How to manage suspected polycythemia vera?

Management of Suspected Polycythemia Vera

Initial Diagnostic Workup

Begin with serum erythropoietin (EPO) level measurement as the first-line test, followed by JAK2 mutation testing if EPO is low or normal. 1, 2

Your patient's laboratory values show:

• Hemoglobin 15.8 g/dL with hematocrit 47.0% (elevated for males if >16.5 g/dL or females if >16.0 g/dL) 3
• MCV 104.7 fL (macrocytic, which is atypical for polycythemia vera where microcytosis from iron deficiency is more common) 2

Step 1: Confirm True Polycythemia

First, exclude apparent (relative) polycythemia by assessing for plasma volume depletion. 4 Look for:

• Dehydration, diarrhea, vomiting 4
• Diuretic use 4
• Smoking history (smoker's polycythemia from chronic carbon monoxide exposure) 4, 5

The concept of chronic "stress polycythemia" or Gaisböck syndrome has little foundation, and red cell mass measurements are generally unnecessary when clinical context is clear. 4

Step 2: Measure Serum EPO Level

Order serum EPO as the critical discriminating test: 1, 2

• Low EPO: Highly suggestive of polycythemia vera (specificity >90%) 1, 2
• Normal EPO: Does NOT rule out polycythemia vera (sensitivity <70%) 1, 2
• High EPO: Indicates secondary polycythemia requiring further evaluation 1, 2

Step 3: JAK2 Mutation Testing

If EPO is low or normal, proceed with JAK2 V617F mutation testing, as this mutation is present in >95% of polycythemia vera patients. 2, 3, 6

Bone Marrow Examination Indications

Perform bone marrow biopsy after abnormal EPO results (low or normal) to confirm the diagnosis. 1, 2 Look for:

• Hypercellularity 2
• Increased megakaryocytes with cluster formation and pleomorphic giant forms 2
• Decreased bone marrow iron stores (characteristic of polycythemia vera) 1

If Secondary Polycythemia is Suspected (High EPO)

Evaluate for hypoxia-driven causes first: 1, 5

• Chronic lung disease, sleep apnea (order sleep study if suspected) 5
• Smoking history (carbon monoxide binds hemoglobin 200-250 times more avidly than oxygen) 5
• High-altitude habitation 5

Then evaluate for hypoxia-independent causes: 1, 5

• Imaging (abdominal ultrasound/CT) for EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma 1, 5
• Consider high oxygen-affinity hemoglobinopathy in congenital cases 5

Treatment Algorithm for Confirmed Polycythemia Vera

All Patients (Universal Therapy)

Every patient with polycythemia vera requires three interventions: 1, 3, 7

1. Therapeutic phlebotomy to maintain hematocrit <45% (this target reduces thrombotic risk) 1, 3, 7
2. Low-dose aspirin 81 mg once or twice daily (unless contraindications exist) 1, 3, 7
3. Aggressive cardiovascular risk factor management including smoking cessation 1

Risk Stratification for Cytoreductive Therapy

High-risk patients require cytoreductive therapy in addition to phlebotomy and aspirin: 1, 3, 7

High-risk criteria (either one qualifies):

• Age >60 years 1, 3, 7
• History of thrombosis 1, 3, 7
• Extreme thrombocytosis (platelet count >1,000-1,500 × 10⁹/L, which increases bleeding risk from acquired von Willebrand disease) 1, 8

First-line cytoreductive agents: 1, 7

• Hydroxyurea (preferred first-line) 1, 7
• Interferon-α (alternative first-line, especially in younger patients) 1, 7

Second-line options: 7

• Ruxolitinib (JAK1/2 inhibitor) for patients intolerant of or resistant to hydroxyurea, particularly with severe pruritus or marked splenomegaly 3, 7
• Busulfan 7

Critical Pitfalls to Avoid

Do not rely solely on traditional markers (splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, vitamin B12 levels) as these lack sensitivity and specificity for polycythemia vera. 2

Do not miss iron deficiency, which can mask erythrocytosis and cause microcytosis—the macrocytosis in your patient (MCV 104.7) makes polycythemia vera less likely and warrants investigation for other causes including B12/folate deficiency or alcohol use. 2

Do not assume normal hemoglobin/hematocrit excludes polycythemia vera if there is documented increase above baseline or if polycythemia vera features are present (thrombocytosis, leukocytosis, splenomegaly, aquagenic pruritus, unusual thrombosis like Budd-Chiari syndrome). 1, 2

Screen for acquired von Willebrand disease before starting aspirin if platelet count exceeds 1,000 × 10⁹/L to assess bleeding risk. 8

Prognosis and Monitoring

Median survival ranges from 14.1 to 27.6 years from diagnosis, with younger patients (age ≤40) having median survival of 37 years. 3 The 10-year risk of transformation to myelofibrosis is approximately 10% and to acute myeloid leukemia is approximately 3%. 8 Thrombosis risk exceeds 20% and represents the primary cause of morbidity and mortality. 8