What is the approach to a patient with elevated Hemoglobin (Hgb) and Hematocrit (Hct) with a normal Red Blood Cell (RBC) count?

Approach to Elevated Hemoglobin and Hematocrit with Normal RBC Count

This pattern suggests either a measurement artifact, relative polycythemia from plasma volume depletion, or a hemoglobinopathy causing increased hemoglobin content per cell—repeat the complete blood count using an automated analyzer and assess for dehydration, spurious results, and calculate the Hct/Hb ratio to guide further workup. 1

Initial Verification and Assessment

Confirm the Laboratory Findings

• Repeat the CBC using an automated cell counter to ensure standardized and accurate results, as automated analyzers provide more reliable measurements than manual methods 2
• Calculate the Hct/Hb ratio: The normal ratio is approximately 3:1 (e.g., Hct 30% with Hgb 10 g/dL) 3
  • A ratio >3.5 suggests alpha-thalassemia or other hemoglobinopathies 3
  • A normal ratio (2.9-3.2) with elevated Hgb/Hct but normal RBC count suggests relative polycythemia or measurement error 3

Rule Out Spurious Results

Common causes of falsely elevated Hgb/Hct with normal RBC count include: 4, 5

• Hyperlipidemia: Lipids interfere with hemoglobin measurement, causing falsely elevated values 4, 5
• Hyperglycemia: Falsely elevates MCV and calculated Hct by 2-4%, but does not affect hemoglobin measurement 2, 1
• Cold agglutinins or cryoglobulins: Can cause RBC clumping, affecting counts 4, 5
• Elevated WBC counts: Very high leukocyte counts can spuriously elevate hemoglobin readings 4, 5
• Sample storage issues: Hct can increase by 2-4% with prolonged storage (>8 hours at room temperature), while Hgb remains stable 2, 1

Key pitfall: Always check the mean corpuscular hemoglobin concentration (MCHC)—values >37 g/dL are physiologically impossible and indicate a spurious result 5

Assess for Relative Polycythemia

Relative polycythemia (elevated Hgb/Hct due to decreased plasma volume rather than increased RBC mass) is the most common cause of this pattern: 1

• Dehydration: Check volume status, recent fluid losses, diuretic use 1
• Stress polycythemia (Gaisböck syndrome): Typically seen in obese, hypertensive males who smoke 1
• Burns or third-spacing: Causes plasma volume contraction 1

If dehydration is present, rehydrate and recheck labs before pursuing extensive workup 1

Evaluate for Hemoglobinopathies

If the Hct/Hb ratio is >3.5, consider alpha-thalassemia or other hemoglobinopathies: 3

• Order hemoglobin electrophoresis or HPLC to identify variant hemoglobins 6
• Check RBC morphology: Look for microcytosis, target cells, or other abnormal forms 6
• Measure serum ferritin and transferrin saturation: Iron deficiency can coexist with hemoglobinopathies, causing microcytic polycythemia with elevated RBC count but paradoxically normal or reduced hemoglobin 1

Alpha-thalassemia trait commonly presents with normal or slightly elevated Hgb/Hct, normal RBC count, and microcytosis with an elevated Hct/Hb ratio 3

Consider Secondary Causes if True Erythrocytosis

If repeat testing confirms true elevation (not relative or spurious), evaluate for secondary causes: 1

• Smoking history: "Smoker's polycythemia" from chronic carbon monoxide exposure stimulates erythropoietin production 1
• Sleep study: Obstructive sleep apnea causes nocturnal hypoxemia driving erythropoietin production 1
• Chronic lung disease: COPD or other causes of chronic hypoxemia 1
• Testosterone use: Either prescribed or unprescribed, particularly in young adults 1
• Renal pathology: Renal cell carcinoma or other tumors producing erythropoietin 1

Determine Need for Further Workup

Order JAK2 mutation testing only if: 1

• Hemoglobin >18.5 g/dL in men or >16.5 g/dL in women (true polycythemia threshold) 1
• Hematocrit >55% in men or >49.5% in women 1
• No secondary cause identified 1

Do not pursue extensive polycythemia vera workup if values are only mildly elevated or if a secondary cause is identified 1

Management Considerations

• Therapeutic phlebotomy is indicated ONLY if hemoglobin >20 g/dL AND hematocrit >65% with symptoms of hyperviscosity 1
• Avoid repeated routine phlebotomies due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 1
• If iron deficiency is confirmed, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in RBC mass can occur 1
• Treat underlying secondary causes: smoking cessation, CPAP for sleep apnea, adjustment of testosterone therapy 1

Critical Pitfall to Avoid

Never assume true polycythemia without first ruling out relative polycythemia (dehydration) and spurious results (hyperlipidemia, hyperglycemia, sample storage issues)—these are far more common than primary erythrocytosis and require completely different management. 1, 4, 5