The most widely used screening test for sickle cell hemoglobin in adults is called the sickle cell solubility test, often known by its common brand name, Sickledex. But that name only covers the initial screening step. Confirming a diagnosis usually requires a second, more detailed test such as hemoglobin electrophoresis or high-performance liquid chromatography (HPLC), and the test used can differ depending on whether you are an adult being screened, a newborn in a hospital, or a parent seeking prenatal answers. Understanding which test does what helps you make sense of lab results and know what to expect at each stage.
The Sickle Cell Solubility Test
When a doctor orders a quick screen for sickle cell hemoglobin, the test most often used in adults is the sickle cell solubility test, sometimes abbreviated SCST. It works by mixing a blood sample with a chemical solution that removes oxygen from hemoglobin. Normal hemoglobin stays dissolved in the solution and the mixture remains clear. Sickle hemoglobin (HbS), however, clumps together when deoxygenated and turns the mixture cloudy. A cloudy tube means HbS is present; a clear tube suggests it is not.1PubMed Central. Sickle Cell Screening in Adults: A Current Review of Point-of-Care Testing
The most recognized commercial version of this test is called Sickledex. Blood donation centers routinely use it to screen donors, because transfusing sickle hemoglobin into a patient can cause complications. The test is inexpensive, fast, and does not require specialized equipment, which is why it remains a frontline tool in many clinical and blood-bank settings.2Blood. A Comparative Study of Solubility Based Sickle Cell Screening Versus Genomic Method in Blood Donors
What the Solubility Test Cannot Tell You
A positive solubility test tells you that HbS is in the blood, but it does not tell you how much. That matters because someone who carries one copy of the sickle gene (sickle cell trait, or HbAS) and someone who carries two copies (sickle cell disease, or HbSS) will both produce a cloudy tube. The standard solubility test cannot distinguish between the two. A more advanced version using centrifugation has been developed that can separate trait from disease by looking at how the cloudy material settles, but the basic test used in most screening settings does not make this distinction.3American Journal of Clinical Pathology. A Whole Blood Solubility and Centrifugation Test for Sickle Cell Hemoglobin: A Clinical Trial
The solubility test also has known false-positive triggers. High blood lipid levels, abnormal blood protein conditions, and elevated blood cell counts can all make the solution appear cloudy even when no HbS is present.2Blood. A Comparative Study of Solubility Based Sickle Cell Screening Versus Genomic Method in Blood Donors For these reasons, a positive solubility test almost always triggers a follow-up confirmatory test.
Hemoglobin Electrophoresis and HPLC
The confirmatory tests that most people encounter after a positive screen are hemoglobin electrophoresis and HPLC. These are the tests your doctor may simply refer to as “a hemoglobin test” or “hemoglobin analysis.” Both separate the different types of hemoglobin in your blood so they can be identified and measured individually.
Hemoglobin electrophoresis works by placing a blood sample on a gel or paper and running an electrical current through it. Different hemoglobin types move at different speeds depending on their charge, so they spread out into distinct bands. A technician or machine reads which bands appear and how thick they are. HPLC does something similar but uses a liquid-based system that pushes the blood sample through a column, separating hemoglobin types by their chemical properties. Both methods can tell you not just whether HbS is present, but approximately what percentage of your total hemoglobin it makes up. That percentage is what distinguishes sickle cell trait from sickle cell disease.4PLOS ONE. Sickle cell disease: A distinction of two most frequent genotypes (HbSS and HbSC)
These confirmatory methods also pick up other hemoglobin variants such as HbC, HbD, and HbE. That is clinically important because sickle cell disease is not always HbSS. Some people have one sickle gene paired with a different abnormal hemoglobin gene, like HbSC disease, which has its own symptoms and severity profile. A simple solubility test would miss that distinction entirely.
How Newborn Screening Differs
If you have had a baby in the United States or many other countries, your child was almost certainly screened for sickle cell disease within the first few days of life as part of a routine heel-prick blood test. Newborn screening programs do not use the solubility test. The reason is straightforward: a newborn’s blood is dominated by fetal hemoglobin (HbF), which behaves differently from adult hemoglobin. Fetal hemoglobin interferes with the solubility reaction and makes the test unreliable in infants.5IntechOpen. Point‐of‐Care Testing in Sickle Cell Disease
Instead, newborn screening labs typically use one of three methods: isoelectric focusing (IEF), HPLC, or capillary electrophoresis. IEF is particularly popular because it is sensitive and relatively inexpensive. It separates hemoglobin types along a pH gradient with high resolution, producing narrow, crisp bands that clearly show whether HbS, HbC, or other variants are present alongside the normal HbF and HbA.6PubMed Central. Newborn Screening for Sickle Cell Disease and Other Hemoglobinopathies: A Short Review on Classical Laboratory Methods—Isoelectric Focusing, HPLC, and Capillary Electrophoresis HPLC works the same way in newborns as in adults. Many screening programs run two different methods on the same sample to confirm results before reporting.
The public health payoff from newborn screening has been dramatic. In Connecticut, for instance, there were 13 deaths attributed to sickle cell disease among infants in the 18 years before the state implemented universal newborn screening. In the roughly 11 and a half years after universal screening began in 1990, there were zero reported deaths among infants diagnosed at birth with the most severe forms of the disease.7PubMed. Newborn screening coupled with comprehensive follow-up reduced early mortality of sickle cell disease in Connecticut Early identification connects families to preventive treatment, including prophylactic antibiotics that protect young children from life-threatening infections.
Newer Rapid Tests for Low-Resource Settings
One of the biggest challenges in sickle cell testing globally is access. Electrophoresis machines, HPLC systems, and trained laboratory staff are concentrated in well-funded hospitals. In sub-Saharan Africa, where the burden of sickle cell disease is highest, many clinics have none of these. That gap has driven the development of rapid point-of-care tests that can be performed at the bedside with a finger prick, no electricity, and minimal training.
The most studied of these newer tests is called HemoTypeSC. It uses antibodies that recognize specific hemoglobin types (HbA, HbS, and HbC) and displays results as colored lines on a small test strip, similar in concept to a home pregnancy test. In a multi-center evaluation across several countries, HemoTypeSC showed overall sensitivity above 99% and specificity above 99% across all hemoglobin types tested, with perfect accuracy for sickle cell anemia specifically. Each test costs less than two dollars.8PubMed Central. Point-of-care screening for sickle cell disease in low-resource settings: A multi-center evaluation of HemoTypeSC, a novel rapid test A separate validation study found similar performance, with roughly 99% diagnostic accuracy using capillary blood at the bedside.9PubMed Central. Validation of a novel point of care testing device for sickle cell disease
What makes HemoTypeSC different from the solubility test is that it can distinguish between normal hemoglobin, sickle cell trait, and sickle cell disease in a single step. In a study of 100 blood samples covering all the common hemoglobin combinations, the test correctly identified the phenotype in every single case.10PubMed Central. A rapid, inexpensive and disposable point-of-care blood test for sickle cell disease using novel, highly specific monoclonal antibodies For regions where laboratory infrastructure is thin, this kind of test could mean the difference between a child receiving early treatment and going undiagnosed.
Prenatal and Genetic Testing
Testing for sickle cell disease does not have to wait until birth. Couples who know they carry the sickle gene can choose to test during pregnancy. The traditional approach involves chorionic villous biopsy, a procedure where a small sample of placental tissue is collected and the fetal DNA is analyzed. One common molecular method used on this tissue is called ARMS-PCR, which looks for the specific single-letter change in the beta-globin gene that causes sickle hemoglobin.11PubMed Central. Prenatal diagnosis of sickle cell disease by the technique of PCR
The drawback of chorionic villous biopsy is that it is invasive and carries a small risk of miscarriage. That risk has historically discouraged some parents from pursuing prenatal diagnosis. A newer approach sidesteps the problem entirely by analyzing cell-free fetal DNA circulating in the mother’s blood. Researchers have developed a sequencing-based test that can detect the sickle cell mutation from a standard maternal blood draw, with no need for tissue sampling and no risk to the pregnancy. The test does not even require a blood sample from the father or an existing affected child.12PubMed. A novel non-invasive prenatal sickle cell disease test for all at-risk pregnancies This type of non-invasive prenatal diagnosis is expected to make prenatal testing more widely accepted among at-risk couples.
When DNA Testing Is Needed
Standard blood-based tests like electrophoresis and HPLC identify hemoglobin proteins. They work well for the most common patterns, but occasionally a person’s results are ambiguous. An unusual hemoglobin variant might migrate to the same spot as HbS on an electrophoresis gel, producing a result that looks like sickle cell disease but is actually something else. Or a person might have a rare combination of mutations that produces an atypical pattern no one has seen before.
In those cases, DNA-based testing provides a definitive answer. By sequencing the beta-globin gene directly, a lab can identify the exact mutation at the molecular level, leaving no room for ambiguity. In a study from Tanzania, long-read DNA sequencing resolved cases with unusual phenotypes that standard protein-based tests could not clarify. These unusual cases accounted for about 1% of all children tested.13PubMed Central. Using DNA testing for the precise, definite, and low-cost diagnosis of sickle cell disease and other Haemoglobinopathies: findings from Tanzania DNA testing is not necessary for straightforward cases, but for that small percentage of people whose lab results are confusing or inconclusive, it settles the question once and for all.
Which Test Should You Expect?
If you are an adult who has never been tested for sickle cell trait, the first step your doctor is likely to order is a hemoglobin electrophoresis or HPLC panel. Some clinics may start with a solubility screen and then follow up with electrophoresis if it comes back positive, but many skip straight to the confirmatory test since it provides more information. If your doctor mentions “sickle cell prep,” “sickle screen,” or just “hemoglobin test,” they are probably referring to one of these methods.
For a newborn, you generally do not have to ask. Universal newborn screening covers sickle cell disease in all 50 U.S. states and in many countries worldwide. The results come back to your pediatrician, usually within a week or two. If the screen is positive, a follow-up confirmatory test is performed before a diagnosis is made.
If you are pregnant and both you and your partner carry sickle cell trait, your genetic counselor or obstetrician may discuss prenatal diagnostic options. The choice between invasive and non-invasive approaches depends on availability, gestational age, and your personal risk tolerance. Non-invasive prenatal testing from maternal blood is growing more available but may not yet be offered at all centers.
The Financial Weight of a Diagnosis
Understanding the tests is one thing. Living with the results is another. Sickle cell disease is a lifelong condition, and its costs accumulate over decades. An analysis of commercially insured patients in the United States estimated that the total medical costs attributable to sickle cell disease from birth to age 64 are roughly $1.6 million for females and $1.7 million for males. Those figures represent about a ninefold increase over the medical costs of people without the disease. Out-of-pocket costs for patients were estimated at around $42,000 to $45,000 over the same period, nearly four times higher than for people without sickle cell disease.14ASH Publications (Blood Advances). Lifetime medical costs attributable to sickle cell disease among nonelderly individuals with commercial insurance
These numbers help explain why early and accurate testing matters so much. Identifying a child with sickle cell disease at birth means starting preventive care before the first crisis hits, which keeps children out of emergency rooms and reduces the cascade of complications that drives costs up. For adults who were never screened as newborns, or who moved from countries without screening programs, getting tested is a straightforward blood draw that can open the door to treatments they may not have known were available.
Common Misconceptions About Sickle Cell Testing
One persistent misunderstanding is that a negative solubility test means you definitely do not carry any sickle hemoglobin. In most cases that is true, but the solubility test can occasionally give a false negative in patients with very low HbS levels, such as someone who has recently received a blood transfusion. If your clinical picture strongly suggests sickle cell disease but the screen is negative, a confirmatory test with electrophoresis or HPLC is warranted.
Another common confusion involves the difference between sickle cell trait and sickle cell disease. Many people who learn they carry the trait assume it means they have a mild form of the disease. It does not. Sickle cell trait means you have one normal hemoglobin gene and one sickle gene. Your red blood cells function normally under everyday conditions. Sickle cell disease means you have two abnormal genes, and your red blood cells sickle regularly, causing pain crises, organ damage, and a shortened lifespan. The distinction is not a matter of degree; it is a fundamentally different medical reality. The tests described throughout this article exist precisely to make that distinction clear.
A third misconception is that sickle cell testing is only relevant for people of African descent. While sickle cell disease is most common in populations from sub-Saharan Africa, it also occurs at significant rates among people of Mediterranean, Middle Eastern, Indian, and Central and South American ancestry. Universal newborn screening exists partly because limiting testing to one ethnic group would miss affected children in other populations.