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Background: Serious bleeding is a frequent and feared treatment complication in patients treated with oral anticoagulants (OACs). Levels of von Willebrand factor (VWF) antigen have been linked to the risk of bleeding complications, mortality, and cardiovascular events. Objectives: In this longitudinal cohort study of evaluating patients treated with OACs, we aimed to evaluate the relationship between VWF displaying a glycoprotein Ib binding conformation (VWF activation factor) and the risk of cardiovascular events, bleeding complications, or all-cause mortality. Materials and methods: Blood samples were collected at baseline in 356 patients on OACs. Patients were followed for an average of 48 months and bleeding complications leading to admission to hospital or death, cardiovascular events (myocardial infarction, ischemic stroke, and peripheral arterial emboli), and all-cause mortality were recorded and classified. Results: During the study period, 47 bleeding complications, 84 cardiovascular events, and 97 deaths occurred. In multivariate Cox regression analyses, VWF activation factor was significantly associated with all-cause mortality (HR 1.62; 95% CI: 1.25-2.08) and cardiovascular events (HR 1.28; 95% CI: 1.01-1.63). There was no association observed between VWF activation factor and bleeding complications. Conclusions: Patients with high levels of VWF activation factor had an increased risk of cardiovascular events and all cause mortality during OAC treatment. The selectivity for thrombotic complications adds to the potential value of VWF activation factor as a biomarker or pharmacological target. (C) 2015 Elsevier Ltd. All rights reserved.