Elevated Hemoglobin
A
2
: A Molecular Revisited, and Implications to β‐Thalassemia Screening
Kritsada Singha, Anupong Pansuwan, Hataichanok Srivorakun, Attawut Chaibunruang, Supawadee Yamsri, Wanicha Tepakhan, Kanokwan Sanchaisuriya, Goonnapa Fucharoen, Supan Fucharoen ABSTRACT
Background
In Thailand, the Hb A 2 cut‐off value for β‐thalassemia carrier has been changed from 4.0% to 3.6% since 2015. We examined the molecular basis of β‐thalassemia in a large cohort of Thai subjects with this change.
Methods
A total of 36,313 retrospective specimens encountered during January 2016 to June 2025 were reviewed, and 5909 subjects (16.7%) with Hb A 2 ≥ 3.6% were recruited. Diagnosis of thalassemia was based on Hb and DNA analyses.
Results
Among the 5909 subjects, 5395 (91.3%) had Hb A 2 A, 115 (1.9%) carried Hb variants, and the remaining 399 (6.8%) resulted from misinterpretations. Of 5395 subjects, 5117 (94.8%) carried β‐thalassemia, 189 (3.5%) had normal β‐globin genes, and 89 (1.6%) had incomplete molecular analysis. Fifty different β‐thalassemia genes were identified, including nine hitherto undescribed in Thailand and two novel mutations, β CD81(CTC > CTA) and β IVSII‐713(G > A) . Falsely elevated Hb A 2 was found in 364 of 399 (70.8%) subjects with misinterpretation, 20 (3.9%) represented human errors, and 15 (2.9%) resulted from Hb E blood transfusion. A low proportion of β 0 ‐ and a high proportion of β + ‐thalassemias, a normal β‐globin gene, and diagnostic errors were observed at borderline Hb A 2 levels.
Conclusions
A change in the Hb A 2 cut‐off can alter the molecular spectrum of β‐thalassemia in Thailand. The molecular basis of β‐thalassemia was updated to include 50 mutations, both new and known. Misinterpretation at borderline Hb A 2 should be aware and cost‐effectiveness should be considered at the screening of β‐thalassemia in the region.