#949 Factor XIIa inhibitory antibody does not provide sufficient anticoagulation in ex vivo hemodialysis

Abstract Background and Aims Unfractionated heparin (UFH) and low molecular-weight heparin (LMWH) are the most commonly used anticoagulants in haemodialysis (HD). While effective in preventing clotting, they are also associated with complications including increased risk of bleeding and heparin induced thrombocytopenia. The contact activation system is commonly assumed to be the main trigger of coagulation during HD, through autoactivation of factor (F)XII upon contact with the dialyser. FXII deficient individuals do not have an increased risk of bleeding which makes activated FXII (FXIIa) an attractive drug target as it has the potential to inhibit clotting without disrupting haemostasis. The aim of the study was to evaluate the efficacy of CSL312, a monoclonal, humanized IgG4 antibody against activated FXII (FXIIa), in preventing intradialytic coagulation. Method An ex vivo haemodialysisis model was used to test the efficacy of CSL312 as an anticoagulant. CSL312 (400 µg/mL) was compared to standard doses of UFH, LMWH and citrate anticoagulation. The antibody was provided by CSL Limited. Anticoagulant-free haemodialysisis was used as control. Whole-blood was collected from 12 healthy adult donors in blood-transfer bags containing citrate to prevent clotting before dialysis. Each donor provided blood for two HD-sessions, using different anticoagulants. The blood was dialyzed for one hour through paediatric polysulfone high-flux dialysers. Right before the start of HD, calcium was added to reverse the anticoagulant effect of citrate, except in the citrate group. Blood was sampled before and at 5, 15, 30 and 60 minutes after HD start. To quantify the activity of the contact system, the concentrations of enzyme-inhibitor complexes of antithrombin (AT) or C1-inhibitor (C1INH) in conjunction with FXIIa, FXIa, kallikrein, MASP-1, MASP-2 and thrombin were measured in plasma using enzyme-linked immunosorbent assays. Results Using CSL312 to inhibit FXIIa protease activity (n = 5), clotting occurred in all tests (at 30, 31, 36, 49 and 50 minutes) with a mean clotting time of 39.2 minutes compared to 17 and 30 minutes using no anticoagulation (n = 2). No clotting was evident with other anticoagulants. Using CSL312, the plasma concentration of FXIIa-C1INH at 15 minutes was significantly higher than at baseline (mean 26.2 (SD 9.08) vs mean 17.6 (SD 10.6) µg/mL, p = 0.011). Conclusion FXIIa inhibition using a monoclonal antibody does not provide sufficient anticoagulation during HD. This suggests that the contact system may not be solely responsible for clotting during HD.