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Polycythemia Vera

BASICS

  • Definition: Clonal myeloproliferative stem cell disorder marked by increased red blood cell production (erythrocytosis), with excessive erythroid, myeloid, and megakaryocytic elements in bone marrow.
  • Key issues: Morbidity/mortality mostly from blood hyperviscosity complications (thrombosis) and malignant transformation (e.g., to leukemia, myelofibrosis).
  • Untreated survival: 6–18 months; with adequate therapy, >10 years.
  • Synonyms: Primary polycythemia, maladie de Vaquez, PV rubra, Vaquez-Osler disease.

EPIDEMIOLOGY

  • Predominant age: 50–75 years (can occur in early adulthood/childhood)
  • Sex: Slightly more common in males
  • Incidence (US): 2.8/100,000 (men); 1.3/100,000 (women)
  • Prevalence: 45–57/100,000 patients (US)

ETIOLOGY & PATHOPHYSIOLOGY

  • Mutation: JAK2 V617F mutation in >97% (tyrosine kinase gain-of-function)
  • Genetics: JAK2 mutation drives clonal proliferation and erythrocytosis
  • Complications: Myelofibrosis (MF) can develop, with progressive hepatosplenomegaly

RISK FACTORS

  • Slightly more prevalent among Jews of Eastern European descent
  • Familial history is rare

COMMONLY ASSOCIATED CONDITIONS

  • Thromboses: Budd-Chiari syndrome, mesenteric artery thrombosis, MI, CVA/TIA, VTE, PE, ischemic digits
  • Other: Myelofibrosis, peptic ulcer disease, gout

DIAGNOSIS

History

  • May be asymptomatic or present with:
  • Nonspecific: Fatigue, malaise, weight loss, sweating, weakness
  • Vascular: Erythromelalgia (burning pain of hands/feet, erythema), headaches, blurred vision, tinnitus, dizziness, arterial/venous occlusion
  • Pruritus: Especially after bathing (aquagenic)
  • Others: Bruising/bleeding, early satiety (splenomegaly), bone pain, gout, insomnia, depression

Physical Exam

  • Hypertension (46%)
  • Splenomegaly (75%)
  • Hepatomegaly (30%)
  • Facial plethora (ruddy cyanosis)
  • Bone tenderness, skin excoriations, gouty tophi, engorged conjunctival/retinal vessels

Differential Diagnosis

  • Essential thrombocytopenia
  • Secondary erythrocytosis: sleep apnea, COPD, smoking, renal artery stenosis, CO poisoning, drugs (EPO, testosterone), hemoglobinopathies
  • Spurious polycythemia

Diagnostic Criteria (WHO 2016)

  • All 3 major criteria, or first 2 major + minor:

Major: 1. Hgb >16.5 g/dL (men) or >16 g/dL (women), Hct >49% (men) or >48% (women), or ↑ RBC mass 2. Bone marrow biopsy: hypercellularity with trilineage (erythroid, granulocytic, megakaryocytic) proliferation 3. JAK2 V617F or exon 12 mutation

Minor: - Serum EPO level below normal

  • Note: Bone marrow biopsy may be omitted if Hgb >18.5 g/dL (men) or >16.5 g/dL (women) AND JAK2+ AND low EPO.

Initial Tests

  • CBC: Elevated Hgb/Hct, leukocytosis, thrombocytosis
  • Other labs: ↓ EPO, hyperuricemia, hypercholesterolemia, ↑ B12
  • Coags: Prolonged PT/aPTT (low plasma volume)
  • Imaging: Abdominal US/CT for splenomegaly (not required for diagnosis)
  • Cytogenetics: JAK2 mutation testing

TREATMENT

General Measures

  • Risk Stratification:
  • High-risk: Age >60 or history of thrombosis
  • Intermediate: <60 + high platelets (>150,000)

  • Low-risk: <60 + normal platelets + no thrombosis

  • First-line for all: Phlebotomy + low-dose aspirin

  • Phlebotomy: Target Hct <45% (men/women); initially every 2–3 days until target
  • Volume replacement (saline) in frail/elderly to avoid hypotension
  • High-risk/intermediate: Add cytoreductive therapy (hydroxyurea)
  • Address secondary PV causes (if present): Sleep apnea, smoking, renal disease

Medications

  • Phlebotomy: Primary treatment; controls hyperviscosity
  • Low-dose aspirin: 81 mg PO daily (unless contraindicated, e.g., bleeding)
  • Hydroxyurea: For high-risk, intermediate, or those with splenomegaly/hepatomegaly (500–1500 mg PO daily, titrate)
  • Ruxolitinib: For refractory PV or intolerance to hydroxyurea
  • Pegylated interferon Ξ±-2a: For young patients/pregnancy; limited by side effects
  • Radioactive phosphorus (32P): Consider for hydroxyurea-intolerant or poor survival expectancy (mutagenic potential)
  • Symptomatic:
  • Allopurinol for uric acid
  • Cyproheptadine, H1/H2 blockers, SSRIs, oatmeal baths, UV light for pruritus

  • H2 blockers/antacids for GI symptoms

  • Avoid: Iron supplements (chronic iron deficiency is protective)

  • Maintain hydration

Second-line

  • Chlorambucil, busulfan: For advanced/refractory cases in elderly, but ↑ risk of leukemic transformation

ONGOING CARE & MONITORING

  • Frequent CBC and Hct checks
  • Monitor for transformation (myelofibrosis, leukemia) and secondary malignancies
  • Monitor for thrombosis/bleeding, splenomegaly, and iron deficiency
  • Patient education: Hydration, leg/ankle exercises, clot prevention, recognize complications

PROGNOSIS

  • Median survival >15 years with therapy
  • Risks: Transformation to myelofibrosis (10%), acute leukemia (5%), vascular thrombosis (20%, major cause of death), hemorrhage, secondary gout/uric acid stones, surgical complications

ICD-10

  • D45 Polycythemia vera

CLINICAL PEARLS

  • Erythrocytosis: Hgb >16.5 g/dL (men), >16 g/dL (women)
  • JAK2 mutation is a key diagnostic marker
  • Phlebotomy is mainstay of treatment (target Hct <45%)
  • All patients (unless bleeding risk) should receive low-dose aspirin
  • Hydroxyurea for high-risk or those with previous thrombosis/splenomegaly
  • Complications: Thrombosis, myelofibrosis, leukemic transformation
  • Consult hematology for diagnosis/management