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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.

BACKGROUND: Posttraumatic venous thromboembolism (VTE) remains prevalent in severely injured patients despite chemoprophylaxis. Importantly, although platelets are central to thrombosis, they are not routinely targeted in prevention of posttraumatic VTE. Furthermore, platelets from injured patients show ex vivo evidence of increased activation yet impaired aggregation, consistent with functional exhaustion. However, the relationship of this platelet functional phenotype with development of posttraumatic VTE is unknown. We hypothesized that, following injury, impaired ex vivo platelet aggregation (PA) is associated with the development of posttraumatic VTE. METHODS: We performed a secondary analysis of 133 severely injured patients from a prospective observational study investigating coagulation and inflammation (2011-2019). Platelet aggregation in response to stimulation with adenosine diphosphate (ADP), collagen, and thrombin was measured at presentation (preresuscitation) and 24 hours (postresuscitation). Viscoelastic clot strength and lysis were measured in parallel by thromboelastography. Multivariable regression examined relationships between PA at presentation, 24 hours, and the change (δ) in PA between presentation and 24 hours with development of VTE. RESULTS: The 133 patients were severely injured (median Injury Severity Score, 25), and 14% developed VTE (all >48 hours after admission). At presentation, platelet count and PA were not significantly different between those with and without incident VTE. However, at 24 hours, those who subsequently developed VTE had significantly lower platelet counts (126 × 10 9 /L vs. 164 × 10 9 /L, p = 0.01) and lower PA in response to ADP ( p < 0.05), collagen ( p < 0.05), and thrombin ( p = 0.06). Importantly, the magnitude of decrease in PA (δ) from presentation to 24 hours was independently associated with development of VTE (adjusted odds ratios per 10 aggregation unit decrease: δ-ADP, 1.31 [ p = 0.03]; δ-collagen, 1.36 [ p = 0.01]; δ-thrombin, 1.41 [ p < 0.01]). CONCLUSION: Severely injured patients with decreasing ex vivo measures of PA despite resuscitation have an increased risk of developing VTE. This may have implications for predicting development of VTE and for studying platelet targeted chemoprophylaxis regimens. LEVEL OF EVIDENCE: Prognostic/Epidemiological; Level III.

Rationale: Cigarette smoke exposure is associated with an increased risk of developing acute respiratory distress syndrome (ARDS) in trauma, transfusion, and nonpulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if patients with ARDS have differences in underlying biology based on smoking status. Objectives: To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. Methods: We studied a prospective cohort of 592 patients with sepsis from 2009 to 2017. Plasma cotinine and urine NNAL [urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. Measurements and Main Results: Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Among patients with sepsis and ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. Patients with ARDS with cigarette smoke exposure had lower plasma levels of IL-8 (P = 0.01) and sTNFR-1 (soluble tumor necrosis factor 1; P = 0.01) compared with those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. Conclusions: Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and nonpulmonary sepsis. Among patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared with nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.

Burn injury is associated with endothelial dysfunction and coagulopathy and concomitant inhalation injury (IHI) increases morbidity and mortality. The aim of this work is to identify associations between IHI, coagulation homeostasis, vascular endothelium, and clinical outcomes in burn patients. One hundred and twelve patients presenting to a regional burn center were included in this retrospective cohort study. Whole blood was collected at set intervals from admission through 24 hours and underwent viscoelastic assay with rapid thromboelastography (rTEG). Syndecan-1 (SDC-1) on admission was quantified by ELISA. Patients were grouped by the presence (n = 28) or absence (n = 84) of concomitant IHI and rTEG parameters, fibrinolytic phenotypes, SDC-1, and clinical outcomes were compared. Of the 112 thermally injured patients, 28 (25%) had IHI. Most patients were male (68.8%) with a median age of 40 (interquartile range, 29-57) years. Patients with IHI had higher overall mortality (42.68% vs 8.3%; P < .0001). rTEG LY30 was lower in patients with IHI at hours 4 and 12 (P < .05). There was a pattern of increased abnormal fibrinolytic phenotypes among IHI patients. There was a greater proportion of IHI patients with endotheliopathy (SDC-1 > 34 ng/ml) (64.7% vs 26.4%; P = .008). There was a pattern of increased mortality among patients with IHI and endotheliopathy (0% vs 72.7%; P = .004). Significant differences between patients with and without IHI were found in measures assessing fibrinolytic potential and endotheliopathy. Mortality was associated with abnormal fibrinolysis, endotheliopathy, and IHI. However, the extent to which IHI-associated dysfunction is independent of TBSA burn size remains to be elucidated.

BackgroundTrauma-induced coagulopathy (TIC) is a disorder that occurs in one-third of severely injured trauma patients, manifesting as increased bleeding and a 4X risk of mortality. Understanding the mechanisms driving TIC, clinical risk factors are essential to mitigating this coagulopathic bleeding and is therefore essential for saving lives. In this retrospective, single hospital study of 891 trauma patients, we investigate and quantify how two prominently described phenotypes of TIC, consumptive coagulopathy and hyperfibrinolysis, affect survival odds in the first 25 h, when deaths from TIC are most prevalent.MethodsWe employ a joint survival model to estimate the longitudinal trajectories of the protein Factor II (% activity) and the log of the protein fragment D-Dimer ([Formula: see text]g/ml), representative biomarkers of consumptive coagulopathy and hyperfibrinolysis respectively, and tie them together with patient outcomes. Joint models have recently gained popularity in medical studies due to the necessity to simultaneously track continuously measured biomarkers as a disease evolves, as well as to associate them with patient outcomes. In this work, we estimate and analyze our joint model using Bayesian methods to obtain uncertainties and distributions over associations and trajectories.ResultsWe find that a unit increase in log D-Dimer increases the risk of mortality by 2.22 [1.57, 3.28] fold while a unit increase in Factor II only marginally decreases the risk of mortality by 0.94 [0.91,0.96] fold. This suggests that, while managing consumptive coagulopathy and hyperfibrinolysis both seem to affect survival odds, the effect of hyperfibrinolysis is much greater and more sensitive. Furthermore, we find that the longitudinal trajectories, controlling for many fixed covariates, trend differently for different patients. Thus, a more personalized approach is necessary when considering treatment and risk prediction under these phenotypes.ConclusionThis study reinforces the finding that hyperfibrinolysis is linked with poor patient outcomes regardless of factor consumption levels. Furthermore, it quantifies the degree to which measured D-Dimer levels correlate with increased risk. The single hospital, retrospective nature can be understood to specify the results to this particular hospital's patients and protocol in treating trauma patients. Expanding to a multi-hospital setting would result in better estimates about the underlying nature of consumptive coagulopathy and hyperfibrinolysis with survival, regardless of protocol. Individual trajectories obtained with these estimates can be used to provide personalized dynamic risk prediction when making decisions regarding management of blood factors.