What is the initial workup and treatment algorithm for a patient suspected of having polycythemia vera?

Workup Algorithm for Polycythemia Vera

Initial Confirmation of Erythrocytosis

Begin workup when hemoglobin exceeds 16.5 g/dL in men or 16.0 g/dL in women, or when there is a documented sustained increase of at least 2 g/dL above an individual's baseline. 1, 2

• Pursue evaluation even with borderline-high hematocrit if accompanied by thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis (especially Budd-Chiari syndrome), or erythromelalgia 1, 2
• Do not perform red cell mass measurements in most cases—normal RCM does not exclude PV, and with hematocrit >60% without obvious hemoconcentration, it represents costly redundancy 2

Step 1: Measure Serum Erythropoietin Level

Serum EPO is the critical first test after confirming true polycythemia. 3, 1, 2

If EPO is LOW (specificity >90% for PV):

• Proceed directly to bone marrow examination 3, 1, 2
• PV diagnosis is probable 3

If EPO is NORMAL:

• PV remains possible (sensitivity of low EPO for PV is only <70%) 1, 2
• Proceed to bone marrow examination 3, 1

If EPO is HIGH:

• Evaluate systematically for secondary polycythemia 3, 1, 2
• Workup includes: complete blood count with differential, renal function tests, liver function tests, arterial blood gas or pulse oximetry for hypoxemia 2
• Consider imaging of kidney, liver, and central nervous system if initial studies unrevealing 2
• Evaluate for hypoxia-driven causes: chronic lung disease, right-to-left cardiopulmonary shunts, high-altitude habitation, hypoventilation syndromes, smoking, high oxygen-affinity hemoglobinopathy 1, 2
• Evaluate for hypoxia-independent causes: renal cell cancer, hepatocellular carcinoma, other malignant/benign tumors, congenital causes, EPOR mutations, exogenous EPO or androgen use, post-renal transplant erythrocytosis 1, 2

Step 2: Bone Marrow Examination with Cytogenetics

Bone marrow biopsy and aspirate with cytogenetic studies is the cornerstone of PV diagnosis. 1, 2

Findings Supporting PV Diagnosis:

• Hypercellularity with trilineage proliferation 1, 2
• Increased megakaryocytes with cluster formation 1, 2
• Giant megakaryocytes with pleomorphic morphology 1, 2
• Mild reticulin fibrosis (present in 12% of patients) 3, 1
• Decreased bone marrow iron stores 3, 1

Cytogenetic Studies:

• Abnormalities found in only 13-18% of patients at diagnosis (trisomies of chromosomes 9 and 8, deletions of long arms of chromosomes 13 and 20) 3, 1
• Limited diagnostic value but perform routinely 3, 1

Step 3: JAK2 Mutation Testing

JAK2 mutation is present in more than 95% of PV patients (JAK2V617F in >90%, exon 12 mutations in remainder). 3, 4, 5

• JAK2 testing helps distinguish PV from secondary polycythemia 5
• Absence of JAK2 mutation does not exclude PV but requires more rigorous evaluation for secondary causes 3

Step 4: Specialized Testing (Only in Equivocal Cases)

These tests should constitute no more than 10% of diagnostic workups. 3

• Decreased megakaryocyte expression of TPO receptor (c-mpl) by bone marrow immunohistochemistry supports PV diagnosis 3
• Peripheral blood neutrophil assay for PRV-1 expression (high in PV, not detectable in secondary polycythemia) 3, 1
• Spontaneous (endogenous) erythroid colony assays when available 3, 1

Critical Pitfalls to Avoid

• Do not rely on traditional markers alone: Splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack both sensitivity and specificity for PV 1
• Do not miss iron deficiency: Low MCHC may indicate iron deficiency that masks erythrocytosis 1
• Do not assume low EPO always means PV: Low EPO can occur in essential thrombocythemia and rare congenital polycythemia with EPOR mutations 2
• Do not overlook smoking history: Smoker's polycythemia resolves with cessation; risk reduction begins within 1 year and returns to baseline after 5 years 2
• Do not exclude PV based on normal EPO alone: Proceed to bone marrow examination 1, 2

WHO 2008 Diagnostic Criteria Application

Diagnosis requires meeting specific major and minor criteria per WHO classification. 3

Major Criteria:

• Hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, OR hemoglobin >17 g/dL in men or >15 g/dL in women if associated with documented sustained increase of at least 2 g/dL from baseline that cannot be attributed to correction of iron deficiency, OR elevated red cell mass >25% above mean normal predicted value 3
• Presence of JAK2V617F or other functionally similar mutation 3

Minor Criteria:

• Bone marrow biopsy showing hypercellularity for age with trilineage growth 3
• Subnormal serum erythropoietin level 3
• Endogenous erythroid colony formation in vitro 3