Haemostasis including blood coagulation is initiated upon vessel wall injury and indispensable to limit excessive blood loss. However, unregulated pathological coagulation may lead to vessel occlusion, causing thrombotic disorders, most notably
myocardial infarction and
stroke. Furthermore, blood exposure to foreign surfaces activates the intrinsic pathway of coagulation. Hence, various clinical scenarios, such as
extracorporeal membrane oxygenation, require robust anticoagulation consequently leading to an increased
bleeding risk. This study aimed to further assess the antithrombotic efficacy of the
activated factor XII (FXIIa) inhibitor, rHA-Infestin-4, in several
thrombosis models. In mice, rHA-Infestin-4 decreased occlusion rates in the mechanically-induced arterial (Folt's) and the FeCl3 -induced
venous thrombosis model. rHA-Infestin-4 also protected from FeCl3 -induced arterial
thrombosis and from stasis-prompted
venous thrombosis in rabbits. Furthermore, rHA-Infestin-4 prevented occlusion in the arterio-venous shunt model in mice and rabbits where
thrombosis was induced via a foreign surface. In contrast to
heparin, the haemostatic capacity in rabbits was unaffected by rHA-Infestin-4. Using rodent and non-rodent species, our data demonstrate that the FXIIa inhibitor rHA-Infestin-4 decreased arterial, venous and foreign surface-induced
thrombosis without affecting physiological haemostasis. Hence, we provide further evidence that targeting FXIIa represents a potent yet safe antithrombotic treatment approach, especially in foreign surface-triggered
thrombosis.