What hemoglobin concentration levels require starting therapeutic phlebotomy (bloodletting) in patients with polycythemia vera (excessive red blood cell production)?

Hemoglobin Concentration Thresholds for Initiating Therapeutic Phlebotomy in Polycythemia Vera

Therapeutic phlebotomy should be initiated in patients with polycythemia vera when the hematocrit exceeds 45%, regardless of hemoglobin values.

Diagnostic Criteria and Phlebotomy Thresholds

The 2016 WHO diagnostic criteria for polycythemia vera include hemoglobin thresholds of >16.5 g/dL in men and >16.0 g/dL in women, or hematocrit values >49% in men and >48% in women 1. However, these are diagnostic thresholds, not treatment thresholds.

For treatment purposes:

• The European LeukemiaNet (ELN) guidelines recommend maintaining hematocrit <45% in all PV patients through phlebotomy 1
• This target is based on evidence that maintaining hematocrit <45% significantly reduces the risk of cardiovascular death and major thrombosis

Risk Stratification and Treatment Algorithm

1. Diagnosis confirmation:

   • Confirm PV diagnosis using WHO criteria
   • Verify presence of JAK2 V617F or JAK2 exon 12 mutation
   • Rule out secondary causes of erythrocytosis

2. Initial management:

   • Begin therapeutic phlebotomy when hematocrit >45%
   • Target hematocrit <45% for all patients
   • Add low-dose aspirin (unless contraindicated)

3. Risk stratification:

   • High risk: Age >60 years OR history of thrombosis
   • Low risk: Absence of both risk factors

4. Treatment intensification:

   • High-risk patients should receive cytoreductive therapy (hydroxyurea or interferon-α) in addition to phlebotomy
   • Consider cytoreduction for low-risk patients with progressive leukocytosis, extreme thrombocytosis, or significant splenomegaly

Important Considerations

• The value of aggressive phlebotomy in aspirin-treated patients with hematocrit between 40-55% has been questioned by ECLAP investigators 1
• Phlebotomy alone may be insufficient for high-risk patients
• Iron deficiency from repeated phlebotomies may confound hemoglobin/hematocrit interpretation 1
• In cases of extreme thrombocytosis (≥1000 × 10^9/L), assess for acquired von Willebrand disease before initiating aspirin 2

Common Pitfalls to Avoid

1. Using diagnostic thresholds as treatment thresholds:

   • Diagnostic criteria (Hb >16.5/16.0 g/dL or Hct >49%/48%) should not be confused with treatment thresholds
   • Therapeutic phlebotomy should begin at hematocrit >45%

2. Focusing solely on hemoglobin:

   • Hematocrit is the preferred parameter for monitoring and treatment decisions
   • Hematocrit showed better diagnostic accuracy than hemoglobin in studies 3

3. Neglecting concurrent cytoreductive therapy in high-risk patients:

   • Phlebotomy alone is insufficient for high-risk patients
   • Cytoreductive therapy should be added for those >60 years or with prior thrombosis

4. Overly aggressive phlebotomy:

   • Excessive phlebotomy can lead to iron deficiency and associated symptoms
   • The goal is hematocrit <45%, not the lowest possible value

By maintaining hematocrit <45% through appropriate phlebotomy and risk-adapted therapy, the risk of thrombotic complications—the main cause of morbidity and mortality in PV—can be significantly reduced.