Treatment with everolimus is associated with a procoagulant state

Abstract

Introduction: Renal transplant recipients are at increased risk of venous thromboembolic events, which is in part caused by their treatment with maintenance immunosuppressive drugs. Because we observed an increased incidence of venous thromboembolic events in renal transplant recipients treated with the mTOR inhibitor (mTORi) everolimus, we aimed to identify prothrombotic mechanisms of this immunosuppressive drug.

Materials and methods: In a single center study, nested in a multi-center randomized controlled trial, we measured parameters of coagulation, anti-coagulation and fibrinolysis in renal transplant recipients, receiving the mTORi everolimus (n=16, mTOR group) and compared them to a similar patient group, receiving a calcineurin inhibitor and/or mycophenolate sodium (n=20, non-mTOR group). All patients were at least 6 months following transplantation with a stable transplant function.

Results: The use of an mTORi was associated with significantly higher levels of von Willebrand factor, prothrombin fragment 1+2, thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 as compared to a non-mTORi based immunosuppressive regimen.

Conclusions: Treatment with an mTORi leads to increased endothelial activation, thrombin formation and impaired fibrinolysis in renal transplant recipients. This suggests an increased risk of thrombotic events in renal transplant recipients treated with mTOR inhibitors. A prospective study to establish the precise risk of thrombotic events in these patients is urgently needed.

Keywords: AMC; APC; APC sensitivity ratio; APCsr; APTT; AUC; Academic Medical Center; CKD; CNI; CsA; ELISA; ETP; EVL; F1+2; MPS; NS; P; PAI-1; PAP; PI3K; PT; TAFI; TF; VEGF; VTE; activated partial thromboplastin time; activated protein C; area under the curve; calcineurin inhibitor; chronic kidney disease; coagulation; cyclosporine A; eGFR; endogenous thrombin potential; enzyme-linked immunosorbent assay; estimated GFR; everolimus; fibrinolysis; mTOR; mTOR inhibitor; mTORi; mammalian target of Rapamycin; mycophenolate sodium; non significant; phosphoinositide 3-kinase; plasmin-alpha2-antiplasmin complexes; plasminogen activator inhibitor-1; prednisolone; prothrombin fragment 1+2; prothrombin time; renal transplantation; thrombin-activatable fibrinolysis inhibitor; thrombosis; tissue factor; vWF; vascular endothelial growth factor; venous thromboembolism; von Willebrand factor.