What labs are indicated for a patient with suspected polycythemia?

Laboratory Workup for Suspected Polycythemia

For any patient with suspected polycythemia, immediately order: complete blood count (CBC) with differential, serum erythropoietin (EPO) level, and JAK2 mutation testing. 1, 2 These three tests form the essential diagnostic triad that distinguishes polycythemia vera from secondary causes and guides all subsequent management decisions.

Initial Essential Laboratory Tests

Complete Blood Count with Differential

• Confirm elevated hemoglobin/hematocrit (>16.5 g/dL in men, >16.0 g/dL in women for polycythemia vera diagnosis) 2
• Assess for thrombocytosis (present in 53% of polycythemia vera cases) and leukocytosis (present in 49% of cases), as these PV-related features strengthen diagnostic suspicion 2, 3
• Evaluate mean corpuscular hemoglobin concentration (MCHC) - low values may indicate iron deficiency that can mask erythrocytosis 4
• Repeat measurements to confirm true polycythemia rather than transient elevation 4

Serum Erythropoietin (EPO) Level

• **Low EPO (<2 U/L or below reference range)** strongly suggests polycythemia vera with >90% specificity, though sensitivity is only 64-70% 5, 1, 4
• Normal EPO levels do not exclude polycythemia vera - proceed with JAK2 testing as EPO sensitivity for PV is insufficient to rule out the diagnosis 1, 4
• Elevated EPO points toward secondary polycythemia and triggers systematic evaluation for hypoxia-driven or hypoxia-independent causes 5, 1
• Critical pitfall: In chronic hypoxic states (smoker's polycythemia, COPD), EPO may initially be elevated but can normalize once hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera 1, 4

JAK2 Mutation Testing

• JAK2V617F or exon 12 mutations are present in >95% of polycythemia vera patients, making this the most sensitive diagnostic test 2, 6
• Order immediately alongside EPO level rather than waiting for EPO results, as normal EPO does not exclude PV 4
• Positive JAK2 with elevated hemoglobin essentially confirms polycythemia vera diagnosis 2, 6

Secondary Laboratory Tests Based on Initial Results

If EPO is Low or Normal with Negative JAK2

• Bone marrow examination with cytogenetic studies to confirm PV diagnosis through histology showing hypercellularity, increased megakaryocytes with cluster formation, and giant megakaryocytes with pleomorphic morphology 5, 4
• Specialized testing in equivocal cases (constituting <10% of patients): bone marrow immunohistochemistry for c-mpl (thrombopoietin receptor), neutrophil PRV-1 expression assay, or spontaneous erythroid colony assay 5, 4

If EPO is Elevated - Evaluate for Secondary Polycythemia

Hypoxia-Driven Causes:

• Arterial blood gas analysis or pulse oximetry to assess for hypoxemia 1
• Carboxyhemoglobin level if smoking history present (though clinical assessment of smoking status typically sufficient) 1
• Sleep study for suspected sleep apnea 1
• Chest X-ray to evaluate for chronic lung disease 1

Hypoxia-Independent Causes:

• Renal function tests (creatinine, BUN) to screen for kidney disease 1
• Liver function tests (AST, ALT, bilirubin) to screen for hepatocellular carcinoma 1
• Abdominal ultrasound or CT to screen for EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma 1, 4
• Review medication history for exogenous erythropoietin or testosterone use 4

Additional Supporting Laboratory Tests

• Lactate dehydrogenase (LDH) and ESR if suspicion of underlying hematological malignancy with systemic symptoms 1
• Serum calcium, PTH, and phosphorus if evaluating for parathyroid carcinoma as a rare cause of EPO-producing tumor 1

Critical Diagnostic Pitfalls to Avoid

• Do not assume normal EPO excludes polycythemia vera - EPO sensitivity for PV is only 64-70%; always proceed with JAK2 testing when hemoglobin is elevated 1, 4
• Do not perform unnecessary red cell mass measurements - modern JAK2 testing and EPO levels have largely replaced the need for these studies except in truly equivocal cases 5, 1
• Do not rely on traditional markers alone (splenomegaly, leukocyte alkaline phosphatase, vitamin B12 levels) as these lack both sensitivity and specificity for PV 4
• Beware of "masked" polycythemia vera - patients with iron deficiency, blood loss, or plasma volume expansion may have normal hemoglobin/hematocrit despite underlying PV; investigate for myeloproliferative neoplasm if unusual site thrombosis occurs even with normal blood counts 7
• Do not miss smoker's polycythemia - this is a real condition from chronic carbon monoxide exposure that resolves with smoking cessation and is the most common cause of secondary polycythemia 1, 3

Clinical Features That Trigger Immediate Laboratory Workup

• Sustained hemoglobin increase ≥2 g/dL from baseline, even if within normal reference range 4
• Unusual thrombosis (Budd-Chiari syndrome, splanchnic vein thrombosis, cerebral venous sinus thrombosis) 4, 2
• Aquagenic pruritus (itching after water exposure) 4
• Erythromelalgia (burning pain in extremities with erythema) 4, 2
• Splenomegaly (present in 36% of PV cases) 2