Background Hemoglobin A1c (HbA1c) is central to diabetes diagnosis and monitoring, yet analytical interference remains a challenge. Elevated fetal hemoglobin (HbF) is often overlooked in adults because it is assumed to be clinically insignificant outside pediatric or hematologic settings. However, HbF occurs in contemporary adult populations and can cause clinically meaningful HbA1c bias, particularly with immunoassay based methods. This study highlights HbF as an underrecognized source of HbA1c discordance in routine clinical practice. Methods A laboratory review algorithm was implemented to identify HbA1c results potentially affected by HbF. Samples with HbF >5% and HbA1c >8% measured by HPLC (Bio Rad D 100) were prospectively flagged for secondary evaluation using an immunoassay (Siemens Healthineers DCA). Flagged cases were categorized into three groups: (1) patients with HbF >10% due to conditions such as hereditary persistence of fetal hemoglobin (age 14–71 years); (2) patients with sickle cell disease after curative CRISPR based gene therapy with intentionally induced high HbF (30–50%); and (3) cases with falsely elevated HbF and HbA1c due to Hb Wayne on the Bio Rad D 100. Results Clinically significant HbA1c discordance was observed across all groups, reflecting distinct failure modes related to HbF burden and measurement approach. In patients with HbF >10% (12.3–27.1%, n=19), Siemens DCA HbA1c values showed a consistent relative negative bias compared with Bio Rad D 100 HPLC (−11.5% to −64.3%, mean −23.7%). Among gene therapy recipients (n=2), mean HbF was 41.8%, exceeding validated limits for both methods; HbA1c results were unreliable overall, but immunoassay values remained persistently lower than HPLC despite stable glycemia. In contrast, cases with Hb Wayne demonstrated falsely elevated HbA1c by HPLC (10.2–12.2%) with modestly increased reported HbF (7.0–7.4%, n=8), while corresponding immunoassay HbA1c values (4.7–5.8%) aligned with fasting glucose, indicating analytical artifact due to chromatographic co migration. Hb Wayne was confirmed by capillary electrophoresis. Conclusion Elevated fetal hemoglobin is common in adults and is often overlooked when HbA1c is used to assess glycemic control. Our findings show that HbF can produce misleading HbA1c results, with the direction of error dependent on the testing method. Clinicians typically receive a single HbA1c value without indication that the result may be unreliable, a problem that is amplified in gene therapy recipients with very high HbF. Methods that display hemoglobin fractions allow recognition of this issue, while immunoassays do not. When HbA1c is unreliable, alternative markers such as fructosamine should guide care.
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