How should I evaluate and manage a patient with elevated hemoglobin, hematocrit, and red blood cell count?

Evaluation and Management of Elevated Hemoglobin, Hematocrit, and RBC Count

Confirm true erythrocytosis with repeat hemoglobin and hematocrit measurements, then immediately test for JAK2 mutations while simultaneously evaluating for secondary causes—therapeutic phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with hyperviscosity symptoms, not for routine management. 1, 2

Initial Diagnostic Confirmation

Use hemoglobin rather than hematocrit for diagnosis and monitoring because hematocrit falsely increases by 2-4% when blood samples are stored longer than 8 hours, whereas hemoglobin remains stable. 1 Additionally, hyperglycemia can falsely elevate mean corpuscular volume and calculated hematocrit but does not affect hemoglobin measurement. 1

• Repeat measurements to confirm persistent elevation: hemoglobin >18.5 g/dL in men (>16.5 g/dL in women) or hematocrit >55% in men (>49.5% in women) defines true erythrocytosis. 1, 3
• Male patients with hematocrit over 60% and female patients with hematocrit over 55% always have absolute polycythemia. 4

Essential Laboratory Workup

Obtain the following tests immediately:

• Complete blood count with red cell indices (MCV, MCH, MCHC, RDW) using an automated analyzer to assess all three cell lines and identify concurrent thrombocytosis or leukocytosis that suggests myeloproliferative disorder. 1, 2
• JAK2 mutation testing (both exon 14 V617F and exon 12) as the cornerstone diagnostic test—present in up to 97% of polycythemia vera cases. 1, 3
• Serum ferritin and transferrin saturation to identify coexisting iron deficiency, which commonly causes microcytic polycythemia with elevated RBC count but reduced hemoglobin. 1, 2
• Reticulocyte count to evaluate bone marrow response. 1, 2
• C-reactive protein as part of minimum workup. 1, 2
• Serum erythropoietin level to differentiate primary from secondary causes—low or normal EPO suggests polycythemia vera, while elevated EPO indicates secondary erythrocytosis. 1
• Peripheral blood smear review by a qualified hematologist to evaluate cell morphology and rule out acute leukemia or other primary bone marrow disorders. 1, 2

Systematic Evaluation for Secondary Causes

Before pursuing polycythemia vera diagnosis, exclude these common secondary causes:

• Smoking history and carbon monoxide exposure—"smoker's polycythemia" results from chronic tissue hypoxia stimulating erythropoietin production and resolves with smoking cessation. 1, 2
• Sleep study for obstructive sleep apnea if nocturnal hypoxemia is suspected, which produces erythropoietin-driven erythrocytosis. 1, 2
• Pulmonary function tests and chest imaging for chronic obstructive pulmonary disease or other pulmonary conditions causing chronic hypoxemia. 1, 2
• Testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis and requires dose adjustment or discontinuation. 1, 2
• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease that can produce erythropoietin. 1
• Assess hydration status clinically and review medication list for diuretics causing volume depletion—repeat CBC after 48-72 hours of adequate hydration to determine if erythrocytosis persists. 5

Diagnosis of Polycythemia Vera

WHO 2016 diagnostic criteria require all three major criteria OR the first two major criteria plus one minor criterion:

Major Criteria

1. Hemoglobin >16.5 g/dL (women) or >18.5 g/dL (men), OR hematocrit >48% (women) or >49% (men). 1, 3
2. Presence of JAK2 mutation (V617F or exon 12). 1, 3
3. Bone marrow biopsy showing hypercellularity with trilineage myeloproliferation. 1

Minor Criterion

• Subnormal serum erythropoietin level (below normal reference range). 1

If JAK2 mutation is positive, perform bone marrow aspirate and biopsy to confirm polycythemia vera diagnosis and assess for trilineage myeloproliferation. 1, 2

Management of Polycythemia Vera

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk—the CYTO-PV trial demonstrated that hematocrit <45% reduced cardiovascular death or major thrombosis to 2.7% compared with 9.8% in patients with hematocrit 45-50% (hazard ratio 3.91; P=0.007). 1, 3

• A slightly lower target of approximately 42% is recommended for women and African-American patients due to physiological differences in baseline hematocrit values. 1
• Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention. 1, 2, 3
• Remove approximately 300-450 mL of blood per phlebotomy session with careful hemodynamic monitoring. 1
• When phlebotomy is performed, replace removed blood volume with equal amount of dextrose or saline to prevent further hemoconcentration and reduce stroke risk. 1

Patients at higher risk of thrombosis (age ≥60 years or prior thrombosis) and those with persistent symptoms may benefit from cytoreductive therapy with hydroxyurea or interferon. 3

Critical Management Principles for Secondary Erythrocytosis

Routine therapeutic phlebotomy is contraindicated in secondary erythrocytosis because it causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1, 2, 5

Phlebotomy in secondary erythrocytosis is indicated ONLY when ALL of the following criteria are met:

• Hemoglobin >20 g/dL AND hematocrit >65%. 1, 2, 5
• Documented hyperviscosity symptoms (headache, blurred vision, confusion, bleeding). 1
• Patient is adequately hydrated. 1
• Iron deficiency has been excluded (transferrin saturation ≥20%). 1
• Hematocrit remains elevated above baseline despite hydration. 1

First-line therapy for suspected hyperviscosity in secondary erythrocytosis is aggressive rehydration with oral fluids or intravenous normal saline (2.5-3 liters/m²/day), not phlebotomy. 1, 2

Iron Deficiency Considerations

Iron deficiency frequently coexists with erythrocytosis and requires opposite management—iron supplementation rather than phlebotomy. 1, 2

• Mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis; serum ferritin, transferrin saturation, and iron levels are required for accurate diagnosis. 1
• Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1
• If transferrin saturation <20%, initiate cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur. 1
• Iron deficiency can mimic hyperviscosity symptoms but requires iron supplementation, not phlebotomy. 1

Referral Indications

Refer immediately to hematology if:

• JAK2 mutation is positive. 1, 2
• Hemoglobin >20 g/dL with symptoms of hyperviscosity. 1
• Unexplained splenomegaly. 1
• Diagnosis remains unclear after initial workup. 1
• Unexplained cytopenias occur with erythrocytosis. 1

Common Pitfalls to Avoid

• Never perform routine or repeated phlebotomies in secondary erythrocytosis—this leads to iron depletion, reduced oxygen-carrying capacity, and paradoxical increase in stroke risk. 1, 2
• Never perform phlebotomy without equal-volume fluid replacement—this raises hemoconcentration and stroke risk. 1
• Do not overlook coexisting iron deficiency—it mimics hyperviscosity but requires iron supplementation, not phlebotomy. 1
• Do not use standard polycythemia vera diagnostic thresholds at high altitude without adjustment—physiologic adaptation to altitude can increase hemoglobin by 0.2-4.5 g/dL depending on elevation. 1
• Avoid rapid increases in hematocrit (>8 percentage points per month) in patients on erythropoietin therapy. 1