Dataset Information

Von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury.

ABSTRACT: von Willebrand factor (VWF) is an adhesive ligand, and its activity is proteolytically regulated by the metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat 13). An elevated level of plasma VWF has been widely considered a marker for endothelial cell activation in trauma and inflammation, but its causal role in these pathological conditions remains poorly defined. Using a fluid percussion injury mouse model, we demonstrated that VWF released during acute traumatic brain injury (TBI) was activated and became microvesicle-bound. The VWF-bound microvesicles promoted vascular leakage and systemic coagulation. Recombinant ADAMTS-13 given either before or after TBI reduced the VWF reactivity with minimal influence on VWF secretion. rADAMTS-13 protected the integrity of endothelial cell barriers and prevented TBI-induced coagulopathy by enhancing VWF cleavage without impairing basal hemostasis. Promoting microvesicle clearance by lactadherin had efficacy similar to that of rADAMTS-13. This study uncovers a novel synergistic action between VWF and cellular microvesicles in TBI-induced vascular leakage and coagulopathy and demonstrates protective effects of rADAMTS-13.

SUBMITTER: Wu Y

PROVIDER: S-EPMC6128082 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury.

Wu Yingang Y Liu Wei W Zhou Yuan Y Hilton Tristan T Zhao Zilong Z Liu Wei W Wang Min M Yeon Jason J Houck Katie K Thiagarajan Perumal P Zhang Fangyi F Shi Fu-Dong FD Wu Xiaoping X Li Min M Dong Jing-Fei JF Zhang Jianning J

Blood 20180625 10

von Willebrand factor (VWF) is an adhesive ligand, and its activity is proteolytically regulated by the metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat 13). An elevated level of plasma VWF has been widely considered a marker for endothelial cell activation in trauma and inflammation, but its causal role in these pathological conditions remains poorly defined. Using a fluid percussion injury mouse model, we demonstrated that VWF released during acute ...[more]

PMID: 29941674

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Project description:Traumatic microbleeds are small foci of hypointensity seen on T2*-weighted MRI in patients following head trauma that have previously been considered a marker of axonal injury. The linear appearance and location of some traumatic microbleeds suggests a vascular origin. The aims of this study were to: (i) identify and characterize traumatic microbleeds in patients with acute traumatic brain injury; (ii) determine whether appearance of traumatic microbleeds predict clinical outcome; and (iii) describe the pathology underlying traumatic microbleeds in an index patient. Patients presenting to the emergency department following acute head trauma who received a head CT were enrolled within 48 h of injury and received a research MRI. Disability was defined using Glasgow Outcome Scale-Extended ≤6 at follow-up. All magnetic resonance images were interpreted prospectively and were used for subsequent analysis of traumatic microbleeds. Lesions on T2* MRI were stratified based on 'linear' streak-like or 'punctate' petechial-appearing traumatic microbleeds. The brain of an enrolled subject imaged acutely was procured following death for evaluation of traumatic microbleeds using MRI targeted pathology methods. Of the 439 patients enrolled over 78 months, 31% (134/439) had evidence of punctate and/or linear traumatic microbleeds on MRI. Severity of injury, mechanism of injury, and CT findings were associated with traumatic microbleeds on MRI. The presence of traumatic microbleeds was an independent predictor of disability (P < 0.05; odds ratio = 2.5). No differences were found between patients with punctate versus linear appearing microbleeds. Post-mortem imaging and histology revealed traumatic microbleed co-localization with iron-laden macrophages, predominately seen in perivascular space. Evidence of axonal injury was not observed in co-localized histopathological sections. Traumatic microbleeds were prevalent in the population studied and predictive of worse outcome. The source of traumatic microbleed signal on MRI appeared to be iron-laden macrophages in the perivascular space tracking a network of injured vessels. While axonal injury in association with traumatic microbleeds cannot be excluded, recognizing traumatic microbleeds as a form of traumatic vascular injury may aid in identifying patients who could benefit from new therapies targeting the injured vasculature and secondary injury to parenchyma.

Project description:Background: Traumatic brain injury-induced coagulopathy (TBI-IC), is a disease with poor prognosis and increased mortality rate. Objectives: Our study aimed to identify predictors as well as develop machine learning (ML) models to predict the risk of coagulopathy in this population. Methods: ML models were developed and validated based on two public databases named Medical Information Mart for Intensive Care (MIMIC)-IV and the eICU Collaborative Research Database (eICU-CRD). Candidate predictors, including demographics, family history, comorbidities, vital signs, laboratory findings, injury type, therapy strategy and scoring system were included. Models were compared on area under the curve (AUC), accuracy, sensitivity, specificity, positive and negative predictive values, and decision curve analysis (DCA) curve. Results: Of 999 patients in MIMIC-IV included in the final cohort, a total of 493 (49.35%) patients developed coagulopathy following TBI. Recursive feature elimination (RFE) selected 15 variables, including international normalized ratio (INR), prothrombin time (PT), sepsis related organ failure assessment (SOFA), activated partial thromboplastin time (APTT), platelet (PLT), hematocrit (HCT), red blood cell (RBC), hemoglobin (HGB), blood urea nitrogen (BUN), red blood cell volume distribution width (RDW), creatinine (CRE), congestive heart failure, myocardial infarction, sodium, and blood transfusion. The external validation in eICU-CRD demonstrated that adapting boosting (Ada) model had the highest AUC of 0.924 (95% CI: 0.902-0.943). Furthermore, in the DCA curve, the Ada model and the extreme Gradient Boosting (XGB) model had relatively higher net benefits (ie, the correct classification of coagulopathy considering a trade-off between false- negatives and false-positives)-over other models across a range of threshold probability values. Conclusions: The ML models, as indicated by our study, can be used to predict the incidence of TBI-IC in the intensive care unit (ICU).

Dataset Information

Von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury.

Publications

von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury.

Similar Datasets

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