What labs to order for a patient with erythrocytosis (excessive red blood cell count) of unclear etiology, without a history of smoking, exogenous steroid or Erythropoietin (EPO) use, lung disease, or sleep apnea?

Diagnostic Workup for Erythrocytosis of Unclear Etiology

For a patient with erythrocytosis of unclear etiology without history of smoking, exogenous steroid or EPO use, lung disease, or sleep apnea, the initial laboratory workup should include serum erythropoietin level measurement, JAK2 mutation testing (V617F and exon 12), and complete blood count with peripheral smear examination to distinguish between primary and secondary causes.

Initial Laboratory Evaluation

First-line Tests

• Complete blood count (CBC) with differential and red cell indices
• Peripheral blood smear examination
• Serum erythropoietin (EPO) level - critical for distinguishing primary from secondary causes 1
• JAK2 V617F mutation testing (sensitivity >95% for polycythemia vera) 1
• Reticulocyte count - to assess bone marrow response 2
• Comprehensive metabolic panel including renal function tests
• Iron studies (serum ferritin, transferrin saturation) 2, 1
• C-reactive protein (CRP) - to assess for inflammation 1

Second-line Tests (Based on Initial Results)

• If JAK2 V617F is negative but PV still suspected: JAK2 exon 12 mutation testing 1
• Hemoglobin electrophoresis - to rule out high-oxygen-affinity hemoglobinopathy 3
• Arterial blood gas analysis - to assess oxygen saturation and P50 4
• Abdominal ultrasound - to evaluate for hepatomegaly, splenomegaly, or renal masses
• Bone marrow biopsy and aspiration - if primary erythrocytosis is suspected 1

Diagnostic Algorithm Based on EPO Level

Low EPO Level

• Suggests primary erythrocytosis (polycythemia vera)
• An EPO level <3.3 IU/L has 97% specificity for PV with 97.8% positive predictive value 5
• An EPO level <1.4 IU/L is highly specific for untreated PV 5
• Proceed with JAK2 mutation testing if not already done
• Consider bone marrow biopsy to assess for hypercellularity with trilineage growth 1

Normal or Elevated EPO Level

• Suggests secondary erythrocytosis
• EPO level >13.7 IU/L is highly specific for secondary erythrocytosis 5
• Consider the following causes:

  1. Hypoxia-driven secondary polycythemia:

     • Echocardiography to evaluate for right-to-left cardiac shunts
     • Pulmonary function tests
     • Sleep study (if sleep apnea still suspected despite negative history)
     • Carbon monoxide level

  2. Non-hypoxia-driven secondary polycythemia:

     • Abdominal/pelvic CT or MRI to evaluate for EPO-producing tumors (renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)
     • Genetic testing for congenital causes in younger patients or those with family history:
       • VHL gene mutations (Chuvash polycythemia)
       • EPOR mutations (primary familial and congenital polycythemia)
       • PHD2, HIF2A mutations (familial erythrocytosis)

Important Clinical Considerations

• The combination of JAK2 mutation testing and serum EPO measurement can distinguish between PV and secondary erythrocytosis in most cases 3
• Bone marrow examination should be considered when peripheral blood findings are inconclusive 1
• Patients with normal EPO levels and negative JAK2 testing may have idiopathic erythrocytosis and require further investigation 6
• Congenital causes should be particularly considered in young patients or those with family history of erythrocytosis 4

Common Pitfalls to Avoid

1. Failing to measure serum EPO level as a first-line test, which is crucial for directing further investigation 5
2. Not testing for JAK2 exon 12 mutations when JAK2 V617F is negative but PV is still suspected 1
3. Overlooking rare congenital causes in young patients with lifelong erythrocytosis 3
4. Missing secondary causes of erythrocytosis that may indicate underlying malignancy 7
5. Neglecting to evaluate iron status, which can affect interpretation of red cell parameters 1

This systematic approach to erythrocytosis evaluation will help identify the underlying cause and guide appropriate management to reduce morbidity and mortality associated with this condition.