What is the most likely diagnosis and recommended work‑up for a patient with hemoglobin 8.1 g/dL, mean corpuscular volume 58 fL, and hemoglobin A2 3.6%?

Beta-Thalassemia Trait (Minor)

The most likely diagnosis is beta-thalassemia trait, given the combination of microcytic anemia (MCV 58 fL), moderate anemia (Hb 8.1 g/dL), and elevated HbA2 (3.6%). 1

Diagnostic Interpretation

The elevated HbA2 level of 3.6% is the key diagnostic finding here. HbA2 levels above 3.5% are characteristic of beta-thalassemia heterozygotes (trait/minor), particularly when accompanied by microcytosis. 1 This pattern—low MCV with elevated HbA2—is the most typical feature of heterozygous beta-thalassemia. 2

Critical Caveat About Hemoglobin Level

The hemoglobin of 8.1 g/dL is unusually low for isolated beta-thalassemia trait, which typically causes mild anemia or normal hemoglobin with microcytosis. 1 This degree of anemia (moderate, by definition) suggests either:

• Concurrent iron deficiency (most common)
• Co-inheritance with alpha-thalassemia
• Other superimposed cause of anemia

Iron deficiency can suppress HbA2 levels, so the fact that HbA2 remains elevated at 3.6% despite this degree of anemia actually strengthens the diagnosis of beta-thalassemia trait. 1, 3 If iron deficiency is present and corrected, the HbA2 level would likely rise even higher. 1

Recommended Work-Up

Immediate Laboratory Testing

• Complete iron studies: serum ferritin, transferrin saturation (TSAT), and serum iron with TIBC to identify concurrent iron deficiency 4

  • Ferritin <30 μg/L confirms iron deficiency in the absence of inflammation 4
  • TSAT <15-20% supports iron deficiency 4

• Peripheral blood smear: to assess for target cells, microcytes, and red cell morphology characteristic of thalassemia 5

• Reticulocyte count: to evaluate bone marrow response and exclude hemolysis or bleeding 5

• Hemoglobin electrophoresis or HPLC: to confirm HbA2 quantification and exclude other hemoglobinopathies 1

Additional Testing to Consider

• Alpha-thalassemia genetic testing: Co-inheritance of alpha-thalassemia with beta-thalassemia trait can result in more severe anemia and lower MCV than beta-thalassemia trait alone 6, 7

• Vitamin B12 and folate levels: to exclude combined deficiency, though less likely given microcytosis 5

Management Approach

1. If iron deficiency is confirmed: Initiate oral iron supplementation with ferrous sulfate 325 mg (65 mg elemental iron) 1-3 times daily between meals 4

   • Expect hemoglobin increase of 1-2 g/dL every 2-4 weeks 4
   • Continue iron for 3-6 months after hemoglobin normalizes to replenish stores 4

2. Investigate the underlying cause of iron deficiency: detailed menstrual history (if female), dietary assessment, and consideration of gastrointestinal evaluation if losses don't explain severity 4

3. Genetic counseling: Once beta-thalassemia trait is confirmed, provide counseling about inheritance patterns and screening recommendations for partners, particularly if planning pregnancy 1

Common Pitfalls to Avoid

• Do not assume iron deficiency alone explains this presentation: The elevated HbA2 indicates beta-thalassemia trait, which requires separate genetic counseling 1

• Do not overlook the severity of anemia: Hb 8.1 g/dL is too low for isolated beta-thalassemia trait and mandates investigation for concurrent iron deficiency or other causes 4, 1

• Do not rely on MCV alone: While MCV 58 fL is severely microcytic, the HbA2 level is what distinguishes beta-thalassemia trait from iron deficiency anemia 3, 7

• Recheck HbA2 after iron repletion: If iron deficiency is present and treated, repeat HbA2 measurement to confirm the diagnosis, as iron deficiency can suppress HbA2 levels 1, 3