In a patient with an eight‑year history of borderline‑elevated hemoglobin, normal spleen size, normal white‑blood‑cell and platelet counts, no constitutional symptoms, and an inappropriately low serum erythropoietin level, what is the most likely diagnosis and what are the recommended next diagnostic and therapeutic steps?

Polycythemia Vera is the Most Likely Diagnosis

In a patient with borderline-elevated hemoglobin persisting for eight years, normal spleen size, normal white blood cell and platelet counts, no constitutional symptoms, and an inappropriately low serum erythropoietin level, polycythemia vera (PV) is the most likely diagnosis, and the next step is JAK2 mutation testing followed by bone marrow biopsy. 1, 2

Why Low EPO Points to Polycythemia Vera

• Low serum erythropoietin has >90% specificity for polycythemia vera, making it a highly reliable diagnostic marker even when hemoglobin values are only borderline elevated 1, 2
• The finding of inappropriately low EPO in the context of elevated or borderline-high hemoglobin essentially excludes secondary polycythemia, where EPO would be elevated or appropriately normal 1, 3
• Low EPO remains diagnostically useful even in treated PV patients with normal hemoglobin levels from phlebotomy, with 64-72% showing subnormal EPO values 3

Critical Diagnostic Pitfall: Masked Polycythemia Vera

• This patient likely has "masked PV"—a variant where true polycythemia is concealed by coincidental factors such as iron deficiency (causing microcytosis), plasma volume expansion, or occult blood loss 4
• The eight-year history of borderline elevation strongly suggests an indolent myeloproliferative process rather than a transient or reactive phenomenon 2
• Normal platelet and white blood cell counts do NOT exclude PV, as some patients present with isolated erythrocytosis without other cytopenias 4

Recommended Diagnostic Algorithm

Step 1: JAK2 Mutation Testing

• Order JAK2 V617F mutation testing (exon 14) immediately, as this is positive in >95% of PV cases 5, 2
• If JAK2 V617F is negative, proceed to JAK2 exon 12 mutation testing, which captures an additional ~3% of PV cases 5, 2

Step 2: Bone Marrow Biopsy

• Bone marrow examination is essential after confirming low EPO, regardless of JAK2 mutation status 1
• Look for characteristic PV features: hypercellularity for age with trilineage growth (panmyelosis), increased megakaryocytes with clustering and pleomorphic morphology, and decreased iron stores 5, 1, 2
• Bone marrow biopsy is particularly critical before initiating any cytoreductive therapy 6

Step 3: Apply WHO Diagnostic Criteria

• WHO criteria require either:
  • Both major criteria (hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women, AND JAK2 mutation) plus 1 minor criterion, OR
  • First major criterion plus 2 minor criteria 2
• Minor criteria include: bone marrow hypercellularity with panmyelosis, serum EPO below normal range, and endogenous erythroid colony formation 2
• In this patient with borderline hemoglobin, the combination of low EPO (minor criterion) plus characteristic bone marrow findings (minor criterion) plus JAK2 mutation would establish the diagnosis 2

Why This Patient Needs Urgent Hematology Referral

• All patients with suspected or confirmed PV require hematology referral for diagnosis confirmation, risk stratification, and treatment planning 6
• The eight-year duration without diagnosis represents a missed opportunity for thrombosis prevention, as untreated PV carries significant thrombotic risk 6, 4
• Even with normal blood counts, JAK2-positive PV presenting with unusual thrombosis has a poor prognosis, particularly in older patients 4

Common Diagnostic Pitfalls to Avoid

• Do not dismiss borderline hemoglobin elevations when accompanied by low EPO—this combination is highly suspicious for PV 1, 2
• Do not wait for hemoglobin to reach ≥18.5 g/dL (men) or ≥16.5 g/dL (women) before investigating, as sustained increases ≥2 g/dL from baseline warrant full workup 2
• Do not assume normal EPO rules out PV—sensitivity of low EPO for PV is only ~70%, meaning 30% of PV patients have normal EPO 1
• Do not order red cell mass measurement—this is a costly redundancy in modern practice and does not rule out PV 1
• Iron deficiency can mask true polycythemia—assess iron stores on bone marrow biopsy, as decreased stores are characteristic of PV 1, 2

Risk Stratification After Diagnosis

• Once PV is confirmed, classify the patient as low-risk (age <60 years and no prior thrombosis) or high-risk (age ≥60 years or prior thrombosis history) 6
• High-risk patients require cytoreductive therapy (hydroxyurea, interferon-α, or ruxolitinib) in addition to phlebotomy and aspirin 6
• Low-risk patients are typically managed with phlebotomy to maintain hematocrit <45% and low-dose aspirin 5, 6