Jul 19, 2018
Bioxodes to present up-to-date preclinical data during the annual ISTH SSC meeting on Thursday 19 July 2018 in Dublin.
Ir-CPI: an original inhibitor of thrombosis and thrombosis-associated with cancer
Darbousset R.3, Pireaux V.1, Crescence L.2, Demoulin S.1, Panicot-Dubois L.2, Godfroid E.1, Dubois C.2
1Bioxodes, Marche-en-Famenne, Belgium; 2Aix-Marseille University, Center for CardioVascular and Nutrition Research, Marseille, France; 3The University of Sydney, Heart Research Institute, Sydney, Australia.
Background: Ir-CPI, a protein derived from saliva of the tick Ixodes ricinus, is an inhibitor of the activated form of factor XI (FXIa) and XII (FXIIa). In vitro, this molecule inhibits specifically the contact phase pathway.
Aims: Our aims were to assess the efficacy of Ir-CPI in the prevention of thrombosis dependent on the Tissue Factor (TF) pathway in mouse models of thrombosis.
Methods: Two thrombosis models dependent on TF activation were studied. First, we used a laser-injury model on a cremaster muscle arteriole that is strictly dependent on TF and independent of FXII. Second, we used a laser-induced thrombosis model in mice bearing a pancreatic tumor. This model is mainly dependent on TF expressed by cancer cell-derived microparticles. As control, we assessed the efficacy of Ir-CPI in the Deep Vein Thrombosis (DVT) model in which FXII plays a central role in thrombus formation.
Results: As expected, Ir-CPI significantly reduced thrombus weight in the DVT model. Surprisingly, Ir-CPI inhibited thrombus formation, platelet accumulation and fibrin generation in the laser-injury model in normal mice. The effects of Ir-CPI on thrombosis were confirmed in tumor-bearing mice despite their procoagulant state. Since neutrophils play a key role in the activation of the TF dependent pathway in the laser model, the presence and activation of neutrophils were compared in control and Ir-CPI-treated mice. In vivo, Ir-CPI significantly inhibited neutrophil accumulation and their secretion of Neutrophil Elastase at the site of injury. In vitro, Ir-CPI strongly diminished the activation of neutrophils leading to NETs formation.
Conclusion: As expected, Ir-CPI is an effective antithrombotic in the FXII-dependent mouse model. Surprisingly, it is effective in a laser-injury model, even in a prothrombotic tumoral state. The inhibitory effect on neutrophil recruitment in vivo and NETs formation in vitro strongly suggests that Ir-CPI has additional targets and offers new therapeutic opportunities in thrombosis-associated diseases.Return