Summary
Human plasma-derived C1-esterase inhibitor (C1–INH) is an efficacious and safe treatment
for hereditary angioedema. However, thrombotic events in subjects treated with C1–INH
at recommended or offlabel, high doses have been reported. In this study, we addressed
the potential prothrombotic risk of C1–INH treatment in high doses using a non-clinical
rabbit model. Following intravenous infusion of C1–INH to rabbits at doses up to 800
IU/kg, the exposure and the pharmacodynamic efficacy of C1–INH in rabbits were confirmed
by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively.
Potential prothrombotic effects were assessed following induction of venous and arterial
thrombosis using in vivo models of venous and arterial stasis, complemented by various
in vitro assays of coagulation markers. Administration of C1–INH at doses up to 800
IU/ kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition
of arterial occlusion was observed upon C1–INH administration when compared with isotonic
saline treatment, indicating antithrombotic rather than prothrombotic activity of
high dose C1–INH treatment in vivo. This was further confirmed in vitro by decreased
thrombin generation, increased activated partial thromboplastin time, clotting time
and clot formation time, and inhibition of platelet aggregation. No relevant changes
in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin
fragment 1+2 were observed upon high dose C1–INH treatment. The data suggest that
treatment of healthy rabbits with high doses of C1–INH could potentially inhibit coagulation
and thrombus formation rather than induce a prothrombotic risk.
Keywords
Animal model - C1-esterase inhibitor - coagulation - contact activation system - thrombosis
