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

Rômulo A. Nazareth, Luana S. Tomaz, Susana Ortiz-Costa, Geórgia C. Atella, José M.C. Ribeiro, Ivo M.B. Francischetti, Robson Q. Monteiro

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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 μg/kg and 10 μg/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 μg/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 μg/kg) was not associated with bleeding 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 agent in vivo.

Original languageEnglish (US)
Pages (from-to)7-13
Number of pages7
JournalThrombosis and Haemostasis
Issue number1
StatePublished - Jul 2006
Externally publishedYes


  • Anticoagulant
  • Factor Xa
  • Ixodes scapularis
  • Ixolaris
  • Tick saliva
  • Tissue factor
  • Venous thrombosis

ASJC Scopus subject areas

  • Hematology


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