In an adult male with a normal hemoglobin (≈15.8–17 g/dL) and a low serum erythropoietin (EPO), what does this indicate and what steps should be taken for evaluation and management?

Normal Hemoglobin with Low Erythropoietin: Evaluation and Management

In an adult male with normal hemoglobin (15.8–17 g/dL) and low serum erythropoietin, the primary concern is polycythemia vera (PV), though this presentation falls below diagnostic thresholds and requires careful evaluation to exclude early or masked myeloproliferative disease.

Understanding the Clinical Significance

Low EPO with normal hemoglobin is paradoxical and warrants investigation. Normal endogenous erythropoietin levels range between 10-30 mU/mL 1, 2. When hemoglobin is normal, EPO should also be normal or slightly elevated if there were any physiologic stress on erythropoiesis. A suppressed EPO in this context suggests:

• Autonomous red cell production independent of normal EPO regulation, characteristic of PV 1
• The hemoglobin may represent the upper limit of this patient's normal range, potentially masking underlying polycythemia 3
• Iron deficiency may be concealing a higher hemoglobin that would otherwise meet PV diagnostic criteria 3

Diagnostic Thresholds and When to Suspect PV

The WHO diagnostic criteria for PV require hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women 3. Your patient's hemoglobin of 15.8–17 g/dL does not meet these thresholds 3.

However, PV should still be considered if 1:

• There is a documented sustained increase ≥2 g/dL from the patient's previous baseline hemoglobin 3
• PV-related features are present: thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis (including Budd-Chiari syndrome), or erythromelalgia 1
• The hemoglobin is at the upper end of normal with borderline elevation 1

A low serum EPO level has >90% specificity for PV but only <70% sensitivity 1, meaning PV can exist with normal EPO, but low EPO strongly suggests a myeloproliferative process even when hemoglobin appears normal.

Recommended Evaluation Algorithm

Step 1: Verify and Contextualize the Hemoglobin

• Repeat complete blood count to confirm hemoglobin stability 2
• Review prior hemoglobin values to identify any sustained increase ≥2 g/dL from baseline 3
• Assess for hemoconcentration: smoking increases hemoglobin by 0.3-1.0 g/dL; altitude adjusts values by 0.9 g/dL per 1,000 meters elevation 3

Step 2: Complete Iron Studies

Iron deficiency can mask polycythemia vera by preventing hemoglobin from rising to diagnostic levels 3. Order:

• Serum ferritin (should be >100 μg/dL) 1
• Transferrin saturation (should be >20%) 1
• Serum iron and total iron-binding capacity 1, 2

If iron deficiency is present, this may explain why hemoglobin hasn't reached PV diagnostic thresholds despite autonomous erythropoiesis 3. Iron replacement could unmask polycythemia 3.

Step 3: Assess for PV-Related Features

Examine for 1:

• Thrombocytosis (platelet count >450,000/μL)
• Leukocytosis (WBC >12,000/μL without infection)
• Splenomegaly on physical examination or imaging
• Microcytosis (MCV <80 fL) suggesting iron deficiency from increased utilization
• History of unusual thrombosis, aquagenic pruritus, or erythromelalgia

Step 4: Molecular Testing

If any PV-related features are present or if there's a sustained hemoglobin increase from baseline 3:

• JAK2 V617F mutation testing (positive in ~95% of PV cases) 3
• JAK2 exon 12 mutation if JAK2 V617F is negative 3

Step 5: Bone Marrow Biopsy

If molecular testing is positive, proceed to bone marrow biopsy showing 1, 3:

• Hypercellularity with trilineage growth (panmyelosis)
• Increased megakaryocytes with clustering and pleomorphism
• Decreased iron stores
• Mild reticulin fibrosis (in 12% of cases)

Management Considerations

If PV is Diagnosed (Even with "Normal" Hemoglobin)

Masked polycythemia vera (JAK2-positive with hemoglobin below WHO thresholds) still carries thrombotic risk 3:

• Aspirin 81 mg daily for thrombosis prevention, particularly if JAK2-positive 3
• Monitor hemoglobin every 3 months initially 2
• Phlebotomy if hemoglobin rises above 16.5 g/dL in men 1
• Correct iron deficiency cautiously, as this may unmask higher hemoglobin levels requiring phlebotomy 3

If PV is Excluded

• Repeat serum EPO measurement to confirm persistent suppression 2
• Check vitamin B12 and folate levels to exclude nutritional causes of dysregulated erythropoiesis 2
• Evaluate for secondary causes of EPO suppression: chronic kidney disease, testosterone use, or other exogenous androgens
• Monitor hemoglobin and EPO every 4-8 weeks for 3-6 months 2

Critical Pitfalls to Avoid

Do not dismiss low EPO simply because hemoglobin is "normal" 1. This combination is physiologically inappropriate and demands explanation.

Do not order red cell mass measurement unless hemoglobin is borderline and clinical features strongly suggest PV, as it adds cost without changing management in most cases 1.

Do not assume iron deficiency excludes PV—it may actually be masking it 3. Iron replacement in unrecognized PV can precipitate dangerous hyperviscosity.

Do not wait for hemoglobin to reach 18.5 g/dL before investigating if there are PV-related features or documented hemoglobin increase from baseline 1, 3.

Erythropoietin resistance (baseline EPO >500 IU/L) indicates exogenous EPO therapy would be ineffective if anemia develops 1, though this is not the current scenario.