Combined Use of a Factor XIIa Inhibitor with a Polycarboxybetaine Coating Creates Potent Anticoagulation with Preserved Hemostasis during Ambulatory, 24-hour, Rabbit Extracorporeal Life Support.

Abstract

Thrombosis causes life-threatening thromboembolic complications and failure of blood-contacting medical devices. Systemic anticoagulation, such as intravenous (IV) heparin, is used to mitigate thrombosis but increases the risk of significant, life-threatening bleeding complications. This study evaluated the anticoagulation efficacy and effects on hemostatic function of a selective FXIIa inhibitor (FXII900) and zwitterionic polycarboxybetaine (PCB) coating. Both acute (4 hr, under anesthesia) and survival (24 hr, awake) experiments were performed. Rabbits underwent pumpless, arteriovenous extracorporeal life support (ECLS) with a miniaturized oxygenator (mini-lung) to compare two means of anticoagulation (acute: n=4 ea, survival: n=5 ea): 1) heparin with an uncoated circuit, and 2) FXII900 with a PCB-coated circuit. In the acute experiments, the FXII900+PCB group demonstrated significantly prolonged anticoagulation compared with the heparin group, as evidenced by activated clotting time (1216 ± 80 s vs. 249 ± 10 s; p < 10-6) and activated partial thromboplastin time (427 ± 80 s vs. 75 ± 30 s; p < 10-5). In contrast, the bleeding time was significantly reduced in the FXII900+PCB group (175 ± 3 s vs. 226 ± 10 s; p < 0.05). In the survival experiments, mini-lung survival time was significantly prolonged in the FXII900+PCB group (15 ± 5 hr vs. 3 ± 4 hr; p < 0.05). The log(resistance) was also significantly lower in the FXII900+PCB group (2.24 ± 0.06 mmHg/(L/min) vs. 2.8 ± 0.1 mmHg/(L/min); p < 0.05). These results demonstrate that the combined use of FXII900 and PCB coating provides potent anticoagulation while preserving hemostatic function for at least 15 hours. This strategy could provide effective anticoagulation while improving hemostatic preservation during ECLS. STATEMENT OF SIGNIFICANCE: Blood-contacting medical devices such as extracorporeal life support (ECLS) can be lifesaving but often fail due to clot formation. Current anticoagulation methods, such as intravenous heparin, are used to slow clot formation but cause life-threatening bleeding complications. Thus, new anticoagulation strategies are needed that reduce clot formation on devices while preserving hemostatic function. This work examined the combined use of a selective FXIIa inhibitor with a zwitterionic, anticoagulant surface coating, polycarboxybetaine. This strategy provided potent protection against clot formation while preserving hemostatic function relative to heparin during 24-hour ECLS in rabbits. These findings demonstrate a promising path toward safer anticoagulation during ECLS.