Factor XI and XIa Inhibitors for Venous Thromboembolism Prophylaxis After Total Knee Arthroplasty: A Review From Mechanism to Phase III Trials.

Abstract

Venous thromboembolism (VTE) prophylaxis after total knee arthroplasty (TKA) has improved substantially, yet the field continues to balance two competing priorities: reduction of symptomatic deep vein thrombosis and pulmonary embolism while minimizing bleeding, wound complications, and downstream infection risk. Contemporary practice has shifted toward aspirin as prophylaxis for many low-risk patients after TKA, with direct oral anticoagulants (DOAC) and low-molecular-weight heparin (LMWH) reserved for higher-risk patients; however, these agents still affect common-pathway thrombin generation and can increase bleeding or compromise wound healing. Aspirin is not an anticoagulant and, despite its widespread use, does not directly address coagulation-driven thrombosis while still increasing bleeding risk, particularly gastrointestinal bleeding. Factor XI (FXI) and activated FXI (FXIa) sit upstream in the intrinsic pathway and may contribute disproportionately to thrombosis relative to hemostasis. In orthopaedic surgery, multiple Phase II programs, including antisense oligonucleotide knockdown of FXI, monoclonal antibody blockade of FXI or FXIa, and small-molecule FXIa inhibitors, have demonstrated large reductions in venographic VTE with low bleeding profiles comparable to enoxaparin. These data have accelerated late-stage development, as there are two ongoing pivotal Phase III programs of anti-FXI molecules, designed to align with modern arthroplasty practice patterns and to address the evidence gaps most relevant to surgeons. This review summarizes the biologic rationale for FXI targeting, synthesizes completed orthopaedic clinical evidence across various FXI/XIa modalities, and details the design features of ongoing Phase III trials that may define the next generation of post-TKA thromboprophylaxis.