How should I evaluate and manage a 46‑year‑old woman with mild erythrocytosis (RBC 5.46 ×10⁶/µL, hemoglobin 16.4 g/dL, hematocrit 50 %)?

Evaluation and Management of Mild Erythrocytosis in a 46-Year-Old Woman

This patient requires a systematic diagnostic workup to distinguish primary polycythemia vera from secondary causes, starting with JAK2 mutation testing and serum erythropoietin measurement, but therapeutic phlebotomy is NOT indicated at these mild elevations.

Initial Diagnostic Confirmation

• Repeat hemoglobin and hematocrit measurements to confirm true erythrocytosis, as a single measurement is insufficient for diagnosis; hemoglobin is preferred over hematocrit because it remains stable during sample storage whereas hematocrit can falsely increase by 2-4% with prolonged storage. 1

• This patient's values (RBC 5.46 × 10⁶/µL, Hb 16.4 g/dL, Hct 50.0%) exceed the WHO diagnostic threshold for women (Hb >16.5 g/dL or Hct >48%), though the hemoglobin is just below the major criterion cutoff. 1, 2

• The hematocrit of 50% is definitively elevated for a woman, as the 95th percentile for adult females is approximately 47-48%. 1

Essential Laboratory Workup

Order immediately:

• JAK2 V617F mutation testing (exon 14 and exon 12), which detects mutations in >95% of polycythemia vera cases and serves as the cornerstone molecular diagnostic test. 1, 2

• Serum erythropoietin level to differentiate primary from secondary erythrocytosis; a low or inappropriately normal EPO (below 10-30 mU/mL) indicates autonomous red-cell production and suggests polycythemia vera with >90% specificity. 2, 3

• Complete blood count with differential to assess for concurrent leukocytosis or thrombocytosis, which would strongly suggest an underlying myeloproliferative disorder. 1, 2

• Serum ferritin and transferrin saturation because iron deficiency frequently coexists with erythrocytosis and profoundly influences management decisions; mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis. 1

• Reticulocyte count to evaluate bone marrow response. 1

• Peripheral blood smear review to assess red-cell morphology and identify abnormalities. 1

Systematic Evaluation for Secondary Causes

If JAK2 mutation is negative, evaluate:

• Smoking history and carbon monoxide exposure, as chronic smoking causes "smoker's polycythemia" through tissue hypoxia stimulating erythropoietin production; this resolves with smoking cessation. 1, 2

• Sleep study if nocturnal hypoxemia is suspected, as obstructive sleep apnea produces hypoxemia that drives erythropoietin production. 1

• Pulmonary function tests and chest imaging to exclude chronic obstructive pulmonary disease or other pulmonary causes. 1

• Renal imaging (ultrasound or CT) to screen for renal cell carcinoma, hepatocellular carcinoma, or other erythropoietin-secreting tumors. 1, 3

• Medication review for testosterone or androgen use, which can cause erythrocytosis and should be considered in the differential diagnosis. 1

• Arterial oxygen saturation to rule out occult hypoxemia; saturation <92% indicates secondary polycythemia due to hypoxemia. 1

Management Based on Diagnosis

If Polycythemia Vera is Confirmed (JAK2 positive):

• Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk; the CYTO-PV trial demonstrated that maintaining Hct <45% reduced cardiovascular death or major thrombosis to 2.7% versus 9.8% with Hct 45-50% (HR 3.91, P=0.007). 1

• Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention. 1

• Refer immediately to hematology for bone marrow biopsy to confirm diagnosis and assess for trilineage myeloproliferation, which is required to fulfill WHO diagnostic criteria. 1, 2

If Secondary Erythrocytosis is Identified:

• Treat the underlying condition (smoking cessation, CPAP for sleep apnea, management of COPD) rather than performing phlebotomy. 1

• Therapeutic phlebotomy is contraindicated in secondary erythrocytosis except in rare circumstances when hemoglobin >20 g/dL AND hematocrit >65% with documented hyperviscosity symptoms after excluding dehydration. 1, 3

Current Management for This Patient:

• Do NOT perform phlebotomy at these levels (Hb 16.4 g/dL, Hct 50.0%), as therapeutic phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with hyperviscosity symptoms. 1

• Serial monitoring with hemoglobin checks every 4-8 weeks initially is appropriate while awaiting diagnostic workup results. 3

Critical Pitfalls to Avoid

• Never perform routine or repeated phlebotomies without a confirmed diagnosis, as this causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1

• Do not overlook coexisting iron deficiency, which can mimic hyperviscosity symptoms but requires iron supplementation rather than phlebotomy; if transferrin saturation <20%, cautious oral iron supplementation with close hemoglobin monitoring is necessary. 1

• Never perform phlebotomy without equal-volume fluid replacement if it becomes indicated, as this increases hemoconcentration and stroke risk. 1

• Do not dismiss this as benign variation simply because values are only mildly elevated; a documented rise above individual baseline warrants full investigation regardless of absolute values. 2

Strength of Evidence

The recommendations prioritize high-quality guideline evidence from the WHO diagnostic criteria for polycythemia vera, the CYTO-PV randomized trial demonstrating hematocrit targets, and consensus guidelines from the American Heart Association, American College of Cardiology, and National Comprehensive Cancer Network regarding phlebotomy thresholds and management algorithms. 1, 2, 3