What labs should be ordered for a patient with erythrocytosis (excessive red blood cell count)?

Diagnostic Laboratory Workup for Erythrocytosis

The essential laboratory workup for erythrocytosis should include complete blood count with peripheral blood smear, JAK2 V617F mutation testing, and serum erythropoietin level as first-line tests to differentiate between primary and secondary causes. 1

Initial Laboratory Assessment

First-line Testing

• Complete blood count (CBC) with differential - To confirm erythrocytosis and assess other cell lines 2, 1
• Peripheral blood smear - To evaluate red cell morphology and identify abnormalities in other cell lines 1
• JAK2 V617F mutation testing - To identify the most common genetic marker of polycythemia vera 1, 3
• Serum erythropoietin level - To distinguish between primary and secondary erythrocytosis 1, 3
  • Low levels (<3.3 IU/L) are highly specific (97%) for polycythemia vera 4
  • Normal or elevated levels suggest secondary erythrocytosis 3

Second-line Testing

• JAK2 exon 12 mutation testing - If JAK2 V617F is negative but PV still suspected 1
• Bone marrow aspirate and biopsy with immunohistochemistry - To assess cellularity and exclude other myeloproliferative disorders 2, 1
• Serum ferritin and transferrin saturation - To evaluate iron status 2
• Reticulocyte count - To assess bone marrow response to erythrocytosis 2

Diagnostic Algorithm

1. Confirm true erythrocytosis:

   • Elevated hemoglobin/hematocrit above the 95th percentile adjusted for sex and race 1
   • Rule out relative erythrocytosis due to dehydration

2. Determine if primary or secondary:

   • If JAK2 mutation positive AND low/normal serum erythropoietin: Likely polycythemia vera 1, 3
   • If JAK2 mutation negative AND elevated serum erythropoietin: Likely secondary erythrocytosis 3
   • If JAK2 mutation negative AND low/normal serum erythropoietin: Consider JAK2 exon 12 testing and bone marrow biopsy 1

3. For suspected secondary erythrocytosis, evaluate:

   • Oxygen saturation and arterial blood gas - To assess for hypoxic causes 1
   • Abdominal ultrasound - To evaluate for renal masses or polycystic kidney disease 5
   • Sleep study - If obstructive sleep apnea suspected 5
   • Hemoglobin electrophoresis - If high-oxygen-affinity hemoglobinopathy suspected 3

Special Considerations

• Caution with interpretation: Some patients with polycythemia vera may have normal or even elevated erythropoietin levels, especially during acute bleeding episodes or early in disease course 6
• Iron deficiency: Can mask true hemoglobin/hematocrit levels in PV patients 1
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors: Can induce erythrocytosis or unmask underlying PV 5
• Primary thrombocythemia: May present with low erythropoietin levels and high-normal hemoglobin 7

Pitfalls to Avoid

• Relying solely on erythropoietin levels: While low levels are highly specific for PV, approximately 13% of PV patients may have normal erythropoietin levels 4
• Overlooking JAK2 exon 12 mutations: These account for ~3% of PV cases that are JAK2 V617F negative 1
• Repeated phlebotomies without diagnosis: Can lead to iron deficiency, decreased oxygen-carrying capacity, and increased stroke risk 2, 1
• Missing secondary causes: Comprehensive evaluation for hypoxic conditions, renal disease, and medications (especially androgens) is essential 1, 5

By following this systematic approach to laboratory testing, the underlying cause of erythrocytosis can be identified efficiently, allowing for appropriate management to reduce morbidity and mortality from thrombotic complications.