In a man with a baseline hemoglobin of 15.8–16 g/dL and a current level of ~16.2 g/dL, how reliable is a low serum erythropoietin level for diagnosing polycythemia vera?

Reliability of Low EPO in Borderline-High Hemoglobin

A low serum erythropoietin level remains highly reliable for diagnosing polycythemia vera even when hemoglobin is only minimally elevated above baseline (15.8→16.2 g/dL), because subnormal EPO has >90% specificity for PV and reflects autonomous JAK2-driven erythropoiesis that suppresses normal EPO feedback regardless of absolute hemoglobin value. 1, 2

Why Low EPO Is Diagnostically Valid in Your Scenario

The Pathophysiology Explains the Paradox

• In polycythemia vera, JAK2 mutations (present in >95% of cases) render erythroid progenitors hypersensitive to EPO, allowing autonomous red cell production with minimal EPO stimulation 1, 3
• This autonomous clonal erythropoiesis suppresses normal EPO feedback mechanisms, keeping EPO inappropriately low even when hemoglobin rises only modestly from baseline 2, 3
• Subnormal EPO reflects the underlying disease mechanism—not the absolute hemoglobin level—which is why it remains diagnostically valid at Hb 16.2 g/dL 1, 2

Diagnostic Performance of Low EPO

• EPO below the reference range (typically <3.3–5.3 IU/L depending on assay) has 92–100% specificity and 97.8% positive predictive value for PV 4
• Sensitivity is 64–94%, meaning low EPO correctly identifies most but not all PV cases 2, 4, 5
• In one large multicenter study, 87% of PV patients had EPO below normal range, and using a threshold of <1.4 IU/L allowed specific diagnosis of 65.6% of untreated PV cases 4

Critical Context: Sustained Increase From Baseline Matters More Than Absolute Value

• The American Society of Hematology recommends investigating any sustained hemoglobin increase ≥2 g/dL from baseline, even if values remain within normal reference ranges 1
• Your scenario (baseline 15.8–16.0 → current 16.2 g/dL) represents a modest but potentially sustained rise that warrants full evaluation 1
• PV can present with hemoglobin values well below the WHO major criterion threshold (18.5 g/dL in men), especially when masked by iron deficiency or early disease 1, 6

The Diagnostic Algorithm When Low EPO Meets Borderline-High Hemoglobin

Step 1: Confirm the EPO Result and Hemoglobin Stability

• Repeat complete blood count with differential and red-cell indices to confirm sustained elevation and evaluate mean corpuscular volume; a low MCV suggests iron deficiency that can mask true PV 3
• Measure serum ferritin, iron, and transferrin saturation because iron deficiency can suppress hemoglobin and create fluctuating values that obscure PV diagnosis 3

Step 2: Perform JAK2 Mutation Testing (Mandatory)

• JAK2 V617F mutation testing should be performed first because the mutation is present in >95% of PV cases, providing definitive differentiation between primary and secondary erythrocytosis 1, 3
• If JAK2 V617F is negative, proceed to JAK2 exon 12 mutation testing, which captures the remaining ~3% of PV cases 1, 3
• Combined JAK2 testing (V617F + exon 12) achieves 97–99% sensitivity for PV 3

Step 3: Evaluate for PV-Related Features That Lower the Diagnostic Threshold

• Check for thrombocytosis, leukocytosis, splenomegaly, aquagenic pruritus, unusual thrombosis (e.g., portal vein thrombosis), or erythromelalgia—any of these accompanying borderline-high hematocrit triggers immediate workup for PV 1, 3
• Microcytosis (low MCV) is a strong surrogate for iron deficiency in PV and signals that hemoglobin may be artificially suppressed below its true pathologic level 3

Step 4: Exclude Secondary Causes (Even With Low EPO)

• Obtain detailed smoking history and consider carboxyhemoglobin measurement, as smoker's polycythemia is the most common secondary cause and resolves with cessation 2, 3
• Order sleep study for obstructive sleep apnea because nocturnal hypoxemia can drive compensatory erythrocytosis 3
• Perform arterial oxygen saturation and chest imaging to rule out chronic lung disease or right-to-left cardiopulmonary shunts 3
• Abdominal ultrasound or CT to screen for EPO-producing tumors (renal cell carcinoma, hepatocellular carcinoma, uterine leiomyoma, pheochromocytoma, parathyroid carcinoma) 2, 3
• Review medications for exogenous testosterone, anabolic steroids, or administered erythropoietin 3

Common Pitfalls and How to Avoid Them

Pitfall 1: Assuming Normal EPO Excludes PV

• Normal EPO levels do not exclude PV; EPO sensitivity for PV is only 64–70% 2, 3
• Normal EPO with elevated hemoglobin still requires JAK2 testing 2

Pitfall 2: Dismissing the Diagnosis Because Hemoglobin Is "Only Slightly High"

• Iron deficiency can mask PV by suppressing hemoglobin to within or near the normal range 3, 6
• PV can present with normal hemoglobin and hematocrit (masked PV), especially when accompanied by thrombosis, splenomegaly, or JAK2 mutation 6
• One case series documented JAK2-positive PV presenting with Hb 14.1 g/dL and normal platelet count, emphasizing that normal blood counts do not exclude the diagnosis 6

Pitfall 3: Misinterpreting EPO in Chronic Hypoxic States

• In hypoxia-driven secondary polycythemia, EPO may initially be elevated but can normalize once hemoglobin stabilizes at a compensatory higher level, potentially mimicking PV 2, 3
• However, in your scenario with low EPO, this pattern argues against secondary polycythemia 2

Pitfall 4: Overlooking the Rare Case of PV With Elevated EPO

• Although rare, PV can present with elevated EPO (documented in case reports), so JAK2 mutation testing and bone marrow biopsy remain the gold standard when clinical suspicion is high 7
• One case report described JAK2-positive PV with elevated EPO, confirming that EPO alone cannot definitively exclude PV 7

What the Evidence Shows About EPO Reliability

High Specificity, Moderate Sensitivity

• Low EPO (<3.3 IU/L) has 97% specificity and 97.8% positive predictive value for PV 4
• Using a threshold of <1.4 IU/L increases specificity to allow direct diagnosis of 65.6% of untreated PV cases 4
• A 2024 study proposed using 5.3 IU/L as the "subnormal" limit, which identified all three JAK2-negative PV cases and increased sensitivity to 97.6% 8

EPO Remains Low Even After Treatment

• In treated PV patients maintained at normal hematocrit for 6–7 years, EPO levels remained subnormal, demonstrating that low EPO reflects the underlying clonal disorder rather than the hemoglobin level 5
• After phlebotomy treatment to normal hematocrit, EPO remained subnormal in most PV patients even after 18 months 5

Bottom Line: Low EPO Is Reliable—Proceed With JAK2 Testing

Your clinical scenario (baseline Hb 15.8–16.0 → current 16.2 g/dL with low EPO) has high pretest probability for polycythemia vera and mandates JAK2 mutation testing regardless of the modest hemoglobin elevation. 1, 2, 3 Low EPO is not a false signal—it reflects autonomous erythropoiesis that defines PV, and its >90% specificity makes it one of the most reliable screening tests available. 1, 2, 4