Factor XI and Atrial Fibrillation: A Mismatched Pairing?

Area of Science:

• Coagulation cascade biology
• Pharmacological targeting of hemostasis

Background:

• Factor XI (FXI) is a liver-produced zymogen with unique molecular features.
• FXI circulates in complex with high-molecular-weight kininogen.
• Pharmacological blockade of FXI was developed with a bleeding-free anticoagulation hypothesis.

Observation:

• Phase II trials for FXI inhibitors in various thrombotic conditions were dose-finding studies.
• Limited results from these trials were interpreted as supporting the bleeding-free hypothesis.
• The Phase III OCEANIC-AF trial failure prompted re-evaluation of FXI targeting.

Findings:

• Analysis of FXI's molecular, disease-related, and pharmacological features is crucial.
• Peculiarities in the coagulation cascade and potential bypass mechanisms of FXI activity require investigation.
• Clinical evidence from FXI deficiency and pro-thrombotic states informs FXI blockade pathophysiology.

Implications:

• Reconsidering the bleeding-free hypothesis for FXI inhibitors is necessary.
• Understanding FXI pathophysiology is key to explaining recent trial outcomes.
• Further research into FXI's role in thromboembolic disorders is warranted.