What is the appropriate management for a patient with an elevated red blood cell (RBC) count?

Workup of Elevated Red Blood Cell Count

The first priority is to confirm true erythrocytosis by ensuring adequate hydration and repeating measurements, then systematically evaluate for secondary causes before considering primary polycythemia vera, with therapeutic phlebotomy reserved only for extreme elevations with hyperviscosity symptoms. 1

Initial Confirmation and Assessment

• Repeat hemoglobin and hematocrit measurements after ensuring adequate hydration, as a single measurement is insufficient and dehydration can cause relative (spurious) erythrocytosis. 1

• Confirm true erythrocytosis using sex-specific thresholds: hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women. 1

• Assess for hyperviscosity symptoms including headache, visual disturbances, fatigue, poor concentration, or dizziness that would indicate need for urgent intervention. 1

• Evaluate for cardiopulmonary symptoms suggesting chronic hypoxemia as a potential secondary cause. 1

Essential Laboratory Workup

Order the following tests immediately to distinguish primary from secondary erythrocytosis:

• Complete blood count with red cell indices, reticulocyte count, and differential to assess white blood cell and platelet counts, as elevations suggest myeloproliferative disorder. 1

• Serum ferritin and transferrin saturation to evaluate iron status, as iron deficiency can mask the full extent of erythrocytosis while paradoxically increasing stroke risk. 1

• Peripheral blood smear to evaluate red cell morphology and identify abnormalities such as spherocytes or other membrane disorders. 1, 2

• Red cell distribution width (RDW), as high RDW with normal or low MCV suggests coexisting iron deficiency. 1

• Serum erythropoietin (EPO) level: low or low-normal suggests polycythemia vera, while elevated levels indicate secondary erythrocytosis. 1

Systematic Evaluation for Secondary Causes

Investigate the following potential secondary causes before diagnosing primary polycythemia:

• Smoking history and carbon monoxide exposure, which causes "smoker's polycythemia" through chronic tissue hypoxia stimulating erythropoietin production. 1

• Obstructive sleep apnea through sleep study if nocturnal hypoxemia is suspected based on snoring, witnessed apneas, or daytime somnolence. 1

• Chronic lung disease including COPD through pulmonary function testing and arterial oxygen saturation measurement. 1

• Testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis particularly in younger adults. 1

• Cyanotic congenital heart disease with right-to-left shunting causing compensatory erythrocytosis. 1

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

• Erythropoietin-producing tumors including renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma through appropriate imaging. 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 with bronchodilators and supplemental oxygen if indicated. 1

• Dose adjustment or discontinuation of testosterone if causative. 1

• Monitor hemoglobin and hematocrit periodically without routine phlebotomy. 1

For polycythemia vera (JAK2 positive):

• Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, with a lower target of 42% reasonable for women and African Americans. 1

• Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention. 1

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

• 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

• Iron deficiency should be corrected 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. 1

• Do not use hemoglobin level alone as a phlebotomy trigger; consider intravascular volume status, evidence of shock, and cardiopulmonary parameters. 3, 1

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

• Do not apply standard polycythemia vera diagnostic thresholds at high altitude without adjustment for physiologic adaptation. 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 thrombocyte or leukocyte count suggesting myeloproliferative disorder. 1, 4