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.
Decrem
Yves
Y
Service de Biologie Moléculaire des Ectoparasites, Institut de Biologie et Médecine Moléculaires, Université Libre de Bruxelles, Gosselies B-6041, Belgium.
Rath
Géraldine
G
Blasioli
Virginie
V
Cauchie
Philippe
P
Robert
Séverine
S
Beaufays
Jérôme
J
Frère
Jean-Marie
JM
Feron
Olivier
O
Dogné
Jean-Michel
JM
Dessy
Chantal
C
Vanhamme
Luc
L
Godfroid
Edmond
E
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D019774:Blood Coagulation Factor Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D015956:Factor XIIa / Q000378:metabolism; D015945:Factor XIa / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D018884:Ixodes / Q000737:chemistry*; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D051379:Mice; D010314:Partial Thromboplastin Time; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology; D020539:Sequence Analysis, Protein; D013917:Thrombin / Q000096:biosynthesis; D013927:Thrombosis / Q000473:pathology / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000473:pathology / Q000517:prevention & control
D019774:Blood Coagulation Factor Inhibitors; D011994:Recombinant Proteins; D007610:Kallikreins; D015945:Factor XIa; D015956:Factor XIIa; D013917:Thrombin; D005341:Fibrinolysin