A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

Abstract

Therapeutic targeting of blood coagulation is a challenging task as it interferes with the delicate balance of pro- and anticoagulant activities. Anticoagulants are employed in millions of thrombophilic patients worldwide each year. The treatment and prevention of venous thromboembolism has changed drastically with the replacement of traditional anticoagulant vitamin K antagonists by direct oral anticoagulants (DOACs), which selectively target coagulation factors Xa or IIa. However for a growing population with comorbidities satisfying therapeutic options are still lacking and the quest for novel therapeutics continues. Recently targeting factors XI or XII have emerged as new therapeutic strategies. As these factors play important roles in thrombosis, nevertheless are practically functionally dispensable for hemostasis, they may potentially overcome the functional obstacle of treating or preventing thrombosis without affecting hemostasis. Based on the recent elucidation of the hemostatic miRNA targetome, we introduce and discuss a hitherto unrecognized rationale for the therapeutic targeting of factor XI. This is based on mimicking endogenous factor XI expression control by therapeutic delivery of miRNA mimics. We discuss the functional difference between various gene targeting approaches, and propose the hemostatic system to represent an ideal model for assessment of the efficacy and safety of such therapeutic components, ushering in a novel therapeutic era with broad applicability.