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Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2009 Oct 26; Vol. 206 (11), pp. 2381-95. Date of Electronic Publication: 2009 Oct 05. - Publication Year :
- 2009
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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 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.
- Subjects :
- Animals
Blood Coagulation Factor Inhibitors chemistry
Disease Models, Animal
Factor XIIa metabolism
Factor XIa metabolism
Fibrinolysin metabolism
Fibrinolysis drug effects
Humans
Kallikreins metabolism
Male
Mice
Partial Thromboplastin Time
Protein Binding drug effects
Rats
Recombinant Proteins isolation & purification
Recombinant Proteins pharmacology
Sequence Analysis, Protein
Thrombin biosynthesis
Thrombosis pathology
Venous Thrombosis pathology
Venous Thrombosis prevention & control
Blood Coagulation drug effects
Blood Coagulation Factor Inhibitors pharmacology
Ixodes chemistry
Thrombosis prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 206
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 19808248
- Full Text :
- https://doi.org/10.1084/jem.20091007