Personalized anticoagulant therapy in venous thromboembolism: current role of direct oral anticoagulants, unmet clinical needs, and future perspectives on Factor XI inhibition

Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, remains a major cause of morbidity and mortality worldwide. The introduction of direct oral anticoagulants (DOACs) has transformed the management of VTE by providing effective and convenient alternatives to vitamin K antagonists. However, despite their favorable efficacy–safety profile, clinically relevant bleeding, treatment individualization, and the management of patients with competing thrombotic and hemorrhagic risks remain important unmet clinical needs. Contemporary VTE management increasingly requires a personalized approach integrating clinical characteristics, comorbidities, biomarkers, and real-world evidence to optimize anticoagulant selection, treatment intensity, and duration. Large prospective registries have expanded our understanding of VTE across heterogeneous clinical settings, including cancer-associated thrombosis, postoperative VTE, incidental and subsegmental pulmonary embolism, and other high-risk populations frequently underrepresented in randomized clinical trials. In parallel, emerging prognostic tools, including D-dimer, hemoglobin, inflammatory indices, lipid-related biomarkers, and machine-learning-based prediction models, are contributing to a more refined assessment of thrombotic and bleeding risk. These emerging therapies are being evaluated as potential strategies to reduce bleeding while maintaining antithrombotic efficacy; however, recent phase III findings have demonstrated heterogeneous efficacy across clinical indications, emphasizing that their future role is likely to be indication-specific. This narrative review examines the current role of DOACs in VTE management, discusses the clinical and biological determinants of individualized anticoagulant therapy, and critically appraises the evolving and heterogeneous evidence for Factor XI inhibition as a potential future anticoagulant strategy.