Thrombin generation and thrombin dynamics are associated with recurrent venous thromboembolism after anticoagulation withdrawal

Abstract

Background Recurrent venous thromboembolism (VTE) is a major concern after stopping anticoagulation. Thrombin generation (TG) parameters—including thrombomodulin (TM) sensitivity—have been proposed as biomarkers of recurrence, but findings remain inconsistent. The role of thrombin dynamic (TD) parameters, including prothrombin conversion and thrombin inactivation, is unclear. Objectives This study evaluated whether TG and TD parameters are associated with VTE recurrence. Methods In 589 patients from the prospective VISTA study, TG was measured during anticoagulation and 1 month after stopping vitamin K antagonist therapy. TM sensitivity was quantified as the percentage inhibition of endogenous thrombin potential (ETP) and peak thrombin concentration. TD parameters were derived computationally from TG curves. Cox regression was used to evaluate associations with recurrent VTE >2 years, including subgroup analyses excluding hormone-related events. Results During the 2-year follow-up, 63 patients experienced recurrent VTE. In multivariable Cox regression adjusted for age, sex, index event type, and hormone use, reduced thrombin inactivation by antithrombin was associated with recurrence (per 100-unit decrease—hazards ratio [HR], 1.10; 95% CI, 1.00-1.20). In patients without hormone-related VTE, lower ETP and reduced TM-mediated inhibition of peak thrombin concentration were also significantly associated with recurrence (ETP per 100-unit decrease—HR, 1.11; 95% CI, 1.01-1.21; TM sensitivity per 10% decrease—HR, 1.26; 95% CI, 1.00-1.58). Other TG parameters were not significantly associated with recurrence. Conclusion Reduced ETP, TM sensitivity, and thrombin inactivation were associated with VTE recurrence in people with unprovoked VTE. These biomarkers may have potential to identify patients at higher risk of recurrence.