What is the management approach for a patient with severe polyglobulia (excessive red blood cell count)?

Management of Severe Polyglobulia

All patients with severe polyglobulia (polycythemia vera) must undergo immediate phlebotomy to maintain hematocrit below 45%, combined with daily low-dose aspirin (81-100 mg), and high-risk patients require cytoreductive therapy with hydroxyurea or interferon-α as first-line treatment. 1

Immediate Phlebotomy Protocol

• Induction phase: Remove 300-450 mL of blood weekly or twice weekly until hematocrit target (<45%) is achieved 1
• Maintenance phase: Continue same blood volume removal per phlebotomy, with intervals determined by hematocrit levels 1
• The CYTO-PV trial definitively demonstrated that maintaining hematocrit <45% versus 45-50% reduced cardiovascular death or major thrombotic events from 9.8% to 2.7% (HR 3.91,95% CI 1.45-10.53) 1
• This hematocrit target of <45% is non-negotiable for all patients regardless of risk category 1

Risk Stratification for Treatment Intensity

High-risk patients (requiring cytoreductive therapy in addition to phlebotomy and aspirin):

• Age >60 years 1
• Any prior thrombotic event at any age 1

Low-risk patients (phlebotomy and aspirin only):

• Age ≤60 years AND no thrombosis history 1

Additional Indications for Cytoreductive Therapy

Beyond age and thrombosis history, cytoreduction is strongly indicated for: 1

• Poor tolerance to phlebotomy (frequent requirement, severe symptoms)
• Symptomatic or progressive splenomegaly
• Severe disease-related symptoms (pruritus, microcirculatory symptoms)
• Platelet count >1,500 × 10⁹/L
• Leukocyte count >15 × 10⁹/L
• Documented severe tissue iron deficiency with detrimental symptoms (pica, mouth paresthesia, esophagitis, restless legs) that worsens hematocrit when iron is supplemented

First-Line Cytoreductive Therapy

Either hydroxyurea OR recombinant interferon-α (rIFNα) is recommended as first-line cytoreductive therapy at any age. 1

• Hydroxyurea: Standard first-line agent, but use cautiously in young patients (age <40 years) due to potential long-term leukemogenic risk 1
• Interferon-α: Preferred in younger patients and those of childbearing potential; pegylated formulations show clinical efficacy with decreased JAK2V617F allele burden 1
• Busulfan: May be considered in elderly patients (age >70 years) 1

Second-Line Cytoreductive Options

For patients resistant or intolerant to hydroxyurea (defined by specific ELN criteria): 1

• Switch to rIFNα if hydroxyurea was first-line
• Switch to hydroxyurea if rIFNα was first-line
• Ruxolitinib: FDA and EMA approved for PV patients with inadequate response or intolerance to hydroxyurea, though evidence quality was downgraded due to performance bias and indirectness 1

Ruxolitinib should be reserved for: 1

• Severe and protracted pruritus unresponsive to conventional therapy
• Marked splenomegaly not responding to hydroxyurea or interferon-α

Aspirin Therapy

• Daily low-dose aspirin (81-100 mg) is mandatory for all patients unless contraindicated 1
• The ECLAP study demonstrated significant reduction in thrombotic events with aspirin versus placebo without significant increase in major bleeding 1
• Screen for acquired von Willebrand syndrome (AvWS) before administering aspirin if platelet count >1,500 × 10⁹/L to assess bleeding risk 2, 3

Cardiovascular Risk Factor Management

• All patients must have aggressive management of cardiovascular risk factors including hypertension, diabetes, hypercholesterolemia, and metabolic syndrome 1
• Smoking cessation is essential 1

Iron Supplementation Considerations

• Iron supplementation is indicated only for documented severe tissue iron deficiency with detrimental symptoms (pica, mouth paresthesia, esophagitis, restless legs) 1
• If iron therapy causes undesired hematocrit worsening, this mandates initiation of cytoreductive therapy 1

Critical Pitfalls to Avoid

• Never maintain hematocrit at 45-50%: This nearly quadruples thrombotic risk compared to <45% target 1
• Do not withhold cytoreductive therapy in high-risk patients: Age >60 or prior thrombosis are absolute indications 1
• Do not use hydroxyurea liberally in young patients (<40 years): Consider interferon-α preferentially due to leukemogenic concerns 1
• Do not give aspirin with extreme thrombocytosis (>1,500 × 10⁹/L) without screening for AvWS: Risk of bleeding may outweigh benefit 2, 3

Monitoring Requirements

• Monitor hematocrit levels to guide phlebotomy intervals 1
• Monitor complete blood counts including platelet and leukocyte counts 1
• Assess for thrombotic and hemorrhagic complications 1
• Monitor for disease-related symptoms (pruritus, splenomegaly, microcirculatory symptoms) 1