What are the causes of an elevated red blood cell (RBC) count (erythrocytosis)?

Causes of Elevated Red Blood Cell Count (Erythrocytosis)

Elevated RBC count results from either primary bone marrow disorders (most commonly polycythemia vera with JAK2 mutation) or secondary causes including chronic hypoxia from sleep apnea, smoking, lung disease, high altitude, or inappropriate erythropoietin production from renal tumors, testosterone therapy, and other endocrine disorders. 1, 2, 3

Primary Causes (Clonal Disorders)

Polycythemia vera (PV) is the most important primary cause, characterized by:

• JAK2 mutation present in >95% of cases (either V617F in exon 14 or exon 12 mutations) 2, 4
• Constitutive activation of JAK-STAT signaling causing erythropoietin-independent red cell production 2
• Often accompanied by thrombocytosis (53%) and leukocytosis (49%) 4
• Can be masked by concurrent iron deficiency, presenting as microcytic polycythemia with elevated RBC count but normal hemoglobin/hematocrit 2, 5

Rare genetic causes include:

• High-oxygen-affinity hemoglobin variants 2
• Erythropoietin receptor mutations 2, 6
• Chuvash polycythemia (VHL gene mutation) 2, 7

Secondary Causes (Reactive Erythrocytosis)

Hypoxia-Driven Causes

Obstructive sleep apnea (OSA) is a critical and often overlooked cause:

• Strongly associated with obesity (BMI >30) 1
• Produces chronic intermittent nocturnal hypoxemia driving erythropoietin production 1, 2
• Patients often report chronic fatigue despite "adequate sleep" 1
• Polysomnography should be ordered if OSA suspected based on obesity, snoring, and daytime somnolence 1

Smoking causes "smoker's polycythemia":

• Carbon monoxide exposure creates chronic tissue hypoxia 2, 3
• Stimulates compensatory erythropoietin production 2
• Resolves with smoking cessation 2

Chronic lung disease:

• COPD with chronic hypoxemia 1, 2
• Cyanotic congenital heart disease with right-to-left shunting 8, 2

High-altitude residence:

• Physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters) 2
• Diagnostic thresholds must be adjusted for altitude of residence 2

Hypoxia-Independent Causes

Inappropriate erythropoietin production:

• Renal cell carcinoma 1, 2
• Renal cysts 1
• Hepatocellular carcinoma 2
• Pheochromocytoma, uterine leiomyoma, meningioma 2

Endocrine and pharmacologic causes:

• Testosterone therapy or abuse (critical consideration in young adults) 1, 2
• Cushing syndrome 1
• Erythropoietin-stimulating agent overdosage 9
• SGLT2 inhibitors (may activate HIF-2α and unmask PV) 9

Post-renal transplant erythrocytosis 9

Relative Polycythemia (Plasma Volume Depletion)

Not true erythrocytosis but appears elevated:

• Dehydration 2
• Diuretic use 2
• Burns 2
• Stress polycythemia (Gaisböck syndrome) 2

Diagnostic Approach Algorithm

Step 1: Confirm True Erythrocytosis

• Repeat hemoglobin/hematocrit to confirm persistent elevation (single measurement unreliable) 2
• Diagnostic thresholds: Hgb >18.5 g/dL (men) or >16.5 g/dL (women); Hct >55% (men) or >49.5% (women) 2
• Adjust thresholds for altitude of residence 2

Step 2: Initial Laboratory Workup

• Complete blood count with red cell indices, reticulocyte count, differential 2
• Serum ferritin, transferrin saturation (iron deficiency can mask PV) 2, 5
• Serum erythropoietin level (low/normal suggests PV; elevated suggests secondary cause) 1, 2
• Oxygen saturation measurement (if <92%, suggests hypoxic cause) 2

Step 3: Test for Primary Cause

• JAK2 mutation testing (exon 14 V617F and exon 12) if erythropoietin low/normal 2, 4
• Bone marrow biopsy if JAK2 positive to confirm PV diagnosis 2

Step 4: Evaluate Secondary Causes if JAK2 Negative

Assess for hypoxic causes:

• Sleep study if obesity, snoring, daytime somnolence present 1, 2
• Pulmonary function tests and chest imaging for COPD 2
• Smoking history and carbon monoxide exposure 2
• Echocardiography if cyanotic heart disease suspected 2

Assess for non-hypoxic causes:

• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, cysts 2
• Medication review for testosterone, erythropoietin, SGLT2 inhibitors 2, 9
• Endocrine evaluation if Cushing syndrome suspected 1

Critical Diagnostic Pitfalls

Iron deficiency masking polycythemia vera:

• Up to 73.9% of masked PV cases have elevated RBC count despite normal Hgb/Hct 5
• Microcytic indices (low MCV) with elevated RBC count should raise suspicion 2, 5
• Mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis—must check ferritin and transferrin saturation 2
• 100% of masked PV cases in one series were JAK2 positive 5

Dehydration causing spurious elevation:

• Always assess hydration status before pursuing extensive workup 2
• Relative polycythemia resolves with rehydration 2

Altitude adjustment failure:

• Standard PV thresholds cannot be applied at high altitude without adjustment 2
• Physiologic increases range from 0.2 g/dL at 1000m to 4.5 g/dL at 4500m 2

Overlooking secondary causes before myeloproliferative workup:

• The American College of Physicians recommends assessing for OSA, COPD, and high-altitude residence before pursuing JAK2 testing 1
• Detailed history focusing on obesity, snoring, smoking, and medications is essential 1, 2