Thalassemia Trait (Most Likely Diagnosis)
The combination of low MCV, low MCH, low MCHC with increased RBC count and normal hemoglobin is most consistent with thalassemia trait (alpha or beta thalassemia minor), not iron deficiency anemia. This pattern represents a compensatory erythropoiesis where the bone marrow produces more red cells to maintain normal oxygen-carrying capacity despite each cell being smaller and containing less hemoglobin 1.
Key Distinguishing Features
The elevated RBC count is the critical discriminating factor that points away from iron deficiency anemia and toward thalassemia trait 2:
- Thalassemia trait: Increased RBC count with microcytosis (MCV typically <70 fL), with the MCV often disproportionately low relative to the degree of anemia 1
- Iron deficiency: Normal or decreased RBC count with microcytosis 1, 3
The normal hemoglobin in this case further supports thalassemia trait, as patients with thalassemia minor typically have minimal or no anemia, whereas iron deficiency severe enough to cause marked microcytosis would be expected to lower hemoglobin 4, 5.
Diagnostic Algorithm
Step 1: Check Red Cell Distribution Width (RDW)
This is the single most useful discriminating test after the CBC indices 1, 4.
Step 2: Assess Iron Studies
Check serum ferritin to definitively exclude iron deficiency 1:
- Ferritin <30 μg/L indicates iron deficiency 1
- Ferritin >100 μg/L essentially excludes iron deficiency 1
- Ferritin 30-100 μg/L may require transferrin saturation for clarification 1
Important caveat: Ferritin is an acute phase reactant and can be falsely elevated in inflammation, infection, or malignancy 1. In these contexts, ferritin up to 100 μg/L may still be consistent with iron deficiency 1.
Step 3: Hemoglobin Electrophoresis
If microcytosis persists with normal iron studies, proceed to hemoglobin electrophoresis 1, 6:
- Beta-thalassemia trait: Elevated HbA2 (>3.5%) 4, 5
- Alpha-thalassemia trait: Normal hemoglobin electrophoresis (requires genetic testing for confirmation) 4, 5
- Hemoglobin E trait: Characteristic pattern on electrophoresis 4
This is particularly important in patients of Mediterranean, African, Middle Eastern, or Southeast Asian descent 1.
Common Pitfalls to Avoid
Do not assume all microcytic anemia is iron deficiency 6. Empiric iron therapy without confirming iron deficiency can:
- Delay diagnosis of thalassemia trait
- Lead to unnecessary iron supplementation and potential iron overload in thalassemia patients receiving transfusions 5
- Miss other important causes like anemia of chronic disease 1
Do not overlook combined deficiencies: A patient with thalassemia trait can also develop iron deficiency, which may normalize the MCV (microcytosis from thalassemia + macrocytosis from iron deficiency) 1. A high RDW can help identify this situation 1, 4.
Secondary Considerations
If both thalassemia and iron deficiency are excluded, consider rarer causes of microcytic anemia with elevated RBC count 2:
- Polycythemia vera with concurrent iron deficiency: Elevated RBC count persists even after iron repletion, but MCV normalizes 2
- Secondary polycythemia with iron deficiency: From chronic hypoxia (COPD, cyanotic heart disease) or erythropoietin-secreting tumors 2
In these cases, the RBC count remains elevated after iron supplementation, distinguishing them from simple iron deficiency 2.