hemoglobin A2

**Structure and normal values** - HbA2 = 2 alpha + 2 delta chains (α2δ2). The delta gene (HBD) is on chromosome 11 in the beta-globin cluster. - Normal adult Hb distribution: HbA (α2β2) ~95–98%, HbA2 ~1.5–3.5%, HbF (α2γ2) <1–2%. - HbA2 is expressed at low levels because the delta promoter is weak. It has no major role in oxygen delivery under normal conditions.

**Pathophysiology in thalassemia** - Beta-thalassemia involves reduced (β+) or absent (β0) beta-chain synthesis. Excess alpha chains are unpaired and precipitate, causing ineffective erythropoiesis and hemolysis. - With less beta chain available, alpha chains pair more with delta (and gamma) chains. This raises HbA2 (and often HbF). - Beta-thalassemia minor (trait): HbA2 elevated, typically 3.5–7%, with mild microcytic anemia, a high RBC count, and a Mentzer index <13 (MCV/RBC count). - Beta-thalassemia major: HbF predominates (~90%), HbA is absent (β0/β0) or very low, and HbA2 is variable. Patients are transfusion-dependent, with hepatosplenomegaly, "crew-cut" skull on X-ray, and extramedullary hematopoiesis. - Alpha-thalassemia: HbA2 is normal or low. Excess gamma chains form Hb Barts (γ4) in neonates, and excess beta chains form HbH (β4) in adults (HbH disease, 3-gene deletion).

**Diagnosis** - Hemoglobin electrophoresis or HPLC quantifies HbA2. This is the standard way to diagnose beta-thalassemia trait. - Peripheral smear: microcytosis, hypochromia, target cells, basophilic stippling. - Iron studies are normal or high, which distinguishes it from iron deficiency.

**Pitfalls (high-yield for Step 2)** - Iron deficiency can lower HbA2 and mask beta-thalassemia trait. Replete iron, then repeat testing if suspicion remains. - Coexisting delta-thalassemia (δβ) or alpha-thalassemia can lower HbA2 into the normal range. - Elevated HbA2 can also occur in megaloblastic anemia, HIV on zidovudine, and hyperthyroidism, though much less prominently. - In sickle cell disease (HbSS), HbA is absent, HbS is 80–95%, HbF is raised, and HbA2 is normal or slightly elevated. HbA2 is also used in HPLC interpretation of hemoglobinopathies, for example in sickle-beta-thalassemia.

**Quick comparison of microcytic anemias** | Condition | Ferritin | TIBC | HbA2 | |---|---|---|---| | Iron deficiency | Low | High | Normal/low | | Beta-thal trait | Normal | Normal | **High** | | Alpha-thal trait | Normal | Normal | Normal/low | | Anemia of chronic disease | High | Low | Normal | | Sideroblastic anemia | High | Normal/low | Normal |

**Management** - Beta-thalassemia trait needs no treatment but warrants genetic counseling. - Beta-thalassemia major is managed with chronic transfusions, iron chelation (deferasirox, deferoxamine), and possibly hematopoietic stem cell transplant or gene therapy.