What is the diagnosis for a 54-year-old female patient presenting with leukocytosis, erythrocytosis, hyperhemoglobinemia, and hyperhematocritemia over a one-year period?

Polycythemia Vera (PV) is the Most Likely Diagnosis

This 54-year-old woman presenting with progressive erythrocytosis (RBC 5.2→5.91, hemoglobin 14→16.6 g/dL, hematocrit 42→50.9%) combined with leukocytosis (WBC 8.2→14.3) over one year most likely has polycythemia vera, a JAK2-mutated myeloproliferative neoplasm. 1, 2

Why This Presentation Suggests PV

The clinical picture meets key diagnostic triggers for PV evaluation:

• Documented rise in hemoglobin/hematocrit above baseline (14→16.6 g/dL and 42→50.9%), which is one of three scenarios that should prompt PV investigation, even when values remain within or near reference ranges 1

• PV-related feature present: The concurrent leukocytosis (8.2→14.3) accompanying the rising hematocrit is a characteristic PV-associated finding that strengthens diagnostic suspicion 1, 3

• Hemoglobin now exceeds diagnostic threshold: At 16.6 g/dL, this surpasses the WHO major criterion of >16 g/dL for women 4, 5

• Leukocytosis in PV results from clonal proliferation affecting multiple cell lines, with erythrocytosis often appearing first, followed by leukocytosis, and later thrombocytosis 3, 6, 7

Immediate Diagnostic Algorithm

Step 1: JAK2 Mutation Testing (First Priority)

• Order JAK2V617F mutation testing immediately - present in >95% of PV cases 6, 7, 4, 5

• If JAK2 mutation is positive with hemoglobin >16 g/dL in a woman, this highly suggests PV and fulfills the first WHO major criterion 1, 4

Step 2: Serum Erythropoietin Level

• Measure serum EPO level - typically low or inappropriately normal in PV (specificity >90%), which helps differentiate from secondary causes 1, 2

• If EPO is elevated, this argues against PV and suggests secondary polycythemia from hypoxia (COPD, sleep apnea, smoking) or EPO-secreting tumors 2

• Critical distinction: PV is unlikely with an increased serum EPO level 1

Step 3: Exclude Secondary Causes

Before proceeding to bone marrow biopsy, systematically evaluate for:

• Smoking history - causes "smoker's polycythemia" through chronic carbon monoxide exposure stimulating EPO production 2, 3

• Sleep apnea symptoms - nocturnal hypoxemia drives EPO production 2

• Testosterone or androgen use - commonly causes erythrocytosis 2

• Chronic lung disease - COPD causes compensatory erythrocytosis 2

• Renal imaging - to exclude EPO-secreting renal cell carcinoma if EPO is elevated 2

Step 4: Bone Marrow Biopsy (If JAK2 Positive)

• Bone marrow examination with cytogenetics confirms diagnosis and fulfills WHO criteria 1, 4, 5

• Characteristic findings include hypercellularity, increased megakaryocytes with clustering, giant megakaryocytes, pleomorphism, and decreased iron stores 1

• Abnormal karyotype found in 15-20% of cases, most commonly +9, loss of Y chromosome, +8, and 20q- 5

Critical Pitfalls to Avoid

Do not dismiss this as "normal variation" simply because hematocrit is <60% - the documented progressive rise above baseline with concurrent leukocytosis mandates investigation 1

Do not order red cell mass (RCM) measurement - this is costly, rarely changes management, and can miss PV cases at the lower extreme of RCM distribution 1

Do not assume dehydration or relative polycythemia - the concurrent leukocytosis and progressive nature over one year argues against simple hemoconcentration 2

Screen for thrombosis risk factors - age >60 years (she is 54, approaching this threshold) and cardiovascular risk factors increase thrombotic risk in PV 6, 5

Prognostic Considerations

If PV is confirmed:

• Median survival approximately 15 years, but can exceed 35 years in younger patients 5

• 20-year thrombosis risk approximately 26% - the primary cause of morbidity and mortality 5

• Risk of progression to myelofibrosis approximately 16% at 20 years, and to acute leukemia approximately 4% 5

• Adverse prognostic factors include leukocytosis (already present), abnormal karyotype, and mutations in SRSF2, IDH2, RUNX1, or U2AF1 5

Next Steps After Diagnosis

If JAK2 mutation is positive and PV is confirmed:

• Immediate hematology referral for risk stratification and treatment planning 3

• Therapeutic phlebotomy with hematocrit target <45% to reduce thrombotic risk 6, 4, 5

• Low-dose aspirin 81 mg daily (unless contraindicated) to prevent thrombosis 6, 4, 5

• Cytoreductive therapy consideration if high-risk features develop (age >60 years, thrombosis history, extreme leukocytosis) 6, 5