Management of Elevated RBC, Hemoglobin, and Hematocrit
The first priority is to confirm true erythrocytosis by repeating measurements after ensuring adequate hydration, then systematically evaluate for secondary causes (smoking, sleep apnea, COPD, testosterone use) before considering polycythemia vera—therapeutic phlebotomy should be reserved only for extreme elevations (Hgb >20 g/dL and Hct >65%) with hyperviscosity symptoms, as routine phlebotomy paradoxically increases stroke risk through iron depletion. 1
Initial Confirmation and Assessment
Repeat hemoglobin and hematocrit measurements after ensuring adequate hydration, as a single measurement is insufficient and dehydration causes relative erythrocytosis that mimics true disease 1, 2
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, 2
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 secondary cause, including dyspnea on exertion or orthopnea 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 thrombocytosis or leukocytosis suggests myeloproliferative disorder 1, 2
Serum erythropoietin (EPO) level: low or low-normal suggests polycythemia vera, while elevated levels indicate secondary erythrocytosis 1, 2
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, 2
Peripheral blood smear to evaluate red cell morphology and identify abnormalities such as microcytosis suggesting coexisting iron deficiency 1, 2
Red cell distribution width (RDW), as high RDW with normal or low MCV suggests coexisting iron deficiency 1, 2
Systematic Evaluation for Secondary Causes
Before considering polycythemia vera, systematically exclude these common secondary causes:
Hypoxia-Driven Causes
Smoking history and carbon monoxide exposure, which causes "smoker's polycythemia" through chronic tissue hypoxia stimulating erythropoietin production—this resolves with smoking cessation 1, 2
Obstructive sleep apnea through sleep study if nocturnal hypoxemia is suspected, as CPAP therapy can normalize erythrocytosis 1, 2
Chronic lung disease including COPD through pulmonary function testing and arterial oxygen saturation measurement 1, 2
Cyanotic congenital heart disease with right-to-left shunting causing compensatory erythrocytosis to optimize oxygen transport 1, 2
Altitude of residence, as physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters)—standard diagnostic thresholds must be adjusted accordingly 1, 2
Non-Hypoxic Secondary Causes
Testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis in younger adults—dose adjustment or discontinuation typically normalizes values 1, 2
Erythropoietin-producing tumors including renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma—renal imaging with ultrasound or CT should be performed 1, 2
Evaluation for Polycythemia Vera
If secondary causes are excluded and EPO is low or low-normal:
Order JAK2 mutation testing (both exon 14 and exon 12), as up to 97% of polycythemia vera cases carry this mutation 1, 2
Polycythemia vera diagnosis requires both major criteria (elevated hemoglobin/hematocrit/RBC mass AND presence of JAK2 mutation) plus at least one minor criterion, OR first major criterion plus at least two minor criteria 2
Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal serum erythropoietin level, and endogenous erythroid colony formation 2
Bone marrow biopsy is required if JAK2 mutation is positive to confirm diagnosis and assess for trilineage myeloproliferation 2
Management Based on Etiology
For Secondary Erythrocytosis
Treat the underlying condition rather than performing phlebotomy:
- Smoking cessation for smoker's polycythemia 1, 2
- CPAP therapy for obstructive sleep apnea 1, 2
- Management of chronic lung disease with supplemental oxygen if indicated 1, 2
- Dose adjustment or discontinuation of testosterone if causative 1, 2
- Monitor hemoglobin and hematocrit periodically without routine phlebotomy 1, 2
For Confirmed Polycythemia Vera
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, 2
Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention 1, 2
Refer immediately to hematology for consideration of cytoreductive therapy if high-risk features present 1, 2
Therapeutic Phlebotomy: Strict Indications Only
Phlebotomy is indicated ONLY in these specific circumstances:
Hemoglobin >20 g/dL AND hematocrit >65% with symptoms of hyperviscosity (headache, visual disturbances, dizziness), after excluding dehydration 1, 2
Confirmed polycythemia vera requiring hematocrit maintenance <45% 1, 2
When performing phlebotomy, replace with equal volume of dextrose or saline to prevent further hemoconcentration 1, 2
Iron Management: Critical Considerations
Avoid routine phlebotomies as they cause iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 1, 2
Iron deficiency should be corrected even in the presence of erythrocytosis, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1, 2
If iron deficiency is confirmed (ferritin low, transferrin saturation <20%), provide cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur 1, 2
Critical Pitfalls to Avoid
Never perform aggressive or repeated routine phlebotomies without specific indications, as this depletes iron stores and paradoxically increases thrombotic risk through reduced red cell deformability 1, 2
Do not use hemoglobin level alone as a phlebotomy trigger; consider intravascular volume status, symptoms of hyperviscosity, and underlying etiology 3, 1
Do not overlook coexisting iron deficiency, which can mask the full extent of erythrocytosis while still contributing to hyperviscosity symptoms and stroke risk 1, 2
Do not apply standard polycythemia vera diagnostic thresholds at high altitude without adjustment for physiologic adaptation (hemoglobin increases 0.2-4.5 g/dL depending on elevation) 1, 2
Do not assume elevated values represent disease in patients on testosterone therapy—dose adjustment or temporary discontinuation is first-line management 1, 2
Hematology Referral Indications
Refer immediately to hematology if: