In hemorrhaging trauma patients, the endothelium is activated, resulting in excessive endothelial synthesis of von Willebrand Factor (vWF), which may enhance micro-thrombi formation, resulting in obstruction of the microcirculation and endothelial injury, aggravating bleeding, as well as contributing to organ failure. Under normal conditions, vWF is cleaved by the metalloprotease ADAMTS-13. After trauma, ADAMTS-13 levels are reduced. To assess whether recombinant human ADAMTS-13 inhibits endothelial injury and organ failure in a rat trauma-transfusion model. Blood products were prepared from syngeneic rat blood according to blood bank standards. Polytrauma was induced in rats by crush injury to the intestines and liver and by fracture of the femur. The rats were hemorrhaged until a mean arterial pressure (MAP) of 40 mmHg was reached. Rats were randomized to receive transfusion of RBCs, FFPs, and platelets in a 1:1:1 ratio to achieve a MAP of 70 mmHg, with or without the addition of ADAMTS-13 (50 μg/kg). Blood samples were assessed for biochemistry and rotational thromboelastometry (ROTEM). Syndecan-1 and VE-cadherin levels were measured as a reflection of endothelial integrity. The amount of leakage of dextran-FITC from the vascular system to the parenchyma in lungs was quantified. To assess inflammation, IL-6 and IL-8 levels were determined. Organ damage was assessed by histopathology. All rats were severely shocked, with no significant differences in shock parameters between groups. Rats treated with ADAMTS-13 showed signs of a more effective shock reversal (higher blood pressure, lower lactate levels) compared to controls. Also, ROTEM parameters of clot formation in rats receiving ADAMTS-13 improved compared to controls, which was mainly platelet-dependent. Syndecan-1 levels relative to baseline trended to be lower in ADAMTS-13 treated rats compared to controls (107 vs 149%, p = 0.08). ADAMTS-13 reduced albuminuria (1.7 vs 4.4 g/L, p < 0.01) and organ-specific inflammation (pulmonary IL-6 243 vs 369 pg/mL, p = 0.08; splenic IL-6 253 vs 307, p = 0.03) compared to controls, but did not improve histopathological scores. The use of ADAMTS-13 in a rat trauma-transfusion model improves parameters of shock, platelet-driven coagulation, endothelial damage, and organ inflammation. These results suggest that ADAMTS-13 is important in mediating outcome of trauma. Whether ADAMTS-13 can be used as a therapeutic adjunct to treat bleeding trauma patients remains to be determined.

中文翻译：

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重组人ADAMTS-13的治疗应用改善外伤出血和输血大鼠模型的休克逆转和凝血状态

外伤患者出血时，内皮细胞被激活，导致血管内皮细胞过度合成血管性血友病因子（vWF），可能促进微血栓形成，导致微循环受阻和内皮损伤，加重出血，并导致器官功能障碍。失败。在正常条件下，vWF 被金属蛋白酶 ADAMTS-13 切割。创伤后，ADAMTS-13 水平降低。评估重组人 ADAMTS-13 是否抑制大鼠创伤输血模型中的内皮损伤和器官衰竭。根据血库标准从同种大鼠血液制备血液制品。大鼠肠道和肝脏的挤压伤以及股骨骨折可诱发多发性创伤。大鼠出血直至平均动脉压 (MAP) 达到 40 mmHg。大鼠随机接受以 1:1:1 的比例输注 RBC、FFP 和血小板，以达到 70 mmHg 的 MAP，添加或不添加 ADAMTS-13（50 μg/kg）。对血液样本进行生物化学和旋转血栓弹力测定 (ROTEM) 评估。Syndecan-1 和 VE-钙粘蛋白水平被测量为内皮完整性的反映。右旋糖酐-FITC 从血管系统到肺实质的泄漏量被量化。为了评估炎症，确定了 IL-6 和 IL-8 水平。通过组织病理学评估器官损伤。所有大鼠都受到严重电击，组间电击参数没有显着差异。与对照组相比，用 ADAMTS-13 治疗的大鼠表现出更有效的休克逆转迹象（更高的血压，更低的乳酸水平）。还，与对照组相比，接受 ADAMTS-13 的大鼠血凝块形成的 ROTEM 参数有所改善，这主要是血小板依赖性的。与对照组相比，ADAMTS-13 治疗的大鼠中 Syndecan-1 水平相对于基线趋于较低（107 对 149%，p = 0.08）。ADAMTS-13 减少白蛋白尿（1.7 对 4.4 g/L，p < 0.01）和器官特异性炎症（肺 IL-6 243 对 369 pg/mL，p = 0.08；脾 IL-6 253 对 307，p = 0.03）与对照组相比，但没有改善组织病理学评分。ADAMTS-13 在大鼠创伤输血模型中的使用改善了休克、血小板驱动的凝血、内皮损伤和器官炎症的参数。这些结果表明 ADAMTS-13 在调节创伤结果方面很重要。ADAMTS-13 是否可以用作治疗出血性创伤患者的辅助治疗仍有待确定。