What is the evaluation and management approach for a patient with elevated hemoglobin (Hb) and hematocrit (Hct) with increased red blood cell (RBC) count?

Evaluation of Elevated Hemoglobin and Hematocrit with Increased RBC Count

Begin by confirming true erythrocytosis with repeat measurements showing hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women, then proceed with a systematic workup to distinguish primary from secondary causes. 1

Initial Laboratory Workup

The first step requires comprehensive laboratory testing to characterize the erythrocytosis and identify potential causes:

• Complete blood count with red cell indices using an automated analyzer to assess all cell lines and detect abnormalities in white blood cells or platelets that might suggest a myeloproliferative disorder 1
• Reticulocyte count to evaluate bone marrow response 2
• Serum ferritin and transferrin saturation to assess iron status, as iron deficiency can coexist with erythrocytosis, particularly in polycythemia vera 1
• C-reactive protein (CRP) to evaluate for inflammatory conditions 1
• Peripheral blood smear review to assess red cell morphology and identify abnormalities 2

Hemoglobin is the preferred measurement over hematocrit because it is more reproducible across laboratories and remains stable during sample storage, whereas hematocrit can falsely increase by 2-4% with prolonged storage and is affected by hyperglycemia 2, 1

Distinguishing Primary from Secondary Erythrocytosis

Measure serum erythropoietin level as the critical next step: 1, 3

• Low erythropoietin indicates primary erythrocytosis (polycythemia vera or other primary causes)
• Normal or elevated erythropoietin indicates secondary erythrocytosis (hypoxia-driven or other secondary causes)

Evaluation for Primary Erythrocytosis (Low Erythropoietin)

When erythropoietin is low, test for JAK2 mutations (both exon 14 V617F and exon 12) as the definitive diagnostic step for polycythemia vera 1, 3

Polycythemia vera diagnosis requires: 1

• Both major criteria: elevated hemoglobin/hematocrit/RBC mass AND presence of JAK2 mutation, PLUS at least one minor criterion
• OR first major criterion plus at least two minor criteria

If JAK2 testing is negative in a young patient or those with family history, consider referral to hematology for evaluation of rare congenital primary causes including erythropoietin receptor mutations, high-oxygen-affinity hemoglobin variants, or Chuvash polycythemia 1, 3

Evaluation for Secondary Erythrocytosis (Normal/Elevated Erythropoietin)

Hypoxia-Driven Causes

Systematically evaluate for conditions causing tissue hypoxemia:

• Smoking history and carbon monoxide exposure: "Smoker's polycythemia" results from chronic carbon monoxide exposure causing tissue hypoxia and stimulating erythropoietin production 1
• Sleep study if nocturnal hypoxemia suspected: Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production 1
• Pulmonary function testing: Evaluate for chronic obstructive pulmonary disease (COPD) or other chronic lung diseases 1
• Cyanotic congenital heart disease: Right-to-left shunting causes hypoxemia, and erythrocytosis is a compensatory mechanism to optimize oxygen transport 1
• Altitude history: Normal hemoglobin increases occur with altitude adaptation (e.g., +0.8 g/dL at 2,000 meters, +1.9 g/dL at 3,000 meters) 1

Hypoxia-Independent Secondary Causes

• Imaging studies to evaluate for erythropoietin-producing tumors: renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, or meningioma 1
• Medication review for exogenous erythropoietin therapy or testosterone use (prescribed or unprescribed), which can cause erythrocytosis particularly in young adults 1
• Renal function assessment for renal dysfunction that may affect erythropoietin regulation 1

Relative Polycythemia (Plasma Volume Depletion)

Assess for dehydration, diuretic use, burns, or stress polycythemia (Gaisböck syndrome) by evaluating hydration status and clinical context 1

Special Diagnostic Considerations

Iron deficiency can coexist with erythrocytosis, particularly in cyanotic heart disease or polycythemia vera, causing microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin 1. Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; serum ferritin, transferrin saturation, and iron levels are required for accurate diagnosis 1.

High RDW with normal or low MCV suggests possible iron deficiency coexisting with erythrocytosis 1

Management Principles

When Phlebotomy is Indicated

Therapeutic phlebotomy is indicated ONLY when: 1

• Hemoglobin >20 g/dL AND hematocrit >65%
• Patient has symptoms of hyperviscosity
• Dehydration has been excluded

Critical pitfall: Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and increased stroke risk 1. When phlebotomy is performed, replace with equal volume of dextrose or saline to prevent further hemoconcentration 1.

Iron Management in Erythrocytosis

Iron deficiency should be avoided even in the presence of erythrocytosis because iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1. If iron deficiency is confirmed, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur 1.

Treatment of Secondary Causes

For secondary erythrocytosis, treat the underlying condition: 1

• Smoking cessation for smoker's polycythemia
• CPAP therapy for obstructive sleep apnea
• Management of COPD or other pulmonary disease
• Dose adjustment or discontinuation of testosterone if causative

Polycythemia Vera Management

For confirmed polycythemia vera, maintain hematocrit strictly below 45% through phlebotomy to efficiently reduce thrombotic risk 2. Low-dose aspirin is recommended as the second cornerstone of therapy 2. Hydroxyurea is recommended as first-line cytoreductive therapy for high-risk patients (>60 years or history of vascular events) 2.

Referral Indications

Refer to hematology when: 1, 3

• JAK2-positive polycythemia vera confirmed
• Young patient with erythrocytosis (consider congenital causes)
• Family history of erythrocytosis
• JAK2-negative with low erythropoietin (rare primary causes)
• Unclear etiology after initial workup