Treatment with everolimus is associated with a procoagulant state |
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Authors: | Marije C Baas Victor EA Gerdes Ineke JM ten Berge KM Heutinck S Florquin Joost CM Meijers Frederike J Bemelman |
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Affiliation: | 1. Renal Transplant Unit, Department of Nephrology, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands;2. Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands;3. Department of Internal Medicine, Slotervaartziekenhuis, Amsterdam, the Netherlands;4. Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands;5. Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands |
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Abstract: | IntroductionRenal 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 MethodsIn 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.ResultsThe 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.ConclusionsTreatment 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. |
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Keywords: | AMC Academic Medical Center APC activated protein C APCsr APC sensitivity ratio APTT activated partial thromboplastin time AUC area under the curve CKD chronic kidney disease CNI calcineurin inhibitor CsA cyclosporine A eGFR estimated GFR ELISA enzyme-linked immunosorbent assay EVL everolimus ETP endogenous thrombin potential F1 + 2 prothrombin fragment 1 + 2 MPS mycophenolate sodium mTOR mammalian target of Rapamycin mTORi mTOR inhibitor NS non significant P prednisolone PAI-1 plasminogen activator inhibitor-1 PAP plasmin-alpha2-antiplasmin complexes PI3K phosphoinositide 3-kinase PT prothrombin time TAFI thrombin-activatable fibrinolysis inhibitor TF tissue factor VEGF vascular endothelial growth factor VTE venous thromboembolism vWF von Willebrand factor |
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