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 using an automated cell counter, as hemoglobin is more accurate than hematocrit for diagnosis and monitoring. 1

Initial Verification and Laboratory Assessment

Hemoglobin is superior to hematocrit for evaluating erythrocytosis because hematocrit can falsely increase by 2-4% with sample storage beyond 8 hours, while hemoglobin remains stable. 1, 2 Additionally, hyperglycemia falsely elevates mean corpuscular volume (MCV) and calculated hematocrit but does not affect hemoglobin measurement. 1, 2

Define True Erythrocytosis

• Men: Hemoglobin >18.5 g/dL or hematocrit >52-55% 2
• Women: Hemoglobin >16.5 g/dL or hematocrit >48-49.5% 2

Essential Initial Laboratory Tests

• Complete blood count with red cell indices (MCV, MCH, MCHC, RDW) using automated analyzer 1, 2
• Reticulocyte count to assess bone marrow response 1, 2
• Serum ferritin and transferrin saturation (iron deficiency frequently coexists with erythrocytosis) 1, 2
• Peripheral blood smear review for red cell morphology 2
• White blood cell differential and platelet count (thrombocytosis or leukocytosis suggests myeloproliferative disorder) 1, 2

Common pitfall: Mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis—always measure serum ferritin and transferrin saturation directly. 2

Distinguish Relative from Absolute Polycythemia

Assess for Relative Polycythemia (Decreased Plasma Volume)

• Dehydration, diuretic use, burns, or third-spacing 2, 3
• Stress polycythemia (Gaisböck syndrome)—typically obese, hypertensive males who smoke 2, 3
• Management: Rehydration is first-line therapy; repeat measurements after adequate hydration 2

Evaluate for Secondary Causes of Absolute Erythrocytosis

If true erythrocytosis is confirmed, systematically evaluate secondary causes before pursuing polycythemia vera workup:

Hypoxia-Driven Causes

• Smoking history: "Smoker's polycythemia" from chronic carbon monoxide exposure stimulates erythropoietin production; resolves with smoking cessation 2
• Sleep study for obstructive sleep apnea (nocturnal hypoxemia drives erythropoietin) 2
• Pulmonary function tests and chest imaging for chronic obstructive pulmonary disease 2
• Arterial oxygen saturation <92% indicates hypoxic secondary polycythemia 2
• Cyanotic congenital heart disease with right-to-left shunting causes compensatory erythrocytosis to optimize oxygen transport 2

Non-Hypoxic Secondary Causes

• Testosterone use (prescribed or unprescribed)—common in young adults 2
• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease producing erythropoietin 2
• Other erythropoietin-producing tumors: hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma 2
• Erythropoietin therapy 2

Rare Genetic Causes

• High-oxygen-affinity hemoglobin variants 2
• Erythropoietin receptor mutations 2
• Chuvash polycythemia (von Hippel-Lindau gene mutation) 2

Test for Polycythemia Vera

Order JAK2 mutation testing (both exon 14 V617F and exon 12) if hemoglobin and hematocrit meet diagnostic thresholds and no secondary cause is identified. 2 JAK2 mutations are present in up to 97% of polycythemia vera cases. 2

WHO Diagnostic Criteria for Polycythemia Vera

Diagnosis requires EITHER:

• Both major criteria PLUS one minor criterion, OR
• First major criterion PLUS two minor criteria 2

Major Criteria:

1. Hemoglobin >16.5 g/dL (women) or >18.5 g/dL (men); OR hematocrit >48-49% (women) or >52% (men) 2
2. Presence of JAK2 mutation (V617F or exon 12) 2
3. Bone marrow biopsy showing hypercellularity with trilineage myeloproliferation 2

Minor Criteria:

1. Subnormal serum erythropoietin level 2
2. Endogenous erythroid colony formation in vitro 2

When to Perform Bone Marrow Biopsy

• If JAK2 mutation is positive: Bone marrow biopsy is required to confirm polycythemia vera diagnosis and assess for trilineage myeloproliferation 2
• If diagnosis remains unclear after initial workup to exclude other myeloid neoplasms 2

Management Based on Etiology

For Polycythemia Vera

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk. 2 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). 2 A slightly lower target of approximately 42% is reasonable for women and African Americans. 2

• Initiate low-dose aspirin (81-100 mg daily) as second cornerstone of therapy for thrombosis prevention 2
• Phlebotomy technique: Remove 300-450 mL per session with hemodynamic monitoring 2
• Refer immediately to hematology for confirmed polycythemia vera 2

For Secondary Erythrocytosis

Treatment of the underlying condition is necessary—therapeutic phlebotomy is rarely indicated and potentially harmful. 2

• Smoking cessation for smoker's polycythemia 2
• CPAP therapy for obstructive sleep apnea 2
• Management of chronic lung disease 2
• Testosterone dose adjustment or discontinuation if causative 2
• Supplemental oxygen if arterial oxygen saturation <92% 2

Critical Phlebotomy Guidelines for Secondary Erythrocytosis

Routine or repeated phlebotomies are explicitly contraindicated in secondary polycythemia due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 2

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

• Hemoglobin >20 g/dL AND hematocrit >65% 2
• Documented symptoms of hyperviscosity (headache, blurred vision, confusion, bleeding) 2
• Patient is adequately hydrated (rehydration with oral fluids or IV normal saline is first-line therapy) 2
• Iron deficiency has been excluded (transferrin saturation ≥20%) 2
• Hematocrit remains elevated above baseline despite hydration 2

When phlebotomy is performed, replace the removed blood volume with equal amount of dextrose or saline to prevent hemoconcentration and reduce stroke risk. 2

Iron Management in Erythrocytosis

Iron deficiency frequently coexists with erythrocytosis and requires opposite management—iron supplementation rather than phlebotomy. 2 Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 2

• If transferrin saturation <20%: Initiate cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur 2
• Never perform phlebotomy in the presence of iron deficiency 2

Special Populations and Considerations

Cyanotic Congenital Heart Disease

• Secondary erythrocytosis is a compensatory mechanism to optimize oxygen transport 2
• Evaluate for intercurrent issues (dehydration, iron deficiency, infection) rather than performing phlebotomy 2
• Phlebotomy indicated only if hematocrit >65% with hyperviscosity symptoms after excluding dehydration 2

Altitude Adaptation

• Physiologic adaptation to altitude increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters) 2
• Adjust diagnostic thresholds for altitude of residence 2

Monitoring for Asymptomatic Mild Erythrocytosis

• If hematocrit remains below sex-specific thresholds (≤52% men, ≤48% women), observation with serial hemoglobin/hematocrit measurements every 6-12 months is appropriate 2
• Avoid routine phlebotomy in mild asymptomatic cases 2

Referral Indications

Refer immediately to hematology if:

• JAK2 mutation is positive 2
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 2
• Unexplained splenomegaly 2
• Unexplained cytopenias in other cell lines 2
• Diagnosis remains unclear after initial workup 2

Common Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement—this increases hemoconcentration and stroke risk 2
• Never perform routine or repeated phlebotomies in secondary erythrocytosis—this causes iron depletion and paradoxically increases stroke risk 2
• Never overlook coexisting iron deficiency—it mimics hyperviscosity but requires iron supplementation, not phlebotomy 2
• Never rely on MCV alone to screen for iron deficiency in erythrocytosis—always measure ferritin and transferrin saturation 2
• Never use standard polycythemia vera diagnostic thresholds at high altitude without adjustment for physiologic adaptation 2