What are the appropriate diagnostic and treatment steps for a patient with an elevated red blood cell (RBC) count?

Management of Elevated Red Blood Cell Count

The first priority is to confirm true erythrocytosis through repeat measurements after ensuring adequate hydration, then systematically evaluate for secondary causes (smoking, sleep apnea, chronic hypoxemia, testosterone use) before considering polycythemia vera, reserving therapeutic phlebotomy only for confirmed polycythemia vera or extreme elevations (hemoglobin >20 g/dL with hematocrit >65%) accompanied by hyperviscosity symptoms. 1

Initial Confirmation and Assessment

Repeat hemoglobin and hematocrit measurements after ensuring adequate hydration, as a single elevated value is insufficient for diagnosis and dehydration commonly causes relative (false) erythrocytosis. 2, 1

Confirm true erythrocytosis using sex-specific diagnostic thresholds:

• Men: hemoglobin >18.5 g/dL or hematocrit >55% 2, 1
• Women: hemoglobin >16.5 g/dL or hematocrit >49.5% 2, 1

Assess for hyperviscosity symptoms including headache, visual disturbances, fatigue, poor concentration, dizziness, or transient visual changes, which occur in 14% of polycythemia vera patients. 1, 3

Essential Laboratory Workup

Order a complete blood count with differential immediately to assess all three cell lines, as thrombocytosis (53%) and leukocytosis (49%) commonly accompany polycythemia vera. 2, 3

Obtain peripheral blood smear review to evaluate red cell morphology and identify abnormalities that may suggest underlying bone marrow disorders. 2, 1

Measure serum erythropoietin (EPO) level as a critical differentiating test: low or low-normal EPO suggests polycythemia vera, while elevated levels indicate secondary erythrocytosis from hypoxemia or other causes. 2, 1

Test for JAK2 mutations (both exon 14 and exon 12) as the cornerstone diagnostic test, which is present in more than 95% of polycythemia vera cases and helps distinguish primary from secondary causes. 2, 3

Check iron studies including serum ferritin and transferrin saturation, as iron deficiency commonly coexists with erythrocytosis and causes microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin. 2, 1

Measure reticulocyte count to evaluate bone marrow response and red cell production rate. 2

Systematic Evaluation for Secondary Causes

Obtain detailed smoking history and assess for carbon monoxide exposure, as "smoker's polycythemia" results from chronic tissue hypoxia stimulating erythropoietin production and resolves with smoking cessation. 2, 1, 4

Screen for obstructive sleep apnea with sleep study if nocturnal hypoxemia is suspected, which produces erythropoietin-driven erythrocytosis that responds to CPAP therapy. 2, 1

Evaluate for chronic obstructive pulmonary disease or other pulmonary conditions through pulmonary function testing and arterial oxygen saturation measurement, as chronic hypoxemia is a common secondary cause. 2, 1

Assess for testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis in younger adults and requires dose adjustment or discontinuation. 2, 1

Consider erythropoietin-producing tumors including renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma through upper abdominal ultrasonography. 1, 4

Evaluate altitude of residence, as physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters). 1

Management Based on Etiology

For Secondary Erythrocytosis

Treat the underlying condition rather than performing phlebotomy:

• Smoking cessation for smoker's polycythemia 1
• CPAP therapy for obstructive sleep apnea 1
• Management of chronic lung disease 1
• Dose adjustment or discontinuation of testosterone if causative 1
• Monitor hemoglobin and hematocrit periodically 1

For Confirmed Polycythemia Vera (JAK2 Positive)

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, as demonstrated by the CYTO-PV study, with a lower target of 42% reasonable for women and African Americans. 2, 1, 3

Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention, unless contraindications exist. 2, 1, 3

Consider cytoreductive therapy with hydroxyurea or interferon for patients aged 60 years or older, those with prior thrombosis, or those with persistent symptoms despite phlebotomy and aspirin. 3

Therapeutic Phlebotomy: Specific Indications Only

Phlebotomy is indicated ONLY in these specific circumstances:

• Hemoglobin >20 g/dL AND hematocrit >65% with symptoms of hyperviscosity, after excluding dehydration 1
• Confirmed polycythemia vera requiring hematocrit maintenance <45% 1, 3

When performing phlebotomy, replace with equal volume of dextrose or saline to prevent further hemoconcentration. 1

Iron Management Considerations

Avoid routine phlebotomies as they cause iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1

Correct iron deficiency even in the presence of erythrocytosis, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing thrombotic risk. 1

If iron deficiency is confirmed, provide cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur. 1

Critical Pitfalls to Avoid

Never perform aggressive or repeated routine phlebotomies without specific indications, as this depletes iron stores and paradoxically increases thrombotic risk rather than reducing it. 1

Do not overlook coexisting iron deficiency, which can mask the full extent of erythrocytosis while still contributing to hyperviscosity symptoms and increased stroke risk. 1

Do not use hemoglobin level alone as a phlebotomy trigger; consider intravascular volume status, evidence of hyperviscosity symptoms, and cardiopulmonary parameters. 1

Hematology Referral Indications

Refer immediately to hematology if:

• JAK2 mutation is positive 1
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 1
• Unexplained splenomegaly is present 1
• Diagnosis remains unclear after initial workup 1
• Elevated platelet count (>1000 × 10⁹/L) or leukocyte count suggesting myeloproliferative disorder 1, 3

Monitoring Strategy

Use hemoglobin rather than hematocrit for ongoing monitoring, as hemoglobin remains stable during sample storage while hematocrit can falsely increase by 2-4%. 2

Monitor hemoglobin levels weekly until any steroid tapering process is complete if immunosuppression is initiated for immune-related causes. 2