Department of Cardiology, The 3rd Xiangya Hospital, Central South University, Changsha, China.
Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
Ann Surg. 2022 Oct 1;276(4):673-683. doi: 10.1097/SLA.0000000000005610. Epub 2022 Jul 19.
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.
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.
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.
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).
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.
作者试图通过对多组学数据库进行中介分析，确定能够解释创伤性脑损伤（TBI）患者接受院前解冻血浆（TP）治疗选择性获益的因果因素。
Prehospital Air Medical Plasma（PAMPer）试验表明，伴有明显全身损伤反应的 TBI 患者（定义为 2 型内表型（E2）），院前接受 TP 治疗有生存获益。高维蛋白质组学、脂质组学和代谢组学的分析以前曾在接受院前 TP 治疗的患者的循环生物标志物中显示出独特的模式，这表明更深入的分析可能揭示出特定于 TBI 患者的因果特征。
使用来自 PAMPer 试验的一组患者（n=149）的入院血样，生成了一个新的蛋白质组数据库（SomaLogic Inc.，基于适配子的检测，7K 平台）。该蛋白质组数据集与来自同一患者的先前报告的代谢组学和脂质组学数据集相结合。使用线性和多变量潜在因子回归分析对数据进行了 2 步分析，以确定能够促进接受早期 TP 的 E2-TBI 患者生存的因素。首先，使用线性和多变量潜在因子回归分析选择特征。然后，将选定的特征输入因果中介分析。
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，其中介效应比例（>50%）高，可解释 E2-TBI 患者早期 TP 治疗的生存获益。多变量潜在因子回归分析还揭示了 5 个具有比例效应（>30%）的潜在特征簇，其中许多与可观察特征相同。在可观察特征和潜在特征中，包括已知可抑制激活蛋白 C 和阻止纤溶的蛋白酶抑制剂（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）-XIIA）。
这些发现表明，伴有 TBI 的严重受伤患者对院前外源性血浆的处理方式与无 TBI 患者不同。E2-TBI 患者早期接受 TP 治疗的有益效果可能是改善凝血和独立于凝血的脑保护因子的作用的结果。
