Abstract ISTH 2015
Sophie CombeA, Yves FromesB, Chantal KrezelC, Pierre GueretD, Michel GuyauxC, Edmond GodfroidC, Jean AmiralE
- A Hopitaux Universitaires Paris Centre, Paris, France
- B University Pierre and Marie Curie, Paris
- C Bioxodes, Marche-en-Famenne, Belgium
- D Hemostasis Unit Hematology Laboratory, University Hospital, Rennes
- E Hyphen Biomed, Neuville sur Oise, France
Ir-CPI, a protein derived from the tick Ixodes ricinus salivary, is a serine protease inhibitor of both FXIIa and FXIa. Heparins remain suboptimal in managing bleeding complications when extracorporeal life support is required.
The aim of this study was to evaluate whether inhibition of the contact phase of the coagulation cascade might confer antithrombotic activity.
Twelve Beagle dogs were included. A pediatric ECMO system was connected between the carotid artery and the jugular vein, and a cardiopulmonary bypass was maintained for 90 min at the level of full-flow systemic perfusion. Anticoagulation was performed by UFH (300 IU kg-1) with protamine reversal at the end of the procedure (N = 3). Three investigative groups (3x N = 3) received various doses of Ir-CPI (bolus and infusion) total dose 4.5 to 24 mg kg-1. After disconnection, circuits and cannulae were examined for clot and protein deposits. All animals were followed-up and sampled for determination of Ir-CPI plasma concentration (Mass Spectrometry), aPTT, FXI and FXII residual activities, before necropsy on Day 7.
All 12 animals completed procedure. First Ir-CPI group showed fibrin deposits, increased pressure gradient in the circuit, and subsequent decreased gas exchanges. In further animals perfusion of Ir-CPI was initiated earlier in order to decrease the observed clot initiation and to improve gas exchanges. High dose achieved close to optimal control. Low dose was less satisfactory but perfusion remained possible. A dose-dependent and related increase in Ir-CPI plasma concentration, increase in aPTT ratio and inhibition of factors XI and XII (20% and >70% respectively) were measured over the course of the procedure. No side effects were observed and necropsies confirm the absence of thrombosis or hemorrhage.
Ir-CPI can be used as a single agent to inhibit the intrinsic coagulation pathway and achieve anticoagulation. Efficiency can be improved without increasing bleeding risk.