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Background: Patients with type O blood may have an increased risk of hemorrhagic complications because of lower baseline levels of von Willebrand factor and factor VIII, but the transition to a mortality difference in trauma is less clear. We hypothesized that type O trauma patients will have differential proteomic and metabolomic signatures in response to trauma beyond von Willebrand factor and factor VIII alone., Methods: Patients meeting the highest level of trauma activation criteria were prospectively enrolled. Blood samples were collected upon arrival to the emergency department. Proteomic and metabolomic (multiomics) analyses of these samples were performed using liquid chromatography-mass spectrometry. Demographic, clinical, and multiomics data were compared between patients with type O blood versus all other patients., Results: There were 288 patients with multiomics data; 146 (51%) had type O blood. Demographics, injury patterns, and initial vital signs and laboratory measurements were not different between groups. Type O patients had increased lengths of stay (7 vs. 6 days, p = 0.041) and a trend toward decreased mortality secondary to traumatic brain injury compared with other causes (traumatic brain injury, 44.4% vs. 87.5%; p = 0.055). Type O patients had decreased levels of mannose-binding lectin and mannose-binding lectin-associated serine proteases 1 and 2, which are required for the initiation of the lectin pathway of complement activation. Type O patients also had metabolite differences signifying energy metabolism and mitochondrial dysfunction., Conclusion: Blood type O patients have a unique multiomics signature, including decreased levels of proteins required to activate the lectin complement pathway. This may lead to overall decreased levels of complement activation and decreased systemic inflammation in the acute phase, possibly leading to a survival advantage, especially in traumatic brain injury. However, this may later impair healing. Future work will need to confirm these associations, and animal studies are needed to test therapeutic targets., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Platelets are well known for their roles in hemostasis, but they also play a key role in thromboinflammatory pathways by regulating endothelial health, stimulating angiogenesis, and mediating host defense through both contact dependent and independent signaling. When activated, platelets degranulate releasing multiple active substances. We hypothesized that the soluble environment formed by trauma platelet releasates (TPR) attenuates thromboinflammation via mitigation of trauma induced endothelial permeability and metabolomic reprogramming., Methods: Blood was collected from injured and healthy patients to generate platelet releasates and plasma in parallel. Permeability of endothelial cells when exposed to TPR and plasma (TP) was assessed via resistance measurement by electric cell-substrate impedance sensing (ECIS). Endothelial cells treated with TPR and TP were subjected to mass spectrometry-based metabolomics., Results: TP increased endothelial permeability, whereas TPR decreased endothelial permeability when compared with untreated cells. When TP and TPR were mixed ex vivo, TPR mitigated TP-induced permeability, with significant increase in AUC compared with TP alone. Metabolomics of TPR and TP demonstrated disrupted redox reactions and anti-inflammatory mechanisms., Conclusion: Trauma platelet releasates provide endothelial barrier protection against TP-induced endothelial permeability. Our findings highlight a potential beneficial action of activated platelets on the endothelium in injured patients through disrupted redox reactions and increased antioxidants. Our findings support that soluble signaling from platelet degranulation may mitigate the endotheliopathy of trauma. The clinical implications of this are that activated platelets may prove a promising therapeutic target in the complex integration of thrombosis, endotheliopathy, and inflammation in trauma., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Both healthy plasma and cytoprotective aPC (3K3A-aPC) have been shown to mitigate the endotheliopathy of trauma (EoT), but optimal therapeutics remain unknown. Our aim was therefore to determine optimal therapies to mitigate EoT by investigating the effectiveness of 3K3A-aPC with and without plasma-based resuscitation strategies., Methods: Electric cell-substrate impedance sensing (ECIS) was used to measure real-time permeability changes in endothelial cells. Cells were treated with a 2-μg/mL solution of aPC 30 minutes prior to stimulation with plasma taken from severely injured trauma patients (ISS > 15 and BD < -6) (TP). Healthy plasma, or plasma frozen within 24 hours (FP24), was added concomitantly with TP. Cells treated with thrombin and untreated cells were included in this study as control groups., Results: A dose-dependent difference was found between the 5% and 10% plasma-treated groups when human umbilical vein endothelial cells were simultaneously stimulated with TP (μd, 7.346; 95% confidence interval [CI], 4.574-10.12). There was no difference when compared with TP alone in the 5% (μd, 5.713; 95% CI, -1.751 to 13.18) or 10% group (μd, -1.633; 95% CI, -9.097 to 5.832). When 3K3A-aPC was added to plasma and TP, the 5% group showed improvement in permeability compared with TP alone (μd, 10.11; 95% CI, 2.642 to 17.57), but there was no difference in the 10% group (μd -1.394; 95% CI, -8.859 to 6.070). The combination of 3K3A-aPC, plasma, and TP at both the 5% plasma (μd, -28.52; 95% CI, -34.72 to -22.32) and 10% plasma concentrations (μd, -40.02; 95% CI, -46.22 to -33.82) had higher intercellular permeability than the 3K3A-aPC preincubation group., Conclusion: Our data show that FP24, in a posttrauma environment, pretreatment with 3K3A-aPC can potentially mitigate the EoT to a greater degree than FP24 with or without 3K3A-aPC. Although further exploration is needed, this represents a potentially ideal and perhaps superior therapeutic treatment for the dysregulated thromboinflammation of injured patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Smoking is a public health threat because of its well-described link to increased oxidative stress-related diseases including peripheral vascular disease and coronary artery disease. Tobacco use has been linked to risk of inpatient trauma morbidity including acute respiratory distress syndrome; however, its mechanistic effect on comprehensive metabolic heterogeneity has yet to be examined., Methods: Plasma was obtained on arrival from injured patients at a Level 1 trauma center and analyzed with modern mass spectrometry-based metabolomics. Patients were stratified by nonsmoker, passive smoker, and active smoker by lower, interquartile, and upper quartile ranges of cotinine intensity peaks. Patients were substratified by high injury/high shock (Injury Severity Score, ≥15; base excess, <-6) and compared with healthy controls. p Value of <0.05 following false discovery rate correction of t test was considered significant., Results: Forty-eight patients with high injury/high shock (7 nonsmokers [15%], 25 passive smokers [52%], and 16 active smokers [33%]) and 95 healthy patients who served as controls (30 nonsmokers [32%], 43 passive smokers [45%], and 22 active smokers [23%]) were included. Elevated metabolites in our controls who were active smokers include enrichment in chronic inflammatory and oxidative processes. Elevated metabolites in active smokers in high injury/high shock include enrichment in the malate-aspartate shuttle, tyrosine metabolism, carnitine synthesis, and oxidation of very long-chain fatty acids., Conclusion: Smoking promotes a state of oxidative stress leading to mitochondrial dysfunction, which is additive to the inflammatory milieu of trauma. Smoking is associated with impaired mitochondrial substrate utilization of long-chain fatty acids, aspartate, and tyrosine, all of which accentuate oxidative stress following injury. This altered expression represents an ideal target for therapies to reduce oxidative damage toward the goal of personalized treatment of trauma patients., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Activated Protein C (aPC) plays dual roles after injury, driving both trauma-induced coagulopathy (TIC) by cleaving, and thus inactivating, factors Va and VIIIa and depressing fibrinolysis while also mediating an inflammomodulatory milieu via protease activated receptor-1 (PAR-1) cytoprotective signaling. Because of this dual role, it represents and ideal target for study and therapeutics after trauma. A known aPC variant, 3K3A-aPC, has been engineered to preserve cytoprotective activity while retaining minimal anticoagulant activity rendering it potentially ideal as a cytoprotective therapeutic after trauma. We hypothesized that 3K3A-aPC would mitigate the endotheliopathy of trauma by protecting against endothelial permeability., Methods: We used electric cell-substrate impedance sensing to measure permeability changes in real time in primary endothelial cells. These were cultured, grown to confluence, and treated with a 2 μg/mL solution of 3K3A-aPC at 180 minutes, 120 minutes, 60 minutes, 30 minutes prior to stimulation with ex vivo plasma taken from severely injured trauma patients (Injury Severity Score > 15 and BD < -6) (trauma plasma [TP]). Cells treated with thrombin and untreated cells were included in this study as control groups. Permeability changes were recorded in real time via electric cell-substrate impedance sensing for 30 minutes after treatment with TP. We quantified permeability changes in the control and treatment groups as area under the curve (AUC). Rac1/RhoA activity was also compared between these groups. Statistical significance was determined by one-way ANOVA followed by a post hoc analysis using Tukey's multiple comparison's test., Results: Treatment with aPC mitigated endothelial permeability induced by ex vivo trauma plasma at all pre-treatment time points. The AUC of the 30-minute 3K3A-aPC pretreatment group was higher than TP alone (mean diff. 22.12 95% CI [13.75, 30.49], p < 0.0001) (Figure). Moreover, the AUC of the 60-minute, 120-minute, and 180-minute pretreatment groups was also higher than TP alone (mean diff., 16.30; 95% confidence interval [CI], 7.93-24.67; 19.43; 95% CI, 11.06-27.80, and 18.65; 95% CI, 10.28-27.02;, all p < 0.0001, respectively). Rac1/RhoA activity was higher in the aPC pretreatment group when compared with all other groups ( p < 0.01)., Conclusion: Pretreatment with 3K3A-aPC, which retains its cytoprotective function but has only ~5% of its anticoagulant function, abrogates the effects of trauma-induced endotheliopathy. This represents a potential therapeutic treatment for dysregulated thromboinflammation for injured patients by minimizing aPC's role in trauma-induced coagulopathy while concurrently amplifying its essential cytoprotective function., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Appropriate prehospital trauma triage ensures transport of children to facilities that provide specialized trauma care. There are currently no objective and generalizable scoring tool for emergency medical services to facilitate such decisions. An abnormal reverse shock index times Glasgow Coma Scale (rSIG), which is calculated using readily available parameters, has been shown to be associated with severely injured children. This study sought to determine if rSIG could be used in the prehospital setting to identify injured children who require the highest levels of care., Methods: Patients (1-18 years old) transferred from the scene to a level 1 pediatric trauma center from 2010 to 2020 with complete prehospital and emergency department vital signs, and Glasgow Coma Scale (GCS) scores were included. Reverse shock index times GCS was calculated as previously described ((systolic blood pressure/heart rate) × GCS), and the following cutoffs were used: ≤13.1, ≤16.5, and ≤20.1 for 1- to 6-, 7- to 12-, and 13- to 18-year-old patients, respectively. Trauma activation level and clinical outcomes upon arrival to the pediatric trauma center were collected., Results: There were 247 patients included in the analysis; 66.0% (163) had an abnormal prehospital rSIG. Patients with an abnormal rSIG had a higher rate of highest-level trauma activation compared with those with a normal rSIG (38.7% vs. 20.2%, p = 0.013). Patients with an abnormal prehospital rSIG also had higher rates of intubation (28.8% vs. 9.52%, p < 0.001), intracranial pressure monitor (9.20 vs. 1.19%, p = 0.032), need for blood (19.6% vs. 8.33%, p = 0.034), laparotomy (7.98% vs. 1.19%, p = 0.039), and intensive care unit admission (54.6% vs. 40.5%, p = 0.049)., Conclusion: Reverse shock index times GCS may assist emergency medical service providers in early identification and triage of severely injured children. An abnormal rSIG in the emergency department is associated with higher rates of intubation, need for blood transfusion, intracranial pressure monitoring, laparotomy, and intensive care unit admission. Use of this metric may help to speed the identification, care, and treatment of any injured child., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)