title: FXIIa inhibitor rHA-Infestin-4: Safe thromboprotection in experimental venous, arterial and foreign surface-induced thrombosis.
abstract: 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.
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: May
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Krupka
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Fries
authors.affiliation: Chair of Vascular Medicine, University Hospital Wuerzburg and Rudolf Virchow Centre for Experimental Biomedicine, Wuerzburg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Thielmann
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimer
authors.affiliation: CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
authors.forename: Con
authors.initials: C
authors.lastname: Panousis
authors.affiliation: Chair of Vascular Medicine, University Hospital Wuerzburg and Rudolf Virchow Centre for Experimental Biomedicine, Wuerzburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Department of Neurology, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D015956:Factor XIIa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006487:Hemostasis / Q000187:drug effects; D019476:Insect Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D007700:Kinetics; D051379:Mice; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D012709:Serum Albumin / Q000494:pharmacology* / Q000627:therapeutic use; D000075462:Serum Albumin, Human; D013927:Thrombosis / Q000188:drug therapy* / Q000209:etiology; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000188:drug therapy / Q000209:etiology
chemical_list: D005343:Fibrinolytic Agents; D019476:Insect Proteins; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; C000609004:rHA-infestin-4 protein; D015956:Factor XIIa; D000075462:Serum Albumin, Human
keywords: Thrombosis; coagulation factor XII; contact activation; experimental animal models; inhibitors