What is polycythemia vera?

What is Polycythemia Vera

Polycythemia vera (PV) is a clonal stem cell–derived myeloproliferative neoplasm characterized by uncontrolled overproduction of red blood cells (erythrocytosis), frequently accompanied by elevated white blood cells and platelets, driven by an acquired JAK2 mutation in >95% of cases. 1, 2

Disease Classification and Pathophysiology

PV belongs to the chronic myeloproliferative disorders (CMPDs), grouped alongside essential thrombocythemia (ET) and myelofibrosis with myeloid metaplasia (MMM), distinct from chronic myeloid leukemia which carries the Philadelphia chromosome. 1

Molecular Basis

• The JAK2 V617F mutation is present in >95% of PV patients, representing the principal acquired somatic driver mutation that occurs during a person's lifetime in bone marrow cells, not inherited from parents. 2, 3
• JAK2 exon 12 mutations account for 2-4% of cases in patients who test negative for JAK2 V617F, making comprehensive JAK2 testing essential when clinical suspicion is high. 2
• PV is fundamentally a clonal stem cell disease with trilineage myeloid involvement (red cells, white cells, platelets), though normal hematopoietic stem cells coexist with the malignant clone. 1

Bone Marrow Characteristics

• Bone marrow shows hypercellularity with atypical megakaryocytic hyperplasia and clustering, distinguishing it from secondary causes of elevated red blood cells. 1
• The clinical distinction from other CMPDs is made by demonstrating clonal erythrocytosis without substantial bone marrow fibrosis (which defines myelofibrosis) or isolated thrombocytosis (which defines essential thrombocythemia). 1

Epidemiology

• Incidence is approximately 2.3 per 100,000 population with stable trends over time. 1, 4
• Median age at diagnosis is 60 years with a slight male predominance (1.2:1); approximately 7% are diagnosed before age 40, and children are rarely affected. 1, 3
• Higher incidence occurs in persons of Jewish ancestry and among parent-offspring pairs, suggesting genetic predisposition to acquiring JAK2 mutations rather than direct disease inheritance. 1, 3

Clinical Manifestations

Hematologic Features

• True polycythemia represents a real increase in red blood cell mass (RCM), distinguished from apparent polycythemia (reduced plasma volume) or spurious elevation from laboratory variation. 1
• Erythrocytosis is often accompanied by leukocytosis, thrombocytosis, and splenomegaly in variable combinations. 1

Thrombotic and Hemorrhagic Complications

• Thrombotic events represent the most significant morbidity, with 20-year thrombosis rates of 26% including myocardial infarction, stroke, and peripheral ischemic events. 1, 4, 5
• Suboptimal cerebral blood flow occurs with hematocrit values between 46-52%, establishing the pathophysiologic basis for strict hematocrit control. 4
• Acquired von Willebrand disease occurs in more than one-third of patients, particularly with extreme thrombocytosis, causing paradoxical bleeding despite elevated platelet counts. 1, 4

Disease Progression

• Natural history includes potential transformation to myelofibrosis (16% at 20 years) or acute leukemia (4% at 20 years), though median survival exceeds 35 years in patients ≤40 years at diagnosis. 4, 5

Diagnostic Approach

Diagnosis requires demonstrating clonal erythrocytosis in the context of JAK2 mutation and excluding secondary causes of elevated red blood cells. 1

Key Diagnostic Elements

• JAK2 V617F mutation testing should be performed first on whole blood or purified granulocyte DNA, as this mutation is present in >95% of cases. 2
• If JAK2 V617F is negative but clinical suspicion remains high (elevated hemoglobin/hematocrit, low serum erythropoietin, splenomegaly), order JAK2 exon 12 mutation analysis on purified granulocyte DNA to detect the 2-4% of cases with this alternative mutation. 2
• Hemoglobin/hematocrit thresholds for diagnosis are >16.5 g/dL/49% in men or >16 g/dL/48% in women when associated with JAK2 mutation. 4
• Serum erythropoietin levels are characteristically low or inappropriately normal, helping distinguish PV from secondary polycythemia where EPO is typically elevated. 1, 6

Diagnostic Pitfalls

• Co-existing iron deficiency can mask the diagnosis by lowering hemoglobin below diagnostic thresholds while red cell count remains elevated with microcytosis. 2
• No specific disease marker exists beyond JAK2 mutations; diagnosis relies on constellation of clinical, laboratory, and bone marrow histological findings. 1
• Bone marrow biopsy showing panmyelosis with JAK2 V617F versus isolated erythroid hyperplasia with JAK2 exon 12 mutations helps distinguish mutation subtypes, though both are managed similarly. 2

Distinguishing from Secondary Polycythemia

Secondary polycythemia may be hypoxia-driven (chronic lung disease, high altitude, sleep apnea, smoking, cyanotic heart disease) or hypoxia-independent (renal tumors, hepatocellular carcinoma, EPO-secreting tumors, testosterone use). 1, 6

• Smoker's polycythemia is real and secondary to chronic carbon monoxide exposure, resolving with smoking cessation, and should not trigger extensive workup for PV in the absence of other features. 1
• Relative polycythemia from plasma volume contraction (dehydration, diuretics, burns) is clinically obvious and does not require red cell mass measurements. 1