Corn trypsin inhibitor coating attenuates the prothrombotic properties of catheters in vitro and in vivo

Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits

“…Alternatively, surface modification using CTI, an fXIIa inhibitor, provides a method for rendering catheters and other blood-contacting devices less thrombogenic. 12,[40][41][42] The utility of these agents for the prevention and treatment of catheter thrombosis requires further investigation.…”

“…[8][9][10] Recently, we showed that (1) catheters have prothrombotic activity in plasma and initiate clotting by activating fXII and (2) corn trypsin inhibitor, a potent inhibitor of fXIIa, attenuates catheter-induced clotting. 11,12 If the same is true in vivo, we hypothesized that the use of liver-directed antisense oligonucleotides (ASOs) to selectively knock down contact pathway factors fXII, fXI, and HK in rabbits would attenuate catheter thrombosis, whereas fVII knockdown would have little or no effect. To further explore the involvement of the extrinsic pathway in catheter-induced clotting, we also examined the effect of combined knockdown of fVII plus fXI.…”

Factor XII full and partial null in rat confers robust antithrombotic efficacy with no bleeding

“…Indeed, in recent years, a multitude of inhibitors for FXII(a) have been generated and described in various preclinical models in vitro and/or in vivo. They include monoclonal antibodies [9,10], natural peptide or protein inhibitors [11,12], small molecule inhibitors [6,13], RNA aptamer [14], and antisense oligonucleotide (ASO) [15]. Although results with these various tool molecules in aggregate clearly strengthen the notion that targeting FXII may provide strong antithrombotic efficacy without conferring bleeding diathesis, some of the reagents bear the limitation of insufficient selectivity [13,16].…”

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

“…31 Thus, catheters coated with corn trypsin inhibitor, which inhibits FXIIa, remain patent longer than control catheters when inserted in the jugular veins of rabbits. 32 Likewise, in the same rabbit model, FXII knockdown prolongs the catheter-induced occlusion time by >2-fold, 33 and a FXIIa-directed antibody is as effective as heparin at preventing clotting in an extracorporeal membrane oxygenation circuit in rabbits but produces less bleeding. 34 Therefore, these studies suggest that contact activation of FXII initiates clotting on artificial surfaces.…”