How to manage a patient with polycythemia and normal ferritin levels?

Evaluation and Management of Polycythemia with Normal Ferritin in a Non-Smoker

This patient requires immediate evaluation for polycythemia vera (PV), as the elevated hemoglobin (155 g/L), RBC count (5.55 × 10¹²/L), and hematocrit (0.49) meet diagnostic criteria for erythrocytosis, and normal ferritin does not exclude this diagnosis—in fact, iron deficiency commonly coexists with PV and may mask even higher hematocrit values. 1

Diagnostic Workup Required

Confirm True Polycythemia

• Erythrocytosis is defined as hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, which this patient meets 1
• The hematocrit of 49% exceeds the diagnostic threshold and requires further investigation 1
• Normal ferritin in this context is actually typical of PV patients, as virtually all PV patients are iron deficient at presentation and/or during disease course 2

Essential Diagnostic Tests

• JAK2 V617F mutation testing is mandatory, as more than 95% of PV patients harbor this mutation, which distinguishes PV from secondary causes 1, 3
• Serum erythropoietin (EPO) level should be measured—decreased or inappropriately normal EPO in the setting of erythrocytosis strongly suggests PV 3, 4
• Complete metabolic panel to assess for secondary causes 1
• Oxygen saturation to exclude hypoxia-driven erythrocytosis 3

Additional Evaluation

• Physical examination for splenomegaly, present in 36% of PV patients 1
• Assess for PV-associated symptoms: aquagenic pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), headaches 1, 4
• Screen for thrombotic history, as 16% have prior arterial thrombosis and 7% have venous events at diagnosis 1
• Bone marrow aspiration with cytological examination if JAK2 is negative or diagnosis remains uncertain 3

Critical Diagnostic Pitfall

The normal ferritin is misleading and should NOT provide false reassurance. Iron deficiency and polycythemia represent a "physiological disconnect" that is characteristic of PV 2. The iron deficiency in PV results from:

• Increased iron utilization by the expanded erythroid mass 2
• Dysregulated hepcidin metabolism despite iron deficiency 2
• The microcytic indices often seen would be masked by the current normal MCV 4

Immediate Management Pending Diagnosis

If Polycythemia Vera is Confirmed

All PV patients require therapeutic phlebotomy with a target hematocrit <45% to reduce thrombotic risk 1, 5:

• Remove 400-500 mL of blood weekly or biweekly initially 5
• Check hemoglobin/hematocrit before each phlebotomy 5
• Monitor ferritin levels, though phlebotomy will further deplete iron stores 5

Low-dose aspirin (75-100 mg daily) is indicated for all patients unless contraindicated to reduce thrombotic complications 1

Risk Stratification for Cytoreductive Therapy

High-risk patients (age ≥60 years OR prior thrombosis) should receive cytoreductive therapy in addition to phlebotomy 1:

• Hydroxyurea is first-line cytoreductive therapy 1, 5
• Interferon is an alternative, particularly in younger patients 1
• Ruxolitinib (JAK inhibitor) is reserved for patients intolerant of or resistant to hydroxyurea, particularly effective for pruritus and splenomegaly 1, 5

Monitoring Requirements

• CBC every 2-4 weeks until hematocrit stabilized <45%, then as clinically indicated 5
• Comprehensive metabolic panel with uric acid and LDH 5
• Surveillance for thrombotic complications, including unusual sites like splanchnic veins 1, 6
• Screen for progression to myelofibrosis (12.7% risk) or acute myeloid leukemia (6.8% risk) 1

If Secondary Polycythemia is Suspected

Evaluate for:

• Sleep apnea (assess sleep quality, snoring, daytime somnolence) 4
• Chronic lung disease (pulmonary function tests if indicated) 3
• Renal pathology (renal ultrasound, assess for EPO-secreting tumors) 3
• Smoking history (already excluded in this case) 1

Prognosis and Long-Term Considerations

• Median survival ranges from 14.1 to 27.6 years from diagnosis 1
• Thrombosis remains the primary cause of morbidity and mortality, emphasizing the importance of maintaining hematocrit <45% 1
• Iron deficiency from therapeutic phlebotomy contributes to non-hematological symptoms (fatigue, restless legs, cognitive impairment) but is necessary to control disease 2
• Cytoreductive therapy works more effectively in iron-deficient patients to reverse PV-associated symptoms 2

The combination of erythrocytosis with normal ferritin in a non-smoker mandates urgent hematologic evaluation with JAK2 mutation testing and EPO level measurement to establish or exclude polycythemia vera.