What are the causes of polycythemia vera in adults over 60?

Causes of Polycythemia Vera

Polycythemia vera is a clonal myeloproliferative neoplasm caused by acquired somatic mutations in the JAK2 gene, most commonly the JAK2 V617F mutation present in over 95% of cases, though the ultimate etiology of why these mutations arise remains unknown. 1, 2

Molecular Pathogenesis

Primary Genetic Driver:

• The JAK2 V617F mutation in exon 14 is the proximate genetic cause, present in >95% of PV patients, and induces constitutive STAT5-mediated signaling that drives erythropoietin-independent red blood cell production. 1, 3, 2
• The remaining <5% of patients harbor JAK2 exon 12 mutations or other JAK2 variants. 4
• This is an acquired somatic mutation in a multipotent hematopoietic progenitor cell, not an inherited condition. 5, 3

Additional Molecular Abnormalities:

• Over 50% of patients harbor additional DNA sequence variants beyond JAK2, most frequently TET2 (18%) and ASXL1 (15%). 4
• Abnormal karyotypes occur in 15-20% of cases, with the most common being trisomy 9 (5%), loss of Y chromosome (4%), trisomy 8 (3%), and 20q deletion (3%). 4
• Defective thrombopoietin (TPO) clearance due to reduced c-mpl membrane expression contributes to the thrombocytosis despite elevated platelet mass. 6, 5

Clonal Stem Cell Disorder

Multipotent Progenitor Cell Involvement:

• PV originates from a clonal disorder affecting multipotent hematopoietic progenitor cells, explaining why it produces panmyelosis with increased red cells, white cells, and platelets—not just isolated erythrocytosis. 5, 3
• The disorder affects erythroid, myeloid, and even lymphoid lineages. 5

Unknown Ultimate Etiology

Fundamental Cause:

• The deepest etiology—why JAK2 mutations arise in the first place—remains fundamentally unknown. 5, 3
• There is no identified environmental trigger, infectious agent, or inherited predisposition that explains the development of these somatic mutations in most cases. 3
• PV is more prevalent in persons of Ashkenazi Jewish ancestry, suggesting possible genetic susceptibility factors, but no specific inherited mutations have been identified. 3

Critical Distinction: Primary vs. Secondary Polycythemia

This is NOT secondary polycythemia:

• PV is a primary clonal stem cell disorder, distinct from secondary causes of erythrocytosis (hypoxia-driven EPO production from lung disease, sleep apnea, smoking, or inappropriate EPO secretion from renal tumors). 7
• Serum erythropoietin levels are suppressed (below normal) in PV, whereas they are elevated or high-normal in secondary polycythemia. 7
• The JAK2 V617F mutation is absent in secondary causes of polycythemia. 7

Age and Epidemiology Context

Incidence in Adults Over 60:

• Annual incidence is 0.5 to 4.0 cases per 100,000 persons, with PV affecting approximately 65,000 people in the US. 1
• Age >60 years is a major risk factor for thrombotic complications, but PV can occur at any adult age. 1, 4
• Median age at diagnosis is typically in the sixth decade of life. 4