Lepirudin prevents lethal effects of Shiga toxin in a canine model.
Lepirudin prevents lethal effects of Shiga toxin in a canine model.
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来匹卢定可防止犬类模型中志贺毒素的致命作用。
DOI：
10.1160/th03-12-0759
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发表时间：
2004
影响因子：
6.7
通讯作者：
Fenwick,Brad
中科院分区：
文献类型：
--
作者：
Raife,Thomas;Friedman,KennethD;Fenwick,Brad
微血管血栓形成是志贺毒素介导的溶血性尿毒症综合征（Stx-HUS）器官损害的主要原因。体外和临床研究暗示凝血酶介导的机制在Stx微血管血栓形成的发病机制。在灰狗模型中，给药0.03μg/kg至0.05μg/kg Stx1或Stx2可在65小时内引起严重血性腹泻和溶血性尿毒综合征并伴有微血管血栓形成，需要人道安乐死。使用灰狗Stx- hus模型，我们分析了早期止血变化，并验证了用lepirudin阻断凝血酶可以预防致命Stx效应的假设。分析了两只暴露于stx1的灰狗在出现临床表现之前的止血变化。Stx1攻击后的一系列止血研究显示aPTT、纤维蛋白原水平和凝血酶原片段1+2升高的趋势，并出现异常大的血管性血液病因子多聚体。用lepirudin对3只灰狗进行抗凝治疗，使活化的部分凝血活素（aPTT）维持在正常水平的2.5倍，然后给予Stx2并观察临床反应。在接受麻风素治疗的3只感染了stx2病毒的灰狗中，有一只患上了严重的疾病，需要安乐死。值得注意的是，3只灰狗中有2只出现了唾液分泌过多和烦躁不安的症状（与14只历史对照相比，P <.03）。注射Stx后74小时，这两只灰狗的临床、血液学和生化指标正常，远远超过了以往任何灰狗安乐死的时间。这项研究表明，接触Stx的灰狗会发生与人类相似的促凝血变化，凝血酶可能是Stx- hus发病和治疗的关键因素。
Microvascular thrombosis is a major cause of organ damage in Shiga toxin-mediated hemolytic uremic syndrome (Stx-HUS).In vitroand clinical studies implicate thrombin-mediated mechanisms in the pathogenesis of Stx microvascular thrombosis. In a greyhound model, administration of 0.03μg/kg to 0.05μg/kg Stx1 or Stx2 causes severe bloody diarrhea and HUS with microvascular thrombosis requiring humane euthanasia within 65 hours. Using a greyhound model of Stx-HUS we analyzed early hemostatic changes, and tested the hypothesis that thrombin blockade with lepirudin would prevent lethal Stx effects. Two Stx1-exposed greyhounds were analyzed for hemostatic changes prior to onset of clinical manifestations. Serial hemostasis studies after Stx1 challenge revealed trends of increased aPTT, fibrinogen levels, and prothrombin fragment 1+2, and appearance of abnormally large von Willebrand factor multimers. Three greyhounds were anticoagulated with lepirudin to maintain activated partial thromboplastin times (aPTT) >2.5-fold normal, followed by administration of Stx2 and observation of clinical responses. Among the 3 lepirudin-treated, Stx2-challenged greyhounds, one developed severe illness requiring euthanasia. Remarkably, 2 of the 3 greyhounds developed only hypersalivation and restlessness that resolved (P <.03 compared to 14 historical controls). These two greyhounds were clinically, hematologically and biochemically normal 74 hours after Stx administration, well beyond the time of euthanasia of any previous greyhound. This study suggests that greyhounds exposed to Stx develop procoagulant changes similar to humans, and that thrombin may be a critical factor in the pathogenesis and treatment of Stx-HUS.