Polycythemia Vera Workup
Begin the diagnostic workup by measuring serum erythropoietin (EPO) level followed by bone marrow examination with cytogenetic studies when PV is clinically suspected. 1
When to Suspect PV
Consider PV in the following scenarios:
- Hemoglobin/hematocrit above the 95th percentile for sex and race (hemoglobin >16.5 g/dL in men or >16.0 g/dL in women) 1, 2
- Documented sustained increase of at least 2 g/dL from baseline that cannot be attributed to iron deficiency correction 3
- Clinical features suggestive of PV:
Step-by-Step Diagnostic Algorithm
Step 1: Serum Erythropoietin Level
- Low EPO level: Highly suggestive of PV with >90% specificity; proceed to bone marrow examination 3, 1
- Normal EPO level: Does not exclude PV (sensitivity of low EPO is <70%); still proceed to bone marrow examination if clinical suspicion remains 3, 1
- High EPO level: Evaluate for secondary polycythemia causes 3, 1
Critical pitfall: A normal EPO level does NOT rule out PV—you must proceed with further workup if clinical suspicion persists. 3, 1
Step 2: JAK2 Mutation Testing
- JAK2V617F mutation is present in >95% of PV patients 4, 2
- When present, JAK2 mutation confirms clonal proliferation and distinguishes PV from secondary causes 3, 5
- When absent with normal/high EPO: PV is effectively excluded 5, 6
- Consider JAK2 exon 12 mutations if JAK2V617F is negative but clinical suspicion remains high 4
Step 3: Bone Marrow Examination
Bone marrow biopsy findings characteristic of PV include:
- Hypercellularity with trilineage proliferation 3, 1
- Increased megakaryocytes with cluster formation 3, 1
- Giant megakaryocytes with pleomorphic morphology 3, 1
- Mild reticulin fibrosis (present in 12% at diagnosis) 3
- Decreased bone marrow iron stores 3
Cytogenetic studies show abnormalities (trisomy 9, trisomy 8, deletions of 13q or 20q) in only 13-18% of patients and have limited diagnostic value. 3, 1
Step 4: Specialized Testing (for Equivocal Cases Only)
These tests should be needed in <10% of cases:
- Decreased megakaryocyte c-mpl (TPO receptor) expression supports PV diagnosis 3, 1
- PRV-1 expression in peripheral blood neutrophils (high in PV, not detectable in secondary polycythemia) 3, 1
- Spontaneous erythroid colony assays (limited availability, requires expertise) 3, 1
Critical Pitfalls to Avoid
Do NOT Rely on Red Cell Mass (RCM) Measurement
- Normal RCM does NOT exclude PV because some PV patients fall at the left tail of the distribution and overlap with normal values 3, 1
- Iron deficiency or bleeding can lower RCM into the normal range despite underlying PV 3, 1
- RCM is redundant when hematocrit >60% without obvious hemoconcentration 3
- RCM measurement is costly and adds little diagnostic value compared to EPO and bone marrow examination 3
Do NOT Rely on Traditional PVSG Criteria Alone
The following lack sensitivity and specificity:
- Splenomegaly 3, 1
- Leukocytosis 3, 1
- Thrombocytosis 3, 1
- Elevated leukocyte alkaline phosphatase 3, 1
- Increased vitamin B12 or B12 binding capacity 3, 1
Watch for Iron Deficiency Masking Erythrocytosis
- Low MCHC may indicate iron deficiency that is concealing the true degree of erythrocytosis 1
- Iron replacement therapy failure to increase hemoglobin to PV range (in presence of low ferritin) should prompt continued PV evaluation 3
Distinguishing PV from Secondary Polycythemia
Secondary Polycythemia Causes to Exclude:
Hypoxia-driven:
- Chronic lung disease 3, 1
- Sleep apnea/hypoventilation syndromes 3
- High altitude habitation 3, 1
- Smoking/carbon monoxide exposure 3, 1
- Right-to-left cardiopulmonary shunts 3
- Renal artery stenosis 3
Pathologic EPO production:
- Renal cell carcinoma 3, 1
- Hepatocellular carcinoma 3, 1
- Cerebellar hemangioblastoma 3
- Uterine leiomyomas 3
- Renal cysts/polycystic kidney disease 3
Congenital causes:
Drug-associated: