Antithrombin nanoparticles inhibit stent thrombosis in ex vivo static and flow models

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Abstract

Objective:

Despite significant advances in intravascular stent technology, safe prevention of stent thrombosis over prolonged periods after initial deployment persists as a medical need to decrease device failure. The objective of this project was to assess the potential of perfluorocarbon nanoparticles (NP) conjugated with the direct thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone (PPACK-NP) to inhibit stent thrombosis.

Methods:

In a static model of stent thrombosis, 3 × 3-mm pieces of stainless steel coronary stents were cut and adsorbed with thrombin to create a procoagulant surface that would facilitate thrombus development. After treatment with PPACK-NP or control NP, stents were exposed to platelet-poor plasma (PPP) or platelet-rich plasma (PRP) for set time points up to 60 minutes. Measurements of final clot weight in grams were used for assessing the effect of NP treatment on limiting thrombosis. Additionally, groups of stents were exposed to flowing plasma containing various treatments (saline, free PPACK, control NP, and PPACK-NP) and generated thrombi were stained and imaged to investigate the treatment effects of PPACK-NP under flow conditions.

Results:

The static model of stent thrombosis used in this study indicated a significant reduction in thrombus deposition with PPACK-NP treatment (0.00067 ± 0.00026 g; n = 3) compared with control NP (0.0098 ± 0.0015 g; n = 3; P = .026) in PPP. Exposure to PRP demonstrated similar effects with PPACK-NP treatment (0.00033 ± 0.00012 g; n = 3) vs control NP treatment (0.0045 ± 0.00012 g; n = 3; P = .000017). In additional studies, stents were exposed to both PRP pretreated with vorapaxar and PPACK-NP, which illustrated adjunctive benefit to oral platelet inhibitors for prevention of stent thrombosis. Additionally, an in vitro model of stent thrombosis under flow conditions established that PPACK-NP treatment inhibited thrombus deposition on stents significantly.

Conclusions:

This study demonstrates that antithrombin perfluorocarbon NPs exert marked focal antithrombin activity to prevent intravascular stent thrombosis and occlusion.

Clinical Relevance:

Despite significant improvements in procedural technique and stent technology, intravascular stent thrombosis occurs with devastating end-organ consequences, such as limb loss. The findings of this study demonstrate that a targeted, nanomedicine-based, antithrombin approach results in decreased clotting of ex vivo stents, decreased clotting of intravascular stents in flow loops, and improved endothelial cell proliferation. Ultimately, this strategy may provide physicians with a treatment to decrease intravascular stent thrombosis and maintain endothelial cell viability without the systemic bleeding risks associated with dual antiplatelet therapy and systemic anticoagulation.

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