Objectives: 

The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database.

Background: 

The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients.

Methods: 

A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis.

Results: 

Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA).

Conclusions: 

These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation.

中文翻译：

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高维多元组学揭示多发伤 TBI 患者早期血浆给药的独特特征

目标： 

作者试图利用多组学数据库的中介分析来确定因果因素，以解释创伤性脑损伤(TBI) 患者院前注射解冻血浆 (TP) 的选择性益处。

背景： 

院前空气医疗血浆 (PAMPer) 试验表明，TBI 患者和对损伤有明显的全身反应 [定义为内型 2 (E2)] 的患者，可以从院前给予 TP 中获得生存获益。先前对高维蛋白质组学、脂质组学和代谢组学的研究表明，接受院前 TP 的患者循环生物标志物具有独特的模式，这表明更深入的分析可以揭示 TBI 患者特有的因果特征。

方法： 

使用来自 PAMPer 试验的一部分患者 (n=149) 的入院血液样本生成了一个新型蛋白质组数据库（SomaLogic Inc.，基于适体的检测，7K 平台）。该蛋白质组数据集与先前报道的来自这些相同患者的代谢组学和脂质组学数据集相结合。进行两步分析以确定促进接受早期 TP 的 E2-TBI 患者生存的因素。首先，使用线性和多元潜在因素回归分析来选择特征。然后，将选定的特征输入因果中介分析。

结果： 

对可观察特征的因果中介分析确定了 16 种蛋白质和 41 种脂质具有高比例的介导效应 (>50%)，以解释早期 TP 对 E2-TBI 患者的生存益处。多变量潜在因素回归分析还发现了 5 个潜在特征簇，其比例效应 >30%，许多与可观察到的特征相同。可观察到的和潜在的特征包括蛋白酶抑制剂，已知可抑制活化蛋白 C 并阻止纤维蛋白溶解（SERPINA5 和 CPB2）、凝血因子（因子 XI）以及参与脂质转运和代谢的蛋白质（APOE3 和 sPLA(2)-）十二).

结论： 

这些发现表明，严重受伤的 TBI 患者处理外源血浆的方式与未患 TBI 的患者不同。早期 TP 对 E2-TBI 患者的有益作用可能是改善血液凝固以及独立于凝血的脑保护因素的作用的结果。