Traumatic brain injury (TBI) is a leading cause of death and disability. Patients with isolated TBI lose a limited amount of blood to primary injury, but they often develop secondary coagulopathy, ...resulting in delayed or recurrent intracranial and intracerebral hematoma. TBI‐induced coagulopathy is closely associated with poor outcomes for these patients, including death. This secondary coagulopathy is consumptive in nature, involving not only brain‐derived molecules, coagulation factors, and platelets, but also endothelial cells in a complex process now called blood failture. A key question is how a localized injury to the brain is rapidly disseminated to affect systemic hemostasis that is not directly affected the way it is in trauma to the body and limbs, especially with hemorrhagic shock. Increasing evidence suggests that the adhesive ligand von Willebrand factor (VWF), which is synthesized in and released from endothelial cells, plays a paradoxical role in both facilitating local hemostasis at the site of injury and also propagating TBI‐induced endotheliopathy and coagulopathy systemically. This review discusses recent progress in understanding these diverse activities of VWF and the knowledge gaps in defining their roles in TBI and associated coagulopathy.
Traumatic brain injury (TBI) is recognized as a global health problem due to its increasing occurrence, challenging treatment, and persistent impacts on brain pathophysiology. Neural cell death in ...patients with TBI swiftly causes inflammation in the injured brain areas, which is recognized as focal brain inflammation. Focal brain inflammation causes secondary brain injury by exacerbating brain edema and neuronal death, while also exerting divergent beneficial effects, such as sealing the damaged limitans and removing cellular debris. Recent evidence from patients with TBI and studies on animal models suggest that brain inflammation after TBI is not only restricted to the focal lesion but also disseminates to remote areas of the brain. The dissemination of inflammation has been detected within days after the primary injury and persists chronically. This state of inflammation may be related to remote complications of TBI in patients, such as hyperthermia and hypopituitarism, and may lead to progressive neurodegeneration, such as chronic traumatic encephalopathy. Future studies should focus on understanding the mechanisms that govern the initiation and propagation of brain inflammation after TBI and its impacts on post-trauma brain pathology.
We study the holographic dark energy (HDE) model by using the future gravitational wave (GW) standard siren data observed from the Einstein Telescope (ET) in this work. We simulate 1000 GW standard ...siren data based on a 10-year observation of the ET to make this analysis. We find that all the cosmological parameters in the HDE model can be tremendously improved by including the GW standard siren data in the cosmological fit. The GW data combined with the current cosmic microwave background anisotropies, baryon acoustic oscillations, and type Ia supernovae data will measure the cosmological parameters
Ω
m
,
H
0
, and
c
in the HDE model to be at the accuracies of 1.28%, 0.59%, and 3.69%, respectively. A comparison with the cosmological constant model and the constant-
w
dark energy model shows that, compared to the standard model, the parameter degeneracies will be broken more thoroughly in a dynamical dark energy model. We find that the GW data alone can provide a fairly good measurement for
H
0
, but for other cosmological parameters the GW data alone can only provide rather weak measurements. However, due to the fact that the parameter degeneracies can be broken by the GW data, the standard sirens can play an essential role in improving the parameter estimation.
Traumatic brain injury (TBI)–induced coagulopathy is a common and well-recognized risk for poor clinical outcomes, but its pathogenesis remains poorly understood, and treatment options are limited ...and ineffective. We discuss the recent progress and knowledge gaps in understanding this lethal complication of TBI. We focus on (1) the disruption of the brain-blood barrier to disseminate brain injury systemically by releasing brain-derived molecules into the circulation and (2) TBI-induced hypercoagulable and hyperfibrinolytic states that result in persistent and delayed intracranial hemorrhage and systemic bleeding.
Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to ...measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post‐ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus‐pituitary‐adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.—Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang,Z.,Yu,C.,Zhang,F.,Song,L.,Dong,J.‐F.,LaCava,A.,Sheth,K.N.,Shi,F.‐D.Organ‐andcell‐specificimmune responses are associated with the outcomes of intracerebral hemorrhage. FASEB J. 32,220‐229 (2018). www.fasebj.org
Abstract
Traumatic brain injury (TBI) is a leading cause of injury-related disability and death around the world, but the clinical stratification, diagnosis, and treatment of complex TBI are limited. ...Due to their unique properties, extracellular vesicles (EVs) are emerging candidates for being biomarkers of traumatic brain injury as well as serving as potential therapeutic targets. However, the effects of different extracellular vesicle subtypes on the pathophysiology of traumatic brain injury are very different, or potentially even opposite. Before extracellular vesicles can be used as targets for TBI therapy, it is necessary to classify different extracellular vesicle subtypes according to their functions to clarify different strategies for EV-based TBI therapy. The purpose of this review is to discuss contradictory effects of different EV subtypes on TBI, and to propose treatment ideas based on different EV subtypes to maximize their benefits for the recovery of TBI patients.
Coagulopathy after traumatic brain injury (TBI) is common and has been closely associated with poor clinical outcomes for the affected patients. Traumatic brain injury-induced coagulopathy (TBI-IC) ...is consumptive in nature and evolves rapidly from an injury-induced hypercoagulable state. Traumatic brain injury-induced coagulopathy defined by laboratory tests is significantly more frequent than clinical coagulopathy, which often manifests as secondary, recurrent, or delayed intracranial or intracerebral hemorrhage. This disparity between laboratory and clinical coagulopathies has hindered progress in understanding the pathogenesis of TBI-IC and developing more accurate and predictive tests for this severe TBI complication. In this review, we discuss laboratory tests used in clinical and research studies to define TBI-IC, with specific emphasis on what the tests detect and what they do not. We also offer perspective on developing more accurate and predictive tests for this severe TBI complication.
Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on ...immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation.
We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke.
Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis.
Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.
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