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Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents
European Heart Journal, 07/02/09

Camici GG et al. – Rapamycin increases tissue factor (TF) activity and promotes arterial thrombosis in vivo at concentrations relevant in pts undergoing drug-eluting stents (DES) implantation; this effect may increase the thrombogenicity of DES. Since everolimus and zotarolimus augment endothelial TF expression and activity in vitro in a similar manner as rapamycin, these findings may also be relevant for second generation DES.

• Study of effect of mammalian target of rapamycin (mTOR) inhibition on TF activity and thrombus formation in vivo
• Investigation of whether second-generation DES substances everolimus and zotarolimus have an effect on endothelial TF expression
• Use of a mouse carotid artery photochemical injury model

• In mouse model, rapamycin (182 ± 27.5 µg/L) decreased time to thrombotic occlusion by 40%, increased TF activity, and abrogated p70S6K phosphorylation vs controls
• In vitro, rapamycin, everolimus, and zotarolimus (each 10–7 mol/L) enhanced TNF-{alpha}-induced TF expression by 2.2-, 1.7-, and 2.4-fold, respectively, which was paralleled by an increase in TF surface activity
• Similar to rapamycin, everolimus and zotarolimus abrogated TNF-{alpha}-induced p70S6K phosphorylation under these conditions

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