TY - JOUR
T1 - Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass
AU - Pireaux, Valérie
AU - Tassignon, Joël
AU - Demoulin, Stéphanie
AU - Derochette, Sandrine
AU - Borenstein, Nicolas
AU - Ente, Angélique
AU - Fiette, Laurence
AU - Douxfils, Jonathan
AU - Lancellotti, Patrizio
AU - Guyaux, Michel
AU - Godfroid, Edmond
N1 - Funding Information:
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.
Publisher Copyright:
© 2019 The Authors
PY - 2019/10/29
Y1 - 2019/10/29
N2 - 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.
AB - 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.
KW - antithrombotic
KW - bleeding
KW - coagulation
KW - extracorporeal circulation
KW - intrinsic pathway
KW - thrombosis
UR - http://www.scopus.com/inward/record.url?scp=85072968329&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2019.08.1028
DO - 10.1016/j.jacc.2019.08.1028
M3 - Article
AN - SCOPUS:85072968329
SN - 0735-1097
VL - 74
SP - 2178
EP - 2189
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 17
ER -