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Rmulo A. Nazareth, Luana S. Tomaz, Susana Ortiz-Costa, Gergia C. Atella, Jos M. C. Ribeiro, Ivo M. B. Francischetti, Robson Q. Monteiro

Antithrombotic properties of Ixolaris, a potent inhibitor of the extrinsic pathway of the coagulation cascade

Keywords: Anticoagulant, ixolaris, Venous thrombosis, factor Xa, Tissue factor, tick saliva, Ixodes scapularis

Ixolaris is a two-Kunitz tick salivary gland protein identified in Ixodes scapularis that presents extensive sequence homology to TFPI. It binds to FXa or FX as scaffolds and inhibits tissue factor/FVIIa complex (extrinsic Xnase). Differently from TFPI, ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite, which may also results in decreased FXa activity into the prothrombinase complex. In this report, we show that recombinant 125I-ixolaris interacts with rat and human FX in plasma and prolongs the prothrombin time (PT) and activated partial thromboplastin time (aPTT) in vitro. We have also investigated the effects of ixolaris in vivo, using a venous thrombosis model. Subcutaneous (s.c.) or intravenous (i.v.) administration of ixolaris in rats caused a dose-dependent reduction in thrombus formation, with complete inhibition attained at 20 g/kg and 10 g/kg, respectively. Antithrombotic effects were observed 3 h after s.c. administration of ixolaris and lasted for 24 h thereafter. Ex vivo experiments showed that ixolaris (up to 100 g/kg) did not affect the aPTT, while the PT was increased by 0.4-fold at the highest ixolaris concentration. Remarkably, effective antithrombotic doses of ixolaris (20 g/kg) was not associated with bleeding which was significant only at higher doses of the anticoagulant (40 g/kg). Our experiments demonstrate that ixolaris is an effective and possibly safe antithrombotic agent in vivo.

Thrombosis and Haemostasis, Schattauer

Print ISSN: 0340-6245
Volume: 96, 07/2006
Pages: 7 - 13

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