High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI

Abstract

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.

High-dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma

“…1). We also examined these biomarkers across injury severity groups (mild [ISS, ≤15], moderate [ISS, [16][17][18][19][20][21][22][23][24], severe [ISS, >25]). This identified an early (time point 0 hours) outcome and injury severity-based near-indiscriminate release of the analyzed biomarkers.…”

Time to early resuscitative intervention association with mortality in trauma patients at risk for hemorrhage

“…Thus, the early introduction of blood products and/or TXA may mitigate the early immune and inflammatory effects of hemorrhagic shock including endotheliopathy that may lead to longer term improved outcomes. [24][25][26][27] Indirect evidence of the benefits of earlier resuscitation in hemorrhagic shock after injury exists. In a secondary analysis of a randomized trial, reducing the time to massive transfusion protocol activation at the trauma center was associated with lower 24-hour and 30-day mortality, with a 5% increase for every 1-minute delay in the arrival of the first cooler of blood products.…”

Plasma proteomics reveals early, broad release of chemokine, cytokine, TNF, and interferon mediators following trauma with delayed increases in a subset of chemokines and cytokines in patients that remain critically ill

“…The 150 patient samples were chosen as a representative subset of patients that also had metabolome, lipidome, cytokine, and endotheliopathy marker data previously acquired. The multi-omic analysis of these patients has been previously published ( 26 , 29 ), and the present study represents an analysis of four families of protein mediators present within the proteomic analysis. Twenty-nine low or no-injury trauma patients transported by air medical transport in the STAAMP trial ( 28 ), sampled upon arrival, were included as minimally injured (Injury Severity Score [ISS]=1 or less) controls.…”

“…With advances in high-dimensional proteomic analysis, it is now feasible to measure entire families of proteins simultaneously ( 25 ). Here, we used longitudinal proteomic databases derived from the SomaLogic 7.5K Proteomic Platform ( 26 ) assay of plasma samples obtained from the Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock(PAMPer) ( 27 ) and Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury (STAAMP) ( 28 ) trials to characterize the protein immune mediator landscape in severely injured humans. This allowed the association of patterns of 115 immune mediators and 69 soluble cytokine receptors with patient outcomes.…”