What are the diagnostic steps and management options for polycythemia (excessive red blood cell count)?

Diagnostic Approach to Polycythemia

The diagnosis of polycythemia requires a systematic approach that first distinguishes true polycythemia (increased red cell mass) from apparent polycythemia (hemoconcentration), followed by determining whether true polycythemia is primary (polycythemia vera) or secondary. 1

Initial Diagnostic Steps

Step 1: Confirm True Polycythemia

• Evaluate hemoglobin/hematocrit levels:

  • Men: Hemoglobin >18.5 g/dL or hematocrit >99th percentile for age/sex/altitude
  • Women: Hemoglobin >16.5 g/dL or hematocrit >99th percentile for age/sex/altitude
  • Alternative criteria: Documented sustained increase of ≥2 g/dL from baseline not due to iron deficiency correction 1

• Rule out relative/apparent polycythemia:

  • Check for dehydration, diuretic use, severe burns, diarrhea, vomiting
  • Note: Conditions like Gaisböck syndrome (stress polycythemia) are controversial and poorly understood 1

Step 2: Test for JAK2 Mutation

• JAK2 V617F mutation testing (present in >95% of PV cases)
• If negative but strong suspicion of PV, test for JAK2 exon 12 mutations 1, 2

Step 3: Measure Serum Erythropoietin Level

• Low levels suggest polycythemia vera
• Normal/elevated levels suggest secondary polycythemia 1

Step 4: Bone Marrow Biopsy (if diagnosis remains unclear)

• Look for hypercellularity with trilineage growth (panmyelosis)
• Prominent erythroid, granulocytic, and megakaryocytic proliferation 1

Diagnostic Criteria for Polycythemia Vera (WHO 2008)

Diagnosis requires both major criteria and one minor criterion OR first major criterion plus two minor criteria:

Major Criteria:

1. Hemoglobin >18.5 g/dL (men), >16.5 g/dL (women) or other evidence of increased red cell mass
2. Presence of JAK2 V617F or functionally similar mutation (e.g., JAK2 exon 12)

Minor Criteria:

1. Bone marrow biopsy showing hypercellularity with trilineage growth
2. Serum erythropoietin level below reference range
3. Endogenous erythroid colony formation in vitro 1

Evaluation for Secondary Polycythemia

If JAK2 mutation is negative and erythropoietin is normal/elevated, investigate for secondary causes:

Hypoxia-Driven Causes:

• Chronic lung disease (pulmonary function tests, arterial blood gases)
• Sleep apnea (sleep study)
• High altitude residence
• Smoking (carbon monoxide levels)
• Right-to-left cardiac shunts (echocardiogram)
• High-affinity hemoglobinopathy (hemoglobin electrophoresis)

Non-Hypoxic Causes:

• Tumors (renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)
  • Abdominal/pelvic imaging (CT or ultrasound)
• Renal disorders (polycystic kidney disease)
• Endocrine disorders (Cushing's syndrome)
• Exogenous erythropoietin use or androgen preparations 1, 2

Management Approach

For Polycythemia Vera:

1. Risk stratification:

   • High risk: Age >60 years or history of thrombosis
   • Low risk: Absence of both risk factors 3, 4

2. All patients should receive:

   • Therapeutic phlebotomy (target hematocrit <45%)
   • Low-dose aspirin (81mg) once daily if no contraindications 2, 3

3. High-risk patients should also receive cytoreductive therapy:

   • First-line: Hydroxyurea
   • Second-line options: Interferon-α (especially in younger patients and women of reproductive age) or busulfan (in older patients)
   • Ruxolitinib for patients with severe pruritus or splenomegaly not responding to other treatments 3, 4

For Secondary Polycythemia:

• Treat the underlying cause (e.g., CPAP for sleep apnea, smoking cessation)
• Phlebotomy may be considered if symptomatic or hematocrit is extremely elevated
• Low-dose aspirin if no contraindications and high thrombotic risk 1

Common Pitfalls to Avoid

• Failing to distinguish true from apparent polycythemia
• Performing unnecessary red cell mass measurements when clinical dehydration is obvious
• Missing secondary causes of polycythemia by not conducting appropriate testing
• Overlooking iron deficiency which can mask the degree of polycythemia
• Failing to consider polycythemia vera in patients with thrombosis in unusual sites (e.g., splanchnic veins) 1, 4

Monitoring

• Regular follow-up with complete blood counts
• Monitor for thrombotic and hemorrhagic complications
• Assess for disease progression to myelofibrosis (12.7%) or acute myeloid leukemia (6.8%) 2