How should I evaluate and manage a patient with elevated hemoglobin (Hgb) and hematocrit (Hct)?

Evaluation and Management of Elevated Hemoglobin and Hematocrit

Begin by confirming true erythrocytosis with repeat hemoglobin and hematocrit measurements, then systematically distinguish between primary polycythemia vera (requiring JAK2 testing and hematology referral) and secondary causes (requiring treatment of the underlying condition), while avoiding routine phlebotomy except in specific high-risk scenarios. 1

Initial Confirmation and Laboratory Assessment

Repeat hemoglobin and hematocrit measurements using an automated cell counter to verify persistent elevation, as a single measurement is unreliable. 1 True erythrocytosis is defined by hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >52% in men or >48% in women. 1

Use hemoglobin rather than hematocrit for ongoing monitoring and clinical decisions. 1, 2 Hematocrit can falsely increase by 2-4% with prolonged sample storage (>8 hours), while hemoglobin remains stable. 1 Additionally, hyperglycemia falsely elevates mean corpuscular volume and calculated hematocrit but does not affect hemoglobin measurement. 1

Essential Initial Laboratory Tests

Order the following tests immediately: 1

• Complete blood count with red cell indices (MCV, MCH, MCHC, RDW) to assess red cell morphology and identify concurrent cytopenias
• Reticulocyte count to evaluate bone marrow response
• Serum ferritin and transferrin saturation to detect coexisting iron deficiency (mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis) 1
• White blood cell differential and platelet count to identify thrombocytosis or leukocytosis suggesting myeloproliferative disorder
• C-reactive protein to assess for inflammatory conditions 1

Distinguishing Primary from Secondary Erythrocytosis

Test for Polycythemia Vera

Order JAK2 mutation testing (both exon 14 V617F and exon 12) immediately, as this detects mutations in up to 97% of polycythemia vera cases. 1 This is the cornerstone molecular test for distinguishing primary from secondary erythrocytosis.

WHO diagnostic criteria for polycythemia vera require either: 1

• Both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus at least one minor criterion, OR
• First major criterion plus at least two minor criteria

Minor criteria include: 1

• Bone marrow hypercellularity with trilineage myeloproliferation
• Subnormal serum erythropoietin level
• Endogenous erythroid colony formation

If JAK2 is positive, obtain bone marrow aspirate and biopsy to confirm diagnosis and assess for trilineage myeloproliferation. 1

Evaluate for Secondary Causes (if JAK2 negative)

Systematically assess the following: 1

Hypoxic causes:

• Sleep study for obstructive sleep apnea (nocturnal hypoxemia drives erythropoietin production) 1
• Pulmonary function tests and chest imaging for chronic obstructive pulmonary disease 1
• Arterial oxygen saturation (<92% indicates hypoxia-driven secondary polycythemia) 1
• Smoking history (carbon monoxide exposure causes "smoker's polycythemia" which resolves with cessation) 1

Non-hypoxic causes:

• Testosterone use (prescribed or unprescribed)—particularly important in young adults 1, 3
• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease producing erythropoietin 1
• Serum erythropoietin level to differentiate primary (low) from secondary (normal or elevated) causes 1

Physiologic variations to consider:

• Altitude adaptation (hemoglobin increases 0.2-4.5 g/dL at elevations 1000-4500 meters) 1
• Gender differences (males have higher baseline hemoglobin due to testosterone effects) 1

Management Based on Etiology

For Confirmed Polycythemia Vera

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk. 1 The CYTO-PV trial demonstrated that hematocrit <45% reduced cardiovascular death or major thrombosis to 2.7% versus 9.8% with hematocrit 45-50% (hazard ratio 3.91, P=0.007). 1 A slightly lower target of approximately 42% is reasonable for women and African Americans due to physiological differences. 1

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

Refer immediately to hematology for ongoing management. 1

For Secondary Erythrocytosis

Treat the underlying condition rather than performing routine phlebotomy: 1

• Smoking cessation for smoker's polycythemia
• CPAP therapy for obstructive sleep apnea
• Management of chronic lung disease
• Testosterone dose adjustment or discontinuation if causative 1, 4

Phlebotomy in secondary erythrocytosis is indicated ONLY when ALL of the following criteria are met: 1

• Hemoglobin >20 g/dL AND hematocrit >65%
• Documented symptoms of hyperviscosity (headache, blurred vision, confusion, bleeding)
• Patient is adequately hydrated (rehydrate with oral or IV normal saline first)
• Iron deficiency has been excluded (transferrin saturation ≥20%)
• Hematocrit remains elevated above baseline despite hydration

When phlebotomy is performed, remove approximately 300-450 mL per session and replace with equal volume of dextrose or saline to prevent further hemoconcentration. 1

Special Considerations for Cyanotic Congenital Heart Disease

Do NOT perform routine phlebotomy in patients with cyanotic congenital heart disease, as the erythrocytosis is a compensatory mechanism to optimize oxygen transport. 1 Evaluate for intercurrent issues (dehydration, iron deficiency, infection) rather than phlebotomy. 1

Critical Management Pitfalls to Avoid

Never perform repeated routine phlebotomies in secondary erythrocytosis, as this causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1

Never overlook coexisting iron deficiency in patients with erythrocytosis. 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. 1

Never perform phlebotomy without equal-volume fluid replacement, as this increases hemoconcentration and stroke risk. 1

Do not rely on mean corpuscular volume to screen for iron deficiency in erythrocytosis—it is unreliable. 1 Use serum ferritin, transferrin saturation, and iron levels instead.

Monitoring Strategy

For asymptomatic patients with JAK2-negative erythrocytosis and hematocrit <65%, serial hematologic assessment every 6-12 months is appropriate to detect progression or complications. 1

For patients on testosterone therapy, measure hemoglobin/hematocrit at baseline, 1-2 months after initiation, every 3-6 months during the first year, and annually thereafter if stable. 4 If hematocrit exceeds 54%, temporarily withhold testosterone or reduce dosage. 4

For confirmed polycythemia vera, monitor hemoglobin at least every 4 weeks during dose titration and after each therapeutic intervention. 1