In a 56-year-old patient presenting with erythrocytosis, is it more likely to be polycythemia vera (PV) or secondary erythrocytosis?

Likelihood of Polycythemia Vera vs Secondary Erythrocytosis at Age 56

At age 56, erythrocytosis is more likely to be polycythemia vera (PV) than secondary erythrocytosis, particularly if accompanied by thrombocytosis, leukocytosis, splenomegaly, or characteristic symptoms like aquagenic pruritus. 1, 2

Age and Epidemiologic Context

• The median age at PV diagnosis is approximately 60 years, making a 56-year-old patient fall squarely within the typical age range for PV presentation 1
• Age >60 years is a major risk factor for thrombosis in PV, placing this 56-year-old patient just below but near this threshold 3
• Approximately 7% of PV patients are diagnosed before age 40, indicating that diagnosis at 56 represents the peak incidence period rather than an unusually early presentation 1
• The disease likely begins years before reaching diagnostic thresholds, so a 56-year-old may have had subclinical PV developing gradually over time 1

Key Distinguishing Features Favoring PV

Look for these specific clinical clues that strongly suggest PV over secondary causes:

• Trilineage involvement: Concurrent thrombocytosis (present in 53% of PV patients) and leukocytosis (present in 49%) strongly favor PV over secondary erythrocytosis 2, 4
• Splenomegaly: Present in 36% of PV patients due to extramedullary hematopoiesis; this is rare in secondary erythrocytosis 1, 2
• Aquagenic pruritus: Occurs in approximately 33-48% of PV patients and is highly characteristic of the disease 3, 1, 2
• Erythromelalgia: Painful burning sensation of extremities with erythema, present in approximately 3-5.3% of PV cases, responds to aspirin within hours 3, 2
• Microvascular symptoms: Headaches, visual disturbances (14%), light-headedness from hyperviscosity 1, 2

Diagnostic Algorithm

Follow this stepwise approach to distinguish PV from secondary causes:

Step 1: Confirm True Erythrocytosis

• Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women is required for PV diagnosis 1, 2
• Hematocrit >48% in women or >49% in men suggests true erythrocytosis 1

Step 2: Measure Serum Erythropoietin (EPO)

• Low EPO level has >90% specificity for PV and makes the diagnosis highly probable 1, 4
• Normal EPO makes PV possible but requires further testing 1
• High EPO suggests secondary polycythemia, though rare PV cases can present with elevated EPO 5

Step 3: JAK2 Mutation Testing

• JAK2 V617F mutation is present in >95% of PV patients and is a major WHO diagnostic criterion 1, 6, 2, 7
• JAK2 exon 12 mutations account for most remaining PV cases 1
• Presence of JAK2 mutation excludes reactive forms of erythrocytosis 3

Step 4: Assess for Secondary Causes

If JAK2 is negative or EPO is elevated, evaluate for:

• Tobacco smoking, sleep apnea, chronic lung disease 2
• Renal pathology, high altitude exposure
• Testosterone use or other exogenous erythropoietin sources

Step 5: Bone Marrow Biopsy (if needed)

• Shows hypercellularity with trilineage growth and pleomorphic megakaryocytes in PV 1
• Required when JAK2 testing and EPO levels are inconclusive

Critical Pitfalls to Avoid

• Do not assume normal hematocrit excludes PV in young women: Plasma volume expansion can mask erythrocytosis, requiring direct red cell mass measurement 6
• Do not rely solely on EPO levels: While typically low in PV, rare cases present with elevated EPO, requiring JAK2 testing for confirmation 5
• Do not overlook isolated thrombocytosis with positive JAK2: This may represent masked PV with plasma volume expansion rather than essential thrombocythemia 6
• Do not delay evaluation of borderline elevations: The disease develops gradually over years, and early intervention with phlebotomy significantly improves outcomes 1

Prognostic Implications

• Median survival in PV is 14.1 to 27.6 years from diagnosis, emphasizing the importance of accurate diagnosis at age 56 2
• Thrombotic events occur in 16% (arterial) and 7% (venous) of patients prior to or at diagnosis, making early identification crucial 2
• The 10-year risk of thrombosis exceeds 20%, far outweighing the risk of leukemic transformation (<3%) or myelofibrosis (10%) 4
• Untreated PV historically had median survival <2 years, but modern therapy with phlebotomy and aspirin extends survival beyond 10-20 years 3, 1