Clonal hematopoiesis of indeterminate potential and incidence of venous thromboembolism in older adults

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases, but its association with venous thromboembolic events (VTE) is unclear. Objectives: We investigated the association between CHIP and incident VTE in older adults and evaluated whether risk varies by CHIP driver gene. Methods: Participants from the community-based Atherosclerosis Risk in Communities Study without a history of VTE or hematologic malignancies were included. Whole-exome sequencing from peripheral blood was used to ascertain CHIP (variant allele frequency ≥ 2%) and common gene-specific CHIP subtypes (DNMT3A, TET2, and ASXL1). The primary outcome was incident VTE (adjudicated by experts from medical record review), defined as symptomatic and asymptomatic pulmonary embolism and lower extremity deep vein thrombosis. Multivariable Cox proportional hazard models were used to study the association between CHIP and VTE. Results: Of 3980 participants included (median [25th-75th percentiles] age, 75.0 [71.0-79.0] years), 2359 (59.3%) were female, 1621 (40.7%) were male, 890 (22.4%) identified as Black, and 3090 (77.6%) identified as White; 985 (24.7%) had CHIP. Over a median 7.1-year follow-up, VTE occurred in 44 (4.5%) CHIP carriers vs 96 (3.2%) noncarriers (hazard ratio, 1.49; 95% CI, 1.02-2.17; P = .038). TET2 mutation was significantly associated with VTE risk (hazard ratio, 2.25; 95% CI, 1.27-4.00; P = .006). Conclusion: In this cohort study of older adults, we identified a modestly increased risk of VTE in individuals with CHIP, mainly driven by TET2 mutation. Future research should explore the mechanisms driving these associations and assess potential therapeutic and preventive strategies.