What causes elevated red blood cells (RBCs)?

Elevated Red Blood Cell Count: Causes and Diagnostic Approach

Elevated red blood cell count (erythrocytosis) results from either primary bone marrow disorders like polycythemia vera or secondary causes including chronic hypoxia (sleep apnea, COPD, smoking), renal disorders, testosterone use, and relative polycythemia from dehydration. 1, 2

Primary vs. Secondary Causes

Primary Polycythemia

• Polycythemia vera is a myeloproliferative disorder with JAK2 mutation present in up to 97% of cases, causing autonomous overproduction of red blood cells independent of erythropoietin levels 2, 3
• Rare genetic causes include high-oxygen-affinity hemoglobin variants, erythropoietin receptor mutations, and Chuvash polycythemia (von Hippel-Lindau gene mutation) 2

Secondary Causes (Hypoxia-Driven)

• Obstructive sleep apnea (OSA) is particularly common in patients with BMI >30, causing chronic intermittent nocturnal hypoxemia that stimulates compensatory erythropoietin production, often presenting with chronic fatigue despite "adequate sleep" 1, 2
• Chronic obstructive pulmonary disease (COPD) and other chronic lung diseases cause persistent hypoxemia leading to compensatory erythrocytosis 1, 4
• Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure, which creates tissue hypoxia and stimulates erythropoietin production; this resolves with smoking cessation 2, 5
• High-altitude residence causes physiological erythrocytosis as an adaptive response, with specific hemoglobin increases based on altitude (e.g., +0.8 g/dL at 2,000 meters, +1.9 g/dL at 3,000 meters) 2
• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport 6, 2

Secondary Causes (Hypoxia-Independent)

• Renal disorders including renal cell carcinoma and renal cysts produce inappropriate erythropoietin, causing elevated RBC count 1
• Testosterone therapy or abuse directly stimulates erythropoiesis and is a common cause in young adults 1, 2
• Other malignancies including hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently 2
• Cushing syndrome and other endocrine disorders can be associated with elevated RBC count 1

Relative Polycythemia (Apparent)

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause plasma volume depletion without true increase in red cell mass 2, 7

Diagnostic Algorithm

Step 1: Confirm True Polycythemia

• Repeat hemoglobin and hematocrit measurements, as single values are unreliable; true polycythemia is defined as hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women 2
• Hemoglobin is more accurate than hematocrit because hematocrit can falsely increase by 2-4% with prolonged sample storage and is affected by hyperglycemia, while hemoglobin remains stable 2

Step 2: Initial Laboratory Workup

• Complete blood count with red cell indices, reticulocyte count, and differential to assess for isolated erythrocytosis versus other cytopenias 1, 2
• Serum ferritin, transferrin saturation, and C-reactive protein to evaluate iron status and inflammation 1, 2
• Peripheral blood smear review by a qualified hematologist to identify abnormal morphology 6, 2
• High RDW with normal or low MCV suggests coexisting iron deficiency with erythrocytosis, which is common and requires specific evaluation 2

Step 3: Assess for Secondary Causes First

• Detailed history focusing on: obesity, snoring, daytime somnolence (OSA); smoking history and pack-years; chronic lung disease symptoms; high-altitude residence; testosterone use (prescribed or unprescribed); renal disease history 1, 2
• Oxygen saturation measurement and consider arterial blood gas if hypoxemia suspected 1
• Order polysomnography (sleep study) if OSA suspected based on obesity (BMI >30), snoring, and daytime somnolence 1
• Chest imaging if COPD or other pulmonary disease suspected 2
• Renal imaging if renal pathology suspected (ultrasound or CT) 1

Step 4: Measure Serum Erythropoietin Level

• Low or inappropriately normal erythropoietin suggests primary polycythemia (polycythemia vera) 1, 2
• Elevated erythropoietin suggests secondary polycythemia from hypoxia or inappropriate production 1, 2

Step 5: JAK2 Mutation Testing

• Test for JAK2 V617F (exon 14) and JAK2 exon 12 mutations if primary polycythemia suspected 2
• Positive JAK2 mutation with elevated hemoglobin/hematocrit confirms polycythemia vera and requires hematology referral 2, 3

Critical Management Considerations

When to Perform Phlebotomy

• Therapeutic phlebotomy is indicated ONLY when hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity (headache, dizziness, visual disturbances), and only after excluding dehydration 2
• When phlebotomy is performed, replace with equal volume of dextrose or saline to prevent further hemoconcentration 2
• Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and increased stroke risk 2

Iron Management Pitfall

• Avoid iron deficiency even in the presence of erythrocytosis, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk 2
• If iron deficiency is confirmed (ferritin low, transferrin saturation low), provide cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur 2
• Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; always use ferritin and transferrin saturation 2

Treatment of Underlying Causes

• For OSA: CPAP therapy is the primary treatment and will reduce erythrocytosis 2
• For smoking: Smoking cessation resolves smoker's polycythemia 2, 5
• For testosterone use: Dose reduction or temporary discontinuation with close hematocrit monitoring 2
• For polycythemia vera: Maintain hematocrit strictly <45% through phlebotomy to reduce thrombotic risk, plus low-dose aspirin as second cornerstone of therapy 2

Common Pitfalls to Avoid

• Don't assume anemia of chronic disease protects against erythrocytosis—patients with cyanotic heart disease can have both conditions simultaneously 6
• Don't perform aggressive phlebotomy without volume replacement, as this worsens hyperviscosity through hemoconcentration 2
• Don't overlook coexisting iron deficiency, particularly in cyanotic heart disease or polycythemia vera, which causes microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin 2
• Don't rely on single measurements—confirm with repeat testing before pursuing extensive workup 2
• Don't forget physiological variations: males have higher hemoglobin than females (15.5±2.0 vs 14.0±2.0 g/dL), and altitude adjustments are necessary 2