Renal Transplant Unit, Department of Nephrology, Division of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Thromb Res. 2013 Aug;132(2):307-11. doi: 10.1016/j.thromres.2013.07.004. Epub 2013 Jul 29.
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.
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.
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.
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.
肾移植受者发生静脉血栓栓塞事件的风险增加，部分原因是他们接受维持性免疫抑制药物治疗。由于我们观察到接受 mTOR 抑制剂（mTORi）依维莫司治疗的肾移植受者静脉血栓栓塞事件的发生率增加，我们旨在确定这种免疫抑制剂的促血栓形成机制。
在一项单中心研究中，我们在一项多中心随机对照试验中进行了嵌套研究，测量了接受 mTORi 依维莫司（n=16，mTOR 组）治疗的肾移植受者的凝血、抗凝和纤溶参数，并将其与接受钙调神经磷酸酶抑制剂和/或吗替麦考酚酯钠（n=20，非 mTOR 组）的类似患者组进行比较。所有患者均在移植后至少 6 个月，且移植肾功能稳定。
与基于非 mTORi 的免疫抑制方案相比，使用 mTORi 与更高水平的血管性血友病因子、凝血酶原片段 1+2、血栓调节蛋白激活的纤溶抑制剂和纤溶酶原激活物抑制剂-1 相关。
mTORi 治疗导致肾移植受者内皮激活、凝血酶形成和纤溶受损增加。这表明接受 mTOR 抑制剂治疗的肾移植受者发生血栓事件的风险增加。迫切需要一项前瞻性研究来确定这些患者发生血栓事件的确切风险。
