Abstract
Objective: To compare the prophylactic and thrombolytic effects of RNA aptamer (9.14T79VRT7) on ex vivo canine platelet function. Approach and Results: We previously demonstrated that inhibition of von Willebrand Factor (VWF) by a targeted RNA aptamer prevents thrombosis and thrombolyses stabilized clots in a FeCl 3 -induced murine vascular injury model suggesting a pivotal role for VWF in the pro-thrombotic and anti-thrombotic milieu. We hypothesize that 9.14T79VRT7, which demonstrated no hemorrhagic complications and greater re-perfusion compared to rTPA in murine and canine thrombotic models, may affect additional agonist pathways to mitigate platelet activation, aggregation, and adhesion. Platelet aggregation before and after 9.14T79VRT7 addition was analyzed utilizing WB aggregometry based on impedance in five adult beagles. Agonist concentrations were selected from previous publications which had optimized platelet reactivity in canine WB and included: collagen (3.2 ug/ul), ADP (20 uM), arachidonic acid (0.5 mM), and botrocetin (1 ug/ul). The 9.14T79VRT7 concentration used (25 nM) was selected as the most effective as assessed by Total Thrombus Analysis System (TTAS). Botrocetin elicited the greatest response before 9.14T79VRT7 addition, followed by Collagen, ADP, and Arachidonic acid. Impedance resulting from prophylactic addition of 9.14T79VRT7 before Collagen, ADP, and Botrocetin resulted in a 50.00%, 34.83%, and 38.26% change in amplitude, respectively and a 43.70%, 14.28%, and 35.14% change in slope, respectively (p<.0001). There was no significant difference in response after Arachidonic acid. Impedance resulting from thrombolytic addition of 9.14T79VRT7 after agonist response to Collagen, ADP, and Botrocetin resulted in a 78.66%, 94.08%, and 84.58% change in amplitude, respectively and a 67.28%, 61.28%, and 63.73% change in slope, respectively (p<.0001). Although amplitude and slope decreased with 9.14T79VRT7 addition after Arachidonic acid, the change was not significant. Both control groups (9.14T79VRT7 and platelet buffer diluent) resulted in no significant changes. Conclusion: 9.14T79VRT7 markedly changes platelet response both before and after agonist treatment in canine ex vivo impedance analysis.
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