Hypercoagulability in clonal hematopoiesis: A hidden contributor to thrombosis in the elderly

Abstract

Abstract Introduction: Clonal hematopoiesis (CH) is characterized by the expansion of hematopoietic cells bearing somatic mutations such as TET2, DNMT3A, and JAK2 in individuals without overt hematologic malignancy. CH prevalence increases with age and has been linked to an elevated risk of cardiovascular events, including thrombosis. Methods: We searched PubMed-indexed literature articles and cohort studies using PRISMA guidelines for studies that analyzed the association between CH driver mutations and thrombosis up to August 2025, with emphasis on mutation-specific risk and mechanism. Results: In a cohort of 11,265 individuals, JAK2 V617F carriers had a hazard ratio (HR) of 5.44 (95% CI, 2.04–14.55) for venous thromboembolism (VTE) compared to non-carriers, suggesting that the JAK2 V617F mutation is strongly associated with increased thrombosis risk. Similarly, mutations in TET2 and DNMT3A are linked to increased inflammation and thrombotic risk through mechanisms such as inflammasome activation and cytokine release. In another prospective cohort of 3,063 patients, mutation carriers of CH had a two-fold increased risk of coronary heart disease and ischemic stroke. Mechanistic studies depict TET2-deficient macrophages that increase IL-1β release, promote atherosclerosis, and thrombosis. Neutrophil extracellular trap (NET) formation is enhanced in JAK2-mutant CH and has implications for thrombosis as well. Conclusions: Findings from multiple large cohorts confirm that CH, particularly with mutations such as JAK2 V617F, is associated with a significantly increased risk of thrombotic complications. This is attributed to the proinflammatory and prothrombotic phenotype of mutant hematopoietic cells. Although screening for CH is not yet part of routine practice, its detection in elderly patients or those with recurrent or unexplained thrombotic events may refine risk stratification and inform decisions on anticoagulation duration or intensity. These insights also highlight potential therapeutic targets, such as inflammatory cytokine pathways, and underscore the need for prospective studies to define optimal management strategies in this emerging high-risk population. Though formal guidelines are lacking, evidence suggests that CH carriers with thrombotic complications could benefit from prolonged anticoagulation, paralleling management strategies for unprovoked thrombosis with high recurrence risk. In addition, the proinflammatory state promoted by mutant hematopoietic clones supports exploring anti-inflammatory therapies, such as IL-1β inhibition, to potentially mitigate thrombotic risk, although these approaches require further clinical validation. Future research with a focus on prospective studies would be valuable in guiding evidence-based management approaches for this emerging high-risk population.