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

Yves Decrem, Géraldine Rath, Virginie Blasioli, Philippe Cauchie, Séverine Robert, Jérôme Beaufays, Jean Marie Frère, Olivier Feron, Jean Michel Dogné, Chantal Dessy, Luc Vanhamme, Edmond Godfroid

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Abstract

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 Kunitztype 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.

Original languageEnglish
Pages (from-to)2381-2395
Number of pages15
JournalJournal of Experimental Medicine
Volume206
Issue number11
DOIs
Publication statusPublished - 26 Oct 2009

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Ixodes
Ticks
Hemostasis
Thrombosis
Blood Coagulation
Blood Vessels
Salivary Proteins and Peptides
Kallikreins
Fibrinolytic Agents
Partial Thromboplastin Time
Thromboembolism
Vascular Endothelium
Venous Thrombosis
Intravenous Administration
Epinephrine
Collagen
Hemorrhage
Proteins

Cite this

Decrem, Yves ; Rath, Géraldine ; Blasioli, Virginie ; Cauchie, Philippe ; Robert, Séverine ; Beaufays, Jérôme ; Frère, Jean Marie ; Feron, Olivier ; Dogné, Jean Michel ; Dessy, Chantal ; Vanhamme, Luc ; Godfroid, Edmond. / Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 11. pp. 2381-2395.
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abstract = "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 Kunitztype 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.",
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Decrem, Y, Rath, G, Blasioli, V, Cauchie, P, Robert, S, Beaufays, J, Frère, JM, Feron, O, Dogné, JM, Dessy, C, Vanhamme, L & Godfroid, E 2009, 'Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis', Journal of Experimental Medicine, vol. 206, no. 11, pp. 2381-2395. https://doi.org/10.1084/jem.20091007

Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis. / Decrem, Yves; Rath, Géraldine; Blasioli, Virginie; Cauchie, Philippe; Robert, Séverine; Beaufays, Jérôme; Frère, Jean Marie; Feron, Olivier; Dogné, Jean Michel; Dessy, Chantal; Vanhamme, Luc; Godfroid, Edmond.

In: Journal of Experimental Medicine, Vol. 206, No. 11, 26.10.2009, p. 2381-2395.

Research output: Contribution to journalArticle

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T1 - Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis

AU - Decrem, Yves

AU - Rath, Géraldine

AU - Blasioli, Virginie

AU - Cauchie, Philippe

AU - Robert, Séverine

AU - Beaufays, Jérôme

AU - Frère, Jean Marie

AU - Feron, Olivier

AU - Dogné, Jean Michel

AU - Dessy, Chantal

AU - Vanhamme, Luc

AU - Godfroid, Edmond

PY - 2009/10/26

Y1 - 2009/10/26

N2 - 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 Kunitztype 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.

AB - 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 Kunitztype 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.

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