What are the management strategies for erythrocytosis?

Management of Erythrocytosis

For patients with erythrocytosis, therapeutic phlebotomy is indicated when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with hyperviscosity symptoms, removing 400-500 mL per session with equal volume isotonic saline replacement; however, in polycythemia vera specifically, maintain hematocrit strictly below 45% regardless of sex through regular phlebotomy plus aspirin therapy. 1, 2, 3

Initial Assessment and Risk Stratification

Before initiating treatment, determine whether erythrocytosis is primary (polycythemia vera) or secondary (hypoxemia, sleep apnea, cyanotic heart disease, renal tumors). 2, 4

For Polycythemia Vera (Primary Erythrocytosis)

Risk stratification determines treatment intensity: 5, 6

• High-risk patients (age >60 years OR prior thrombosis history): Require phlebotomy + aspirin + cytoreductive therapy with hydroxyurea 1, 5
• Low-risk patients (age ≤60 years AND no thrombosis history): Require phlebotomy + aspirin only 5, 6

For Secondary Erythrocytosis

First-line management is treating the underlying cause (supplemental oxygen for hypoxemia, CPAP for sleep apnea, etc.) and ensuring adequate hydration. 2, 4 Avoid routine phlebotomy in secondary erythrocytosis unless meeting specific criteria below. 2

Therapeutic Phlebotomy Protocol

Indications for Phlebotomy

Perform therapeutic phlebotomy only when ALL of the following are met: 1, 2, 7

• Hemoglobin >20 g/dL AND hematocrit >65%
• Hyperviscosity symptoms present (headache, visual disturbances, fatigue, poor concentration)
• Dehydration and anemia have been excluded

Exception: In polycythemia vera, phlebotomy is mandatory regardless of symptoms to maintain hematocrit <45%. 1, 3 This target is based on the landmark CYTO-PV trial showing a 3.91-fold higher rate of cardiovascular death and major thrombosis when hematocrit was maintained at 45-50% versus <45%. 3

Phlebotomy Technique

Standard protocol: 1, 7

• Remove 400-500 mL blood per session
• Replace with 750-1000 mL isotonic saline simultaneously to prevent hemodynamic instability
• Perform weekly or fortnightly during induction phase until target achieved

Modified protocol for high-risk patients: 1

• Elderly patients or those with cardiovascular disease: Remove only 250-300 mL per session to minimize hemodynamic stress

Target Hematocrit Levels

• Polycythemia vera: <45% (mandatory for all patients regardless of sex) 1, 3
• Secondary erythrocytosis with cyanotic heart disease: ~60% may be reasonable to alleviate hyperviscosity 7
• General erythrocytosis: Individualize based on symptoms, but typically <65% 2, 7

Critical Monitoring Requirements

Monitor iron status with EVERY phlebotomy session using peripheral blood smear and serum ferritin. 1, 2 This is the most dangerous pitfall in erythrocytosis management—iron deficiency paradoxically worsens symptoms by reducing oxygen-carrying capacity, decreasing red cell deformability, and increasing stroke risk. 2, 7

Never perform routine repeated phlebotomies without monitoring iron status. 1, 2

During the induction phase for conditions like hemochromatosis, target serum ferritin of 50 μg/L but not lower to avoid iron deficiency. 7 In patients planning pregnancy, avoid iron deficiency by maintaining ferritin >45 μg/L. 8

Adjunctive Pharmacotherapy

For Polycythemia Vera

All patients should receive: 1, 5, 6

• Low-dose aspirin 81-100 mg once or twice daily (unless contraindications exist)
• High-risk patients additionally require cytoreductive therapy with hydroxyurea as first-line agent

Second-line cytoreductive options: 5, 6

• Interferon-α
• Busulfan
• Ruxolitinib (reserved only for severe protracted pruritus or marked splenomegaly unresponsive to other drugs)

For Secondary Erythrocytosis

Aspirin is not routinely recommended unless there are other cardiovascular indications. 4 Focus on treating the underlying cause. 2, 4

Alternative Treatment Modalities

Erythrocytapheresis is superior to traditional phlebotomy when available, extending intervals between treatments from 20 days-2 months to 2-7 months, and should be considered particularly during the induction phase. 1, 7 This technique removes red cells while returning plasma and other blood components, causing fewer hemodynamic changes. 7

Iron chelation with deferasirox can be considered as a second-line option when phlebotomy is not possible, after careful risk-benefit assessment, but should not be used in patients with advanced liver disease. 1, 7

Special Clinical Situations

Pregnancy

In pregnant women with mild to moderate iron overload without advanced liver disease, phlebotomy can be paused for the duration of pregnancy in most patients. 8, 7 Iron deficiency should be avoided before and during pregnancy as it increases risk of adverse maternal and fetal outcomes. 8

Pre-operative Management

Pre-operative phlebotomy may occasionally be indicated to improve coagulation before elective surgery in patients with severe erythrocytosis. 7

Patients with Hemochromatosis

These patients require iron depletion therapy with phlebotomy as first-line treatment, with evidence showing reduced morbidity and mortality when initiated before development of cirrhosis or diabetes. 8 Phlebotomy may improve fatigue, arthralgias, liver function tests, and result in regression of liver fibrosis in a subset of patients. 8

Common Pitfalls and How to Avoid Them

Do NOT perform routine phlebotomies without meeting established criteria (Hgb >20 g/dL, Hct >65% with symptoms in secondary erythrocytosis). 2, 7 Repeated phlebotomies without proper indication lead to iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 2

Do NOT perform phlebotomy in the presence of dehydration or anemia—correct these conditions first. 1, 7 Dehydration can falsely elevate hematocrit levels. 2

Do NOT neglect iron status monitoring—creating iron deficiency through excessive phlebotomy worsens symptoms and increases thrombotic risk. 1, 2

Do NOT use the same hematocrit targets for polycythemia vera and secondary erythrocytosis—PV requires strict maintenance <45% based on high-quality randomized trial evidence, while secondary erythrocytosis has more flexible targets. 3

Ongoing Monitoring

• Complete blood counts regularly to monitor hemoglobin and hematocrit 2
• Periodic iron studies (ferritin, transferrin saturation) to avoid iron deficiency 2, 7
• Assessment for hyperviscosity symptoms before each phlebotomy session 7
• In polycythemia vera, monitor for progression to myelofibrosis, myelodysplasia, or leukemic transformation 5, 3
• Evaluate renal function as chronic erythrocytosis can affect renal glomeruli 2