What causes an elevated red blood cell (RBC) count?

Causes of Elevated Red Blood Cell Count

An elevated RBC count results from either primary bone marrow disorders (most importantly polycythemia vera) or secondary causes driven by increased erythropoietin production from chronic hypoxia, with obstructive sleep apnea being a frequently overlooked but common etiology in obese patients.

Primary Causes: Myeloproliferative Disorders

Polycythemia vera (PV) is the most important primary cause, characterized by clonal proliferation of hematopoietic progenitor cells with erythrocytosis (hemoglobin >16.5 g/dL in men or >16.0 g/dL in women) as the required diagnostic criterion 1.

• More than 95% of PV patients harbor a JAK2 V617F mutation, which is essential for distinguishing PV from secondary causes 1.
• PV typically presents with more marked hemoglobin elevations (often >18.5 g/dL in men), along with thrombocytosis (53% of cases) and leukocytosis (49% of cases) 1.
• Associated symptoms include pruritus (33%), splenomegaly (36%), erythromelalgia (5.3%), and transient visual changes (14%) 1.
• The condition carries significant thrombotic risk, with 16% experiencing arterial thrombosis and 7% venous thrombosis at or before diagnosis 1.

Primary familial and congenital polycythemia (PFCP) represents an autosomal dominant primary polycythemia caused by defects intrinsic to erythroid progenitor cells, and must be distinguished from PV particularly in familial or childhood cases 2.

Secondary Causes: Hypoxia-Driven Erythrocytosis

Chronic Hypoxemia

Obstructive sleep apnea (OSA) is a critical and frequently missed cause, particularly in obese patients 3.

• Obesity (BMI >30) is the strongest risk factor for OSA, which causes chronic intermittent hypoxia leading to compensatory erythrocytosis 3.
• Patients typically present with chronic fatigue despite reporting "adequate sleep" because they are unaware of sleep fragmentation and nocturnal hypoxemia 3.
• The polycythemia is usually mild (hemoglobin 17-18 g/dL range), which is more consistent with secondary causes than PV 3.
• Serum erythropoietin levels are elevated or high-normal in hypoxia-driven secondary polycythemia 3.

Other hypoxic conditions that elevate RBC counts include 3:

• Chronic obstructive pulmonary disease (COPD)
• Chronic tobacco smoking 1
• High-altitude residence
• Chronic lung diseases causing sustained hypoxemia

Other Secondary Causes

Renal disorders can cause inappropriate erythropoietin production 4:

• Renal cell carcinoma
• Renal cysts
• Post-renal transplantation

Endocrine disorders associated with elevated RBC counts include:

• Testosterone therapy or abuse
• Cushing syndrome
• Pheochromocytoma

Diagnostic Algorithm

Initial Evaluation

1. Confirm true polycythemia by documenting elevated hemoglobin/hematocrit on repeat testing, distinguishing from relative polycythemia due to dehydration or plasma volume contraction 1.

2. Assess for secondary causes first before pursuing myeloproliferative workup 3:

   • Obtain detailed history focusing on obesity, snoring, daytime somnolence, smoking history
   • Check oxygen saturation; consider arterial blood gas if hypoxemia suspected
   • Order polysomnography (sleep study) if OSA suspected based on obesity and symptoms 3
   • Measure serum erythropoietin level (elevated in secondary causes, low-normal in PV) 3

3. Evaluate for polycythemia vera if secondary causes excluded 1:

   • Test for JAK2 V617F mutation (present in >95% of PV cases) 1
   • Assess complete blood count for thrombocytosis and leukocytosis (present in approximately half of PV cases) 1
   • Examine for splenomegaly (present in 36% of PV patients) 1
   • Consider bone marrow biopsy if JAK2 mutation positive, showing panmyelosis with prominent erythroid and megakaryocytic proliferation 3

Critical Pitfalls to Avoid

• Never assume "adequate sleep" rules out sleep apnea—patients with OSA are typically unaware of their sleep fragmentation and nocturnal arousals 3.
• Do not rush to diagnose polycythemia vera without excluding secondary causes, especially in obese patients with fatigue and only mild hemoglobin elevation 3.
• Recognize that mild hemoglobin elevation (less than 18.5 g/dL in men) is less typical of PV and should prompt thorough evaluation for secondary causes 3.
• Be aware that ICD coding alone is unreliable for distinguishing PV from secondary erythrocytosis, with 11% of patients having concurrent diagnosis codes requiring individual chart review for accurate classification 5.