Abstract Number: PB0073
Meeting: ISTH 2021 Congress
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.
To cite this abstract in AMA style:Whitney S, Clermont A, Murugesan N, Edwards H, Duckworth E, Pethen S, Hampton S, Feener E. Selective Small Molecule Factor XIIa Inhibitor KV998083 Protects against FeCl3 Induced Arterial Thrombosis in Mice [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/selective-small-molecule-factor-xiia-inhibitor-kv998083-protects-against-fecl3-induced-arterial-thrombosis-in-mice/. Accessed November 29, 2023.
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