Diagnosis of Polycythemia Vera
Polycythemia vera is diagnosed when both major criteria plus one minor criterion are met, or when the first major criterion plus two minor criteria are present. 1
Major Diagnostic Criteria
The two major criteria required for PV diagnosis are:
Elevated hemoglobin or hematocrit:
- Hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women 1, 2
- Hematocrit >52% in men or >48% in women 2, 3
- Alternative: Hemoglobin >99th percentile for age, sex, and altitude 1, 2
- Alternative: Elevated red cell mass >25% above mean normal predicted value 1, 2
- Alternative: Sustained increase in hemoglobin ≥2 g/dL from baseline (not due to iron deficiency correction) 1, 2
Presence of JAK2 mutation:
Minor Diagnostic Criteria
At least one of these three minor criteria must be present:
Bone marrow biopsy showing:
Serum erythropoietin level below normal reference range 1
Endogenous erythroid colony formation in vitro 1
Practical Diagnostic Algorithm
Step 1: Initial Laboratory Assessment
When you suspect PV (erythrocytosis, thrombocytosis, leukocytosis, splenomegaly, aquagenic pruritus, or unusual thrombosis):
- Measure hemoglobin/hematocrit to confirm erythrocytosis 5, 4
- Check complete blood count (thrombocytosis in 53%, leukocytosis in 49%) 4
- Assess iron studies (iron deficiency can mask true polycythemia) 1, 2
Step 2: Serum Erythropoietin Level
- Low EPO: Highly suggestive of PV (specificity >90%) 1, 5
- Normal EPO: Does not exclude PV (sensitivity of low EPO <70%) 1, 5
- High EPO: Evaluate for secondary polycythemia causes 1, 5
Step 3: JAK2 Mutation Testing
- Order JAK2V617F mutation testing 1, 4
- If negative, consider JAK2 exon 12 mutation testing 1
- Presence of JAK2 mutation plus elevated hemoglobin/hematocrit captures >97% of PV cases 1
Step 4: Bone Marrow Biopsy
This is essential for diagnosis and should not be skipped 6:
- Provides baseline histomorphology 6
- Shows characteristic hypercellularity with trilineage growth 1
- Demonstrates increased megakaryocytes with clustering and pleomorphism 1, 5
- May show mild reticulin fibrosis (12% of cases) 1
- Include cytogenetic studies (abnormalities in 13-18% at diagnosis) 1, 5
Step 5: Specialized Testing (Only in Equivocal Cases <10%)
If diagnosis remains uncertain after above steps:
- Decreased megakaryocyte c-mpl (TPO receptor) expression 1, 5
- Peripheral blood neutrophil PRV-1 expression assay 1, 5
- Spontaneous erythroid colony assay (limited availability) 1, 5
Clinical Features That Suggest PV
Look for these specific findings:
- Aquagenic pruritus (itching after warm water exposure) in 33% 5, 4
- Erythromelalgia (burning pain in extremities) in 5.3% 5, 4
- Splenomegaly in 36% 4
- Unusual thrombosis sites (Budd-Chiari syndrome, splanchnic veins) 5, 4
- Transient visual changes in 14% 4
Excluding Secondary Polycythemia
Rule out these causes before diagnosing PV 5:
- Hypoxia-driven: Chronic lung disease, high altitude, smoking, sleep apnea 5, 4
- Pathologic EPO production: Renal cell cancer, hepatocellular carcinoma 5
- Congenital: High oxygen-affinity hemoglobinopathy, truncated EPO receptor 1, 5
- Drug-associated: EPO doping, androgen preparations 5
Critical Pitfalls to Avoid
Iron deficiency masks erythrocytosis: Always check iron studies; low MCHC suggests iron deficiency 2, 5. For research purposes, confirm WHO criteria are met after iron replacement, though in clinical practice you can make a working diagnosis despite iron deficiency 1
Don't rely on traditional markers alone: Splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack sensitivity and specificity 5
Normal red cell mass doesn't exclude PV: Don't use this as a sole criterion 5
Bone marrow biopsy is mandatory: This is essential for accurate diagnosis and distinguishing PV from other JAK2-positive myeloproliferative neoplasms 6
False-positive JAK2 results: Even with positive JAK2 mutation, require at least one minor criterion to ensure diagnostic specificity 1