Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis

Blood coagulation starts immediately after damage to the vascular endothelium. This system is essential for minimizing blood loss from an injured blood vessel but also contributes to vascular thrombosis. Although it has long been thought that the intrinsic coagulation pathway is not important for clotting in vivo, recent data obtained with genetically altered mice indicate that contact phase proteins seem to be essential for thrombus formation. We show that recombinant Ixodes ricinus contact phase inhibitor (Ir-CPI), a Kunitz-type protein expressed by the salivary glands of the tick Ixodes ricinus, specifically interacts with activated human contact phase factors (FXIIa, FXIa, and kallikrein) and prolongs the activated partial thromboplastin time (aPTT) in vitro. The effects of Ir-CPI were also examined in vivo using both venous and arterial thrombosis models. Intravenous administration of Ir-CPI in rats and mice caused a dose-dependent reduction in venous thrombus formation and revealed a defect in the formation of arterial occlusive thrombi. Moreover, mice injected with Ir-CPI are protected against collagen- and epinephrine-induced thromboembolism. Remarkably, the effective antithrombotic dose of Ir-CPI did not promote bleeding or impair blood coagulation parameters. To conclude, our results show that a contact phase inhibitor is an effective and safe antithrombotic agent in vivo.

Yves Decrem1, Géraldine Rath2, Virginie Blasioli1, Philippe Cauchie3, Séverine Robert4, Jérôme Beaufays1, Jean-Marie Frère5, Olivier Feron2, Jean-Michel Dogné4, Chantal Dessy2, Luc Vanhamme1,6 and Edmond Godfroid1. J. Exp. Med. Vol. 206 No. 11 2381-2395. 2009.

1Service de Biologie Moléculaire des Ectoparasites, Institut de Biologie et Médecine Moléculaires, Université Libre de Bruxelles, Gosselies B-6041, Belgium
2Unit of Pharmacology and Therapeutics (FATH 5349), Université Catholique de Louvain, Brussels B-1200, Belgium
3Experimental Medecine Laboratory, Université de Bruxelles, Montigny-Le-Tilleul B-6110, Belgium
4Department of Pharmacy, Facultés Universitaires Notre Dame de la Paix Namur, B-5000, Belgium
5Centre d’Ingénierie des Protéines, Institut de Chimie B6a, Université de Liège, B-4000 Liège, Belgium
6Service de Parasitologie Moléculaire, Institut de Biologie et Médecine Moléculaires, Université Libre de Bruxelles, Gosselies B-6041, Belgium.

Link : www.jem.org/cgi/doi/10.1084/jem.20091007

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