What is Polycythemia Vera?
Polycythemia vera (PV) is a clonal stem cell-derived myeloproliferative neoplasm characterized by excessive red blood cell production (erythrocytosis), often accompanied by elevated white blood cells and platelets, caused by an acquired JAK2 mutation in over 95% of cases. 1
Disease Classification and Pathophysiology
PV is classified as one of three chronic myeloproliferative disorders (CMPDs), alongside essential thrombocythemia and myelofibrosis with myeloid metaplasia. 1
The disease arises from an acquired somatic mutation (not inherited) in the JAK2 gene (JAK2V617F mutation present in >95% of cases), which occurs during a person's lifetime in bone marrow cells. 2
PV is fundamentally a clonal stem cell disease with trilineage myeloid involvement (affecting red cells, white cells, and platelets), distinguishing it from secondary causes of elevated red blood cells. 1
The clinical distinction of PV from other myeloproliferative disorders is made by demonstrating clonal erythrocytosis without substantial bone marrow fibrosis or isolated thrombocytosis. 1
Epidemiology and Demographics
The incidence is approximately 2.3 per 100,000 population with stable trends over time. 1, 3
Median age at diagnosis is approximately 60 years, with a slight male predominance (1.2:1 ratio). 1, 3
Only 7% of patients are diagnosed before age 40 years, and children are rarely affected. 1, 2
Higher disease incidence occurs in persons of Jewish ancestry and among parent-offspring pairs, suggesting genetic predisposition to acquiring the JAK2 mutation rather than direct inheritance. 1, 2
Clinical Manifestations
The disease presents with increased red blood cell mass and characteristic physical findings:
Plethora (ruddy or reddish-purple facial discoloration) is a classic finding, caused by increased red blood cell mass and engorged superficial blood vessels, particularly noticeable in sun-exposed areas. 4
Engorged superficial veins that are visibly distended due to increased blood volume, and conjunctival injection with redness of the eyes. 4
Splenomegaly, leukocytosis, and thrombocytosis may be present but are variable. 1
Bone marrow demonstrates hypercellularity with atypical megakaryocytic hyperplasia and clustering. 1
Prognosis and Complications
Median survival is approximately 15 years overall, but exceeds 35 years for patients diagnosed at age ≤40 years. 3, 5
The natural history may be interrupted by thrombotic events (26% at 20 years), fibrotic progression (16% at 20 years), or leukemic transformation (4% at 20 years). 5
Myocardial infarction, stroke, and peripheral ischemic events represent the most common arterial complications, with suboptimal cerebral blood flow occurring at hematocrit values between 46-52%. 3
Acquired von Willebrand disease occurs in more than one-third of patients and is associated with bleeding diathesis. 3
Diagnostic Approach
Diagnosis requires JAK2 mutation presence with hemoglobin/hematocrit levels >16.5 g/dL/49% in men or >16 g/dL/48% in women. 3, 6
Subnormal erythropoietin levels help differentiate PV from secondary erythrocytosis causes such as smoking, sleep apnea, and testosterone use. 7
When evaluating young patients with erythrocytosis and family history, measure serum erythropoietin levels and consider hemoglobin electrophoresis to distinguish hereditary erythrocytosis from early-onset familial PV. 2
Bone marrow biopsy showing characteristic abnormalities supports the diagnosis. 6, 7
Treatment Goals and Strategy
Current treatment strategies are directed at preventing thrombotic complications rather than curing the disease, as no medications have been shown to reduce leukemic or fibrotic progression risk. 5, 7
All patients require phlebotomy to maintain hematocrit <45% and once-daily low-dose aspirin (81 mg) in the absence of contraindications. 3, 5
Risk stratification divides patients into high-risk (age >60 years or history of thrombosis) and low-risk (absence of both factors). 3, 5
Cytoreductive therapy is reserved for high-risk disease or symptomatic low-risk disease, with hydroxyurea and pegylated interferon-alfa as first-line drugs of choice. 3, 5
Second-line options include busulfan (preferred in older patients) and ruxolitinib (preferred for symptoms reminiscent of post-PV myelofibrosis or protracted pruritus). 5, 8
Plethora improves with therapeutic phlebotomy reducing hematocrit to target levels. 4