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

Evaluation and Management of Elevated Hemoglobin and Hematocrit

For a patient with elevated hemoglobin and hematocrit, first confirm true erythrocytosis with repeat automated measurements (using hemoglobin preferentially), then systematically evaluate for secondary causes before considering polycythemia vera, and reserve therapeutic phlebotomy only for hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms. 1

Initial Confirmation and Laboratory Assessment

Repeat measurements using an automated cell counter to verify true elevation, as hemoglobin is more reliable than hematocrit for diagnosis and monitoring because hematocrit can falsely increase by 2-4% with prolonged sample storage (>8 hours) while hemoglobin remains stable. 1, 2

• Hyperglycemia can falsely elevate mean corpuscular volume and calculated hematocrit but does not affect hemoglobin measurement, making hemoglobin the preferred parameter. 1, 2

Diagnostic thresholds for true erythrocytosis:

• Men: Hemoglobin >18.5 g/dL or hematocrit >55% 1
• Women: Hemoglobin >16.5 g/dL or hematocrit >49.5% 1

Order the following initial laboratory panel immediately: 1

• Complete blood count with red cell indices (MCV, MCH, MCHC, RDW)
• Reticulocyte count to assess bone marrow response
• Peripheral blood smear review for red cell morphology
• Serum ferritin and transferrin saturation (iron deficiency frequently coexists with erythrocytosis)
• C-reactive protein to identify inflammatory conditions
• White blood cell differential and platelet count (thrombocytosis or leukocytosis suggests myeloproliferative disorder)

Distinguish Relative from Absolute Polycythemia

Assess for relative polycythemia (decreased plasma volume) before pursuing extensive workup, as this is the most common cause of borderline elevations. 2

Evaluate for: 1, 2

• Dehydration status and recent fluid losses
• Diuretic use
• Burns or third-spacing conditions
• Stress polycythemia (Gaisböck syndrome)—typically seen in obese, hypertensive males who smoke

If relative polycythemia is confirmed, address the underlying volume depletion rather than pursuing further hematologic evaluation. 2

Systematic Evaluation for Secondary Causes

Before testing for polycythemia vera, systematically exclude secondary causes of erythrocytosis: 1

Hypoxia-Driven Causes

• Smoking history and carbon monoxide exposure—"smoker's polycythemia" resolves with smoking cessation 1
• 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 measurement—values <92% indicate hypoxemia-driven secondary polycythemia 1

Hypoxia-Independent Causes

• Testosterone use (prescribed or unprescribed)—common in young adults and requires dose adjustment or discontinuation 1
• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease producing erythropoietin 1
• Erythropoietin therapy in chronic kidney disease patients 1
• Other malignancies: hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma 1

Physiological Variations

• Altitude of residence—hemoglobin increases 0.2-4.5 g/dL at elevations of 1,000-4,500 meters; adjust diagnostic thresholds accordingly 1
• Gender differences—males have higher baseline hemoglobin (15.5±2.0 g/dL) than menstruating females (14.0±2.0 g/dL) due to testosterone effects 1

Testing for Polycythemia Vera

Order JAK2 mutation testing (both exon 14 V617F and exon 12) if: 1

• Hemoglobin and hematocrit exceed diagnostic thresholds
• No secondary cause is identified
• JAK2 mutations are present in up to 97% of polycythemia vera cases

WHO diagnostic criteria for polycythemia vera require EITHER: 1

• Both major criteria (elevated hemoglobin/hematocrit/RBC mass 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 growth
• Subnormal serum erythropoietin level
• Endogenous erythroid colony formation

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

Critical Management Principles

When Phlebotomy Is Indicated

Therapeutic phlebotomy is indicated ONLY when ALL of the following are met: 1

• Hemoglobin >20 g/dL AND hematocrit >65%
• Documented symptoms of hyperviscosity (headache, blurred vision, confusion, bleeding)
• Dehydration has been excluded
• Patient is adequately hydrated

For confirmed polycythemia vera specifically, maintain hematocrit strictly <45% through phlebotomy to reduce thrombotic risk (CYTO-PV trial showed 2.7% vs 9.8% event rate, P=0.007); a lower target of 42% is reasonable for women and African Americans. 1

When performing phlebotomy, replace removed blood volume with equal amount of dextrose or saline to prevent further hemoconcentration and reduce stroke risk. 1

When Phlebotomy Is Contraindicated

Repeated routine phlebotomies are explicitly contraindicated in secondary erythrocytosis due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1

Never perform phlebotomy in: 1

• Cyanotic congenital heart disease (erythrocytosis is compensatory for right-to-left shunting)
• Patients with iron deficiency (transferrin saturation <20%)
• Secondary polycythemia with hematocrit <65% without hyperviscosity symptoms

Iron Management

Iron deficiency frequently coexists with erythrocytosis and requires opposite management. 1

• Mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis—use serum ferritin, transferrin saturation, and iron levels 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

Treatment of Underlying Conditions

For secondary erythrocytosis, treatment of the underlying condition is necessary: 1

• Smoking cessation for smoker's polycythemia
• CPAP therapy for obstructive sleep apnea
• Management of chronic lung disease
• Dose adjustment or temporary discontinuation of testosterone therapy
• Supplemental oxygen if arterial saturation <92%

Polycythemia Vera-Specific Management

In addition to maintaining hematocrit <45%, initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention. 1

Consider cytoreductive therapy (hydroxyurea, interferon-α-2a, or ruxolitinib) when phlebotomy volume becomes excessive or when thrombocytosis or leukocytosis is present. 1

Referral Indications

Refer immediately to hematology if: 1

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

Common Pitfalls to Avoid

• Do not rely on a single measurement—borderline values require repeat testing for confirmation 1
• Do not perform aggressive phlebotomy without adequate volume replacement—this increases 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 can increase hemoglobin by 0.2-4.5 g/dL depending on elevation 1
• Do not perform routine phlebotomies in secondary erythrocytosis—this causes harm through iron depletion and increased stroke risk 1

Monitoring for Borderline or Asymptomatic Cases

For patients with borderline elevated hematocrit who do not meet diagnostic thresholds, serial measurements every 6-12 months are appropriate rather than immediate therapeutic intervention. 1