What are the causes of elevated Red Blood Cell (RBC) levels, or erythrocytosis?

Causes of Elevated Red Blood Cell Levels (Erythrocytosis)

Elevated red blood cell levels (erythrocytosis) can be classified into primary and secondary causes, with primary causes stemming from intrinsic defects in red blood cell progenitors and secondary causes resulting from factors external to the erythroid compartment. 1, 2

Classification of Erythrocytosis

True Polycythemia vs. Apparent Polycythemia

• True polycythemia: Actual increase in red blood cell mass, which can be either clonal (polycythemia vera) or non-clonal (secondary polycythemia) 1
• Apparent polycythemia: Spurious increase due to reduced plasma volume (relative polycythemia) without actual increase in red blood cell mass 1
• Inapparent polycythemia: True increase in red blood cell mass masked by normal hemoglobin/hematocrit values due to concurrent increase in plasma volume 1

Primary Erythrocytosis

Acquired Primary Erythrocytosis

• Polycythemia vera (PV): Most common primary acquired cause, a clonal myeloproliferative neoplasm characterized by:
  • JAK2 V617F gene mutation (diagnostic criterion) 2, 3
  • Increased thrombophilia and microvascular disturbances 2
  • Low erythropoietin (EPO) levels 4

Congenital Primary Erythrocytosis

• Erythropoietin receptor (EPOR) gene mutations: Causing hypersensitivity to EPO 5
• Rare congenital disorders: Usually diagnosed at young age 2, 5

Secondary Erythrocytosis

Hypoxia-Driven Secondary Erythrocytosis

• Chronic pulmonary diseases: Leading to tissue hypoxia and increased EPO production 2
• Chronic heart diseases: Causing tissue hypoxia 2
• High altitude exposure: Environmental hypoxia triggering increased EPO production 4
• Smoking: Carbon monoxide exposure leading to smoker's polycythemia 1

Non-Hypoxia Driven Secondary Erythrocytosis

• EPO-secreting tumors: Including renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma 2, 3
• Renal diseases: Particularly renal cysts and hydronephrosis 3
• High-affinity hemoglobin variants: Most common cause of congenital secondary erythrocytosis (20% of cases), including Hb San Diego and others 5, 6
• Exogenous EPO administration: EPO doping 2
• Mutations in oxygen-sensing pathway: Including VHL, PHD2, and HIF2A mutations 4, 5

Molecular Basis of Erythrocytosis

• JAK2 mutations: Critical for diagnosis of polycythemia vera 3
• Oxygen-sensing pathway mutations:
  • VHL gene mutations (Chuvash polycythemia) 5
  • EGLN1 (PHD2) mutations 5
  • EPAS1 (HIF2A) mutations 5
• Hemoglobin variants: Mutations in HBB and HBA genes causing high oxygen affinity hemoglobins 5, 6

Diagnostic Considerations

• Serum erythropoietin measurement: Key diagnostic step to differentiate primary from secondary causes 2
• JAK2 mutation testing: Essential for diagnosing polycythemia vera 3
• Hemoglobin electrophoresis: To identify high-affinity hemoglobin variants 5
• Genetic testing: Including whole exome sequencing for identifying congenital causes 6

Clinical Implications

• Thrombotic risk: Increased risk of thromboembolism, particularly in polycythemia vera 2, 4
• Microvascular disturbances: Including erythromelalgia in polycythemia vera 1
• Management considerations:
  • Aspirin and phlebotomy as first-line treatments for polycythemia vera 2
  • Treatment of underlying causes in secondary erythrocytosis 4

Idiopathic Erythrocytosis

• Despite comprehensive investigation, approximately 64% of congenital erythrocytosis cases remain without identified molecular etiology 5
• These cases are classified as idiopathic erythrocytosis, though this is becoming less common as more genetic causes are discovered 4

Understanding the specific cause of erythrocytosis is essential for appropriate management and prevention of complications such as thromboembolism and microvascular disturbances.