What is the initial workup and treatment for polycythemia?

Initial Workup and Treatment for Polycythemia

The initial diagnostic workup for polycythemia should begin with serum erythropoietin (EPO) level measurement after confirming elevated hemoglobin/hematocrit, followed by JAK2 mutation testing and bone marrow examination in appropriate cases. 1

Diagnostic Approach

When to Initiate Evaluation

• Evaluation should begin when hemoglobin/hematocrit exceeds the 95th percentile of normal distribution adjusted for sex and race 1
• Evaluation is also warranted when there is a documented increase in hemoglobin/hematocrit above the patient's baseline, regardless of where the specific value lies within the reference range 1
• Consider evaluation when polycythemia vera (PV)-related features accompany borderline-high hematocrit values, such as thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, or unusual thrombosis 1

Initial Laboratory Testing

• Serum EPO level is the first recommended test:
  • Low EPO is highly suggestive of PV (specificity >90%) 1
  • Normal EPO does not rule out PV (sensitivity <70%) 1
  • High EPO indicates the need to evaluate for secondary polycythemia 1
• Complete blood count with differential to assess for additional features 1
• JAK2 mutation testing (>95% of PV patients have JAK2 gene variant) 2

Bone Marrow Examination

• Indicated after abnormal serum EPO results (low or normal) 1
• Should include assessment for:
  • Hypercellularity
  • Increased number and abnormal morphology of megakaryocytes
  • Bone marrow iron stores (decreased in PV) 1

Evaluation for Secondary Causes

• If EPO is elevated, investigate secondary polycythemia causes: 1
  • Hypoxia-driven causes:
    • Chronic lung disease
    • Sleep apnea
    • Carbon monoxide exposure (smoker's polycythemia)
  • Hypoxia-independent causes:
    • EPO-producing tumors (renal cell carcinoma, hepatocellular carcinoma)
• Measure arterial hemoglobin-oxygen saturation and carboxyhemoglobin level 1
• Consider imaging studies of kidney, liver, and central nervous system to rule out EPO-producing tumors 1

Treatment Approach

Treatment Goals

• Reduce risk of thrombosis and hemorrhage
• Control symptoms
• Potentially reduce risk of disease progression 3

For All Patients with Polycythemia Vera

• Phlebotomy to maintain hematocrit <45% (shown in randomized clinical trials to efficiently reduce thrombotic events) 3, 2
• Low-dose aspirin (in absence of contraindications) to reduce cardiovascular events 3, 2
• Aggressive management of vascular risk factors (smoking cessation, etc.) 3

Risk Stratification for Additional Therapy

• High-risk patients (age >60 years and/or history of thrombosis):
  • Cytoreductive therapy is recommended 3, 4
  • First-line options:
    • Hydroxyurea 3
    • Interferon-α (alternative for young women of reproductive age or those intolerant to hydroxyurea) 3, 4
• Low-risk patients (absence of both risk factors):
  • Phlebotomy and aspirin alone are typically sufficient 4
  • Consider cytoreductive therapy if symptomatic or requiring frequent phlebotomy 4

Special Considerations

• Extreme thrombocytosis (>1500 × 10^9/l):
  • Indication for cytoreductive therapy 3
  • Caution with aspirin due to increased bleeding risk, especially with acquired von Willebrand disease 2
• Smoker's polycythemia:
  • Primary treatment is smoking cessation 5
  • Hematological parameters should normalize after cessation 5

Common Pitfalls and Caveats

• Red cell mass measurement is generally not necessary in modern practice 1
• Normal EPO does not rule out PV; approximately 30% of PV patients may have normal EPO levels 1, 6
• Elevated EPO levels typically suggest secondary polycythemia but rare cases of PV with elevated EPO have been reported; JAK2 testing should still be performed if clinical suspicion is high 7, 6
• Distinguishing relative polycythemia (plasma volume depletion) is important as most causes are clinically obvious 1
• Monitoring for disease progression is essential as PV can transform to myelofibrosis (12.7%) or acute myeloid leukemia (6.8%) 2