How should an adult with an elevated hematocrit be evaluated and managed?

Evaluation and Management of Elevated Hematocrit in Adults

For adults with elevated hematocrit, first confirm true erythrocytosis with repeat measurements (hemoglobin >18.5 g/dL in men or >16.5 g/dL in women; hematocrit >55% in men or >49.5% in women), then immediately test for JAK2 mutation to distinguish polycythemia vera from secondary causes, as this fundamentally determines whether aggressive hematocrit reduction is beneficial or harmful. 1

Initial Diagnostic Confirmation and Laboratory Workup

Confirm the elevation with repeated measurements, as a single value is unreliable. 1 Serial measurements over time are essential for borderline cases. 1

Once confirmed, obtain the following initial laboratory panel:

• Complete blood count with red cell indices, reticulocyte count, and differential 1
• Serum ferritin and transferrin saturation (iron deficiency commonly coexists and requires opposite management) 2, 1
• C-reactive protein 1
• JAK2 mutation testing (both exon 14 V617F and exon 12) - this is the cornerstone test that detects up to 97% of polycythemia vera cases 1, 3

Note that hemoglobin is more reliable than hematocrit for monitoring, as hematocrit can falsely increase by 2-4% with sample storage and is affected by hyperglycemia, while hemoglobin remains stable. 1

Critical Distinction: Polycythemia Vera vs. Secondary Erythrocytosis

This distinction is absolutely essential because management is fundamentally different:

If JAK2 Mutation is POSITIVE (Polycythemia Vera):

Maintain hematocrit strictly below 45% through therapeutic phlebotomy. 1, 3 This target is evidence-based from the CYTO-PV trial, which demonstrated reduction in cardiovascular death and major thrombotic events from 9.8% to 2.7% (HR 3.91). 3

Phlebotomy protocol for polycythemia vera: 3

• Induction phase: Remove 300-450 mL weekly or twice weekly until hematocrit <45%
• Maintenance phase: Same volume per session with intervals determined by hematocrit monitoring
• Always replace with equal volume of fluid 2

Add low-dose aspirin 100 mg daily for all polycythemia vera patients unless contraindicated. 3

Cytoreductive therapy is mandatory if: 3

• Age ≥60 years
• History of prior thrombosis
• Poor phlebotomy tolerance
• Symptomatic or progressive splenomegaly
• Platelet count >1,500 × 10⁹/L
• Leukocyte count >15 × 10⁹/L

First-line cytoreductive agents include hydroxyurea or interferon alfa/pegylated interferon. 3

If JAK2 Mutation is NEGATIVE (Secondary Erythrocytosis):

Routine phlebotomy is explicitly contraindicated and harmful. 2, 3 Secondary erythrocytosis represents a physiological compensatory response where the body's homeostatic mechanisms optimize oxygen delivery. 2, 3

Phlebotomy in secondary erythrocytosis is indicated ONLY when ALL of the following criteria are met: 2, 1, 3

• Hemoglobin >20 g/dL AND hematocrit >65%
• Documented symptoms of hyperviscosity (headache, blurred vision, confusion, bleeding)
• Patient is adequately hydrated
• Iron deficiency has been excluded
• Hematocrit remains elevated above patient's baseline despite hydration

First-line therapy for suspected hyperviscosity is rehydration with oral fluids or intravenous normal saline—not phlebotomy. 2, 3, 4

Systematic Evaluation for Secondary Causes (if JAK2 negative)

Evaluate the following potential causes systematically: 1

Hypoxic causes:

• Sleep study for obstructive sleep apnea 1
• Pulmonary function tests and chest imaging for COPD 1
• Arterial oxygen saturation (if <92%, indicates hypoxia-driven erythrocytosis) 1
• Smoking history and carbon monoxide exposure 1
• Cyanotic congenital heart disease 2, 3

Non-hypoxic causes:

• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease 1
• Medication review, particularly testosterone use (prescribed or unprescribed) 1
• Erythropoietin-producing tumors (hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma) 1

Relative polycythemia (plasma volume depletion):

• Assess hydration status 1
• Review diuretic use 1
• Consider stress polycythemia (Gaisböck syndrome) 1

Critical Management of Iron Status

Iron deficiency is frequently encountered in erythrocytosis and requires assessment with serum iron, ferritin, and transferrin levels—mean corpuscular volume is NOT a reliable screening test. 2, 1

Iron deficiency in the context of erythrocytosis is particularly dangerous because it:

• Produces symptoms identical to hyperviscosity (creating diagnostic confusion) 2, 4
• Reduces hemoglobin without proportionally lowering hematocrit 2
• Compromises oxygen transport without lowering viscosity 2
• Increases risk of stroke and myocardial ischemia 2, 3
• Requires the opposite treatment (iron supplementation, not phlebotomy) 2

If transferrin saturation <20%, treat with cautious oral iron supplementation until stores are replete, with close hemoglobin monitoring. 2, 1, 3

Common Pitfalls to Avoid

Never perform routine or repeated phlebotomies in secondary erythrocytosis. This causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 2, 1, 3

Never perform phlebotomy without equal volume fluid replacement, as this increases hemoconcentration and stroke risk. 2, 3

Do not overlook coexisting iron deficiency in patients with erythrocytosis—it mimics hyperviscosity but requires opposite management. 2, 3, 4

Do not rely on symptom severity to guide phlebotomy decisions in secondary erythrocytosis, as symptoms do not correlate reliably with measured hematocrit or viscosity levels. 2, 4

Recognize that dehydration must be excluded first, as it exacerbates symptoms and mimics true hyperviscosity. 4

Monitoring and Follow-Up

For polycythemia vera patients: 3

• Monitor complete blood count every 2-4 weeks during induction, then every 3 months
• Assess response using European LeukemiaNet criteria
• Monitor for disease transformation

For secondary erythrocytosis patients: 3

• Monitor hematocrit every 3-6 months
• Assess iron status regularly
• Evaluate for progression of underlying disease
• Treat the underlying condition (smoking cessation, CPAP for sleep apnea, management of COPD) 1, 3

When to Refer to Hematology

Immediate referral is indicated for: 1

• Positive JAK2 mutation
• Hemoglobin >20 g/dL with symptoms of hyperviscosity
• Unexplained splenomegaly
• Diagnosis remains unclear after initial workup
• Unexplained cytopenias in other cell lines 1