What is the best management approach for a 54-year-old female patient with a significant increase in hemoglobin (Hb) levels, from 14 to 16.6, over the course of a year, and a history of elevated hematocrit (Hct), likely indicative of polycythemia vera (PV)?

Management of Rising Hemoglobin from 14 to 16.6 g/dL Over One Year in a 54-Year-Old Female

This patient requires immediate JAK2 mutation testing and complete hematologic workup, as her hemoglobin of 16.6 g/dL exceeds the WHO diagnostic threshold for polycythemia vera (>16.0 g/dL in women), and if confirmed, she needs hematocrit maintained strictly below 45% through phlebotomy and low-dose aspirin to prevent thrombotic complications. 1, 2

Immediate Diagnostic Workup Required

The following tests must be ordered immediately to distinguish polycythemia vera from secondary causes:

• Complete blood count with differential and red cell indices to assess for trilineage involvement (elevated white blood cells and platelets suggest PV) 2
• JAK2 V617F mutation testing (present in 95-97% of PV cases) and JAK2 exon 12 mutation if V617F is negative 1, 2
• Serum erythropoietin level (subnormal in PV, elevated in secondary causes) 1, 2
• Serum ferritin and transferrin saturation to identify concurrent iron deficiency, which can mask the full extent of erythrocytosis 2
• Peripheral blood smear examination by a qualified hematologist to assess red cell morphology 2

Diagnostic Criteria for Polycythemia Vera

According to the 2016 WHO criteria, PV diagnosis requires meeting either all 3 major criteria OR the first 2 major criteria plus the minor criterion 1:

Major Criteria:

1. Hemoglobin >16.0 g/dL in women (this patient meets this at 16.6 g/dL) 1
2. Bone marrow biopsy showing hypercellularity with trilineage growth and pleomorphic megakaryocytes 1
3. Presence of JAK2 V617F or JAK2 exon 12 mutation 1

Minor Criterion:

• Subnormal serum erythropoietin level 1

Important caveat: Bone marrow biopsy may not be required if sustained absolute erythrocytosis is present with hemoglobin >16.5 g/dL in women AND major criterion 3 (JAK2 mutation) plus the minor criterion are present, though biopsy is valuable for detecting early myelofibrosis (present in up to 20% of PV patients at diagnosis) 1

Secondary Causes to Exclude

Before confirming PV, systematically evaluate for secondary erythrocytosis 2:

Hypoxia-driven causes:

• Smoking history (carbon monoxide causes "smoker's polycythemia" through chronic tissue hypoxia) 2
• Obstructive sleep apnea (nocturnal hypoxemia drives erythropoietin production) - consider sleep study if clinically suspected 2
• Chronic lung disease (COPD, pulmonary fibrosis) 2

Non-hypoxic causes:

• Testosterone use (prescribed or unprescribed) - particularly important to assess in any patient 2
• Erythropoietin-producing tumors (renal cell carcinoma, hepatocellular carcinoma, uterine leiomyoma) 2
• Renal disease with abnormal erythropoietin production 2

Relative polycythemia:

• Dehydration or diuretic use (plasma volume depletion can falsely elevate hemoglobin/hematocrit) 2

Management if Polycythemia Vera is Confirmed

Immediate Thrombosis Prevention

Hematocrit control is the cornerstone of therapy:

• Target hematocrit strictly <45% through therapeutic phlebotomy, as the CYTO-PV trial demonstrated a 3.91-fold increased risk of cardiovascular events with hematocrit 45-50% 2, 3
• Given physiological differences, a target of <42% is reasonable for women 2
• Perform phlebotomy with adequate volume replacement (equal volume of saline or dextrose) to prevent hypotension and further hemoconcentration 2

Antiplatelet therapy:

• Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of thrombosis prevention 2, 3

Risk Stratification for Cytoreductive Therapy

Cytoreductive therapy is indicated if the patient has any of the following 2, 4:

• Age >60 years (this patient is 54, so age alone does not mandate cytoreduction)
• Previous thrombotic event
• Poor tolerance to phlebotomy
• Symptomatic or progressive splenomegaly
• Severe disease-related symptoms (pruritus, fatigue, bone pain)
• Platelet count >1500 × 10⁹/L or leukocyte count >15 × 10⁹/L

First-line cytoreductive options (if indicated) 1, 4:

• Hydroxyurea (most commonly used first-line agent)
• Recombinant interferon alpha (preferred in younger patients or those desiring pregnancy)
• Ruxolitinib (for hydroxyurea-resistant or intolerant patients) 5

Critical Pitfalls to Avoid

• Do NOT perform aggressive phlebotomy without adequate volume replacement, as this increases thrombotic risk through hemoconcentration 2
• Do NOT ignore concurrent iron deficiency - iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk despite lower hemoglobin 2
• Do NOT use standard PV diagnostic thresholds if patient lives at high altitude without adjusting for physiologic adaptation (hemoglobin can increase 0.2-4.5 g/dL depending on elevation) 2
• Do NOT delay JAK2 testing - this patient's hemoglobin exceeds the WHO major criterion threshold and warrants immediate molecular testing 2

Immediate Referral Indications

Refer immediately to hematology if 2:

• JAK2 mutation is positive
• Hemoglobin >20 g/dL with symptoms of hyperviscosity (headache, visual disturbances, dizziness)
• Unexplained splenomegaly
• Diagnosis remains unclear after initial workup

Monitoring Strategy

If PV is confirmed, the patient requires 3, 6:

• Hematocrit monitoring every 2-4 weeks initially until stable at target <45%
• Complete blood count to monitor white blood cells and platelets (elevated counts increase thrombotic risk)
• Assessment for disease-related symptoms (fatigue, pruritus, splenomegaly, bone pain)
• Long-term surveillance for transformation to myelofibrosis or acute leukemia

This patient's progressive rise in hemoglobin over one year, now exceeding the WHO diagnostic threshold for women, mandates urgent evaluation to distinguish PV from secondary causes and initiate appropriate thrombosis prevention strategies 1, 2, 7.