High Dimensional Proteomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients with TBI
Junru Wu1, Shimena Li1, Upendra K. Kar1, Matthew Neal1, Jason L. Sperry1, Timothy R. Billiar1, Richard Miller2, Brian J Daley3, Brian Harbrecht4, Jeffrey Claridge5, Danielle Sara Gruen1, Herb Phelan6, Francis X Guyette7
1Department of Surgery, University of Pittsburgh, Pittsburgh, PA 2Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 3Department of Surgery, University of Tennessee Health Science Center, Knoxville, TN, 4 Department of Surgery, University of Louisville, Louisville, KY, 5 MetroHealth Medical Center/Case Western Reserve University, Cleveland, OH, 6 Department of Surgery, University of Texas Southwestern/ Parkland Memorial Hospital, Dallas, TX, 7Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
OBJECTIVE(S): The administration of pre-hospital thawed plasma has been shown to reduce the mortality in polytrauma patients with traumatic brain injury (TBI), an effect not seen in trauma patients without TBI (no brain injury: NBI). The mechanistic explanation for the selective benefit of early plasma administration in patients with TBI remains unknown. We hypothesized that proteomic analysis on blood samples obtained after thawed plasma administration would reveal differences between TBI and NBI patients receiving thawed plasma and lead to novel mechanistic insights.
METHODS: We performed a secondary analysis on a subset of patients from The Prehospital Air Medical Plasma (PAMPer) Trial. Levels of over 7000 proteins (SomaLogic Inc., aptamer-based assay) were assessed in 149 patients in citrated plasma samples collected upon admission, the first blood draw after pre-hospital thawed plasma administration. Mediation analysis (implemented in R package mediation) was conducted to screen for possible proteins causally related to the effects of pre-hospital plasma in reducing 30-day mortality in TBI patients (n=87). Nonparametric bootstrapping (1000 x) was used to estimate the 95% confidence intervals and p-values.
RESULTS: Demographic information (age, sex and ethnicity) and shock characteristics (systolic blood pressure, heart rate) were comparable in the TBI (n=87) and NBI (n=62) cohorts (p>0.05). Stratified Kaplan-Meier curves demonstrated an early survival separation for TBI patients that received 2 units of prehospital plasma (n: Plasma arm=38, Standard arm=49, p=0.04) with no separation observed in NBI patients (n: Plasma arm=27, Standard arm=35, p=0.45). Of 7211 proteins that passed the quality control, 3 intrinsic coagulation factors (Coagulation Factors IX, IXab and XI), 2 anti-coagulation factors (Plasma serine protease inhibitor, Vitamin K-dependent protein C), 1 fibrinolysis related protein (Plasminogen) and 4 proteins not associated with coagulation (Matrix metalloproteinase-19, Interleukin-1 Receptor accessory protein, L-Selectin, Insulin-like growth factor-binding protein complex acid labile subunit) were identified as potential mediators of plasma in reducing 30-day mortality in TBI patients (Proportion of mediation effect >20% , total effect p<0.05 and mediated effect p <0.05) (Table). No circulating proteins changes associated with early thawed plasma were identified in NBI patients (total effect p> 0.05).
CONCLUSIONS: We used blood proteomic analysis to show that polytrauma patients with TBI process thawed plasma differently than polytrauma patients without TBI, demonstrating a fundamental biological difference when TBI is part of the injury complex. The selective elevation in both coagulation and non-coagulation proteins suggests that early plasma administration in TBI patients has multiple salutary actions.
Table 10 proteins identified by mediation analysis of prehospital thawed plasma administration for reducing 30-day mortality of TBI patients from PAMPer trial.
| Name | Functional Annotationa | OR,95%Cl (Total effect) | p-value | OR,95%Cl (Mediated Effect)b | p-value | Prop (%)c |
| Plasminogen | Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor. | 0.79(0.65-0.98) | 0.04 | 0.92 (0.83-1) | 0.04 | 33 |
| Matrix metalloproteinase-19 | Endopeptidase that degrades various components of the extracellular matrix. | 0.8 (0.66-0.99) | 0.05 | 0.93 (0.84-0.99) | 0.01 | 32 |
| Plasma serine protease inhibitor | Acts as an anticoagulant factor by inhibiting blood coagulation factors. | 0.8 (0.65-0.99) | 0.04 | 0.93 (0.84-0.99) | 0.02 | 31 |
| Coagulation Factor XI | Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa. | 0.8 (0.66-0.99) | 0.05 | 0.93 (0.85-0.99) | 0.02 | 30 |
| Coagulation factor IXab | Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form. | 0.8 (0.66-0.99) | 0.05 | 0.93 (0.85-0.99) | 0.01 | 29 |
| Interleukin-1 Receptor accessory protein | Coreceptor with IL1R1 in the IL-1 signaling system, binding of IL1RN to IL1R1. | 0.8 (0.66-1) | 0.05 | 0.94 (0.86-0.99) | 0.02 | 27 |
| Coagulation factor IX | Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form. | 0.8 (0.66-0.99) | 0.05 | 0.94(0.86-0.99) | 0.02 | 26 |
| Vitamin K-dependent protein C | A vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa. | 0.8 (0.66-1) | 0.05 | 0.94 (0.86-1) | 0.04 | 26 |
| L-Selectin | Calcium-dependent lectin that mediates cell adhesion by binding to glycoproteins on neighboring cells. | 0.8 (0.66-0.99) | 0.05 | 0.94 (0.86-1) | 0.03 | 24 |
| Insulin-like growth factor-binding protein complex acid labile subunit | Involved in protein-protein interactions that result in protein complexes, receptor-ligand binding or cell adhesion. | 0.8 (0.66-0.99) | 0.05 | 0.94 (0.86-1) | 0.03 | 23 |
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