What is the recommended screening approach for individuals suspected of having sickle cell disease, particularly those with a family history or belonging to high-risk ethnic groups?

Screening for Sickle Cell Disease

All individuals at risk for hemoglobinopathy should be screened for sickle cell disease using a comprehensive hemoglobinopathy screen (high-performance liquid chromatography, capillary electrophoresis, mass spectrometry, or gel electrophoresis), with the exception of those of solely northern or eastern European, Jewish, or South-East Asian heritage who have never been screened previously. 1

Who Should Be Screened

Universal Newborn Screening

• All newborns in the United States, United Kingdom, and Canada are screened through established newborn blood spot screening programs 1, 2, 3
• In the UK, screening was fully established by 2006 in England, 2010 in Scotland, 2012 in Northern Ireland, and 2013 in Wales 1
• Children born after these dates in their respective regions will have already been screened and parents informed if sickle cell disease was detected 1

High-Risk Populations Requiring Screening

• Early-generation immigrants from moderate-to-high incidence regions (≥10-12 per 100,000 people), including sub-Saharan Africa, Eastern Europe, Andean Latin America, East Asia, India, the Mediterranean, and Middle East 1, 4, 2
• First-degree relatives of individuals with sickle cell disease (family history) 1
• Black/African American individuals (8% carry sickle cell trait) 1, 2
• Hispanic Americans and Asian Americans from high-incidence regions when disaggregated by country of origin 1
• Individuals with unexplained normocytic anemia or severe atraumatic pain 2

Populations That May Not Require Routine Screening

• Individuals of solely northern or eastern European, Jewish, or South-East Asian heritage who have been previously screened 1

Recommended Screening Tests

Primary Screening Method

The definitive diagnostic test is a comprehensive hemoglobinopathy screen using one of the following methods: 1, 5

• High-performance liquid chromatography (HPLC)
• Capillary electrophoresis
• Mass spectrometry
• Gel electrophoresis

Critical Testing Considerations

• Never use sickle solubility testing alone as it cannot differentiate between heterozygous (trait), compound heterozygous, or homozygous (disease) states 1, 5
• Sickle solubility tests can produce false-negative results in neonates or heavily transfused patients 1, 5
• If a rapid sickle solubility test is performed first and is positive, it must be followed by a full hemoglobinopathy screen 1
• Confirmation with a second test (such as hemoglobin electrophoresis or solubility testing) is recommended 5

Screening Algorithm by Clinical Context

Pre-operative Screening

• Screen all at-risk patients before surgery, but avoid repeated unnecessary screening 1
• For known sickle cell disease patients undergoing surgery, obtain full blood count, urea and electrolytes, and complete red cell antibody screen, with repeat testing within 72 hours of surgery if transfused within 3 months 6

Athletic Screening

• The NCAA mandates sickle cell trait screening with solubility testing for all Division I student-athletes 1
• All Black individuals and others in the US have been routinely tested for sickle cell trait at birth since 1987 1

Maternal-Neonatal Screening in High-Risk Populations

• In areas with immigration from high-risk populations, selective screening of mothers from sub-Saharan countries and their neonates using HPLC is feasible and cost-effective 4
• This approach achieved 70% participation rates and detected both carriers (28% of mothers) and affected newborns (9.6% of carrier offspring) 4

Additional Testing After Positive Screen

Extended Red Cell Antigen Profiling

• Obtain extended red cell antigen profile by genotype (preferred) or serology at the earliest opportunity, optimally before first transfusion 5
• Minimum antigens to test: K, Jk^a/Jk^b, Fy^a/Fy^b 5
• Genotyping is superior to serologic phenotyping for accuracy, particularly for C antigen and Fy^b antigen matching 5
• Serologic phenotype may be inaccurate if the patient was transfused within the last 3 months 5

Common Pitfalls to Avoid

• Do not rely on sickle solubility testing alone for diagnosis—it misses critical distinctions between trait and disease 1, 5
• Do not assume all non-White patients need screening—risk stratification by specific country/region of origin is essential 1
• Do not fail to document sickle cell disease clearly on laboratory request forms, as this delays appropriate processing 6, 5
• Do not screen patients repeatedly if they have documented prior screening results 1
• Do not overlook Eastern European immigrants who may be categorized as "non-Hispanic White" but are actually high-risk 1