What is HbA2 (Hemoglobin A2)?
HbA2 is a minor hemoglobin variant composed of two alpha-globin chains and two delta-globin chains (α2δ2), normally comprising 2.0-3.3% of total hemoglobin in adults, and serves as the primary diagnostic marker for beta-thalassemia trait. 1, 2
Structure and Normal Physiology
HbA2 forms through the pairing of alpha-globin chains with delta-globin chains (encoded by HBA1/HBA2 and HBD genes respectively), creating a tetrameric structure distinct from the predominant HbA (α2β2) which comprises 96-98% of adult hemoglobin 1, 2
This minor hemoglobin fraction has no known essential physiological role in normal oxygen transport, though it possesses the interesting property of preventing polymerization of deoxy-sickle hemoglobin 3
HbA2 is present in all erythrocytes uniformly (homocellular distribution), unlike fetal hemoglobin which shows heterocellular expression 3
Clinical Significance and Diagnostic Applications
Beta-Thalassemia Screening
Elevated HbA2 levels (>3.3%) represent the most important diagnostic marker for heterozygous beta-thalassemia trait, typically accompanied by microcytosis and hypochromia 4, 5
HbA2 quantification plays the key role in hemoglobinopathy screening programs because even a small increase in this fraction identifies beta-thalassemia carriers who are otherwise clinically silent 4
Normal HbA2 levels (2.0-3.3%) effectively exclude beta-thalassemia trait, as demonstrated by the 2.2% level that rules out this diagnosis 1
Conditions Affecting HbA2 Levels
Elevated HbA2 occurs in:
- Beta-thalassemia heterozygotes (most common cause) 5
- Megaloblastic anemia (highest levels with most severe anemia) 5
- Rare genetic traits causing isolated HbA2 increase without beta-globin gene defects 6
Decreased HbA2 occurs in:
- Iron-deficiency anemia (lowest levels with most severe anemia) 5
- HbH disease (alpha-thalassemia) 7, 5
- Hereditary persistence of fetal hemoglobin 5
Important caveat: Iron or folate deficiency can suppress HbA2 levels even in beta-thalassemia heterozygotes, potentially masking the diagnosis, though vitamin B12 deficiency does not alter HbA2 percentage 5
Measurement Methods
High-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) are the most widely used automated methods for accurate HbA2 quantification 2
Delta-globin gene variants occur with an estimated frequency of 1-2% during screening and can interfere with accurate HbA2 measurement, requiring molecular characterization for definitive diagnosis 2
Recognition of delta variants on hemoglobin analysis is crucial to provide accurate thalassemia diagnosis, particularly for young individuals seeking prenatal or preimplantation genetic diagnosis 2
Conditions NOT Affecting HbA2
The following do not alter HbA2 levels: malignant tumors, renal insufficiency, hepatic insufficiency, chronic infections, chronic inflammation, hemolytic disease, lead poisoning, aplastic anemia, leukemia, myelofibrosis, and hypothyroidism 5