Leveraging Human Genetics to Estimate Clinical Risk Reductions Achievable by Inhibiting Factor XI

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pharmacology

Background:

• Coagulation factor XI (FXI) is a key target for novel antithrombotic therapies.
• The precise impact of FXI inhibition on thrombotic event reduction remains uncertain.

Purpose of the Study:

• To investigate the association between genetic variants affecting FXI levels and thrombotic/bleeding risks.
• To estimate the potential magnitude of risk reduction from pharmacological FXI inhibition.

Main Methods:

• Utilized a genetic score based on 2 FXI-altering variants in 371,695 UK Biobank participants and GWAS data.
• Analyzed the score's association with venous thrombosis, ischemic stroke, and major bleeding events.

Main Results:

• Lower FXI levels genetically correlated with significantly reduced risks of venous thrombosis (OR=0.1) and ischemic stroke (OR=0.47).
• No significant association was found between lower FXI levels and increased major bleeding risk (OR=0.7).
• Risk reductions were consistent across subgroups, with greater absolute benefits in high-risk populations like those with atrial fibrillation.

Conclusions:

• Human genetic data support FXI inhibition as a strategy for substantial ischemic stroke risk reduction.
• Pharmacological FXI modulation appears to offer significant antithrombotic benefits without a clear increase in major bleeding risk.