Thrombosis is a leading cause of death in developed countries. The currently used antithrombotics are associated with an increased risk of severe bleeding, which can be life threatening. The inhibition of a novel target, FXI, was found to efficiently prevent thrombosis without causing bleeding side effects, providing a much safer strategy. We have developed the first peptide-based FXI inhibitor, which shows a superior anti-coagulation effect, lasting for more than 10 hours in mice.