Factor XI: structure, function and therapeutic inhibition.

Area of Science:

• Cardiovascular Medicine
• Hematology
• Pharmacology

Background:

• Thromboembolism remains a significant global health burden, necessitating effective anticoagulation.
• Current anticoagulants (heparin, VKAs, DOACs) carry bleeding risks, driving the search for safer alternatives.
• The intrinsic coagulation pathway, specifically factor XI (FXI), is a promising target for novel anticoagulants with a potentially improved safety profile.

Purpose of the Study:

• To review the rationale for developing FXI inhibitors as safer anticoagulants.
• To present advanced FXI-inhibiting agents currently in development.
• To summarize clinical trial data and ongoing research for FXI inhibitors.

Main Methods:

• Review of preclinical studies and epidemiological data on FXI deficiency and inhibition.
• Analysis of phase 2 clinical trial results across various indications (orthopedic surgery, atrial fibrillation, ESRD, MI, stroke).
• Evaluation of diverse FXI-targeting strategies including oligonucleotides, antibodies, small molecules, peptides, and aptamers.

Main Results:

• Preclinical and epidemiological data suggest FXI inhibition confers antithrombotic protection with reduced bleeding risk.
• Phase 2 studies indicate promising efficacy of FXI inhibitors in diverse clinical settings.
• Multiple FXI-inhibiting agents are in various stages of clinical development, demonstrating feasibility.

Conclusions:

• FXI inhibitors represent a potentially safer anticoagulant strategy compared to traditional therapies.
• Further validation through large-scale phase 3 trials is crucial to establish the optimal balance between efficacy and safety.
• Ongoing research and planned trials aim to define the clinical role and optimal application of FXI inhibitors for various thrombotic conditions.