Most Likely Diagnosis: β-Thalassemia Trait (Thalassemia Minor)
This 15-year-old female most likely has β-thalassemia trait, not iron deficiency anemia, despite the microcytic hypochromic picture. The key discriminating features are the markedly elevated RBC count (6.03 ×10⁶/µL), extreme microcytosis (MCV 66.2 fL) disproportionate to the degree of anemia, normal hemoglobin electrophoresis (HbA₂ and HbF reported as normal), and serum iron of 45 µg/dL that is not severely depleted 1.
Diagnostic Reasoning
Why Thalassemia Trait Is Most Likely
The RBC count of 6.03 ×10⁶/µL is markedly elevated (normal female range ≈ 4.0–5.5), which is characteristic of thalassemia trait where the bone marrow compensates by producing more—albeit smaller—red cells 1, 2.
The degree of microcytosis (MCV 66.2 fL) is extreme relative to the hemoglobin level, a pattern typical of thalassemia rather than iron deficiency 1.
Serum iron of 45 µg/dL is low-normal rather than severely depleted (typical iron deficiency shows iron <30 µg/dL), making pure iron deficiency less likely 1.
The RDW of 16.6% is elevated, but approximately 50% of thalassemia cases show elevated RDW, so this finding does not exclude thalassemia 3, 4. The traditional teaching that thalassemia has normal RDW (≤14%) is oversimplified; nearly half of thalassemia trait patients demonstrate RDW >14% 3, 4.
Critical Caveat About the Hemoglobin Electrophoresis
Normal HbA₂ and HbF do not exclude β-thalassemia trait in the presence of concurrent iron deficiency 1. Iron deficiency can falsely normalize HbA₂ levels, masking the diagnosis of thalassemia 1.
Hemoglobin electrophoresis must be repeated after iron repletion to definitively rule out thalassemia, as the two conditions frequently coexist 1.
Recommended Management Algorithm
Step 1: Complete Iron Studies Immediately
Order a full iron panel including serum ferritin, transferrin saturation (TSAT), and total iron-binding capacity (TIBC) to definitively assess iron status 1.
Ferritin <30 µg/L confirms iron deficiency; ferritin <45 µg/L provides optimal sensitivity and specificity in practice 1.
TSAT <16–20% confirms iron deficiency even when ferritin may be borderline 1.
Step 2: Initiate Empiric Iron Therapy While Awaiting Results
Start oral ferrous sulfate 200 mg (65 mg elemental iron) three times daily immediately, as iron deficiency is common in adolescent females and treatment is safe even if thalassemia coexists 1, 5.
Expect hemoglobin to rise ≥10 g/L within 2 weeks if iron deficiency is present; lack of response suggests thalassemia trait or another diagnosis 1.
Continue iron for at least 3 months after hemoglobin normalization to replenish stores 1, 5.
Step 3: Repeat Hemoglobin Electrophoresis After Iron Repletion
Once ferritin is >50 µg/L and hemoglobin has normalized, repeat hemoglobin electrophoresis to measure HbA₂ accurately 1.
HbA₂ >3.5% confirms β-thalassemia trait; normal HbA₂ after iron correction rules it out 5.
Step 4: Investigate Source of Iron Loss (If Iron Deficiency Confirmed)
In a 15-year-old female, heavy menstrual bleeding is the most common cause of iron deficiency 1.
Assess menstrual history: cycle length, duration, pad/tampon use, and presence of clots 1.
Screen for dietary inadequacy, particularly vegetarian or vegan diets, which increase iron-deficiency risk 6, 1.
Gastrointestinal blood loss is less common in adolescents but must be considered if menstrual losses do not explain the severity 1.
Common Pitfalls to Avoid
Do not assume all microcytic anemia in adolescents is iron deficiency; thalassemia trait is prevalent in Mediterranean, African, Middle Eastern, and Southeast Asian populations 1, 2.
Do not rely on RDW alone to differentiate iron deficiency from thalassemia; nearly half of thalassemia cases show elevated RDW 3, 4.
Do not accept a normal hemoglobin electrophoresis as definitive when iron deficiency is present; iron depletion falsely normalizes HbA₂ 1.
Do not discontinue iron supplementation once hemoglobin normalizes; stores must be fully replenished (ferritin >50 µg/L) to prevent rapid recurrence 1.
Do not overlook combined deficiencies; iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by elevated RDW 1.
Monitoring and Follow-Up
Recheck CBC, ferritin, and TSAT at 2 weeks to assess response to iron therapy 1.
If hemoglobin rises appropriately, continue iron and monitor at 3-month intervals for one year 1.
If no response after 4 weeks despite adherence, consider malabsorption, ongoing blood loss, or rare genetic disorders such as iron-refractory iron deficiency anemia (IRIDA) 1.
Genetic counseling is recommended if β-thalassemia trait is confirmed, particularly for family planning 1.