Elsevier

Thrombosis Research

Volume 71, Issue 4, 15 August 1993, Pages 317-324
Thrombosis Research

Paper
Antithrombotic activity of recombinant tick anticoagulant peptide and heparin in a rabbit model of venous thrombosis

https://doi.org/10.1016/0049-3848(93)90200-8Get rights and content

Abstract

An in vivo rabbit model of venous thrombosis which includes physiological blood flow was used to compare the efficacy of the potent and specific factor Xa inhibitor recombinant tick anticoagulant peptide (rTAP) with standard heparin in the prevention of venous thrombus formation. In anesthetized rabbits, an autologous thrombus was induced with thrombin in a jugular vein and the increase in thrombus size was determined by measuring the accretion of intravenously injected [125I]fibrin(ogen) onto the developing thrombus. The effects of rTAP on hemostasis were monitored by changes in APTT values and template bleeding times. Inhibition of thrombus formation by an intravenous bolus followed by infusion of either rTAP or heparin exhibited a dose-response relationship with an IC50 of 0.9 μg/kg/min and 0.12 units/kg/min, respectively. At the IC50 doses, both rTAP and heparin inhibited fibrin(ogen) deposition without any significant effect on APTT or bleeding times. Bleeding times were modestly elevated at the fully efficacious doses of rTAP and heparin. Significant changes in APTT (1.9 ± 0 .3 fold over baseline) were only evident at the highest dose of rTAP while heparin caused a significant dose-dependent increase from 1.3 ± 0.2 to greater than 4.2 ± 0.6 fold over baseline. Therefore, in this rabbit model of venous thrombosis, specific inhibition of factor Xa by rTAP is an effective antithrombotic mechanism that does not require changes in systemic hemostatic parameters.

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      Structure-and-function investigations of TAP range from thorough kinetic studies of FXa inhibition, including analysis of a large number of point and deletion mutants (Betz et al., 1997; Dunwiddie et al., 1992; Jordan et al., 1992, 1990; Krishnaswamy et al., 1994; Mao et al., 1995; Rezaie, 2004), determination of disulfide bonds and characterization of the folding pathway (Chang, 1996; Chang and Li, 2005; Chang et al., 2000; Sardana et al., 1991), as well as determination of its 3D structure, both unliganded and bound to the cognate proteinase (Antuch et al., 1994; Lim-Wilby et al., 1995; Wei et al., 1998). In addition, the antithrombotic potential of TAP has been assessed in a number of in vivo investigations (see e.g., refs. (Fioravanti et al., 1993; Ragosta et al., 1994; Schaffer et al., 1991; Sitko et al., 1992; Stoll et al., 2007)). Because of its rather low sequence homology to any other member of family I2, TAP has been classified within the same IB clan as Kunitz inhibitors, but as representative of a different family (I52).

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