What is the most likely diagnosis and recommended evaluation and management for a patient with elevated hemoglobin and low erythropoietin level?

Elevated Hemoglobin with Low Erythropoietin: Polycythemia Vera Until Proven Otherwise

A patient presenting with elevated hemoglobin and low erythropoietin most likely has polycythemia vera (PV), and you must immediately test for JAK2 mutations (V617F and exon 12) to confirm the diagnosis. 1, 2

Most Likely Diagnosis

The combination of elevated hemoglobin with suppressed erythropoietin indicates autonomous red cell production independent of normal hypoxic signaling, which is the hallmark of polycythemia vera. 2 Low erythropoietin (below the normal adult range of 10-30 mU/mL) effectively excludes secondary polycythemia, where erythropoietin would be elevated or inappropriately normal. 1, 2

Diagnostic Workup

Immediate Testing Required

• JAK2 V617F mutation testing is mandatory—present in approximately 95% of PV cases. 1, 3, 4
• JAK2 exon 12 mutations must be tested if JAK2 V617F is negative, as these account for most remaining PV cases. 1, 2
• Complete blood count with differential to assess for leukocytosis (>12 × 10⁹/L) and thrombocytosis (>400 × 10⁹/L), which support the diagnosis but are not required. 1
• Bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation is a minor criterion when JAK2 is positive. 1

Exclusion of Secondary Causes

Even with low erythropoietin, you must systematically exclude secondary causes: 2

• Arterial blood gas and oxygen saturation to rule out occult hypoxemia
• Carboxyhemoglobin level if carbon monoxide exposure is possible
• Renal and abdominal imaging (ultrasound or CT) to screen for renal cell carcinoma, hepatic tumors, or renal artery stenosis producing ectopic erythropoietin
• Brain MRI if cerebellar hemangioblastoma is suspected clinically
• Echocardiography to evaluate for right-to-left shunts
• Sleep study if obstructive sleep apnea is a clinical concern

Diagnostic Criteria for Polycythemia Vera

Diagnosis requires BOTH major criteria plus at least one minor criterion: 1

Major Criteria

1. Hemoglobin >18.5 g/dL in men or >16.5 g/dL in women (or hematocrit >60% reliably indicates absolute erythrocytosis) 1, 5
2. Presence of JAK2 V617F or functionally similar JAK2 mutation (exon 12) 1

Minor Criteria

1. Bone marrow biopsy showing panmyelosis with erythroid and megakaryocytic proliferation 1
2. Serum erythropoietin level below the reference range for normal 1
3. Presence of endogenous erythroid colony formation 1

Critical pitfall: A hemoglobin of 18.5 g/dL predicts absolute erythrocytosis in only 35% of male PV patients, so do not rely on hemoglobin alone—always measure erythropoietin and test for JAK2. 5

Management Strategy

High-Risk vs Low-Risk Stratification

High-risk patients (age >60 years OR prior thrombosis history) require cytoreductive therapy. 3, 4, 6

Low-risk patients (age ≤60 years AND no thrombosis history) can be managed with phlebotomy and aspirin alone. 3, 4, 6

All Patients with PV Require

• Phlebotomy to maintain hematocrit <45% (hemoglobin target <16 g/dL in men, <15 g/dL in women). 2, 3, 4, 6
• Low-dose aspirin 81 mg once daily for thrombosis prophylaxis, unless contraindicated. 3, 4, 6
• Monitor iron studies regularly during chronic phlebotomy, as iron depletion paradoxically increases stroke risk. 2

High-Risk Patients Additionally Require

• Hydroxyurea as first-line cytoreductive therapy. 3, 4, 6
• Interferon-α or busulfan as second-line options for hydroxyurea failures. 3, 4, 6

What NOT to Do

Never administer exogenous erythropoietin therapy—endogenous production is already autonomous, and EPO increases thromboembolic risk by 67% (relative risk 1.67,95% CI 1.35-2.06). 2, 7

Monitoring Protocol

• Hemoglobin checks every 4-8 weeks initially, extending intervals once stability is achieved. 8, 2
• Complete blood count periodically to detect emergence of leukocytosis or thrombocytosis indicating disease progression. 2
• Assess for hyperviscosity symptoms (headache, visual changes, dizziness, aquagenic pruritus) at each visit. 2
• Screen for acquired von Willebrand syndrome if platelet count exceeds 1,000 × 10⁹/L before administering aspirin. 3, 4, 6

Prognosis and Transformation Risk

Median survival in PV is approximately 14 years overall, with 24 years for patients under age 60. 4, 6 The 10-year risk of leukemic transformation is <3% and fibrotic transformation is approximately 10%. 3 Thrombotic complications remain the primary cause of morbidity and mortality, with risk exceeding 20%. 3