Manook M, Kwun J, Burghuber C, Samy K, Mulvihill M, Yoon J, Xu H, MacDonald A L, Freischlag K, Curfman V, Branum E, Howell D, Farris A B, Smith R A, Sacks S, Dorling A, Mamode N, Knechtle S J
Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC.
Renal and Transplant Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Am J Transplant. 2017 Aug;17(8):2055-2064. doi: 10.1111/ajt.14234. Epub 2017 Mar 23.
Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel "cytotopic" agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.
凝血的早期激活是先天性免疫启动的一个重要因素，其特征为血栓性微血管病（TMA）。在移植过程中，由于出血，全身抗凝治疗存在困难。一种新型的“细胞靶向”药物血栓来欣（TLN），它结合了一种细胞膜结合型（肉豆蔻酰尾）抗凝血酶（水蛭素样肽[HLL]），可以直接灌注到供体器官或细胞中。采用血栓弹力图法测量恒河猴和人类血液中凝血形成时间（r时间），比较TLN与HLL（无细胞靶向尾）及阴性对照。与高岭土对照相比，经TLN和HLL处理的恒河猴或人类全血的r时间均显著延长。只有经TLN处理的人内皮细胞和新生猪胰岛的凝血形成时间延长。通过免疫组织化学和荧光激活细胞分选仪证实了膜结合型TLN的存在。在体内，在一个致敏的移植模型中，向非人灵长类动物肾脏灌注补充了TLN的保存液，未发现TLN进入全身循环的证据。组织学检查显示，移植后4天内TLN均存在。在经TLN处理的动物中，没有血小板沉积，TMA严重程度以及微血管损伤评分（肾小球炎+肾小管周围毛细血管炎）均较低。尽管有证据表明局部疗效良好，但未显示出生存获益。
