Author + information
- Received July 8, 2019
- Accepted August 1, 2019
- Published online October 21, 2019.
- Valérie Pireaux, PhDa,
- Joël Tassignon, PhDa,
- Stéphanie Demoulin, PhDa,
- Sandrine Derochette, PhDa,
- Nicolas Borenstein, DVM, PhDb,
- Angélique Ente, DVMb,
- Laurence Fiette, DVM, PhDb,
- Jonathan Douxfils, PharmD, PhDc,
- Patrizio Lancellotti, MD, PhDd,
- Michel Guyaux, PhDa and
- Edmond Godfroid, PhDa,∗ ()
- aBioxodes S.A., Marche-en-Famenne, Belgium
- bIMM Recherche, Institut Mutualiste Montsouris, Paris, France
- cQUALIblood S.A., Namur, Belgium
- dGIGA Cardiovascular Sciences, Department of Cardiology, University Hospital of Liège, CHU Sart Tilman, Liège, Belgium
- ↵∗Address for correspondence:
Dr. Edmond Godfroid, Parc d’activités économiques du Wex, Rue de la Plaine 11, 6900 Marche-en-Famenne, Belgium.
Background Exposure of blood to polyanionic artificial surfaces, for example, during cardiopulmonary bypass (CPB), induces a highly procoagulant condition requiring strong anticoagulation. Unfractionated heparin (UFH) is currently used during CPB but can lead to serious bleeding complications or development of a hypercoagulable state culminating in life-threatening thrombosis, highlighting the need for safer antithrombotics. Ixodes ricinus contact phase inhibitor (Ir-CPI) is a protein expressed by I. ricinus ticks, which specifically inhibits both factors XIIa and XIa, 2 factors contributing to thrombotic disease while playing a limited role in hemostasis.
Objectives This study assessed the antithrombotic activity of Ir-CPI in animal contact phase-initiated thrombosis models, including CPB. The safety of Ir-CPI also was evaluated.
Methods The authors evaluated the antithrombotic activity of Ir-CPI by using in vitro catheter-induced clotting assays and rabbit experimental models of catheter occlusion and arteriovenous shunt. During CPB with cardiac surgery in sheep, the clinical applicability of Ir-CPI was investigated and its efficacy compared to that of UFH using an uncoated system suitable for adult therapy. Taking advantage of the similar hemostatic properties of pigs and humans, the authors performed pig liver bleeding assays to evaluate the safety of Ir-CPI.
Results Ir-CPI prevented clotting in catheter and arteriovenous shunt rabbit models. During CPB, Ir-CPI was as efficient as UFH in preventing clot formation within the extracorporeal circuit and maintained physiological parameters during and post-surgery. Unlike UFH, Ir-CPI did not promote bleeding.
Conclusions Preclinical animal models used in this study showed that Ir-CPI is an effective and safe antithrombotic agent that provides a clinically relevant approach to thrombosis prevention in bypass systems, including highly thrombogenic CPB.
This work was supported by grants from the Walloon Region (convention 6823 and 7336). Dr. Douxfils is founder and CEO of QUALIblood S.A.; and has received personal fees from Diagnostica Stago, Roche, Roche Diagnostics, Portola, and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Frits R. Rosendaal, MD, PhD, served as Guest Associate Editor for this paper.
- Received July 8, 2019.
- Accepted August 1, 2019.
- 2019 The Authors