What are the diagnostic criteria for polycythemia vera?

Diagnostic Criteria for Polycythemia Vera

The diagnosis of polycythemia vera requires meeting either all 3 major criteria, OR the first 2 major criteria plus the minor criterion, according to the 2016 WHO revision. 1

Major Criteria

The three major criteria that must be assessed are:

1. Elevated hemoglobin or hematocrit:

   • Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women 1
   • OR Hematocrit >49% in men or >48% in women 1
   • OR Increased red cell mass >25% above mean normal predicted value 1
   • Note: The 2016 WHO revision lowered these thresholds from the 2008 criteria (which required hemoglobin ≥18.5 g/dL in men and ≥16.5 g/dL in women) to capture cases of "masked PV" that were previously missed 1, 2

2. Bone marrow biopsy showing characteristic features:

   • Hypercellularity for age with trilineage growth (panmyelosis) 1
   • Prominent erythroid, granulocytic, and megakaryocytic proliferation 1
   • Pleomorphic, mature megakaryocytes with differences in size 1
   • Important caveat: Bone marrow biopsy may be omitted in cases with sustained absolute erythrocytosis (hemoglobin >18.5 g/dL in men or >16.5 g/dL in women) if major criterion 3 and the minor criterion are present, though this approach will miss initial myelofibrosis present in up to 20% of patients 1

3. Presence of JAK2 mutation:

   • JAK2 V617F (exon 14) mutation OR JAK2 exon 12 mutation 1
   • Found in >95% of polycythemia vera cases 3, 4, 5

Minor Criterion

There is only one minor criterion:

• Subnormal serum erythropoietin (EPO) level below the reference range for normal 1, 3
• This helps differentiate polycythemia vera from secondary causes of erythrocytosis such as smoking, sleep apnea, testosterone use, and hypoxia 4

Diagnostic Algorithm

Two pathways to diagnosis exist:

1. All 3 major criteria are met 1

   • This captures >97% of cases when both hemoglobin/hematocrit elevation and JAK2 mutation are present 1

2. First 2 major criteria (elevated hemoglobin/hematocrit + bone marrow biopsy) plus the minor criterion (low EPO) 1

   • This pathway captures JAK2-negative cases or those with low mutational burden 1
   • Requiring 2 criteria when JAK2 is absent increases diagnostic specificity 1

Critical Considerations and Pitfalls

Exclusion of secondary causes is mandatory:

• Rule out secondary erythrocytosis from hypoxia, chronic lung disease, sleep apnea, high altitude, renal tumors, hepatocellular carcinoma, and other EPO-producing tumors 3, 4
• Confirm normal oxygen saturation to establish primary nature of disease 5

Iron deficiency confounds diagnosis:

• Hemoglobin levels may be falsely lowered in iron-deficient patients 1
• For research/clinical trials, formal diagnosis requires demonstrating WHO criteria are met after iron replacement 1
• In routine practice, a working diagnosis can be made despite iron deficiency if other criteria support it 1

JAK2-negative cases:

• Approximately 2-5% of true polycythemia vera cases are JAK2-negative 3, 4
• These require both bone marrow biopsy showing characteristic features AND low EPO level for diagnosis 1
• Consider testing for JAK2 exon 12 mutations if V617F is negative 1

Features that support but are not formal criteria:

• Splenomegaly, thrombocytosis (platelets >400 × 10⁹/L), and leukocytosis (neutrophils >10 × 10⁹/L) support the diagnosis but are no longer required 3, 6
• Endogenous erythroid colony formation in vitro was removed as a criterion in the 2016 revision 1