Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.
Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.
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DOI：
10.1097/mbc.0000000000001089
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发表时间：
2022-01-01
期刊：
影响因子：
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通讯作者：
A TACTIC Publication
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作者：
Plautz WE;Haldeman SH;Dyer MR;Sperry JL;Guyette FX;Loughran PA;Alvikas J;Hassoune A;Hoteit L;Alsaadi N;Zuckerbraun BS;Rollins-Raval MA;Raval JS;Mota RI;Neal MD;A TACTIC Publication
急性肾损伤（阿基）是常见的创伤后，但其影响因素还不完全清楚。血浆血管性血友病因子（vWF）的增加与ADAMTS 13的同时减少与其他疾病状态下的肾微血管血栓形成相关，但在创伤中未显示类似的结果。我们假设循环vWF和ADAMTS 13的分子变化促进创伤性损伤后阿基。比较了来自16名创伤患者的血浆样本中的vWF抗原、vWF多聚体组成和ADAMTS 13水平，这些患者有和没有创伤诱导的阿基，这些患者从院前空中医疗血浆（PAMPer）生物储存库获得。肾组织病理学和功能，vWF和ADAMTS 13水平在多发性创伤和出血的小鼠模型中平行评估。与健康对照组相比，创伤患者中VWF抗原较高[314%（253-349）vs. 100%（87-117）] [中位数（IQR）]，而ADAMTS 13活性较低[36.0%（30.1-44.7）vs. 100.0%（83.1-121.0）]。与非AKI患者相比，发生阿基的患者在72小时时显示出显著更高水平的高分子量多聚体vWF [32.9%（30.4-35.3）vs. 27.8%（24.6-30.8）]。小鼠多发性创伤模型中，小鼠血浆半胱氨酸蛋白酶抑制剂C和vWF升高，与ADAMTS 13相关的减少，免疫组织学分析表明肾损伤伴小血管栓纤维蛋白原和vWF阳性。创伤性损伤后，vWF-ADAMTS 13轴在创伤患者和小鼠模型中均向血栓前状态转移。我们进一步证明，在创伤后的几天内，随着血栓前变化的持续，同时产生了含vWF的微血管病沉积物，这可能有助于阿基的发展。
Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253–349) vs. 100% (87–117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1–44.7) vs. 100.0% (83.1–121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4–35.3) vs. 27.8% (24.6–30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.