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

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Abstract
Ixolaris is a two-Kunitz tick salivary gland protein identified in Ixodes scapularis that presents extensive sequence homology t 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, comple formation is mediated by the FXa heparin-binding exosite,which may also results in decreased FXa activity into the prothrombi nase complex.In this report,we show that recombinant 125I-ixo laris 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 ixo laris 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 µg/kg and 10 µg/kg, re spectively. 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 µg/kg) did not affect the aPTT,while the PT was increased by ∼0.4-fold at the hig hest ixolaris concentration. Remarkably, effective antithrom botic doses of ixolaris (20 µg/kg) was not associated with bleed ing which was significant only at higher doses of the anticoagulant (40 µg/kg).Our experiments demonstrate that ixolaris is an effective and possibly safe antithrombotic agen in viv .
Funding Information
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health