What is the next step in a 24-year-old female with elevated Red Blood Cell (RBC) count and low Mean Corpuscular Volume (MCV)?

Diagnostic Workup for Elevated RBC Count with Low MCV

The next step is to order a peripheral blood smear, red blood cell distribution width (RDW), serum ferritin, complete iron studies (serum iron, TIBC, transferrin saturation), and reticulocyte index to differentiate between thalassemia trait, polycythemia vera with iron deficiency, and secondary polycythemia with iron deficiency. 1

Initial Laboratory Evaluation

The combination of elevated RBC count with low MCV creates a specific differential diagnosis that requires targeted testing:

• RDW measurement is critical as the first discriminating test: RDW >14% suggests iron deficiency anemia, while RDW ≤14% points toward thalassemia minor 1, 2
• Serum ferritin <30 ng/mL confirms absolute iron deficiency in the absence of inflammation 1
• Transferrin saturation <15% with low ferritin confirms iron-deficient erythropoiesis 1
• Reticulocyte index assesses bone marrow response, with low values (<1.0-2.0) indicating decreased RBC production 1

Peripheral Blood Smear Analysis

Visual examination of RBC morphology provides essential diagnostic clues:

• Target cells suggest thalassemia trait 1
• Basophilic stippling may indicate lead poisoning 1
• RBC size distribution curves can reliably distinguish thalassemia minor from polycythemia with iron deficiency 3

Differential Diagnosis Framework

In a 24-year-old female with elevated RBC count and low MCV, the primary considerations are:

Thalassemia Minor (Most Common)

• Accounts for approximately 74% of cases with this presentation in one study 3
• Characterized by normal or minimally elevated RDW, normal iron studies, and elevated RBC count 1, 3
• Hemoglobin electrophoresis should be ordered if iron deficiency is excluded 1

Polycythemia Vera with Iron Deficiency

• Represents approximately 11% of microcytic polycythemia cases 3
• Distinguished by low serum erythropoietin level (specificity >90% for polycythemia vera) 4
• Bone marrow examination may be needed if serum EPO is low or normal 4

Secondary Polycythemia with Iron Deficiency

• Accounts for approximately 14% of cases 3
• Causes include hypoxia from lung disease, cardiac disease, or high altitude, or rarely renal tumors 3
• When iron is replaced, RBC count remains elevated but MCV normalizes 3

Common Pitfall to Avoid

Iron deficiency is present in 64% of healthy individuals with low MCV and acceptable hemoglobin levels, and may coexist with hemoglobinopathy in 15% of cases 5. This means:

• Do not assume thalassemia trait without checking iron studies first
• Multiple causes can coexist, particularly iron deficiency masking underlying hemoglobinopathy 1, 5
• Iron studies must be interpreted before proceeding to hemoglobin electrophoresis 5

Additional Testing Based on Initial Results

If initial workup suggests polycythemia vera:

• Serum erythropoietin level should be measured next 4
• Low or normal EPO warrants bone marrow examination with cytogenetic studies 4
• Evaluate for secondary causes: oxygen saturation, chest imaging, renal ultrasound if indicated 3

If iron deficiency is confirmed:

• Trial of iron replacement can be diagnostic: if RBC count normalizes with MCV correction, secondary polycythemia with iron deficiency is excluded 3
• If RBC count remains elevated after iron repletion, proceed with polycythemia vera workup 3