What are the causes and management of erythrocytosis?

Causes and Management of Erythrocytosis

Erythrocytosis requires a systematic diagnostic approach to identify the underlying cause, with management strategies focused on reducing thrombotic risk and alleviating hyperviscosity symptoms through targeted interventions based on etiology.

Definition and Classification

Erythrocytosis is defined as an increase in red blood cell mass above normal levels:

• Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women
• Hematocrit >49% in men or >48% in women 1

Primary vs. Secondary Erythrocytosis

1. Primary Erythrocytosis (Polycythemia Vera)

   • Myeloproliferative neoplasm with clonal disorder in bone marrow

   • 95% have JAK2 gene mutation

   • Associated with increased thrombosis risk, bleeding risk, and progression to myelofibrosis or acute myeloid leukemia 2

2. Secondary Erythrocytosis

   • Physiological response to hypoxemia or other stimuli
   • Not a clonal disorder but a compensatory mechanism 3

Causes of Secondary Erythrocytosis

Hypoxia-Driven Causes

• Cardiopulmonary Disorders

  • Congenital heart disease with right-to-left shunting (Eisenmenger syndrome)
  • Chronic obstructive pulmonary disease (COPD)
  • Obstructive sleep apnea (most common cause in some studies - 29%) 4
  • High-altitude living 3

• 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% 5

Non-Hypoxic Causes

• Medication-Related

  • Testosterone replacement therapy (common side effect)
  • Erythropoietin-stimulating agents
  • SGLT2 inhibitors (newer association) 6
  • Androgen therapy 6

• Renal Causes

  • Renal cell carcinoma
  • Renal cysts
  • Post-kidney transplantation
  • Renal artery stenosis 6

• Other Causes

  • Familial/congenital erythrocytosis (variants in EPOR, VHL, EGLN1, EPAS1, EPO, HBB, HBA1, HBA2, BPGM) 7
  • Heavy smoking 6

Clinical Presentation and Complications

Symptoms of Hyperviscosity

• Headache, dizziness, fatigue
• Tinnitus, blurred vision
• Paresthesia of fingers, toes, and lips
• Muscle pain and weakness 3

Complications

1. Thrombotic Events

   • Arterial and venous thrombosis
   • Higher risk in polycythemia vera but also elevated in secondary causes like chronic lung disease 4

2. Bleeding Diathesis

   • Despite increased red cell mass
   • Due to abnormalities in platelets and coagulation pathways 3

3. Other Complications

   • Cerebrovascular accidents
   • Renal dysfunction
   • Hyperuricemia due to increased red cell turnover 3

Diagnostic Approach

Initial Evaluation

1. Complete Blood Count

   • Confirm elevated hemoglobin and hematocrit
   • Check for other abnormalities (thrombocytosis, leukocytosis) 5

2. Peripheral Blood Smear

   • Evaluate for abnormal morphology
   • Rule out pseudo-thrombocytopenia 5

3. Iron Studies

   • Iron deficiency can coexist with erythrocytosis
   • May mimic hyperviscosity symptoms 3

Further Testing Based on Clinical Suspicion

1. JAK2 Mutation Testing

   • To rule out polycythemia vera 2

2. Sleep Study

   • If obstructive sleep apnea is suspected 4

3. Oxygen Saturation and Arterial Blood Gas

   • To evaluate for hypoxemia

4. Cardiac and Pulmonary Evaluation

   • Echocardiogram for congenital heart disease
   • Pulmonary function tests for lung disease

5. Abdominal Imaging

   • If renal or hepatic causes are suspected 6

Management Strategies

General Principles

1. Treat Underlying Cause

   • Address cardiopulmonary disease
   • Correct hypoxemia
   • Discontinue causative medications if possible

2. Hydration Assessment

   • Ensure adequate hydration
   • Dehydration can exacerbate symptoms 3

Specific Management by Etiology

Primary Erythrocytosis (Polycythemia Vera)

• Therapeutic phlebotomy to maintain hematocrit <45%
• Low-dose aspirin if no contraindications
• Cytoreductive therapy (hydroxyurea or interferon) for high-risk patients
• Ruxolitinib for those intolerant to hydroxyurea 2

Secondary Erythrocytosis

1. Testosterone-Induced Erythrocytosis

   • Monitor hematocrit during testosterone therapy
   • Dosage reduction if erythrocytosis develops
   • Consider switching from injections to topical preparations (lower risk)
   • Therapeutic phlebotomy if necessary 5

2. Cyanotic Congenital Heart Disease

   • Avoid routine phlebotomy due to risk of iron depletion
   • Therapeutic phlebotomy only for moderate/severe hyperviscosity symptoms with hematocrit >65% and no dehydration or iron deficiency
   • Maintain iron repletion 5, 3

3. Secondary to Myeloproliferative Disease

   • Low-dose aspirin (especially effective in this group)
   • Dramatic improvement often occurs within days of aspirin initiation 5

Therapeutic Phlebotomy Guidelines

Indications for phlebotomy:

• Moderate to severe hyperviscosity symptoms
• Hematocrit >65%
• Absence of dehydration
• Absence of iron deficiency 3

Contraindications to routine phlebotomy:

• Risk of iron depletion
• Decreased oxygen-carrying capacity
• Increased stroke risk 3

Special Considerations

Iron Deficiency

• Iron deficiency in erythrocytosis leads to:
  • Microcytic, hypochromic red cells
  • Decreased oxygen-carrying capacity
  • Reduced deformability in capillaries
  • Increased risk of stroke 5

Pregnancy

• Women with severe erythrocytosis (especially Eisenmenger syndrome) should avoid pregnancy
• High risk of maternal death
• Appropriate contraception counseling is essential 5

Medication Review

• All medications given to patients with erythrocytosis should be reviewed for potential effects on:
  • Systemic blood pressure
  • Loading conditions
  • Intravascular shunting
  • Renal or hepatic function 5

By systematically evaluating the cause of erythrocytosis and implementing appropriate management strategies, clinicians can reduce the risk of complications and improve outcomes for patients with this condition.