| Summary: | Abstract Direct oral anti–activated factor X and antithrombin agents have largely replaced vitamin K antagonists as the standard of care in treatment of venous thromboembolism. However, gaps in efficacy and safety persist, notably in end‐stage renal disease, implantable heart valves or assist devices, extracorporeal support of the circulation, and antiphospholipid syndrome. Inhibition of coagulation factor XI (FXI) emerges as a promising new therapeutic target. Antisense oligonucleotides offer potential advantages as a prophylactic or therapeutic modality, with one dose‐finding trial in orthopedic surgery already published. In addition, monoclonal antibodies blocking activation and/or activity of activated factor XI are investigated, as are small‐molecule inhibitors with rapid offset of action. Further potential targets include upstream components of the contact pathway such as factor XII, polyphosphates, or kallikrein. Finally, catheter‐directed, pharmacomechanical antithrombotic strategies have been developed for high‐ and intermediate‐risk pulmonary embolism, and large randomized trials aiming to validate their efficacy, safety, and prognostic impact are about to start.
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