What causes erythrocytosis (elevated red blood cells)?

Causes of Elevated Red Blood Cells (Erythrocytosis)

Erythrocytosis is primarily caused by hypoxemia, genetic mutations affecting oxygen sensing pathways, or myeloproliferative disorders, with the most common cause being chronic hypoxia from cardiopulmonary diseases. 1

Primary Causes (Intrinsic to Bone Marrow)

Polycythemia Vera

• Myeloproliferative neoplasm characterized by clonal proliferation of red blood cells
• Associated with JAK2 mutations (found in approximately 95% of cases) 2
• Features include:
  • Elevated hemoglobin/hematocrit
  • Often accompanied by leukocytosis and thrombocytosis
  • Low erythropoietin levels
  • Splenomegaly

Congenital/Familial Erythrocytosis

• Genetic mutations affecting:
  • Erythropoietin receptor (EPOR) - causing hypersensitivity to erythropoietin 3
  • Oxygen-sensing pathway genes (VHL, EGLN1, EPAS1, EPO) 3, 4
  • Hemoglobin genes (HBB, HBA1, HBA2) - causing high oxygen affinity hemoglobins 3
  • BPGM gene - affecting 2,3-bisphosphoglycerate levels and oxygen affinity 4

Secondary Causes (External Stimuli to Bone Marrow)

Hypoxemia-Related Causes

• Chronic cardiopulmonary diseases:
  • COPD/emphysema
  • Pulmonary fibrosis
  • Obstructive sleep apnea
  • Cyanotic congenital heart disease (right-to-left shunting) 2
• High altitude residence
• Smoking (carboxyhemoglobin decreases oxygen delivery)

Kidney-Related Causes

• Cystic kidney diseases
• Renal cell carcinoma and other erythropoietin-secreting tumors
• Post-kidney transplant erythrocytosis
• Renal artery stenosis
• IgA nephropathy 5

Medication-Induced

• Erythropoietin-stimulating agents (excessive dosing)
• Testosterone/androgen therapy 1
• SGLT2 inhibitors (emerging cause via HIF-2α activation) 5

Other Causes

• Hepatocellular carcinoma
• Cerebellar hemangioblastoma
• Pheochromocytoma
• Uterine fibroids

Pathophysiology

Hypoxemia-Induced Erythrocytosis

• Severity-dependent erythropoietic response:
  • Mild hypoxemia (SaO₂ 90-94%): Minimal response
  • Moderate hypoxemia (SaO₂ 80-90%): Moderate response
  • Severe hypoxemia (SaO₂ <80%): Significant response 1
• Sustained hypoxemia more likely to cause erythrocytosis than intermittent episodes 1
• In cyanotic congenital heart disease:
  • Right-to-left shunting leads to arterial hypoxemia
  • Kidneys release erythropoietin to increase red cell production
  • Decompensated erythrocytosis occurs when oxygen saturation <75% 2

Polycythemia Vera Pathophysiology

• JAK2 mutations lead to constitutive activation of JAK-STAT pathway
• Results in erythropoietin-independent erythroid proliferation
• Characterized by low erythropoietin levels 2

Clinical Manifestations and Complications

Symptoms of Hyperviscosity

• Headache
• Dizziness and faintness
• Fatigue
• Tinnitus
• Blurred vision
• Paresthesias of fingers, toes, and lips
• Muscle pain and weakness 1

Complications

• Thrombotic events (arterial and venous)
• Bleeding diathesis (paradoxical due to platelet dysfunction)
• Cerebrovascular accidents
• Renal dysfunction
• Hyperuricemia 1
• In cyanotic congenital heart disease:
  • Hyperviscosity can worsen tissue oxygenation despite increased red cell mass
  • Iron deficiency can exacerbate hyperviscosity by causing microcytic, rigid red cells 2

Diagnostic Approach

1. Confirm erythrocytosis:

   • Elevated hemoglobin (>16.5 g/dL in men, >16 g/dL in women)
   • Elevated hematocrit (>49% in men, >48% in women) 6

2. Assess for secondary causes:

   • Arterial blood gas analysis for hypoxemia
   • Sleep study if obstructive sleep apnea suspected
   • Chest imaging for pulmonary diseases
   • Echocardiography for cardiac shunts
   • Abdominal imaging for renal or hepatic tumors
   • Medication review (androgens, SGLT2 inhibitors)

3. If secondary causes excluded, evaluate for primary causes:

   • Serum erythropoietin level (low in polycythemia vera, normal/high in secondary causes)
   • JAK2 mutation testing (JAK2V617F or exon 12 mutations) 2
   • Bone marrow examination if clinically indicated
   • Consider genetic testing for familial erythrocytosis if appropriate

Management Considerations

• Address underlying cause when identified
• Therapeutic phlebotomy only for moderate to severe hyperviscosity symptoms with hematocrit >65% and no dehydration or iron deficiency 1
• Avoid routine phlebotomies due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 1
• Assess hydration status as dehydration can exacerbate symptoms 1
• Evaluate for iron deficiency which can mimic hyperviscosity symptoms 1

Pitfalls to Avoid

• Failing to distinguish between relative erythrocytosis (due to plasma volume contraction/dehydration) and absolute erythrocytosis (true increase in red cell mass)
• Missing JAK2 mutations in patients with seemingly secondary erythrocytosis
• Overlooking medication causes, particularly testosterone replacement therapy
• Performing excessive phlebotomies leading to iron deficiency, which paradoxically worsens hyperviscosity in patients with cyanotic heart disease
• Neglecting to evaluate for sleep apnea, which is a common but often undiagnosed cause of erythrocytosis