Trauma remains a leading cause of death worldwide, and most early preventable deaths in both the civilian and military settings are due to uncontrolled hemorrhage, despite paradigm advances in modern ...trauma care. Combined tissue injury and shock result in hemostatic failure, which has been identified as a multidimensional molecular, physiologic and clinical disorder termed trauma‐induced coagulopathy (TIC). Understanding the biology of TIC is of utmost importance, as it is often responsible for uncontrolled bleeding, organ failure, thromboembolic complications, and death. Investigations have shown that TIC is characterized by multiple phenotypes of impaired hemostasis due to altered biology in clot formation and breakdown. These coagulopathies are attributable to tissue injury and shock, and encompass underlying endothelial, immune and inflammatory perturbations. Despite the recognition and identification of multiple mechanisms and mediators of TIC, and the development of targeted treatments, the mortality rates and associated morbidities due to hemorrhage after injury remain high. The purpose of this review is to examine the past and present understanding of the multiple distinct but highly integrated pathways implicated in TIC, in order to highlight the current knowledge gaps and future needs in this evolving field, with the aim of reducing morbidity and mortality after injury.
Blood Brain Barrier (BBB) breakdown is a secondary form of brain injury which has yet to be fully elucidated mechanistically. Existing research suggests that breakdown of tight junction proteins ...between endothelial cells is a primary driver of increased BBB permeability following injury, and intercellular signaling between primary cells of the neurovascular unit: endothelial cells, astrocytes, and pericytes; contribute to tight junction restoration. To expound upon this body of research, we analyzed the effects of severely injured patient plasma on each of the cell types in monoculture and together in a triculture model for the transcriptional and translational expression of the tight junction proteins Claudins 3 and 5, (CLDN3, CLDN5) and Zona Occludens 1 (ZO-1). Conditioned media transfer studies were performed to illuminate the cell type responsible for differential tight junction expression. Our data show that incubation with 5% human ex vivo severely injured patient plasma is sufficient to produce a differential response in endothelial cell tight junction mRNA and protein expression. Endothelial cells in monoculture produced a significant increase of CLDN3 and CLDN5 mRNA expression, (3.98 and 3.51 fold increase vs. control respectively, p<0.01) and CLDN5 protein expression, (2.58 fold change vs. control, p<0.01), whereas in triculture, this increase was attenuated. Our triculture model and conditioned media experiments suggest that conditioned media from astrocytes and pericytes and a triculture of astrocytes, pericytes and endothelial cells are sufficient in attenuating the transcriptional increases of tight junction proteins CLDN3 and CLDN5 observed in endothelial monocultures following incubation with severely injured trauma plasma. This data suggests that inhibitory molecular signals from astrocytes and pericytes contributes to prolonged BBB breakdown following injury via tight junction transcriptional and translational downregulation of CLDN5.
Trauma remains the leading cause of death with bleeding as the primary cause of preventable mortality during the first 24 h following trauma. When death occurs, it happens quickly, typically within ...the first 6 h after injury. One of four patients to arrive in the emergency department after trauma is already in the state of acute traumatic coagulopathy and shock. The principal drivers of acute traumatic coagulopathy have been characterized by tissue hypoperfusion, inflammation, and the acute activation of the neurohumoral system. Hypoperfusion leads to an activation of protein C with cleavage of activated factors V and VIII and the inhibition of plasminogen activator inhibitor 1 with subsequent hyperfibrinolysis. Endothelial damage and activation result in Weibel-Palade body degradation and glycocalyx shedding associated with autoheparinization. In contrast, there is an iatrogenic coagulopathy that occurs secondary to uncritical volume therapy leading to acidosis, hypothermia, and hemodilution. This coagulopathy then may be an integral part of the "vicious cycle" when combined with acidosis and hypothermia. The present article summarizes an update on the principal mechanisms and triggers of the coagulopathy of trauma including traumatic brain injury.
Peer influence processes have been documented extensively for a wide range of maladaptive adolescent behaviors. However, peer socialization is not inherently deleterious, and little is known about ...whether adolescents influence each other’s prosocial behaviors, or whether some peers are more influential than others towards positive youth outcomes. This study addressed these questions using an experimental “chat room” paradigm to examine in vivo peer influence of prosocial behavior endorsement. A school-based sample of 304 early adolescents (55 % female, 45 % male;
M
age
= 12.68) believed they were interacting electronically with same-gender grademates (i.e., “e-confederates”), whose peer status was experimentally manipulated. The participants’ intent to engage in prosocial behaviors was measured pre-experiment and in subsequent “public” and “private” experimental sessions. Overall, the adolescents conformed to the e-confederates’ prosocial responses in public; yet, these peer influence effects were moderated by the peer status of the e-confederates, such that youth more strongly conformed to the high-status e-confederates than to the low-status ones. There also was some evidence that these peer influence effects were maintained in the private session, indicating potential internalization of prosocial peer norms. These findings help bridge the positive youth development and peer influence literatures, with potential implications for campaigns to increase prosocial behaviors.
The resuscitation of severely injured bleeding patients has evolved into a multi-modal strategy termed damage control resuscitation (DCR). This guideline evaluates several aspects of DCR including ...the role of massive transfusion (MT) protocols, the optimal target ratio of plasma (PLAS) and platelets (PLT) to red blood cells (RBC) during DCR, and the role of recombinant activated factor VII (rVIIa) and tranexamic acid (TXA).
Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines (PMG) Section of EAST conducted a systematic review using MEDLINE and EMBASE. Articles in English from1985 through 2015 were considered in evaluating four PICO questions relevant to DCR.
A total of 37 studies were identified for analysis, of which 31 met criteria for quantitative meta-analysis. In these studies, mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43-0.87, p = 0.006) and with a high ratio of PLAS:RBC and PLT:RBC (relatively more PLAS and PLT) vs. a low ratio (OR 0.60, 95% CI 0.46-0.77, p < 0.0001; OR 0.44, 95% CI 0.28-0.71, p = 0.0003). Mortality and blood product use were no different with either rVIIa vs. no rVIIa or with TXA vs. no TXA.
DCR can significantly improve outcomes in severely injured bleeding patients. After a review of the best available evidence, we recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of PLAS and PLT to RBC. This is best achieved by transfusing equal amounts of RBC, PLAS, and PLT during the early, empiric phase of resuscitation. We cannot recommend for or against the use of rVIIa based on the available evidence. Finally, we conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients.
Cybermedical systems that regulate patient clotting in real time with personalized blood product delivery will improve treatment outcomes. These systems will harness popular viscoelastic assays of ...clot strength such as thromboelastography (TEG), which help evaluate coagulation status in numerous conditions: major surgery (e.g., heart, vascular, hip fracture, and trauma); liver cirrhosis and transplants; COVID-19; ICU stays; sepsis; obstetrics; diabetes; and coagulopathies like hemophilia. But these measurements are time-consuming, and thus impractical for urgent care and automated coagulation control. Because protein concentrations in a blood sample can be measured in about five minutes, we develop personalized, phenomenological, quick, control-oriented models that predict TEG curve outputs from input blood protein concentrations, to facilitate treatment decisions based on TEG curves. Here, we accurately predict, experimentally validate, and mechanistically justify curves and parameters for common TEG assays (Functional Fibrinogen, Citrated Native, Platelet Mapping, and Rapid TEG), and verify results with trauma patient clotting data.
Acute coagulopathy of trauma has only been described relatively recently. Developing early in the postinjury phase, it is associated with increased transfusion requirements and poor outcomes. This ...review examines the possible initiators, mechanism and clinical importance of acute coagulopathy.
Acute coagulopathy of trauma occurs in patients with shock and is characterized by a systemic anticoagulation and hyperfibrinolysis. Dilution, acidemia and consumption of coagulation proteases do not appear to be significant factors at this stage. There is evidence to implicate activation of the protein C pathway in this process. Diagnosis of acute coagulopathy currently relies on laboratory assessment of clotting times. These tests do not fully characterize the coagulopathy and have significant limitations, which reduce their clinical utility.
Acute coagulopathy results in increased transfusion requirements, incidence of organ dysfunction, critical care stay and mortality. Recognition of an early coagulopathic state has implications for the care of shocked patients and the management of massive transfusion. Identification of novel mechanisms for traumatic coagulopathy may lead to new avenues for drug discovery and therapeutic intervention.
Abstract High-energy neutral solar radiation in the form of γ -rays and neutrons is produced as secondary products in solar flares. The characteristics of this emission can provide key information ...regarding the energization of charged particles, particularly when primary particles remain trapped in the corona. The Integrated Science Investigation of the Sun (IS⊙IS) suite on Parker Solar Probe is composed of instruments primarily intended to measure energetic charged particles. However, the High Energy Telescope (HET) in IS⊙IS was also designed with a supplementary neutral mode intended to measure γ -rays and neutrons. HET observed its first clear solar γ -ray event in connection with a hard X-ray flare, the eruption of a coronal mass ejection, and a solar energetic particle event on 2022 September 5. The X-ray spectral shape was observed to harden over the course of the event, culminating with the observation of γ -rays by HET. A coincident enhancement in the lower-energy Energetic Particle Instrument (EPI-Lo) was also observed, likely produced by incident solar γ -rays despite the EPI-Lo instrument not having any special neutral measurement capabilities. We use Monte Carlo modeling to reconstruct the incident γ -ray spectrum based on the measured spectrum to demonstrate that the combination of IS⊙IS instruments can measure hard X-rays and γ -rays from ∼60 keV–7 MeV. Despite the fact that this is a supplemental science goal of the mission, the capability of the IS⊙IS instruments to measure γ -rays is important for the study of this population due to the very limited instruments currently observing the Sun in γ -rays.
Peer contagion of adolescent males' aggressive/health risk behaviors was examined using a computerized "chat room" experimental paradigm. Forty-three 11th-grade White adolescents (16 - 17 years old) ...were led to believe that they were interacting with other students (i.e., "e-confederates"), who endorsed aggressive/health risk behaviors and whose ostensible peer status was experimentally manipulated. Adolescents displayed greater public conformity, more internalization of aggressive/health risk attitudes, and a higher frequency of actual exclusionary behavior when the e-confederates were high in peer status than low. Participants' level of social anxiety moderated peer contagion. Nonsocially anxious participants conformed only to high-status peers, whereas socially anxious participants were equally influenced by low- and high-status peers. The role of status-maintenance motivations in aggression and risk behavior, and implications for preventive intervention, are discussed.
PDF
