
- HbSC disease: The newborn screen shows an “FSC” pattern, meaning both sickle hemoglobin and hemoglobin C are present alongside fetal hemoglobin.
- HbS/beta-plus thalassemia: Shows an “FSA” pattern on newborn screening. Some normal adult hemoglobin is present, but less than sickle hemoglobin. Doctors use the ratio of normal to sickle hemoglobin (with a cutoff below 1) to distinguish this from simple trait.
- HbS/beta-zero thalassemia: This one is tricky because, like HbSS, it produces no normal adult hemoglobin. The red blood cells tend to be smaller and paler than in HbSS, with more target-shaped cells and fewer sickle-shaped cells visible under the microscope. HbA2 levels run higher, typically 4% to 6% compared to the 2% to 4.5% seen in HbSS.
Telling these genotypes apart matters because they differ in severity and management. Distinguishing HbSS from HbS/beta-zero thalassemia, for instance, relies on subtle differences in red blood cell size, shape, and hemoglobin A2 levels.
When Genetic Testing Is Needed
Standard blood tests can identify most cases, but some situations require DNA analysis of the gene responsible for hemoglobin production (the HBB gene). Compound heterozygotes, people who inherit a sickle hemoglobin gene alongside a rarer hemoglobin variant, are notoriously difficult to diagnose with electrophoresis alone. When blood-based tests give ambiguous results, molecular techniques like gene sequencing provide a definitive answer.
Genetic testing is also required for prenatal diagnosis. If both parents carry the sickle gene, doctors can test the fetus using chorionic villus sampling between 10 and 13 weeks of pregnancy, or amniocentesis after 15 weeks. Both procedures collect fetal cells for DNA analysis to determine whether the baby has inherited two copies of the sickle gene. Chorionic villus sampling offers results weeks earlier, which gives families more time to prepare.
Blood Count Findings
While hemoglobin testing identifies the specific type of disease, a complete blood count reveals how the disease is affecting the body. Most people with sickle cell disease have anemia, with hemoglobin levels below 11 g/dL. Their bodies compensate by ramping up red blood cell production, so the reticulocyte count (a measure of new red blood cells being released from the bone marrow) is often very high. These numbers aren’t used to make the initial diagnosis, but they help doctors gauge severity and establish a baseline for each patient.
Symptoms That Prompt Diagnosis in Unscreened Children
In parts of the world without universal newborn screening, sickle cell disease is often caught when a baby or toddler develops symptoms. The earliest signs typically appear after 4 to 6 months of age, as fetal hemoglobin levels naturally decline and sickle hemoglobin takes over.
Three early symptoms commonly raise a red flag. Jaundice, a yellowish tint to the skin or the whites of the eyes, develops because sickle-shaped red blood cells break down much faster than normal ones. Unusual tiredness or fussiness in an infant can signal anemia. And dactylitis, painful swelling of the hands and feet, is one of the most recognizable early signs. It results from sickle cells blocking blood flow in the small bones of the hands and feet. A child presenting with any combination of these symptoms will typically be sent for hemoglobin testing, which then confirms the diagnosis.
Diagnosis in Older Children and Adults
Adults who were never screened, perhaps because they grew up in a region without universal programs, can be diagnosed at any age. The same hemoglobin tests apply: HPLC or electrophoresis to identify and measure hemoglobin types. HPLC is generally preferred because it can quantify fetal hemoglobin, HbA2, and multiple variants in a single run. Older techniques like alkaline and acid electrophoresis are more time-consuming, require multiple steps, and can miss variants that have similar electrical properties on the test.
For adults, the sickle solubility test can serve as a rapid initial screen, since fetal hemoglobin is no longer a confounding factor. But a positive solubility test only confirms that sickle hemoglobin is present. It cannot distinguish between sickle cell trait and sickle cell disease, and it misses other hemoglobin variants entirely. A full hemoglobin analysis is always needed to make a definitive diagnosis.