With normal erythropoietin, hemoglobin 19.5 g/dL on two draws, hematocrit 55%, a negative peripheral blood smear, and a pending obstructive sleep apnea work‑up, what is the appropriate next step in management?

Management of Erythrocytosis with Normal Erythropoietin

With hemoglobin 19.5 g/dL, hematocrit 55%, and normal erythropoietin levels, you must immediately test for JAK2 V617F and JAK2 exon 12 mutations to rule out polycythemia vera, and initiate phlebotomy to reduce hemoglobin below 16 g/dL (hematocrit <45%) to prevent thrombotic complications. 1, 2

Immediate Diagnostic Work-up

The combination of elevated hemoglobin with normal (not elevated) erythropoietin is highly concerning for autonomous red cell production characteristic of polycythemia vera, even when white blood cell and platelet counts remain normal. 1

Essential Testing

• JAK2 mutation testing (V617F and exon 12) is mandatory to diagnose or exclude polycythemia vera, as this can present with isolated erythrocytosis before other cell lines become involved. 1, 2

• Complete iron studies, vitamin B12, and folate levels to exclude nutritional deficiencies that could mask the true severity of erythrocytosis. 1

• Renal and abdominal imaging (ultrasound or CT) to screen for renal cell carcinoma, hepatic tumors, or renal artery stenosis producing ectopic erythropoietin. 1

• Arterial blood gas with carboxyhemoglobin if carbon monoxide exposure is possible, to rule out occult hypoxemia. 1

Regarding the Pending OSA Work-up

Do not assume OSA explains this degree of erythrocytosis. While you await sleep study results, understand that:

• OSA causes secondary polycythemia in only 2% of mild-to-moderate cases and 6% of severe cases—the vast majority of OSA patients do not develop elevated hemoglobin. 3

• Even when OSA is present, it does not exclude polycythemia vera; the two conditions can coexist, and assuming secondary polycythemia based on OSA history can lead to missed PV diagnoses. 4

• In OSA, erythropoietin levels are typically elevated (not normal) due to intermittent hypoxia, with levels decreasing after CPAP treatment. 5

• Your patient's normal erythropoietin with this degree of erythrocytosis argues strongly against OSA as the primary cause. 1

Immediate Therapeutic Intervention

Phlebotomy

Initiate phlebotomy now given hemoglobin >18.5 g/dL to reduce thrombotic risk:

• Remove 250-500 mL initially to rapidly reduce hemoglobin levels. 2

• Target hemoglobin <16 g/dL (hematocrit <45%) in men, <15 g/dL in women. 6, 2

• Each 400 mL unit removed decreases hemoglobin by approximately 1.5 g/dL. 6, 2

• Therapeutic phlebotomy is indicated for hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms (headache, fatigue), but your patient already exceeds safe thresholds for thrombotic risk at 19.5 g/dL. 6

Critical Medication Contraindication

Never administer erythropoietin-stimulating agents (ESAs) in this setting:

• ESAs are contraindicated because endogenous production is already autonomous. 1

• Exogenous erythropoietin increases thromboembolic risk by 67% (RR 1.67,95% CI 1.35-2.06). 1

• If the patient were on ESAs for any reason, discontinue immediately. 2

Monitoring Strategy

• Recheck complete blood count every 4-8 weeks initially to monitor for emergence of leukocytosis or thrombocytosis indicating myeloproliferative disease progression. 1

• Monitor for development of hyperviscosity symptoms (headache, visual changes, dizziness, pruritus after bathing). 6

Additional Considerations Based on Final Diagnosis

If Polycythemia Vera is Confirmed

• Initiate low-dose aspirin 81-100 mg daily for thrombosis prophylaxis unless contraindicated. 1, 2

• Continue phlebotomy as primary treatment modality. 2

If OSA is Confirmed and Treated

• CPAP treatment reduces hemoglobin by only 3.76 g/L (0.376 g/dL) on average—insufficient to explain or treat your patient's current elevation. 3

• Even with CPAP, hematocrit decreases by only 1.1% on average. 3

• Erythropoietin levels decrease with CPAP (from ~61 mU/mL to ~32 mU/mL), but your patient already has normal EPO, making OSA an unlikely primary cause. 5

Key Pitfalls to Avoid

• Do not dismiss isolated erythrocytosis as benign variation; low or normal erythropoietin with this degree of elevation mandates thorough evaluation for occult malignancy and myeloproliferative neoplasms. 1

• Do not delay phlebotomy while awaiting JAK2 results; the thrombotic risk at hemoglobin 19.5 g/dL is immediate. 2

• Do not attribute this to OSA without confirming elevated erythropoietin levels, as normal EPO argues against hypoxia-driven erythrocytosis. 1, 4

• Avoid repeated routine phlebotomies without iron monitoring, as iron depletion decreases oxygen-carrying capacity and paradoxically increases stroke risk. 6