Glycemic Monitoring in Sickle Cell Anemia
HbA1c cannot be accurately measured in patients with sickle cell disease and should never be used; instead, use fructosamine or plasma glucose measurements for glycemic monitoring and diagnosis. 1
Why HbA1c Fails in Sickle Cell Disease
Patients with sickle cell disease (HbSS) completely lack HbA (normal hemoglobin A), making HbA1c measurement impossible. 1 The increased red blood cell turnover inherent to sickle cell disease causes falsely low HbA1c readings even when measured, as red blood cells have insufficient lifespan for glucose to adequately bind to hemoglobin. 1
The American Diabetes Association explicitly states that in conditions with increased red blood cell turnover such as sickle cell disease, only plasma blood glucose criteria should be used to diagnose diabetes—not HbA1c. 1
Recommended Alternatives for Glycemic Assessment
Fructosamine as the Primary Alternative
Fructosamine is the preferred alternative glycemic marker in sickle cell disease because it measures glycated serum proteins rather than hemoglobin, making it unaffected by hemoglobinopathies. 1 The American Diabetes Association specifically recommends fructosamine or continuous glucose monitoring (CGM) when an alternative to HbA1c is required. 1
Research demonstrates that:
- Fructosamine performs equally well in patients with and without sickle cell trait, showing no statistical difference between groups (median 287 vs 275 μmol/L, p=0.11). 2
- Fructosamine has excellent diagnostic accuracy with an area under the curve of 0.92 for identifying uncontrolled glycemia, independent of sickle cell status. 2
- Fructosamine reflects glycemic control over 2-3 weeks, providing a shorter-term assessment than HbA1c's 2-3 month window. 3
Plasma Glucose Measurements
For diagnosis specifically, use these plasma glucose criteria 1:
- Fasting plasma glucose ≥126 mg/dL
- 2-hour plasma glucose during OGTT ≥200 mg/dL
- Random plasma glucose ≥200 mg/dL with symptoms
Critical technical requirement: Glucose samples must be spun and separated immediately after collection to prevent falsely low readings from ongoing glycolysis. 4
Ensure patients consume at least 150 g of carbohydrate daily for 3 days prior to testing to avoid falsely elevated glucose from carbohydrate restriction. 1, 4
Important Distinction: Sickle Cell Disease vs. Sickle Cell Trait
Patients with sickle cell trait (heterozygous HbS) have different considerations than those with sickle cell disease. 1
For sickle cell trait patients:
- HbA1c can be measured using assays specifically validated to be free from interference with HbS variant. 1
- Check the National Glycohemoglobin Standardization Program (NGSP) website (ngsp.org/interf.asp) for updated lists of assays without interference. 1
- Even with appropriate assays, HbA1c may read approximately 0.3% lower than actual glycemic burden in sickle cell trait carriers. 1
- Fructosamine remains highly accurate and may be preferred even in trait carriers. 2, 5
Clinical Implementation Algorithm
Confirm the diagnosis: Determine if the patient has sickle cell disease (HbSS) versus sickle cell trait (HbAS). 1
For sickle cell disease (HbSS):
For sickle cell trait (HbAS):
Common Pitfalls to Avoid
The most critical error is ordering HbA1c in sickle cell disease patients—this occurs in 11% of cases nationally despite clear contraindications. 6 A large EHR analysis found that only 2.3% of sickle cell patients who inappropriately received HbA1c testing also had the appropriate fructosamine test ordered. 6
Do not assume HbA1c and fructosamine are interchangeable—they measure different aspects of glycemic control over different timeframes and show substantial disparities even in the same patient. 5 Bland-Altman analysis demonstrates inappropriately large limits of agreement between these markers, particularly in sickle cell trait carriers. 5
When marked discrepancies exist between any glycemic marker and clinical presentation, suspect assay interference and switch to plasma glucose measurements. 1, 4