Factor XI and Atrial Fibrillation: A Mismatched Pairing?

Factor XI (FXI) is a liver-produced coagulation zymogen that evolutionarily originated from duplication of the gene encoding for prekallikrein. It circulates in complex with high-molecular-weight kininogen, and consists of two identical subunits that bind thrombin, FXIIa and FIX. Thus, the FXI molecule has features different from other coagulation factors. Pharmacological FXI blockade using small molecules, monoclonal antibodies and antisense oligonucleotides, has been developed, with a hypothesis of a bleeding-free, effective anticoagulation. Dose-finding Phase II trials were performed for thromboprophylaxis in orthopaedic surgery, non-valvular AF and as an add-on strategy to antiplatelet drugs in acute atherothrombosis (stroke or MI). None of those studies were powered for safety or efficacy, but rather, they were used to select the optimal dose for Phase III studies. Nevertheless, their limited results were often (over)interpreted as supporting the hypothesis of the first bleeding-free anticoagulation strategy. The failure of the Phase III OCEANIC-AF trial comparing the FXI inhibitor asundexian to the FXa inhibitor apixaban in AF obliged the scientific community to reconsider the bleeding-free hypothesis and the pathophysiology of FXI. Here, the molecular, disease-related and pharmacological features of FXI were analysed to provide possible explanation(s) and hypotheses for this (temporary) failure of FXI targeting. Specifically, the authors describe the peculiar features of the molecule in the coagulation cascade, the possible mechanisms for the bypassing of FXI activity, the clinical evidence related to FXI congenital deficiency, levels measured in pro-thrombotic settings, the pathophysiology of different thromboembolic disorders and the pharmacodynamics of FXI blockade in Phase I and II studies.