What is the appropriate workup and management for erythrocytosis (excess red blood cells)?

Workup of Erythrocytosis

Begin the diagnostic workup with JAK2 mutation testing (JAK2V617F or exon 12) and serum erythropoietin (EPO) level to distinguish polycythemia vera from secondary erythrocytosis. 1, 2

Initial Laboratory Evaluation

The essential first-line tests include:

• Complete blood count (CBC) with indices including hemoglobin, hematocrit, mean corpuscular volume (MCV), and red cell distribution width (RDW) 1
• Peripheral blood smear to assess red cell morphology and rule out microcytosis from iron deficiency 1, 3
• JAK2 mutation analysis (JAK2V617F and exon 12 mutations) - present in ~95% of polycythemia vera cases 1, 2
• Serum erythropoietin level - low/subnormal in polycythemia vera, normal or elevated in secondary erythrocytosis 2, 4
• Reticulocyte count to assess bone marrow response 1

Diagnostic Algorithm Based on EPO Level

Low EPO Level (Suggests Primary/Clonal Erythrocytosis)

If JAK2 mutation is positive with low EPO:

• Diagnosis is polycythemia vera 1, 2
• Confirm with bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation 1
• Check for endogenous erythroid colony formation if diagnosis remains uncertain 1

If JAK2 mutation is negative with low EPO:

• Consider bone marrow biopsy to evaluate for clonal abnormalities 1
• Test for other myeloproliferative neoplasm markers 1

Normal or High EPO Level (Suggests Secondary Erythrocytosis)

For acquired erythrocytosis in adults:

• Arterial oxygen saturation to detect hypoxemia (target >92%) 1
• Carboxyhemoglobin level to assess for carbon monoxide exposure 2
• Chest imaging and pulmonary function tests if respiratory disease suspected 4
• Renal ultrasound and renal function tests to evaluate for renal tumors or cysts producing EPO 2, 4
• Abdominal imaging to screen for hepatocellular carcinoma, uterine fibroids, or other EPO-secreting tumors 4, 5
• Sleep study if obstructive sleep apnea suspected 4

For congenital/lifelong erythrocytosis:

• EPO receptor (EPOR) gene mutation analysis - causes familial erythrocytosis type 1 with EPO hypersensitivity 2, 5
• VHL gene mutation - familial erythrocytosis type 2, altered oxygen sensing 2, 5
• EGLN1 (PHD2) gene mutation - familial erythrocytosis type 3 5, 6
• EPAS1 (HIF2A) gene mutation - familial erythrocytosis type 4 5, 6
• Hemoglobin oxygen affinity testing (P50 measurement) - detects high-oxygen-affinity hemoglobinopathies 2, 5
• Hemoglobin electrophoresis if hemoglobinopathy suspected 1, 2
• BPGM, HBB, HBA1, HBA2 gene testing for familial erythrocytosis types 6-8 5

Iron Status Assessment - Critical Pitfall

Always evaluate iron status, as iron deficiency in erythrocytosis is dangerous and increases stroke risk: 1, 3

• Serum ferritin and transferrin saturation 1, 3
• Peripheral blood smear to detect microcytic hypochromic cells 1, 3
• Iron deficiency causes rigid, less deformable red cells that worsen hyperviscosity and increase thrombotic risk 1, 3
• Do not perform routine phlebotomy if iron deficiency is present - this reduces oxygen-carrying capacity and increases stroke risk 3

Additional Workup for Specific Clinical Scenarios

If hyperviscosity symptoms present (headache, fatigue, poor concentration, visual disturbances):

• Document hemoglobin >20 g/dL and hematocrit >65% 3
• Exclude dehydration before considering therapeutic intervention 3
• Assess for thrombotic complications 1, 4

If cyanotic congenital heart disease:

• Evaluate for decompensated erythrocytosis (oxygen saturation <75%) 1
• Check for iron deficiency which exacerbates hyperviscosity 1
• Monitor platelet count and function - thrombocytopenia common 1

If thrombocytosis or leukocytosis present:

• Strongly suggests polycythemia vera (platelets >400×10⁹/L, WBC >12×10⁹/L) 1
• Increases likelihood of JAK2 mutation positivity 1

When Diagnosis Remains Unclear

After complete evaluation, if no cause identified:

• Label as idiopathic erythrocytosis 6, 7
• This diagnosis is becoming less common with improved genetic testing 5, 6
• Consider next-generation sequencing panels for rare genetic variants 5
• Monitor for development of polycythemia vera features over time 6

Key Clinical Pitfalls to Avoid

Do not rely on red cell mass measurement - genetic testing has replaced this traditional approach 2

Do not miss iron deficiency - even with elevated hemoglobin, iron deficiency worsens outcomes and increases stroke risk 1, 3

Do not perform phlebotomy without proper evaluation - repeated phlebotomy causes iron depletion and increases thrombotic risk 3

Do not overlook familial causes in young patients - lifelong erythrocytosis suggests congenital etiology requiring different genetic workup 2, 5