6533b852fe1ef96bd12ab7ce

RESEARCH PRODUCT

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

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Abstract The treatment and prevention of thrombosis is currently under a period of rapid change with the replacement of traditional anticoagulant vitamin K antagonists, which impair the biosynthesis of a wide range of blood coagulation factors, with direct oral anticoagulants (DOACs), which specifically target factors FXa or FIIa. Nevertheless therapeutic targeting of blood coagulation is an inherently difficult task as it interferes with the delicate balance of pro- and anticoagulant activities. Although anticoagulants are employed in millions of thrombophilic patients worldwide each year, for a growing population with comorbidities who exhibit an increased risk of bleeding with DOAC treatment satisfying therapeutic options are still lacking and the quest for novel therapeutics continues. Recently the targeting of factors FXI and FXII have emerged as new therapeutic strategies. As these factors play an important roles in thrombosis, however are more or less functionally dispensable for hemostasis, they may potentially overcoming the functional obstacle of treating or preventing thrombosis without affecting hemostasis. A key question in following up this approach is which of these two factors is likely to be the more reliable target? Here we present and discuss a hitherto unrecognized rationale for the therapeutic targeting of FXI. This is based on mimicking endogenous FXI gene expression control by therapeutic delivery of miRNA mimics. Studies are urgently needed to test this therapeutic principle in a clinical setting. This is particularly applicable in hemostaseology where monitoring of therapeutic effects remains a daily routine and thus assessment of the efficacy and safety of such therapeutic components could be simply implemented ushering in a novel therapeutic era with broad applicability.