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Formation of denser fiber networks has been reported in atrial fibrillation and ischemic stroke. In this longitudinal cohort study, we evaluated whether fibrin clot density may predict thromboembolic and bleeding risk in patients with atrial fibrillation on vitamin K antagonists.In 236 patients with atrial fibrillation receiving vitamin K antagonists treatment, we measured ex vivo plasma clot permeability (Ks), a measure of the pore size in fibrin networks.During a median follow-up of 4.3 (interquartile range, 3.7–4.8) years, annual rates of ischemic stroke or transient ischemic attack and major bleeds were 2.96% and 3.45%, respectively. In multivariate Cox regression analysis, patients with lower Ks (<6.8 cm2×10−9, median) had increased risk of ischemic stroke or transient ischemic attack (hazard ratio [HR], 6.55; 95% confidence interval [CI], 2.17–19.82) and major bleeds (HR, 10.65; 95% CI, 3.52–32.22). Patients with elevated Ks (≥6.8 cm2×10−9) had an increased rate of minor bleeding compared with the remainder (11.63% per year versus 3.55% per year; P<0.0001). The independent predictors of stroke or transient ischemic attack were low Ks (<6.8 cm2×10−9; HR, 7.24; 95% CI, 2.53–20.76), age (HR, 1.05; 95% CI, 1.01–1.10), and treatment with angiotensin-converting enzyme inhibitors (HR, 2.27; 95% CI, 1.08–4.77). Major bleeds were predicted by low Ks (<6.8 cm2×10−9; HR, 8.48; 95% CI, 2.99–24.1) and HAS-BLED score ≥3 (HR, 2.22; 95% CI, 1.12–4.38).This study is the first to show that unfavorable fibrin properties reflected by formation of denser fibrin networks determine, in part, the efficacy and safety of anticoagulation with vitamin K antagonists in patients with atrial fibrillation.