What is the best course of action for a middle-aged patient with a history of mild erythrocytosis (increase in red blood cell count) for a year, who has recently developed mild leukocytosis (increase in white blood cell count)?

Workup for Myeloproliferative Neoplasm

This patient requires immediate evaluation for a myeloproliferative neoplasm, specifically polycythemia vera (PV), given the combination of chronic erythrocytosis now progressing to include leukocytosis. The temporal evolution from isolated erythrocytosis to combined erythrocytosis and leukocytosis is a classic presentation pattern for PV 1, 2.

Immediate Diagnostic Workup

Obtain JAK2 mutation testing immediately - JAK2 mutation is present in essentially all PV cases and its presence combined with elevated hemoglobin/hematocrit (>16.5 g/dL/49% in men or >16 g/dL/48% in women) establishes a working diagnosis 2. The absence of JAK2 mutation combined with normal or increased serum erythropoietin makes PV unlikely 3.

Essential Laboratory Tests

• Complete blood count with manual differential to document the degree of erythrocytosis, leukocytosis, and assess for thrombocytosis 2, 4
• Serum erythropoietin level - should be low or inappropriately normal in PV 3
• Comprehensive metabolic panel including LDH and uric acid to assess for metabolic complications 5
• JAK2V617F mutation testing as the primary molecular marker 1, 2

Bone Marrow Examination

Bone marrow aspirate and biopsy with comprehensive analysis is strongly advised to confirm the diagnosis morphologically, though not absolutely mandated if JAK2 mutation is present with characteristic blood findings 2. The bone marrow evaluation must include 6:

• Morphologic examination with cytochemistry
• Conventional cytogenetic analysis (karyotype) - abnormal karyotype is present in 15-20% of PV patients and has prognostic significance 2
• Flow cytometry immunophenotyping
• Molecular genetic testing for additional mutations beyond JAK2

Additional Molecular Testing

Screen for prognostically adverse mutations including SRSF2, IDH2, RUNX1, and U2AF1, which have a combined incidence of 5-10% and affect survival 2. Other relevant mutations include TET2 (18% incidence) and ASXL1 (15% incidence) 2.

Risk Stratification

Once PV is confirmed, classify the patient into risk categories 2, 4:

• High-risk: Age >60 years OR history of thrombosis
• Low-risk: Absence of both factors

Additional thrombosis risk factors to assess include 2:

• Cardiovascular risk factors (for arterial thrombosis)
• Absolute neutrophil count and JAK2V617F allele burden (for venous thrombosis)

Immediate Management Considerations

If Marked Leukocytosis Present (WBC >100,000/μL)

Initiate aggressive IV hydration (2.5-3 liters/m²/day) immediately to prevent tumor lysis syndrome and maintain organ perfusion 5. This represents a medical emergency requiring urgent intervention 5.

Standard PV Management

All patients require phlebotomy to maintain hematocrit <45% - this target significantly reduces thrombotic events (HR 3.91 for hematocrit 45-50% vs <45%) 6, 2, 4.

Initiate once- or twice-daily aspirin 81 mg in the absence of contraindications 2, 4. Low-dose aspirin reduces the combined risk of nonfatal MI, stroke, PE, major venous thrombosis, or cardiovascular death (RR 0.40,95% CI 0.18-0.91) 6.

Cytoreductive Therapy Indications

For high-risk patients, cytoreductive therapy is mandatory 2, 4:

• First-line: Hydroxyurea 6, 2, 4
• Second-line: Pegylated interferon-α or busulfan 2, 4
• Ruxolitinib: Reserved only for severe protracted pruritus or marked splenomegaly unresponsive to other agents 2, 4

Critical Pitfalls to Avoid

• Do not delay JAK2 testing - this is the cornerstone of diagnosis and should be ordered immediately 2, 3
• Do not ignore the leukocytosis - this represents disease progression and may indicate need for cytoreductive therapy even if not yet meeting high-risk criteria by age alone 6
• Do not target hematocrit levels of 45-50% - only <45% reduces thrombotic risk 6, 2
• Do not use ruxolitinib as first-line therapy - reserve for specific refractory symptoms 2, 4
• Do not overlook screening for cardiovascular risk factors - these compound thrombotic risk in PV 2

Prognosis and Long-term Monitoring

Median survival for PV is approximately 15 years overall, but exceeds 35 years for patients aged ≤40 years 2. Twenty-year risks include 2:

• Thrombosis: ~26%
• Post-PV myelofibrosis: 16%
• Acute myeloid leukemia: 4%