What is the management approach for a patient with erythrocytosis, normal Erythropoietin (EPO) levels, and a negative Janus Kinase 2 (JAK2) test?

Management of Erythrocytosis with Normal EPO and Negative JAK2

In a patient with erythrocytosis, normal EPO (12.6 mU/mL), and negative JAK2, you should pursue further diagnostic evaluation for secondary causes and hereditary erythrocytosis before considering any cytoreductive therapy, as phlebotomy is only indicated when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with hyperviscosity symptoms. 1, 2

Diagnostic Approach

Your patient's presentation—erythrocytosis with normal EPO and negative JAK2—effectively rules out polycythemia vera and requires systematic evaluation for other etiologies 3, 4:

Distinguish Longstanding vs. Acquired Erythrocytosis

• Review historical hemoglobin/hematocrit records to determine if this is longstanding (suggesting hereditary causes) or recently acquired (suggesting secondary causes) 3
• Longstanding erythrocytosis with positive family history strongly suggests hereditary erythrocytosis 3

Evaluate for Secondary Causes

With normal EPO levels, investigate the following 5, 3, 4:

• Cardiovascular and pulmonary disorders: Check oxygen saturation, perform chest X-ray, and assess for chronic hypoxia from cardiopulmonary disease 5, 6
• Renal pathology: Obtain renal ultrasound to exclude renal artery stenosis, renal cysts, or EPO-secreting renal tumors 3, 7
• Smoking history: Nicotine abuse is a common cause of secondary erythrocytosis 1, 6
• Medication review: Check for testosterone, erythropoiesis-stimulating agents, or SGLT-2 inhibitors 3
• High-altitude habitat as a contributing factor 3

Consider Hereditary Erythrocytosis

If secondary causes are excluded and erythrocytosis is longstanding 3, 4:

• EPO receptor mutation screening (though less likely given normal rather than subnormal EPO)
• Germline mutation testing for oxygen-sensing pathway genes (HIF2A, PHD2, VHL)
• High-oxygen affinity hemoglobin variants and other rare mutations (PIEZO1, 2,3-BPG deficiency)
• P50 measurement to assess oxygen tension at 50% hemoglobin saturation

Additional Laboratory Assessment

• Iron status evaluation: Check serum ferritin and transferrin saturation, as iron deficiency can paradoxically worsen symptoms 1, 2
• Peripheral blood smear to assess red cell morphology 2

Management Recommendations

When Phlebotomy is NOT Indicated

Avoid routine phlebotomy in your patient unless specific criteria are met 1, 2, 3:

• Phlebotomy is only appropriate when hemoglobin exceeds 20 g/dL AND hematocrit exceeds 65% with documented hyperviscosity symptoms (headache, fatigue, poor concentration) 1, 2
• Repeated phlebotomies risk iron depletion, which decreases oxygen-carrying capacity, reduces red cell deformability, and paradoxically increases stroke risk 1, 2
• Cytoreductive therapy should be avoided in non-clonal erythrocytosis 3

Conservative Management Approach

For most patients with JAK2-negative erythrocytosis 1, 3:

• Ensure adequate hydration, as dehydration can exacerbate relative erythrocytosis 1
• Cardiovascular risk optimization including blood pressure control and lipid management 3
• Consider low-dose aspirin if no contraindications exist, particularly if there are concerns for microvascular symptoms 1
• Symptom-directed phlebotomy may be reasonable if it demonstrates value in symptom control, with frequency determined by symptoms rather than arbitrary hematocrit targets 3

Monitoring Strategy

• Regular complete blood counts to track hemoglobin and hematocrit trends 1
• Periodic iron status assessment to avoid iatrogenic iron deficiency from excessive phlebotomy 1, 2
• Monitor for hyperviscosity symptoms including headache, visual disturbances, or thrombotic complications 1

Critical Pitfalls to Avoid

• Do not perform routine phlebotomies without meeting the established criteria (Hgb >20 g/dL, Hct >65% with symptoms) 1, 2
• Avoid creating iron deficiency through excessive phlebotomy, which worsens oxygen delivery and increases stroke risk 1, 2
• Do not label as "idiopathic erythrocytosis" until completing thorough evaluation for secondary and hereditary causes 3
• Do not use cytoreductive agents (hydroxyurea, interferon) in non-clonal erythrocytosis 3

Special Considerations

If phlebotomy becomes necessary and criteria are met 2:

• Remove one unit (400-500 mL) per session
• Replace with equal volume of isotonic saline (750-1000 mL)
• Perform weekly or fortnightly until target levels reached
• Monitor iron status closely to avoid depletion