What is the recommended diagnostic workup and management for an adult patient with suspected polycythemia vera?

Polycythemia Vera: Diagnostic Workup and Management

Diagnostic Workup

Begin with JAK2 V617F mutation testing and serum erythropoietin (EPO) level immediately after confirming sustained hemoglobin elevation (>16.5 g/dL in men, >16.0 g/dL in women), as this combination distinguishes polycythemia vera from secondary causes with >90% specificity. 1, 2

Initial Laboratory Assessment

• Complete blood count with differential and red cell indices to document erythrocytosis and identify accompanying thrombocytosis (present in 53% of cases) or leukocytosis (49% of cases). 3, 4

• JAK2 V617F mutation testing is present in >95% of polycythemia vera cases, making it the single most definitive diagnostic test. 1, 3, 5

  • An additional 2-4% of cases harbor JAK2 exon 12 mutations, raising overall molecular sensitivity to 97-99%. 6

• Serum erythropoietin level interpretation:

  • Low or inappropriately normal EPO has >90% specificity for polycythemia vera. 1, 2
  • However, EPO sensitivity is only 64-70%, so normal EPO does not exclude polycythemia vera. 7, 6
  • Elevated EPO strongly suggests secondary polycythemia and triggers evaluation for hypoxia-driven or tumor-related causes. 7, 2

• Serum ferritin, iron, and transferrin saturation are mandatory because iron deficiency can mask polycythemia vera by suppressing hemoglobin into the normal range despite active clonal proliferation. 7, 6

Bone Marrow Examination

• Bone marrow biopsy is the cornerstone of diagnosis when EPO is low or when JAK2 is positive with borderline hemoglobin. 2

• Characteristic findings include:

  • Hypercellularity with trilineage proliferation (panmyelosis). 1, 2
  • Increased megakaryocytes with cluster formation, giant forms, and pleomorphic morphology. 2
  • Decreased bone marrow iron stores. 2
  • Mild reticulin fibrosis may be present. 2

WHO 2016 Diagnostic Criteria

Diagnosis requires either:

1. All three major criteria: elevated hemoglobin/hematocrit + JAK2 mutation + characteristic bone marrow morphology, OR
2. First two major criteria + subnormal serum EPO. 7

Evaluation for Secondary Causes (When EPO is Elevated)

• Detailed smoking history and carboxyhemoglobin measurement – smoker's polycythemia is the most common secondary cause and resolves with cessation. 7, 2

• Arterial oxygen saturation and chest imaging to exclude chronic lung disease, right-to-left cardiopulmonary shunts, or sleep apnea. 7, 2

• Sleep study if obstructive sleep apnea is suspected. 7

• Abdominal ultrasound or CT to screen for EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma. 7, 2

• Medication review for exogenous testosterone, anabolic steroids, or erythropoietin administration. 7

• Renal function testing to evaluate for post-renal transplant erythrocytosis. 7

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Risk Stratification

Patients are classified as high-risk if age >60 years OR prior history of thrombosis. 1

• High-risk patients require cytoreductive therapy in addition to phlebotomy and aspirin. 1
• Low-risk patients are managed with phlebotomy and aspirin alone. 1

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Management

Universal First-Line Therapy (All Patients)

• Therapeutic phlebotomy to maintain hematocrit <45% reduces thrombotic events and improves survival. 1, 3, 4

• Low-dose aspirin (100 mg daily) significantly reduces vascular events without significantly increasing major bleeding. 1, 3, 4

• Aggressive management of cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia) and smoking cessation are mandatory. 1, 4

Cytoreductive Therapy (High-Risk Patients)

High-risk patients should receive cytoreduction with either hydroxyurea or interferon-α at any age. 1

First-Line Cytoreductive Agents

• Hydroxyurea is the preferred first-line cytoreductive agent for most high-risk patients. 1, 3, 4

  • Use with caution in patients <40 years due to potential leukemogenic risk. 1
  • Dose titrated to maintain platelet count <400 × 10⁹/L and WBC <10 × 10⁹/L. 1

• Interferon-α (including pegylated formulations) is an alternative first-line agent, particularly in younger patients. 1, 8

  • Induces molecular remissions with reduction in JAK2V617F allele burden. 1, 8
  • Currently undergoing phase III trials. 8

• Busulfan may be considered in elderly patients (>70 years). 1

Additional Indications for Cytoreductive Therapy (Beyond Age/Thrombosis Risk)

• Poor tolerance of phlebotomy or frequent phlebotomy requirement. 1
• Symptomatic or progressive splenomegaly. 1
• Severe disease-related symptoms (pruritus, constitutional symptoms). 1
• Platelet count >1,500 × 10⁹/L. 1
• Progressive leukocytosis. 1

Second-Line Therapy

Ruxolitinib (JAK1/JAK2 inhibitor) is approved for patients with resistance or intolerance to hydroxyurea. 8, 3, 5

• Effectively alleviates pruritus and decreases splenomegaly. 3
• Does not reduce thrombotic risk or prevent disease transformation. 8

Criteria for Hydroxyurea Resistance/Intolerance

1. Need for phlebotomy to keep hematocrit <45% after 3 months of ≥2 g/day hydroxyurea, OR
2. Uncontrolled myeloproliferation (platelet count >400 × 10⁹/L AND WBC >10 × 10⁹/L) after 3 months of ≥2 g/day, OR
3. Failure to reduce massive splenomegaly by >50% or relieve splenomegaly symptoms after 3 months of ≥2 g/day, OR
4. Cytopenias (ANC <1.0 × 10⁹/L OR platelet <100 × 10⁹/L OR hemoglobin <10 g/dL) at lowest effective dose, OR
5. Unacceptable hydroxyurea-related toxicity (leg ulcers, mucocutaneous manifestations, GI symptoms, pneumonitis, fever). 1

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Monitoring Response

Use European LeukemiaNet clinicohematologic criteria to monitor response to cytoreductive therapy. 1

• Routine monitoring of JAK2V617F allele burden is not indicated except when using interferon-α, which can induce molecular responses. 1

• Bone marrow monitoring is not indicated for routine clinical follow-up. 1

• Stable patients: Monitor CBC and cause-specific parameters every 3-6 months. 7

• Newly diagnosed or unstable patients: Monitor monthly for the first 3 months. 7

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Critical Diagnostic Pitfalls

• Do not exclude polycythemia vera based on normal EPO alone – sensitivity is only 64-70%. 7, 6, 2

• Do not dismiss polycythemia vera when hemoglobin is normal or borderline-high with microcytosis – iron deficiency can mask the expected hemoglobin rise. 7, 6

  • When microcytosis is present with borderline hemoglobin plus thrombocytosis, leukocytosis, splenomegaly, aquagenic pruritus, or unusual thrombosis, proceed immediately with JAK2 testing. 7, 6

• Do not perform red cell mass measurements routinely – modern JAK2 testing and EPO levels have largely replaced this costly test. 2

• Do not overlook smoking as a reversible cause – smoker's polycythemia resolves with cessation, with risk reduction beginning within 1 year. 7, 2

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Management Pitfalls

• Do not perform aggressive or repeated routine phlebotomies in secondary polycythemia – this depletes iron, reduces oxygen-carrying capacity, and paradoxically increases stroke risk. 7

  • In cyanotic heart disease, phlebotomy is indicated only when hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms after excluding dehydration. 7

• Do not use cytoreductive drugs in low-risk patients with well-controlled cardiovascular risk factors – phlebotomy and aspirin are sufficient. 1

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Prognosis and Complications

• Median survival from diagnosis ranges from 14.1 to 27.6 years. 3

• Thrombotic events: Arterial thrombosis occurs in 16% and venous thrombosis in 7% at or before diagnosis, often involving unusual sites (splanchnic veins). 3

• Disease transformation: 12.7% develop myelofibrosis and 6.8% develop acute myeloid leukemia. 3

• Bleeding risk is increased, especially with extreme thrombocytosis (≥1,000 × 10⁹/L) due to acquired von Willebrand disease. 3