Therapeutic Phlebotomy for Erythrocytosis
For all patients with erythrocytosis, therapeutic phlebotomy should target a hematocrit below 45% regardless of sex, with removal of approximately 400-500 mL of blood per session, replaced with equal volume isotonic saline, performed weekly or fortnightly until target is achieved. 1, 2, 3
Indications for Therapeutic Phlebotomy
Initiate phlebotomy when hematocrit exceeds 50% in patients with confirmed erythrocytosis, particularly in polycythemia vera (PV) where maintaining hematocrit <45% is mandatory for all patients. 1, 3
Phlebotomy is indicated when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with hyperviscosity symptoms (headache, fatigue, poor concentration), provided dehydration and anemia are excluded. 2
In secondary erythrocytosis, phlebotomy should be considered when symptoms of hyperviscosity are present, though treatment should primarily address the underlying cause. 4
Phlebotomy Protocol
Volume and Replacement
Remove one unit (400-500 mL) per session and replace with 750-1000 mL of isotonic saline to prevent hemodynamic instability. 2
In elderly patients or those with cardiovascular disease, consider smaller volume phlebotomies (250-300 mL) to minimize hemodynamic stress, though this is not explicitly stated in guidelines. 1
Target Hematocrit
Maintain hematocrit strictly below 45% in all patients with PV, regardless of sex—this target applies equally to men and women based on the CYTO-PV study showing zero thrombotic events in women maintained below 45% versus 9 events in those with hematocrit 45-50%. 1, 3
For women with progressive vascular symptoms, consider an even lower target of 42%, though this should be based on persistent symptoms despite achieving <45%. 1
In post-transplant erythrocytosis with hypertension, target hematocrit below 45% has been shown to significantly reduce blood pressure. 5
Frequency
Perform phlebotomy weekly during the induction phase until target hematocrit is achieved; once stable, frequency should be adjusted based on the rate of hematocrit rise, typically every 2-4 months. 1, 2
Patients treated with phlebotomy alone typically require repeat procedures every 20 days to 2 months to maintain target levels. 6
Critical Monitoring and Precautions
Iron Status Monitoring
Monitor for iron deficiency with every phlebotomy session using peripheral blood smear and serum ferritin—iron deficiency is dangerous even in erythrocytosis because it reduces oxygen-carrying capacity, decreases red cell deformability, and paradoxically increases stroke risk. 2
In hemochromatosis patients undergoing phlebotomy, target serum ferritin of 50 μg/L but not lower to avoid iron deficiency. 1
Never perform routine repeated phlebotomies without monitoring iron status—this is a common and dangerous pitfall. 2
Contraindications and Cautions
Do not perform phlebotomy in the presence of dehydration or anemia—correct these conditions first. 2
In pregnant women with mild to moderate iron overload without advanced liver disease, phlebotomy can be paused for the duration of pregnancy in most cases. 1
For pregnant PV patients, continue phlebotomy to maintain hematocrit <45% along with aspirin 81-100 mg daily (hold aspirin 3 days before delivery if extreme thrombocytosis present). 1
Adjunctive Therapy
Aspirin
All PV patients should receive low-dose aspirin 81-100 mg daily unless contraindications exist (acquired von Willebrand disease with extreme thrombocytosis >1,000 × 10⁹/L or active bleeding). 1, 3, 7
In essential thrombocythemia (ET), aspirin is recommended if JAK2 mutated or cardiovascular risk factors are present; observation alone is reasonable if JAK2 unmutated without risk factors. 1
Cytoreductive Therapy
High-risk patients (age >60 years or prior thrombosis history) require cytoreductive therapy with hydroxyurea in addition to phlebotomy and aspirin—phlebotomy alone is insufficient for these patients. 1, 7
Hydroxyurea starting dose is 500 mg twice daily orally, with onset of action in 3-5 days. 1
For younger patients or pregnant women requiring cytoreduction, interferon-α is preferred (3 million units subcutaneously 3 times weekly), though it controls erythrocytosis in only 76% of patients and has significant side effects. 1
Alternative to Phlebotomy
Erythrocytapheresis
Erythrocytapheresis is superior to traditional phlebotomy, extending the interval between treatments from 20 days-2 months to 2-7 months, and should be considered when available, particularly during the induction phase. 1, 6
Erythrocytapheresis is cost-effective during induction because fewer interventions are required and represents the preferred treatment in selected cases. 1
Iron Chelation
- If phlebotomy is not possible, iron chelation with deferasirox can be considered after careful risk-benefit assessment, though evidence is weak and it should not be used in patients with advanced liver disease. 1, 2
Common Pitfalls to Avoid
Never allow iron deficiency to develop—this is the most critical error in phlebotomy management as it increases stroke risk despite lowering hematocrit. 2
Do not use phlebotomy as monotherapy in high-risk PV patients (age >60 or prior thrombosis)—these patients require cytoreductive therapy. 1, 3, 7
Do not target "normal" hematocrit ranges by sex—the <45% target applies to all patients with PV regardless of sex. 1
Avoid routine repeated phlebotomies without a clear diagnosis and monitoring plan—this leads to complications. 2
In extreme thrombocytosis (>1,000 × 10⁹/L), rule out acquired von Willebrand disease before starting aspirin to prevent bleeding complications. 1, 3