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

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. Traditional vitamin K antagonists are being replaced 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, yet are essentially dispensable for hemostasis, these strategies may overcome the obstacle of treating or preventing thrombosis without affecting hemostasis. Based on the recent elucidation of the hemostatic microRNA 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 microRNA 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.