When do you initiate a polycythemia (excessive red blood cell count) vera (PV) workup?

When to Initiate Polycythemia Vera Workup

Begin a polycythemia vera workup when hemoglobin exceeds 16.5 g/dL in men or 16.0 g/dL in women, or when hematocrit is ≥49% in men or ≥48% in women. 1, 2

Primary Triggers for Investigation

Hemoglobin/Hematocrit Thresholds:

• Hemoglobin >16.5 g/dL (men) or >16.0 g/dL (women) warrants immediate workup 1, 2
• Hematocrit ≥49% (men) or ≥48% (women) should prompt evaluation 2
• A sustained increase of ≥2 g/dL hemoglobin from baseline that cannot be attributed to iron deficiency correction requires investigation, even if values remain within normal reference ranges 3
• Values above the 99th percentile for age, sex, and altitude-adjusted reference ranges mandate workup 3

Clinical Presentations That Should Trigger Workup:

• Aquagenic pruritus (itching after water exposure) 4
• Unusual thrombosis, particularly Budd-Chiari syndrome or other splanchnic vein thrombosis 4, 1
• Erythromelalgia (burning pain in extremities with redness) 4, 1
• Unexplained splenomegaly with elevated red blood cell parameters 1
• Transient visual disturbances combined with erythrocytosis 1

Confirming True Polycythemia Before Full Workup

First, exclude relative (spurious) polycythemia:

• Verify adequate hydration status and repeat CBC after ensuring proper hydration 5, 6
• Dehydration is the most common cause of falsely elevated hematocrit 6
• If values normalize with hydration, relative polycythemia is confirmed and PV workup is unnecessary 6

Consider iron deficiency masking:

• Low MCHC (<32%) suggests iron deficiency, which can mask true erythrocytosis 4, 6
• Check serum ferritin, iron studies, and transferrin saturation if MCHC is low 6
• In clinical practice, you can make a working diagnosis of PV even with concurrent iron deficiency if other criteria are met, though formal diagnosis for research purposes requires demonstrating elevated hemoglobin/hematocrit after iron replacement 3

Initial Diagnostic Algorithm Once Workup Is Initiated

Step 1: Order JAK2 mutation testing

• JAK2V617F (exon 14) mutation testing is first-line 5
• If negative, proceed to JAK2 exon 12 mutation testing 5
• More than 95% of PV patients harbor a JAK2 mutation 1, 7

Step 2: Measure serum erythropoietin (EPO) level

• Low EPO has >90% specificity for PV 4
• However, normal EPO does not exclude PV (sensitivity <70%) 4
• High EPO suggests secondary polycythemia and should prompt evaluation for hypoxia-driven conditions, pathologic EPO production, or congenital causes 4
• Important caveat: Rare cases of PV can present with elevated EPO levels, so do not exclude PV based solely on high EPO if other features are strongly suggestive 8

Step 3: Bone marrow examination

• Recommended when diagnosis is suspected, particularly before initiating cytoreductive therapy 3, 4
• Look for hypercellularity for age with trilineage growth (panmyelosis) 3
• Increased megakaryocytes with cluster formation and giant pleomorphic megakaryocytes support PV diagnosis 4
• Cytogenetic studies should be obtained but have limited diagnostic value (abnormalities in 13-18% of cases) 4, 7

Formal WHO Diagnostic Criteria Application

Diagnosis requires BOTH major criteria plus 1 minor criterion, OR the first major criterion plus 2 minor criteria: 3

Major Criteria:

1. Hemoglobin ≥18.5 g/dL (men) or ≥16.5 g/dL (women), OR other evidence of increased red cell volume 3
2. Presence of JAK2V617F or JAK2 exon 12 mutation 3

Minor Criteria:

1. Bone marrow biopsy showing hypercellularity with trilineage growth 3
2. Serum erythropoietin below normal reference range 3
3. Endogenous erythroid colony formation in vitro (when available) 3

Critical Pitfalls to Avoid

Do not rely on traditional markers alone:

• Splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack adequate sensitivity and specificity for PV diagnosis 4
• These findings may support the diagnosis but should not be used as primary diagnostic criteria 4

Do not require red cell mass measurement:

• Normal red cell mass does not exclude PV 4
• Red cell mass measurement is no longer required for diagnosis given the availability of JAK2 mutation testing 3
• However, hematocrit between 0.48-0.52 L/L in males or 0.48 L/L in females may warrant red cell mass measurement if diagnosis remains uncertain 9

Do not delay workup in high-risk presentations:

• Patients presenting with thrombosis (especially unusual sites like splanchnic veins) and erythrocytosis require urgent evaluation 1, 7
• Arterial thrombosis occurs in 16% and venous thrombosis in 7% of patients prior to or at diagnosis 1