Background: FXIIa has been implicated as a target for anticoagulants that may prevent thrombosis without affecting hemostasis.

Aims: This study evaluates a selective small molecule FXIIa inhibitor, KV998083, on thrombosis in mice.

Methods: Right carotid artery thrombosis in male mice was initiated by 3.5% FeCl₃ patch for 3 minutes. A Doppler flow probe (Transonic TS420) was used to monitor blood flow for up to 20 minutes. Time to occlusion (TTO) was determined in WT mice administered vehicle or 14.4 mg/kg/day KV998083 by micro-osmotic pump (Alzet, 1003D) implanted subcutaneously at 24 hours prior to FeCl₃ injury and in FXII knockout mice. Tail bleeding time (TBT) was assessed following a 5 mm tail tip transection.

Results: The IC₅₀ of KV998083 for human FXIIa is 36.9 nM and >40μM for FXIa, FXa and thrombin. KV998083 prolongs APTT in both human and mouse plasma and has no effect on PT at the highest dose tested (33 µM). The FeCl₃ induced TTO in WT mice (n=6) was 6.6 ± 1.1 minutes, while all FXII knockout mice (n=6) were completely protected against occlusion. In mice treated with KV998083, 4 out of 6 animals showed no evidence of occlusion, with 2 mice showing TTOs of 10.7 and 12.1 minutes. Vehicle treated animals had a TTO of 9.9 ± 0.9 minutes. At 10 mins post FeCl₃ injury, % of baseline flow was significantly higher in the KV998083 treated animals at 87.9% compared to vehicle at 4.8% (p<0.05). TBT for WT and FXII knockout mice were similar, 1.6 ± 0.6 and 1.6 ± 0.3 minutes, respectively.

Conclusions: KV998083 is a selective FXIIa inhibitor that protects against FeCl₃ induced thrombosis in mice. Selective small molecule FXIIa inhibitors may provide a novel class of antithrombotic that do not increase bleeding risk. 

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/selective-small-molecule-factor-xiia-inhibitor-kv998083-protects-against-fecl3-induced-arterial-thrombosis-in-mice/