Hemoglobin A₂ Lowered by Iron Deficiency and α-Thalassemia: Should Screening Recommendation for β-Thalassemia Change?

Abstract

Screening for β-thalassemia trait (BTT) relies on measuring hemoglobin (Hb) A2. Since multiple factors can affect HbA2 levels, the screening can become unreliable. In 1356 healthy Arabs enrolled into a federally funded premarital BTT screening program, the effects of iron deficiency (ID), α +-thalassemia trait, gender, smoking, and tribalism on HbA2 were studied. The complete blood count and hemoglobin fractions were determined on the entire cohort; serum ferritin (<15 μg/L) in 391 subjects was used to determine ID. BTT was present in 29 (2.1%) subjects (HbA2 > 3.5%). Among 77(20.3%) subjects with ID, the mean HbA2 (2.30 ± 0.23%) was 0.2% lower than in subjects without iron deficiency (2.50 ± 0.24%, P < 0.0001). In 65 (38%)/172 subjects with phenotypic α +-thalassemia trait, the mean HbA2 (2.43 ± 0.24%) was 0.13% lower than in subjects without α +-thalassemia trait, P < 0.0001. The mean HbA2 did not differ between males and females, smokers and nonsmokers, and between the tribes. Thus, 35 (2.6%) subjects with HbA2 between 3.2 and 3.5% were at a risk of false negative diagnosis of BTT. Since iron deficiency and α +-thalassemia are both common and both lower HbA2, modifications in screening recommendations for BTT are proposed.

Effects of α-thalassaemia mutations on the haematological parameters of β-thalassaemia carriers

“…No difference was found in MCV and HbA2 levels between the male and female groups (p>0.05). Denic et al 17 reported that HbA2 is not influenced by gender, smoking or tribal allegiance, which is in agreement with our findings.…”

“…We found that HbA2 levels were significantly decreased in both α +Het , β and α +Hom , β in comparison with simple β carriers (p=0.004 and 0.002, respectively) (table 3). Other studies showed that inheritance of β- and α-thalassaemia mutations in a double heterozygous state decreases or normalises the levels of HbA2 17 18. This is in agreement with the findings of the present study.…”

Present scenario of hemoglobinopathies in West Bengal, India: An analysis of a large population

“…HbA2 value of 3.3% to 3.8% was considered as borderline and a cut-off of over 3.9% was taken for diagnosis of β-thalassemia trait. [4,[7][8][9] In very few cases, which were not interpreted by HPLC, were confi rmed by amplifi cation refractory mutation system, polymerase chain reaction (PCR-ARMS) technique. [10] …”

Higher minor hemoglobin A2 levels in multiple sclerosis patients correlate with lesser disease severity

“…Total Hb levels differ between males and females, and free Hb levels fluctuate depending on the presence of hemolytic conditions, such as infections. On the other hand, sex, race, and infections do not influence HbA2 levels 16,17. Therefore, measuring HbA2 levels would give reliable results pertinent to its involvement in chronic diseases, somewhat analogous to the benefits of HbA1C determination in diabetes, which allows determining the glucose balance for a long period rather than cross-sectional.…”