Coagulation factor XI (FXI) is a promising target for anticoagulation, because of its major role in
thrombosis and relatively minor role in haemostasis. This implies that inhibition of FXI can prevent
thrombosis without causing
bleeding. It was our aim to investigate the antithrombotic properties of two novel inhibitory anti-human FXI
antibodies (αFXI-175 and αFXI-203). The in vitro properties of both
antibodies were analysed using standard clotting assays and calibrated automated thrombography. For the in vivo model we used FXI knockout mice, in which FXI plasma levels were restored with purified human FXI.
Thrombosis was induced by applying
ferric chloride to the vena cava inferior, after which time to occlusion was analysed. A tail
bleeding assay was used to investigate the safety of both
antibodies. Using calibrated automated thrombography, both
antibodies inhibited
thrombin generation initiated via the intrinsic pathway. In contrast, upon
tissue factor (TF)-initiated
thrombin generation, αFXI-203 did not inhibit
thrombin generation, while αFXI-175 inhibited
thrombin generation only at low concentrations of TF. In the murine
thrombosis model, the vena cava inferior remained patent for 25 minutes (min) in mice treated with αFXI-175 and for 12.5 min in αFXI-203 treated animals, which was significantly longer than in placebo-treated animals (5 min, p<0.05). Neither antibody caused severe blood loss in a tail
bleeding assay. In conclusion, the two inhibitory
antibodies against FXI prevented cessation of blood flow in a murine
thrombosis model without inducing a
bleeding tendency.