What are the diagnostic criteria for Polycythemia Vera?

Polycythemia Vera Diagnostic Criteria

Diagnose polycythemia vera using the 2016 WHO criteria, which require either both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria. 1

Major Criteria

The two major criteria that form the foundation of PV diagnosis are:

1. Hemoglobin ≥16.5 g/dL in men or ≥16 g/dL in women (or hematocrit ≥49% in men or ≥48% in women), OR other evidence of increased red cell volume such as a sustained increase in hemoglobin >2 g/dL above baseline 2, 1, 3

2. Presence of JAK2V617F mutation or other functionally similar JAK2 mutation (such as exon 12 mutations), which is found in >95% of PV patients 2, 1, 4

Minor Criteria

Three minor criteria support the diagnosis when major criteria alone are insufficient:

1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation, including increased megakaryocytes with cluster formation and pleomorphic morphology 2, 1

2. Serum erythropoietin level below the reference range for normal, which has >90% specificity for PV (though sensitivity is <70%) 2, 1

3. Presence of endogenous erythroid colony formation in vitro (when available) 2, 1

Diagnostic Algorithm

Start with serum erythropoietin measurement followed by bone marrow examination with cytogenetic studies when PV is clinically suspected. 1

• Low serum EPO is highly suggestive of PV with >90% specificity, but normal EPO does not exclude PV 1
• High serum EPO suggests secondary polycythemia and warrants evaluation for hypoxia-driven conditions (chronic lung disease, high altitude, smoking), pathologic EPO production (renal cell cancer, hepatocellular carcinoma), or drug-associated causes (EPO doping, androgen preparations) 1
• JAK2 mutation testing captures >95% of PV cases when positive, though the diagnosis can still be made without it if sufficient minor criteria are met 2, 4

Key Diagnostic Considerations

Consider PV in patients with hemoglobin/hematocrit above the 95th percentile adjusted for sex and race, or with documented sustained increases above baseline regardless of reference range position. 1

Clinical features that heighten suspicion include:

• Aquagenic pruritus (itching after water exposure) 1
• Unusual thrombosis such as Budd-Chiari syndrome (hepatic vein thrombosis) 1
• Erythromelalgia (burning pain in extremities) 1
• Splenomegaly on examination or imaging 2

Critical Pitfalls to Avoid

Do not rely solely on red cell mass (RCM) measurement, as normal RCM does not rule out PV and adds unnecessary cost. 1, 5

Traditional markers lack sufficient sensitivity and specificity for diagnosis:

• Splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels are not reliable diagnostic markers 1

Iron deficiency can mask erythrocytosis—check MCHC, as values <32% suggest iron deficiency that requires serum ferritin and iron studies. 1, 5

For research or clinical trial purposes, formal PV diagnosis requires demonstrating WHO criteria are met after iron replacement, though in routine practice you should not be prevented from making a working diagnosis of PV in the presence of iron deficiency just because hemoglobin thresholds aren't met. 2

Dehydration is the most common cause of falsely elevated hematocrit and must be excluded before pursuing extensive workup. 5

Distinguishing Primary from Secondary Polycythemia

The key differentiating factors are:

• JAK2 mutation presence (found in >95% of PV, absent in secondary polycythemia) 1, 4
• Serum EPO levels (low in PV, high in secondary causes) 1
• Bone marrow morphology (hypercellular with panmyelosis in PV) 1
• Absence of secondary causes including hypoxia, pathologic EPO production, congenital causes (high oxygen-affinity hemoglobinopathy), and drug-associated causes 1