Polycythemia vera

Polycythemia vera is a chronic myeloproliferative neoplasm most commonly caused by a gain of function mutation in the JAK2 gene, leading to erythrocytosis with or without increases in granulocytes and platelets. The elevated blood cell mass results in hyperviscosity, which may manifest with fatigue, facial flushing, pruritus, erythromelalgia, headaches, dizziness, and, in severe cases, thromboembolic events (e.g., stroke, Budd-Chiari syndrome). Diagnosis is confirmed if other causes of polycythemia are ruled out (e.g., relative polycythemia, hypoxia-induced polycythemia, autonomous EPO production) and diagnostic criteria for polycythemia vera are met. Management of polycythemia vera focuses on preventing thrombotic and bleeding events and treating associated symptoms (e.g., pruritus, gout). Therapeutic phlebotomy and aspirin are indicated in all patients. Additionally, patients with high-risk polycythemia vera require cytoreductive therapies and, possibly, anticoagulation. Patients should be monitored carefully for the development of complications and transformation of polycythemia vera to another hematologic malignancy, e.g., post-PV myelofibrosis, myelodysplasia, or acute myelogenous leukemia (AML).

• Prevalence: approximately 44 per 100,000 population ^[1][2]
• Age at diagnosis: variable; more common in individuals aged > 60 years ^[2][3]
• Risk factors for polycythemia vera ^[3]
  • Older age
  • Male sex
  • White race
  • Hypertension
  • Diabetes mellitus
  • Obesity
  • Hyperlipidemia
  • Smoking

Epidemiological data refers to the US, unless otherwise specified.

• The JAK2 (Janus kinase 2) oncogene codes for a non-receptor tyrosine kinase in hematopoietic progenitor cells. JAK2 is essential for the regulation of erythropoiesis, thrombopoiesis (megakaryopoiesis), and granulopoiesis.
• 98% of patients with polcythemia vera have a mutation in the JAK2 gene (gain of function) → ↑ tyrosine kinase activity → erythropoietin-independent proliferation of the myeloid cell lines → ↑ blood cell mass (erythrocytosis, thrombocytosis, and granulocytosis) → hyperviscosity and slow blood flow → ↑ risk of thrombosis and poor oxygenation.

• Often asymptomatic (incidental finding on routine blood tests)
• Nonspecific symptoms: fatigue, difficulty concentrating, insomnia, abdominal pain
• Constitutional symptoms: weight loss, sweating
• Hyperviscosity syndrome: triad of mucosal bleeding, neurological symptoms, and visual changes
• Plethora; : flushed face with a purple hue; cyanotic lips
• Pruritus; : Itching typically worsens when the skin comes into contact with warm water (aquagenic pruritus).
• Erythromelalgia ^[8]
• Nonspecific neurological symptoms : dizziness, headache, visual disturbances, tinnitus
• Hypertension
• Splenomegaly : associated with early satiety and abdominal discomfort; less commonly hepatomegaly
• Peptic ulcer disease
• Gout
• Symptoms of thrombotic and hemorrhagic complications (see “Complications” below)

Patients with polycythemia vera are at increased risk of thrombosis and bleeding.

Approach ^{[3][9][10][11]}

• Suspect polycythemia vera in:
  • Individuals with elevated hemoglobin and/or hematocrit; and normal oxygen saturation
  • Patients with features or complications associated with polycythemia vera (e.g., hyperviscosity syndrome, splanchnic vein thrombosis)
• Rule out other causes of polycythemia based on a thorough medical history, physical examination, and diagnostics as needed.
• Order confirmatory laboratory studies for polycythemia vera.
  • Serum erythropoietin levels (EPO)
  • Peripheral blood screen for JAK2 mutation ^[3][12]
• Consider bone marrow studies in consultation with hematology. ^[9][10]
• Consider abdominal imaging to evaluate for splenomegaly.
• Confirm diagnosis based on the diagnostic criteria for polycythemia vera.
• Reevaluate for other causes of polycythemia vera if diagnostic criteria are not met.

Erythrocytosis associated with normal oxygen saturation and decreased serum EPO levels is strongly suggestive of polycythemia vera. Erythrocytosis associated with elevated serum EPO or decreased oxygen saturation suggests secondary polycythemia caused by chronic hypoxia.

The first presentation in patients with polycythemia vera may be a thrombotic event, in particular, hepatic vein thrombosis. Maintain a low threshold for working up older patients with new thrombosis. ^[13]

Diagnostic criteria

Hemoglobin levels may be normal in the prepolycythemic (masked) phase of polycythemia vera, elevated during the overt polycythemic phase, and then decreased in post-PV myelofibrosis (the spent phase). ^[13][14]

Bone marrow biopsy may not be routinely required in patients with extremely elevated Hgb and Hct (i.e., ♂: Hgb > 18.5 g/dL, Hct 55.5%; ♀: Hgb > 16.5 g/dL, Hct 49.5%). ^[3][9][10]

Findings on routine laboratory studies ^[3]

Confirmatory laboratory studies are detailed in “Diagnostic criteria for polycythemia vera.” Additional findings on routine laboratory studies for polycythemia include: ^[10][15]

• CBC
  • Normal or ↑ platelets ^[13]
  • Normal or ↑ leukocytes ^[13]
• ESR: ↓ or normal : ^[16]
• Peripheral smear ^[13][17]
  • Normocytic normochromic RBCs
  • If iron deficiency anemia is present, microcytic, hypochromic RBCs
• Serum iron studies: ↓ iron, ↓ ferritin ^[18]
• Markers of cell turnover: ↑ leukocyte alkaline phosphatase, uric acid, and/or LDH ^[17]

Polycythemia vera may manifest with erythrocytosis alone or, in > 50% of patients, erythrocytosis in combination with leukocytosis and/or thrombocytosis. ^[9]

In patients with polycythemia vera and iron deficiency, microscopic findings of iron deficiency anemia (i.e., microcytic hypochromic anemia) are seen on peripheral blood smear, but with elevated rather than decreased hemoglobin levels. ^[13][17]

Microcytic erythrocytosis is only associated with polycythemia vera, beta-thalassemia trait, and hypoxic erythrocytosis. ^[13][17]

• Other causes of polycythemia: See below.
  • Absolute erythrocytosis
    • Caused by an increased production of RBCs (normal plasma volume)
    • Includes primary polycythemia and secondary polycythemia
  • Relative erythrocytosis is caused by a decrease in plasma volume (normal RBC mass).
• Other myeloproliferative disorders: See “Overview of MPNs.”

An elevated EPO suggests secondary polycythemia. ^[17]

The differential diagnoses listed here are not exhaustive.

Approach ^{[3][11][15][24]}

• Consult hematology.
• Assess for acute severe complications, e.g., stroke or pulmonary embolus; if present:
  • Manage complications following standard best practice (see relevant articles for details).
  • Consider erythrocytapheresis in consultation with hematology. ^[25]
• Assess risk category. ^[11][26]
  • Low-risk polycythemia vera: no history of thrombosis and ≤ 60 years of age
  • High-risk polycythemia vera: history of thrombosis and/or > 60 years of age ^[11][15][27]
• All patients
  • Regular therapeutic phlebotomy PLUS low-dose aspirin ^[11]
  • Manage modifiable cardiovascular risk factors of polycythemia vera.
  • Treat associated symptoms, e.g., allopurinol for gout, antihistamines for pruritus.
  • Monitor regularly for complications, including transformation to post-PV myelofibrosis, myelodysplastic syndromes, and AML.
• High-risk patients or low-risk patients with persistent symptoms
  • Start cytoreductive therapy with hydroxyurea.
  • Assess need for anticoagulation.

The management of polycythemia vera focuses on decreasing the risk of thromboembolic events, which are the most common cause of mortality in patients with polycythemia vera. ^[3]

Hemopoietic stem cell transplant is not used in the management of polycythemia vera but may be considered in post-PV myelofibrosis. ^[13][24]

Reduction of blood cell counts ^{[9][11][15][28]}

• Reduction in cell counts decreases hyperviscosity and thromboembolic events.
• Target hematocrit: ≤ 45% ^[9][15][26]

Regular therapeutic phlebotomy

• Indications: all patients ^[3][9][11]
• Procedure: removal of blood (e.g., 250–500 mL) via venipuncture at scheduled intervals
• Frequency: based on the patient's response to treatment . ^[3]

Cytoreductive therapy ^{[3][11][24][26]}

• Indications ^[3][11][26]
  • High-risk polycythemia vera
  • Low-risk polycythemia vera with any of the following:
    • Polycythemia refractory to phlebotomy
    • Persistent or progressive symptoms despite phlebotomy and aspirin therapy ^[17][26]
• First-line: hydroxyurea ^[3][11]
• Alternatives (e.g., refractory to or unable to tolerate hydroxyurea) ^[3][11]
  • JAK2 inhibitor, e.g., ruxolitinib (in patients with symptomatic splenomegaly)
  • Pegylated interferon-alpha
  • Busulfan (in older patients) ^[11][15][26]

JAK2 inhibitors are highly effective at treating symptomatic splenomegaly; splenectomy is now rarely required in patients with polycythemia vera. ^[17]
Do not treat iron deficiency in patients with polycythemia vera; maintaining iron deficiency prevents rapid reexpansion of RBC mass after phlebotomy. ^[17]

Further prevention of thromboembolic events ^[11][15][24]

• All patients: Start antiplatelet drugs (e.g., aspirin ) unless contraindicated. ^[11][15][24]
• High-risk polycythemia vera in patients with previous VTE: Start anticoagulants (e.g., parenteral anticoagulants, oral anticoagulants).

Smoking cessation is associated with a decreased risk of thrombosis. ^[3]

Patients with extreme thrombocytosis may develop acquired von Willebrand disease. If platelet count is > 1 million/μL, perform a ristocetin cofactor assay and consider stopping aspirin if ristocetin cofactor activity is < 20%. ^[15]

Symptomatic management ^[11][17]

• Symptomatic hyperuricemia (e.g., gouty arthritis): Initiate allopurinol. ^[17]
• Pruritus: Treatments include antihistamines, SSRIs, and interferon-alpha. ^[11]
• Erythromelalgia ^[29]
  • Avoidance of triggers, e.g., heat exposure
  • Aspirin therapy
  • Consider adjuvant analgesics, e.g., gabapentin, if symptoms persist despite aspirin.
• Peptic ulcer prophylaxis: PPIs or H₂ receptor blockers

Polycythemia vera is a potentially life-threatening disease because of the numerous complications associated with it.

Thrombotic complications ^[5][30]

• Venous thrombosis
  • Renal vein thrombosis
  • Mesenteric venous thrombosis
  • Portal vein obstruction
  • Splenic vein thrombosis
  • Deep vein thrombosis
  • Pulmonary embolism
  • Budd-Chiari syndrome
• Arterial thrombosis
  • Stroke
  • Peripheral arterial emboli
  • Myocardial infarction (MI)
  • Splenic infarction

Hemorrhagic complications ^[5]

• Petechiae
• Epistaxis
• Bleeding gums

Gout ^[5]

• High cell turnover → increased uric acid

Late stages ^[5]

• AML, myelodysplastic syndrome (MDS): Additional genetic mutations may cause polycythemia vera to transition to other hematologic diseases.
• Post-polycythemia vera myelofibrosis: fibrotic transformation of the bone marrow

We list the most important complications. The selection is not exhaustive.

• Without treatment: mortality within 2 years of diagnosis (typically due to thrombotic complications)
• With treatment: median survival of 13.5 years; 24 years in those diagnosed before 60 years of age
• Progression to post-PV myelofibrosis: 6–15% of patients over 15 years
• Progression to AML or myelodysplastic syndrome: 5–18% of patients over 15 years