Does thalassemia D affect HbA1c measurements?

Does Thalassemia Affect HbA1c Measurements?

Yes, thalassemia significantly interferes with HbA1c measurements, causing either falsely elevated or falsely lowered results depending on the specific type of thalassemia and the assay method used—you must use alternative glycemic markers in these patients.

Understanding the Interference Mechanism

Thalassemia affects HbA1c through two distinct mechanisms:

• Shortened red blood cell lifespan in hemoglobinopathies decreases HbA1c because glycation accumulates over the 120-day erythrocyte lifespan, and reduced cell survival means less time for glucose exposure 1.

• Structural hemoglobin variants can cause assay interference by coeluting with either HbA1c or HbA fractions in ion-exchange high-performance liquid chromatography methods, leading to unpredictable spuriously high or low results 1.

Specific Thalassemia Types and Their Effects

Beta-Thalassemia Trait

• Beta-thalassemia trait generally causes falsely lowered HbA1c due to shortened red cell lifespan 1.
• The Capillarys 2FP system can provide accurate HbA1c in beta-thalassemia trait when HbA2 is >2.8%, though caution is still warranted 2.

S-Beta-Plus-Thalassemia

• S-beta-plus-thalassemia causes dramatically falsely elevated HbA1c with Bio-Rad Variant II Turbo assay, with reported values as high as 30.3% when true glycemic control measured by immunoassay was only 5.8% 3.
• Suspect S-beta-plus-thalassemia when HbS fraction exceeds 50% and HbA1c is unexpectedly elevated 3.

Alpha-Thalassemia

• Alpha-thalassemia can cause discordantly high HbA1c inconsistent with fasting glucose, attributed to elevated hemoglobin H 4.
• HbH disease may prevent HbA1c reporting entirely due to overlapping of HbBart's with the HbA1c fraction on certain assays 2.

Transfusion-Dependent Thalassemia

• In efficiently transfused patients, HbA1c may be more reliable because circulating hemoglobin is from blood donors with normal red cell lifespan, though this remains debated 5.

Critical Clinical Recommendations

When thalassemia is present or suspected, the American Diabetes Association explicitly recommends using only plasma glucose criteria for diabetes diagnosis—never HbA1c 6, 7, 8.

Diagnostic Glucose Thresholds to Use Instead:

• Fasting plasma glucose ≥126 mg/dL 6, 7
• 2-hour oral glucose tolerance test ≥200 mg/dL 6, 7
• Random plasma glucose ≥200 mg/dL with symptoms 6, 7

For Ongoing Glycemic Monitoring:

Fructosamine is the preferred alternative marker because it measures glycated serum proteins over 2-4 weeks and is completely unaffected by hemoglobinopathies, with a target <250 µmol/L 8.

Continuous glucose monitoring (CGM) is recommended by the American Diabetes Association as the optimal method, providing time-in-range metrics without reliance on red blood cell turnover 8.

Glycated albumin may accurately reflect true average glucose when HbA1c is discordant 4.

Practical Algorithm for Clinical Use

Step 1: Identify Thalassemia Status

• Review complete blood count for microcytic anemia pattern 6.
• Order hemoglobin electrophoresis if thalassemia suspected based on ethnicity, family history, or unexplained microcytosis 1, 6.

Step 2: When HbA1c Seems Discordant

• If HbA1c is surprisingly high: Suspect S-beta-plus-thalassemia if HbS >50%; switch to immunoassay method or plasma glucose 3.
• If HbA1c is surprisingly low: Consider shortened red cell lifespan from any thalassemia type; obtain fasting glucose and 2-hour OGTT 6, 7.

Step 3: Choose Appropriate Monitoring Strategy

• For diagnosis: Use plasma glucose criteria exclusively 6, 7, 8.
• For monitoring: Order fructosamine (preferred) or implement CGM 8.
• Never rely on HbA1c alone in confirmed thalassemia 7, 9.

Common Pitfalls to Avoid

The most dangerous error is accepting a normal HbA1c at face value in a patient with thalassemia and symptoms of hyperglycemia, as the shortened red cell lifespan may mask true glycemic burden 6, 8.

Do not assume all assays are equally affected—boronate affinity chromatography methods may be more reliable than ion-exchange HPLC in some hemoglobinopathies, but plasma glucose remains the gold standard 1.

Marked discordance between HbA1c and clinical presentation should always prompt hemoglobin electrophoresis to identify unsuspected variants, as over 700 hemoglobin variants exist and most are clinically silent 1.

In transfusion-dependent patients, timing matters—HbA1c may be more interpretable when measured during periods of stable, efficient transfusion when donor red cells predominate 5.