What is the differential diagnosis and recommended work‑up for a patient with low mean corpuscular volume, high red blood cell count, and either thrombocytosis or thrombocytopenia?

Differential Diagnosis and Work-Up for Low MCV, High RBC, and Platelet Abnormalities

Primary Differential Diagnosis

The combination of low MCV and high RBC count most commonly indicates thalassemia minor (alpha or beta), but polycythemia (primary or secondary) with concurrent iron deficiency must be excluded. 1

Key Distinguishing Features

• Thalassemia minor presents with microcytosis (MCV <70 fL), elevated RBC count, normal or low RDW (<14%), and normal iron studies 1, 2
• Polycythemia with iron deficiency shows microcytosis, elevated RBC count, elevated RDW, and low ferritin; the MCV normalizes after iron replacement while RBC count remains elevated 1
• Essential thrombocythemia (ET) is associated with higher hemoglobin, higher MCV, elevated RDW, and higher mean platelet volume compared to secondary thrombocytosis 2

Immediate Laboratory Work-Up

First-Line Testing (Order Simultaneously)

• Complete blood count with differential including RBC indices (MCV, MCH, MCHC), RDW, and platelet count 3, 2
• Reticulocyte count (corrected for anemia) to distinguish production defects from hemolysis or blood loss 3, 4
• Iron studies: serum ferritin, transferrin saturation, serum iron, and total iron-binding capacity 5, 3
• C-reactive protein (CRP) to assess for inflammation, as ferritin up to 100 μg/L may still indicate iron deficiency in inflammatory states 5, 3
• Peripheral blood smear to evaluate RBC size distribution curves, which reliably distinguish thalassemia from polycythemia with iron deficiency 1, 4

Interpretation of Iron Studies

• Without inflammation: Ferritin <30 μg/L confirms iron deficiency 5
• With inflammation present: Ferritin up to 100 μg/L may still represent iron deficiency 5, 3
• Transferrin saturation <16% suggests absolute iron deficiency 5, 3
• Ferritin >100 μg/L with transferrin saturation <20% indicates anemia of chronic disease 5, 3

Platelet Abnormality Assessment

For Thrombocytosis (Platelets ≥450 × 10⁹/L)

Clinical factors predictive of secondary thrombocytosis include active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency anemia; these should be systematically excluded before pursuing molecular testing. 2

• Secondary thrombocytosis is associated with higher white blood cell count, higher neutrophils, and lower MCV in the setting of iron deficiency 2
• Essential thrombocythemia is associated with higher hemoglobin, higher MCV, elevated RDW, higher MPV, and history of arterial thrombosis 2
• Molecular testing (JAK2, CALR, MPL mutations) should be reserved for patients without identifiable secondary causes 2

For Thrombocytopenia

• Evaluate for bone marrow infiltration, disseminated intravascular coagulation, or medication-induced suppression 3
• Peripheral smear review is essential to assess for dysplastic features or abnormal cell morphology 3

Directed Investigation Based on Initial Results

If Iron Deficiency is Confirmed (Ferritin <30-100 μg/L, Low Transferrin Saturation)

• Stool guaiac testing for occult gastrointestinal bleeding immediately 5, 3
• Upper endoscopy with small bowel biopsy and colonoscopy to exclude gastrointestinal malignancy, angiodysplasia, or celiac disease 5
• After iron replacement: If RBC count remains elevated and MCV normalizes, this confirms underlying polycythemia (primary or secondary) 1

If Iron Studies are Normal with Low MCV and High RBC

• Hemoglobin electrophoresis to diagnose thalassemia minor 1, 6
• RBC size distribution curves on peripheral smear reliably distinguish thalassemia from other causes 1
• Family history of thalassemia or Mediterranean/Asian ancestry supports this diagnosis 6

If Reticulocyte Count is Elevated

• Investigate for hemolysis: indirect and direct bilirubin, haptoglobin, LDH, and direct antiglobulin test (Coombs) 3, 7
• Assess for acute blood loss: clinical history, vital signs, and hemodynamic stability 7

If Reticulocyte Count is Low or Normal

• Renal function tests (serum creatinine, estimated GFR) to evaluate for chronic kidney disease 3, 7
• Inflammatory markers (ESR in addition to CRP) if chronic disease is suspected 3
• Medication review for bone marrow suppressants (NSAIDs, antibiotics, chemotherapy agents) 3

Indications for Bone Marrow Examination

Bone marrow aspiration and biopsy should be performed when unexplained pancytopenia or other cytopenias are present, when peripheral smear shows dysplastic features or blasts, or when anemia progresses despite treatment of identified causes. 3

• Unexplained pancytopenia or abnormalities affecting multiple cell lines 3
• Dysplastic features, blasts, or abnormal morphology on peripheral smear 3
• Progressive anemia despite optimal treatment of underlying condition 3
• Failure to identify a cause after comprehensive noninvasive workup 3
• Clinical suspicion for myelodysplastic syndrome, myeloma, or bone marrow infiltration 3

Critical Pitfalls to Avoid

• Do not assume thalassemia without confirming normal iron studies; iron deficiency can coexist and must be treated first 1, 2
• Do not overlook secondary polycythemia from hypoxia (chronic lung disease, cyanotic heart disease, sleep apnea) or hypernephroma when RBC count is elevated 1
• Do not order molecular testing for thrombocytosis before excluding active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency 2
• Do not interpret ferritin in isolation; levels up to 100 μg/L may still indicate iron deficiency when inflammation is present 5, 3
• Do not miss combined deficiencies; mixed iron and B12/folate deficiency may result in normal MCV with elevated RDW 5, 3