What are the diagnostic criteria and treatment options for Polycythemia Vera?

Polycythemia Vera Diagnosis

Diagnose polycythemia vera when both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus at least one minor criterion are present, or when the first major criterion plus two minor criteria are met. 1, 2

Major Diagnostic Criteria

Major Criterion 1: Evidence of Erythrocytosis

• Hemoglobin ≥16.5 g/dL in women or ≥18.5 g/dL in men 1, 2
• Hematocrit ≥48% in women or ≥49% in men 2, 3
• Alternative: Hemoglobin >17 g/dL in men or >15 g/dL in women if associated with a documented sustained increase of ≥2 g/dL from baseline that cannot be attributed to iron deficiency correction 1
• Alternative: Elevated red cell mass >25% above mean normal predicted value 1

Major Criterion 2: JAK2 Mutation

• Presence of JAK2V617F mutation or functionally similar mutation (such as JAK2 exon 12 mutation) 1, 2
• Found in >95% of PV patients 2, 3

Minor Diagnostic Criteria

Minor Criterion 1: Bone Marrow Histology

• Hypercellularity for age with trilineage growth (panmyelosis) showing prominent erythroid, granulocytic, and megakaryocytic proliferation 1, 2

Minor Criterion 2: Serum Erythropoietin

• Serum erythropoietin level below the reference range for normal 1, 2

Minor Criterion 3: Endogenous Erythroid Colonies

• Formation of endogenous erythroid colonies in vitro 1, 2

Diagnostic Algorithm

Step 1: When to Suspect PV

Consider PV diagnosis if any of the following are present: 1

• Hemoglobin/hematocrit >95th percentile adjusted for sex and race
• Documented increase in hemoglobin/hematocrit above individual baseline, regardless of absolute value
• PV-related features (thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis including Budd-Chiari syndrome, erythromelalgia) accompanying borderline-high hematocrit 1

Step 2: Order JAK2 Mutation Testing

• If JAK2 mutation is positive AND hemoglobin/hematocrit criteria are met, obtain at least one minor criterion to confirm diagnosis 1
• If JAK2 mutation is negative but hemoglobin/hematocrit criteria are met, obtain two minor criteria to confirm diagnosis 1

Step 3: Exclude Secondary Causes

Essential to rule out secondary erythrocytosis from: 2

• Hypoxia (chronic lung disease, sleep apnea, high altitude)
• Tobacco smoking 3
• Renal lesions producing erythropoietin (renal cell carcinoma, cysts)
• Other tumors producing erythropoietin
• Congenital causes (abnormal hemoglobin, erythropoietin receptor mutations)

Critical Diagnostic Pitfalls

Masked Polycythemia Vera

• 15-35% of PV patients present with hemoglobin below WHO diagnostic thresholds but still have true PV 4
• Causes include: iron deficiency, bleeding, hemodilution 1, 4
• These patients may present with thrombosis (especially splanchnic vein thrombosis) despite normal blood counts 5, 6
• In clinical practice, do not withhold PV diagnosis in iron-deficient patients just because WHO hemoglobin criteria are not met—make a working diagnosis and consider iron replacement 1
• Masked PV patients have worse overall survival compared to overt PV 4

JAK2 Mutation Considerations

• A negative JAK2 result does not completely exclude PV 2
• Mutational load can be low in some patients, requiring sensitive detection techniques 2
• If JAK2 is negative but clinical suspicion is high, proceed with bone marrow biopsy and obtain two minor criteria 1

Red Cell Mass Measurement

• Rarely required in modern practice 1
• Not needed when hematocrit >60% without obvious hemoconcentration (RCM almost always elevated) 1
• Normal RCM does not rule out PV (patients at left tail of Gaussian distribution may have normal values) 1
• More cost-effective to use serum erythropoietin and bone marrow examination 1

Supporting Features (Not Formal Criteria)

The following support PV diagnosis but are no longer required: 2

• Splenomegaly (present in 36% at diagnosis) 3
• Thrombocytosis (present in 53%) 3
• Leukocytosis (present in 49%) 3
• Pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%) 3

Practical Clinical Approach

For routine clinical practice: 1

1. Measure hemoglobin/hematocrit and order JAK2 mutation testing
2. Check serum erythropoietin level (low in PV, elevated in secondary causes)
3. If both are consistent with PV, diagnosis can be made without bone marrow biopsy in most cases
4. Reserve bone marrow biopsy for JAK2-negative cases or when diagnosis remains uncertain
5. Always exclude secondary causes of erythrocytosis

For research or clinical trials: 1

• Formal demonstration of meeting WHO criteria after iron replacement is required
• More stringent application of all diagnostic criteria