Blood Work for Secondary Polycythemia
For someone with secondary polycythemia, obtain a complete blood count with differential, serum erythropoietin (EPO) level, arterial blood gas or pulse oximetry, renal and liver function tests, and consider carboxyhemoglobin level if smoking history is present. 1, 2
Initial Laboratory Assessment
The diagnostic workup should systematically distinguish secondary polycythemia from polycythemia vera and identify the underlying cause:
Essential Blood Tests
Complete blood count (CBC) with differential to confirm elevated hemoglobin/hematocrit and assess for accompanying thrombocytosis or leukocytosis (which would suggest polycythemia vera rather than secondary causes) 3, 2
Serum erythropoietin (EPO) level is critical—elevated EPO strongly indicates secondary polycythemia, while low EPO suggests polycythemia vera (>90% specificity) 2
Arterial blood gas analysis or pulse oximetry to evaluate for hypoxemia driving compensatory erythrocytosis 1, 2
Renal function tests (creatinine, BUN) to screen for kidney disease causing inappropriate EPO production 3
Liver function tests (AST, ALT, bilirubin) to evaluate for hepatocellular carcinoma or other liver pathology 3
Additional Targeted Testing Based on Clinical Context
Carboxyhemoglobin level if the patient is a smoker, as carbon monoxide binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia that triggers erythropoiesis 1
JAK2 V617F mutation testing should be performed if EPO is low or normal (not elevated), as this mutation is present in up to 97% of polycythemia vera cases and helps definitively exclude it 3, 4
Lactate dehydrogenase (LDH) and ESR if there is any suspicion of underlying hematological malignancy presenting with pruritus or systemic symptoms 3
Key Diagnostic Pitfalls to Avoid
Do not assume normal EPO levels rule out secondary polycythemia—in chronic hypoxic states, EPO levels may initially be elevated but can normalize once hemoglobin stabilizes at a higher compensatory level. 1
Always assess for relative polycythemia first by evaluating clinical signs of plasma volume depletion (dehydration, diuretic use, vomiting, diarrhea, burns) before pursuing extensive workup for true polycythemia. 1, 2
Do not overlook smoking as a reversible cause—smoker's polycythemia is a real condition that resolves with cessation, with risk reduction beginning within 1 year and return to baseline after 5 years. 1, 2
Imaging and Further Evaluation When Indicated
If EPO is elevated and hypoxia-driven causes are not evident:
- Chest X-ray to evaluate for chronic lung disease 3
- Abdominal ultrasound to screen for renal cell carcinoma, hepatocellular carcinoma, or other EPO-producing tumors 3, 1
- Sleep study if clinical features suggest sleep apnea (snoring, daytime somnolence, obesity) 1
Red cell mass measurement is rarely necessary and should be reserved only for cases where the diagnosis remains unclear after initial evaluation, as it adds little when the cause is clinically obvious. 1