Low thrombin inactivation capacity is associated with an increased risk of recurrent ischemic events after ischemic stroke at a young age.

Background: Patients with ischemic stroke at a young age (18-50 years) have an increased long-term risk of recurrent ischemic events. Hypercoagulability may contribute to this high risk.

Objectives: To investigate associations between in and ex vivo hemostatic parameters and recurrent ischemic events after an ischemic stroke or transient ischemic attack at a young age.

Methods: We included patients with ischemic stroke or TIA between 1980 and 2010 from the prospective FUTURE cohort. Blood samples were collected in 2010 and patients were followed for recurrent ischemic events from 2010 to 2023. Pro- and anticoagulant markers and thrombin generation assay were measured. Thrombin dynamic analysis was used to study underlying pro- and anticoagulant processes. Hazard ratios (HR) per standard deviation increase were assessed with cause-specific hazard models.

Results: Of the initial cohort of 581 patients, 332 were eligible. The median time between the index event and 2010 was 7.6 years. During a mean follow-up of 6.5 years, 70 of 332 (21.1%) patients experienced a recurrent ischemic event. Lower antithrombin levels (adjusted HR=0.77; 95% CI 0.60-0.98) and higher fibrinogen levels (HR=1.35; CI 1.04-1.73) were associated with higher risk of recurrent ischemic events. Plasma thrombin generation was not associated with recurrence. However, the thrombin decay constant (HR=0.67; CI 0.51-0.87) was associated with a lower risk of recurrent ischemic events.

Conclusion: After an ischemic stroke or TIA at a young age, thrombin decay constant, reflecting reduced protection against thrombin (low antithrombin) and decreased potential to inhibit thrombin (high fibrinogen), is associated with recurrent ischemic events.