Anticoagulation in advanced renal failure: do factor XI/XIa inhibitors represent the long-awaited shift?

Advanced chronic kidney disease (CKD), particularly stages G4-G5 and dialysis-dependent kidney failure, is one of the most challenging settings for anticoagulant therapy because thrombotic and bleeding risks coexist and often increase in parallel. Conventional anticoagulants, including vitamin K antagonists, direct oral anticoagulants and heparins, have important limitations in this population, owing to altered pharmacokinetics, limited evidence from randomized trials and an intrinsically unstable hemostatic balance. Inhibitors of factor XI (FXI) and activated factor XI (FXIa) have emerged as a novel strategy designed to attenuate thrombus amplification while preserving physiological hemostasis. Advanced CKD provides a particularly attractive clinical model in which to evaluate this concept, since it combines systemic thrombotic risk with uremic bleeding tendency and, in patients undergoing hemodialysis, repeated activation of the contact pathway by the extracorporeal circuit. This narrative review summarizes the hemostatic abnormalities of advanced CKD, discusses the limitations of currently available anticoagulants, reviews the biological rationale for FXI/FXIa inhibition and critically examines the available phase II clinical evidence in patients with advanced renal disease. Although early studies suggest a favorable safety profile and support the biological plausibility of this therapeutic approach, definitive evidence of clinical benefit is still lacking. Dedicated phase III trials will determine whether selective FXI inhibition can truly improve the net clinical benefit of anticoagulation in advanced CKD by dissociating the protection for pathological thrombosis from the impairment of physiological hemostasis.