Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass

Valérie Pireaux, Joël Tassignon, Stéphanie Demoulin, Sandrine Derochette, Nicolas Borenstein, Angélique Ente, Laurence Fiette, Jonathan Douxfils, Patrizio Lancellotti, Michel Guyaux, Edmond Godfroid

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2178-2189
Number of pages12
JournalJournal of the American College of Cardiology
Volume74
Issue number17
DOIs
Publication statusPublished - 29 Oct 2019

Fingerprint

Factor XIa
Factor XIIa
Ixodes
Cardiopulmonary Bypass
Heparin
Thrombosis
Catheters
Hemorrhage
Swine
Rabbits
Safety
Fibrinolytic Agents
Ticks
Hemostatics
Hemostasis
Thoracic Surgery

Keywords

  • antithrombotic
  • bleeding
  • coagulation
  • extracorporeal circulation
  • intrinsic pathway
  • thrombosis

Cite this

Pireaux, Valérie ; Tassignon, Joël ; Demoulin, Stéphanie ; Derochette, Sandrine ; Borenstein, Nicolas ; Ente, Angélique ; Fiette, Laurence ; Douxfils, Jonathan ; Lancellotti, Patrizio ; Guyaux, Michel ; Godfroid, Edmond. / Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass. In: Journal of the American College of Cardiology. 2019 ; Vol. 74, No. 17. pp. 2178-2189.
@article{68d627e956d94970bcda3784669b56fa,
title = "Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass",
abstract = "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.",
keywords = "antithrombotic, bleeding, coagulation, extracorporeal circulation, intrinsic pathway, thrombosis",
author = "Val{\'e}rie Pireaux and Jo{\"e}l Tassignon and St{\'e}phanie Demoulin and Sandrine Derochette and Nicolas Borenstein and Ang{\'e}lique Ente and Laurence Fiette and Jonathan Douxfils and Patrizio Lancellotti and Michel Guyaux and Edmond Godfroid",
year = "2019",
month = "10",
day = "29",
doi = "10.1016/j.jacc.2019.08.1028",
language = "English",
volume = "74",
pages = "2178--2189",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
publisher = "Elsevier Inc.",
number = "17",

}

Pireaux, V, Tassignon, J, Demoulin, S, Derochette, S, Borenstein, N, Ente, A, Fiette, L, Douxfils, J, Lancellotti, P, Guyaux, M & Godfroid, E 2019, 'Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass', Journal of the American College of Cardiology, vol. 74, no. 17, pp. 2178-2189. https://doi.org/10.1016/j.jacc.2019.08.1028

Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass. / Pireaux, Valérie; Tassignon, Joël; Demoulin, Stéphanie; Derochette, Sandrine; Borenstein, Nicolas; Ente, Angélique; Fiette, Laurence; Douxfils, Jonathan; Lancellotti, Patrizio; Guyaux, Michel; Godfroid, Edmond.

In: Journal of the American College of Cardiology, Vol. 74, No. 17, 29.10.2019, p. 2178-2189.

Research output: Contribution to journalArticle

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

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

VL - 74

SP - 2178

EP - 2189

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 17

ER -