In an adult male with a hemoglobin of 16 g/dL and a low serum erythropoietin level, can the low erythropoietin alone be used to diagnose polycythemia vera?

Can Low Erythropoietin Alone Diagnose Polycythemia Vera in a Male with Hemoglobin 16 g/dL?

No, a low serum erythropoietin level alone cannot diagnose polycythemia vera—it is only a minor criterion in the WHO diagnostic algorithm and must be combined with major criteria (elevated hemoglobin/hematocrit AND/OR JAK2 mutation) plus additional supporting findings. 1, 2

Why EPO Alone Is Insufficient

The WHO diagnostic framework explicitly requires either all 3 major criteria (elevated Hb/Hct, bone marrow findings, JAK2 mutation) or the first major criterion (elevated Hb/Hct) plus at least 2 minor criteria to diagnose polycythemia vera. 1, 2 Low serum erythropoietin is classified as a minor criterion, not a major one, meaning it cannot stand alone for diagnosis. 1

Physiologic Variability of EPO Undermines Its Standalone Value

• 32% of confirmed polycythemia vera patients have EPO levels within the normal range, making a low EPO neither sensitive nor specific enough for solo diagnosis. 3
• EPO levels positively correlate with obesity and smoking status, rendering them unreliable in these common patient populations. 3
• In multivariate analysis, when JAK2V617F mutation status is included, low EPO loses statistical significance as an independent predictor (OR 0.962, p=0.269), whereas JAK2V617F alone demonstrates overwhelming predictive value (OR 670.5, p=0.006). 3

Conditions That Cause Low EPO Without Polycythemia Vera

You correctly identify several scenarios where EPO may be low despite the absence of polycythemia vera:

• Naturally higher red cell set-point in certain individuals (e.g., tall men) can suppress EPO through normal feedback mechanisms without clonal disease. 4
• Long-term stable erythrocytosis from secondary causes (chronic hypoxia, high altitude, sleep apnea) may eventually down-regulate EPO production. 4
• Genetic/idiopathic causes such as high-oxygen-affinity hemoglobin variants or congenital erythropoietin receptor mutations can produce erythrocytosis with low-normal EPO but no JAK2 mutation. 5

The Correct Diagnostic Algorithm

Step 1: Assess Hemoglobin Against WHO Major Criterion Thresholds

• In this case, hemoglobin 16 g/dL in an adult male does NOT meet the standard WHO major criterion (≥18.5 g/dL in men). 1, 6
• However, if there has been a sustained rise of ≥2 g/dL from baseline, the alternative threshold of ≥17 g/dL applies, which this patient also does not meet. 4, 6
• This patient does not fulfill the first major criterion, so polycythemia vera cannot be diagnosed on hemoglobin elevation alone. 1, 2

Step 2: Order JAK2 Mutation Testing

• JAK2 V617F (exon 14) testing is the first-line molecular assay, capturing >90–95% of polycythemia vera cases. 1, 4, 2
• If JAK2 V617F is negative, JAK2 exon 12 mutation testing should follow, as it accounts for an additional 2–3% of cases. 1, 2
• A positive JAK2 mutation constitutes the second major criterion and, when combined with elevated Hb/Hct plus at least one minor criterion, confirms polycythemia vera in >97% of cases. 1, 2

Step 3: Integrate Minor Criteria Only After Major Criteria Are Addressed

• Low serum EPO (below the reference range) serves as a minor criterion to support the diagnosis when major criteria are present. 1, 2
• Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) and pleomorphic megakaryocytes is another minor criterion. 1, 2
• Endogenous erythroid colony formation in vitro is the third minor criterion. 1

Step 4: Rule Out Secondary Causes When JAK2 Is Negative

If JAK2 testing is negative and hemoglobin does not meet major criterion thresholds, systematic evaluation for secondary erythrocytosis is mandatory: 4

• Sleep study for obstructive sleep apnea (common cause of secondary polycythemia). 4
• Pulmonary function testing for COPD or chronic hypoxemia. 4
• Smoking history (smoking is a frequent cause of elevated hematocrit). 4
• Renal imaging for erythropoietin-producing tumors (renal cell carcinoma). 4
• Medication review for testosterone therapy. 4
• Altitude-adjusted hemoglobin norms (at 4000 m, average male Hb ≈17.3 g/dL is physiologic). 4

Critical Pitfalls to Avoid

• Do not diagnose polycythemia vera based on low EPO alone, even if hemoglobin is mildly elevated—this violates WHO criteria and misses secondary causes. 1, 2
• Iron deficiency can mask polycythemia vera by lowering hemoglobin; formal diagnosis requires demonstrating WHO criteria after iron replacement. 6, 2
• Rare cases of polycythemia vera present with normal hemoglobin (masked PV) due to blood dilution or coincidental blood loss, yet still harbor JAK2 mutations and thrombotic risk—these require bone marrow biopsy and low EPO for diagnosis. 7
• Polycythemia vera can occasionally present with elevated EPO (reported case with high EPO and positive JAK2), so a normal or high EPO does not exclude the diagnosis if other criteria are met. 8

Summary of Diagnostic Pathways

Scenario	Diagnostic Pathway	Citation
Hb ≥18.5 g/dL (men) or ≥16.5 g/dL (women) + JAK2+	Confirm with ≥1 minor criterion (low EPO, BM biopsy, or EEC)	[1,2]
Hb ≥18.5 g/dL (men) or ≥16.5 g/dL (women) + JAK2−	Require ≥2 minor criteria (low EPO + BM biopsy, or low EPO + EEC)	[1,2]
Hb <18.5 g/dL (men) or <16.5 g/dL (women) + low EPO	Insufficient for diagnosis; order JAK2 testing and evaluate for secondary causes	[1,4,2]

In your specific case (male, Hb 16 g/dL, low EPO), the low EPO is suggestive but not diagnostic—JAK2 mutation testing is the next mandatory step, and secondary causes must be systematically excluded if JAK2 is negative. 1, 4, 2