What are the diagnostic criteria and management options for an adult patient with suspected polycythemia vera (PV)?

Diagnosis of Polycythemia Vera

Diagnose polycythemia vera using the 2008 WHO criteria, which require both major criteria (hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women, plus JAK2 mutation) and one minor criterion, or the first major criterion with two minor criteria. 1

Initial Diagnostic Approach

Begin with serum erythropoietin (EPO) level measurement when PV is clinically suspected, followed by bone marrow examination with cytogenetic studies if EPO is low. 2

When to suspect PV:

• Hemoglobin/hematocrit above the 95th percentile adjusted for sex and race (hemoglobin >16.5 g/dL in men or >16.0 g/dL in women) 3, 4
• Documented increase in hemoglobin/hematocrit ≥2 g/dL above baseline, regardless of where it falls within the reference range 2, 3
• Borderline-high hematocrit with PV-related features: thrombocytosis (53% of cases), leukocytosis (49%), aquagenic pruritus (33%), erythromelalgia (5.3%), splenomegaly (36%), or unusual thrombosis such as Budd-Chiari syndrome 2, 4

WHO 2008 Diagnostic Criteria

Major Criteria (both required):

1. Hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women, OR other evidence of increased red cell volume (hemoglobin ≥17 g/dL in men or ≥15 g/dL in women if associated with sustained increase of ≥2 g/dL from baseline that cannot be attributed to iron deficiency correction) 1
2. Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation 1

Minor Criteria (need 1 if both major criteria present, or 2 if only first major criterion present):

1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation 1
2. Serum erythropoietin level below the reference range for normal 1
3. Endogenous erythroid colony formation in vitro 1

Diagnostic Algorithm

Step 1: Measure serum EPO level

• Low EPO is highly suggestive of PV with specificity >90% 2, 3
• EPO levels <2 U/L strongly favor PV, while levels >12 U/L favor secondary polycythemia 2
• Normal EPO does not rule out PV (sensitivity <70%) 2, 3
• High EPO suggests secondary polycythemia and requires evaluation for hypoxia-driven causes 2, 3

Step 2: Perform JAK2 mutation testing

• JAK2 V617F mutation is present in >95% of PV patients 1, 4, 5
• JAK2 exon 12 mutations are found exclusively in 2-4% of PV patients who are JAK2 V617F negative 1
• The presence of JAK2 mutation excludes reactive forms of erythrocytosis 1
• Test using whole blood or purified granulocytes; the latter is preferred for low mutation burden cases 1

Step 3: Bone marrow examination (if EPO is low)

• Hypercellularity for age 2, 3
• Increased megakaryocytes with cluster formation and giant megakaryocytes with pleomorphic morphology 2, 3
• Trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation 1
• Decreased bone marrow iron stores 2, 3
• Cytogenetic studies show abnormalities in 13-18% of patients but have limited diagnostic value 2

Critical Diagnostic Pitfalls to Avoid

Do not rely on red cell mass (RCM) measurement:

• Normal RCM does not rule out PV 2, 3
• RCM measurement with hematocrit >60% without obvious hemoconcentration is costly redundancy 3
• Increased plasma volume can mask increased RCM, creating "inapparent polycythemia vera" where hemoglobin/hematocrit remain normal despite true PV 6

Do not use traditional markers alone:

• Splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack both sensitivity and specificity for PV 2, 7

Do not miss iron deficiency:

• Low MCHC (<32%) indicates iron deficiency that can mask true erythrocytosis 2, 7
• Iron deficiency should be corrected before reassessing hemoglobin levels 1

Do not assume low EPO always means PV:

• Low EPO can occur in essential thrombocythemia and rare congenital polycythemia with EPOR mutations 3

Distinguishing PV from Secondary Polycythemia

Hypoxia-driven causes:

• Chronic lung disease, right-to-left cardiopulmonary shunts, high-altitude habitation, smoking, hypoventilation syndromes, high oxygen-affinity hemoglobinopathy 2, 3
• In hypoxia-driven secondary polycythemia, EPO may initially be elevated but can normalize once hemoglobin stabilizes at a compensatory higher level 2

Hypoxia-independent causes:

• Pathologic EPO production: renal cell cancer, hepatocellular carcinoma 2, 3
• Congenital causes and EPOR-mediated polycythemia 3
• Drug-associated: EPO doping, androgen preparations 2

Key differentiating factors:

• JAK2 mutation presence (>95% in PV vs. absent in secondary causes) 1, 4, 5
• Serum EPO levels (low in PV, elevated or normal in secondary) 2, 3
• Bone marrow morphology (trilineage hyperplasia in PV) 1, 2

Additional Testing in Equivocal Cases

When diagnosis remains uncertain after standard workup:

• Peripheral blood neutrophil assay for PRV-1 expression 2
• Spontaneous (endogenous) erythroid colony assays when available 2, 8
• Decreased megakaryocyte expression of TPO receptor (c-mpl) as an alternative marker 2

Clinical Context

PV affects approximately 65,000 people in the US with an annual incidence of 0.5 to 4.0 cases per 100,000 persons. 4 Median survival from diagnosis ranges from 14.1 to 27.6 years across cohorts. 4 At or before diagnosis, 16% of patients have arterial thrombosis and 7% have venous thrombotic events, often in unusual sites such as splanchnic veins. 4 About 12.7% develop myelofibrosis and 6.8% develop acute myeloid leukemia. 4