What is the approach to investigating and managing erythrocytosis (excessive red blood cell production)?

Investigation and Management of Erythrocytosis

Begin the diagnostic workup with JAK2 mutation testing (V617F and exon 12) and serum erythropoietin (EPO) level to distinguish polycythemia vera from secondary causes—this is the most efficient approach that has replaced traditional red cell mass measurement. 1, 2

Initial Diagnostic Thresholds

Investigate erythrocytosis when:

• Men: Hemoglobin >18.5 g/dL or hematocrit >55% 1
• Women: Hemoglobin >16.5 g/dL or hematocrit >48% 1
• Any patient: Sustained increase of ≥2 g/dL from baseline, even below absolute thresholds 1

First-Line Laboratory Testing

Order these tests immediately:

• Complete blood count with differential to assess for thrombocytosis (>400 × 10⁹/L) or leukocytosis (neutrophils >10 × 10⁹/L), which suggest polycythemia vera 1, 3
• JAK2V617F mutation and exon 12 mutations—positive in >95% of polycythemia vera cases 1, 2
• Serum erythropoietin level—low/subnormal (<70% sensitivity, >90% specificity) indicates PV; normal-to-elevated suggests secondary causes 1, 2
• Serum ferritin and complete iron studies—iron deficiency can mask elevated hemoglobin in PV patients 1

Critical pitfall: Microcytosis with concurrent thrombocytosis or leukocytosis strongly suggests iron-deficient polycythemia vera, not simple iron deficiency 1

Diagnostic Algorithm Based on EPO Level

Low/Subnormal EPO (Primary Erythrocytosis)

If JAK2 mutation positive:

• Diagnose polycythemia vera when both major criteria are met (elevated Hgb/Hct AND JAK2 mutation) plus ≥1 minor criterion 1
• Minor criteria include: bone marrow panmyelosis, subnormal serum EPO, endogenous erythroid colony formation 1
• Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) and megakaryocyte clustering confirms diagnosis 1, 2
• Cytogenetic studies may reveal abnormalities (trisomy 8 or 9, deletions of 13q or 20q) in 13-18% of cases 1

If JAK2 mutation negative with low EPO:

• Consider endogenous erythroid colony assay demonstrating spontaneous colony formation without EPO 1, 3
• Bone marrow biopsy becomes essential to establish clonal marrow population 3

Normal/Elevated EPO (Secondary Erythrocytosis)

For acquired cases (adult onset):

• Exclude hypoxemia: arterial blood gas, pulse oximetry, P50 measurement 2, 3
• Screen for renal pathology: renal ultrasound for cysts, masses, or hydronephrosis; consider CT/MRI for erythropoietin-secreting tumors 2, 4
• Evaluate hepatic pathology: liver function tests, imaging for hepatocellular carcinoma or hemangiomas 2
• Assess for obstructive sleep apnea, chronic lung disease, heavy smoking history 4
• Review medications: erythropoietin-stimulating agents, androgens, SGLT2 inhibitors (can unmask PV) 4
• Post-kidney transplant patients require specific consideration for post-transplant erythrocytosis 4

For congenital cases (lifelong erythrocytosis, young age, family history):

• Test for germline mutations affecting EPO effect: erythropoietin receptor mutations 2, 5
• Evaluate oxygen-sensing pathway: VHL, PHD2, HIF2A mutations 2, 5
• Measure P50 for high-oxygen-affinity hemoglobinopathy 2, 3

Management Considerations

Polycythemia Vera Management

Therapeutic phlebotomy is indicated only when:

• Hemoglobin >20 g/dL AND hematocrit >65% with symptoms of hyperviscosity (headache, fatigue, poor concentration) 6
• No evidence of dehydration or iron deficiency 6
• Remove 1 unit of blood with equal volume replacement of dextrose or saline 6

Critical warning: Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 6

Iron Deficiency in Erythrocytosis

• Confirm with peripheral blood smear and serum ferritin or transferrin saturation 6
• Oral iron administration frequently causes rapid, dramatic increase in red cell mass—monitor hemoglobin closely 6
• Discontinue iron supplementation once ferritin/transferrin saturation normalizes 6
• Consider intravenous iron pulses if oral iron intolerant 6

Special Populations

Cyanotic congenital heart disease patients:

• Most have compensated erythrocytosis requiring no intervention 6
• Ensure adequate hydration before procedures with contrast media due to abnormal renal function 6
• Use renally protective strategies (N-acetylcysteine or bicarbonate) with low threshold 6

SGLT2 inhibitor users:

• Screen for JAK2 mutation if erythrocytosis develops, as these agents can unmask polycythemia vera by activating HIF-2α 4

When Diagnosis Remains Unclear

After complete evaluation, some patients have idiopathic erythrocytosis with no identifiable cause 5, 7. In these cases:

• Consider aspirin and venesection to target hematocrit to reduce thromboembolic risk 5
• Monitor for evolution to polycythemia vera with serial JAK2 testing 7
• Refer to hematology for ongoing management 7