bims-heshmo 2021-06-20 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021‒06‒20
fourteen papers selected by
Andreia Luís
Ludwig Boltzmann Institute

Outcomes after ultramassive transfusion in the modern era: An Eastern Association for the Surgery of Trauma multicenter study.
Euglobulin clot lysis time reveals a high frequency of fibrinolytic activation in trauma.
Stress-related changes in the gut microbiome after trauma.
Early Prehospital Tranexamic Acid Following Injury is Associated with a 30-day Survival Benefit: A Secondary Analysis of a Randomized Clinical Trial.
Suppression of Endoplasmic Reticulum Stress by 4-PBA Protects Against Hyperoxia-Induced Acute Lung Injury via Up-Regulating Claudin-4 Expression.
Novel severe traumatic brain injury blood outcome biomarkers identified with proximity extension assay.
Effects of lycopene in intestinal ischemia reperfusion injury via intestinal immunoglobulin A.
Tranexamic acid use in severely injured patients, is it always appropriate?
Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.
Effect of injury location and severity on opioid use after trauma.
The GPIbα intracellular tail - role in transducing VWF- and Collagen/GPVI-mediated signaling.
Substitution of ROTEM FIBTEM A5 for A10 in trauma: an observational study building a case for more rapid analysis of coagulopathy.
Trauma and nontrauma damage-control laparotomy: The difference is delirium (data from the Eastern Association for the Surgery of Trauma SLEEP-TIME multicenter trial).
NRF2 signalling pathway: New insights and progress in the field of wound healing.

J Trauma Acute Care Surg. 2021 Jul 01. 91(1): 24-33

Outcomes after ultramassive transfusion in the modern era: An Eastern Association for the Surgery of Trauma multicenter study.

Zachary A Matthay, Zane J Hellmann, Rachael A Callcut, Ellicott C Matthay, Brenda Nunez-Garcia, William Duong, Jeffry Nahmias, Aimee K LaRiccia, M Chance Spalding, Satya S Dalavayi, Jessica K Reynolds, Heather Lesch, Yee M Wong, Amanda M Chipman, Rosemary A Kozar, Liz Penaloza, Kaushik Mukherjee, Khaled Taghlabi, Christopher A Guidry, Sirivan S Seng, Asanthi Ratnasekera, Amirreza Motameni, Pascal Udekwu, Kathleen Madden, Sarah A Moore, Jordan Kirsch, Jesse Goddard, James Haan, Kelly Lightwine, Julianne B Ontengco, Daniel C Cullinane, Sarabeth A Spitzer, John C Kubasiak, Joshua Gish, Joshua P Hazelton, Alexandria Z Byskosh, Joseph A Posluszny, Erin E Ross, John J Park, Brittany Robinson, Mary Kathryn Abel, Alexander T Fields, Jonathan H Esensten, Ashok Nambiar, Joanne Moore, Claire Hardman, Pranaya Terse, Xian Luo-Owen, Anquonette Stiles, Brenden Pearce, Kimberly Tann, Khaled Abdul Jawad, Gabriel Ruiz, Lucy Z Kornblith.

BACKGROUND: Despite the widespread institution of modern massive transfusion protocols with balanced blood product ratios, survival for patients with traumatic hemorrhage receiving ultramassive transfusion (UMT) (defined as ≥20 U of packed red blood cells [RBCs]) in 24 hours) remains low and resource consumption remains high. Therefore, we aimed to identify factors associated with mortality in trauma patients receiving UMT in the modern resuscitation era.METHODS: An Eastern Association for the Surgery of Trauma multicenter retrospective study of 461 trauma patients from 17 trauma centers who received ≥20 U of RBCs in 24 hours was performed (2014-2019). Multivariable logistic regression and Classification and Regression Tree analysis were used to identify clinical characteristics associated with mortality.
RESULTS: The 461 patients were young (median age, 35 years), male (82%), severely injured (median Injury Severity Score, 33), in shock (median shock index, 1.2; base excess, -9), and transfused a median of 29 U of RBCs, 22 U of fresh frozen plasma (FFP), and 24 U of platelets (PLT). Mortality was 46% at 24 hours and 65% at discharge. Transfusion of RBC/FFP ≥1.5:1 or RBC/PLT ≥1.5:1 was significantly associated with mortality, most pronounced for the 18% of patients who received both RBC/PLT and RBC/FFP ≥1.5:1 (odds ratios, 3.11 and 2.81 for mortality at 24 hours and discharge; both p < 0.01). Classification and Regression Tree identified that age older than 50 years, low initial Glasgow Coma Scale, thrombocytopenia, and resuscitative thoracotomy were associated with low likelihood of survival (14-26%), while absence of these factors was associated with the highest survival (71%).
CONCLUSION: Despite modern massive transfusion protocols, one half of trauma patients receiving UMT are transfused with either RBC/FFP or RBC/PLT in unbalanced ratios ≥1.5:1, with increased associated mortality. Maintaining focus on balanced ratios during UMT is critical, and consideration of advanced age, poor initial mental status, thrombocytopenia, and resuscitative thoracotomy can aid in prognostication.
LEVEL OF EVIDENCE: Prognostic, level III.

DOI: https://doi.org/10.1097/TA.0000000000003121
Thromb Res. 2021 May 31. pii: S0049-3848(21)00348-0. [Epub ahead of print]204 22-28

Euglobulin clot lysis time reveals a high frequency of fibrinolytic activation in trauma.

Anton Ilich, Vaibhav Kumar, Michael J Ferrara, Michael W Henderson, Denis F Noubouossie, Donald H Jenkins, Rosemary A Kozar, Myung S Park, Nigel S Key.

  Activation of the fibrinolytic system plays a central role in the host response to trauma. There is significant heterogeneity in the degree of fibrinolysis activation at baseline that is usually assessed by whole blood thromboelastography (TEG). Few studies have focused on plasma markers of fibrinolysis that could add novel insights into the frequency and mechanisms of fibrinolytic activation in trauma. Global fibrinolysis in plasma was assessed using a modified euglobulin clot lysis time (ECLT) assay in 171 major trauma patients and compared to commonly assessed analytes of fibrinolysis. The median ECLT in trauma patients was significantly shorter at 8.5 h (IQR, 1.3-19.5) compared to 19.9 h (9.8-22.6) in healthy controls (p < 0.0001). ECLT values ≤2.5th percentile of the reference range were present in 83 (48.5%) of trauma patients, suggesting increased fibrinolytic activation. Shortened ECLT values were associated with elevated plasmin-antiplasmin (PAP) complexes and free tissue plasminogen activator (tPA) levels in plasma. Sixteen (9.2%) individuals met the primary outcome for massive transfusion, here defined as the critical administration threshold (CAT) of 3 units of packed red cells in any 60-minute period within the first 24 h. In a univariate screen, plasma biomarkers associated with CAT included D-dimer (p < 0.001), PAP (p < 0.05), free tPA (p < 0.05) and ECLT (p < 0.05). We conclude that fibrinolytic activation, measured by ECLT, is present in a high proportion of trauma patients at presentation. The shortened ECLT is partially driven by high tPA levels and is associated with high levels of circulating PAP complexes. Further studies are needed to determine whether ECLT is an independent predictor of trauma outcomes.

Keywords:  D-dimer; Euglobulin clot lysis time; Fibrinolysis; Plasmin-antiplasmin complexes; Tissue plasminogen activator; Trauma

DOI:  https://doi.org/10.1016/j.thromres.2021.05.017
J Trauma Acute Care Surg. 2021 Jul 01. 91(1): 192-199

Stress-related changes in the gut microbiome after trauma.

Lauren S Kelly, Camille G Apple, Raad Gharaibeh, Erick E Pons, Chase W Thompson, Kolenkode B Kannan, Dijoia B Darden, Philip A Efron, Ryan M Thomas, Alicia M Mohr.

BACKGROUND: The gut microbiome protects the host from infection by promoting epithelial integrity and providing basal immunologic stimulation. Disruption of this delicate ecosystem is linked to morbidity and mortality among critically ill patients, but the impact of traumatic injury on the gut microbiome is poorly understood. This study sought to identify alterations in gut microbiota following trauma and persistent stress in rodents without confounding antibiotics.METHODS: Male Sprague-Dawley rats aged 9 weeks to 11 weeks were randomized to naive, lung contusion with hemorrhagic shock (LCHS), and LCHS plus either 7 (LCHS/CS 7/7) or 14 days (LCHS/CS 14) of restraint cylinder stress for 2 hours daily. Stool was collected on Days 0, 3, 7, and 14 for bacterial whole genome DNA isolation. Alpha diversity, or the number and relative abundance of unique bacterial species within each cohort, was assessed using Chao1 indices. Beta diversity, or the measure of differences in biodiversity across cohorts, was assessed by principle coordinate analysis. False discovery rate correction was applied to all statistical analyses and corrected for cohousing effects.
RESULTS: Rodent groups subject to restraint stress demonstrated a progressive increase in alpha diversity over time. These microbiota changes resolved after cessation of stress (LCHS/CS 7/7) but continued to increase among rats subjected to ongoing stress (LCHS/CS 14). The LCHS/CS 7/7 also demonstrated reductions in class Actinobacteria and increased abundance of the genus Bacteroides by Day 7, which resolved by Day 14. Increased abundance of Bacteroides was also noted in the LCHS/CS 14 cohort, suggesting the role of chronic stress in its destabilization.
CONCLUSION: This study points to persistent stress as a potential source of the destabilization of microbial diversity seen after trauma. This lack of microbiota stability could be associated with worse long-term outcomes in critically ill trauma patients. Further studies are warranted to elucidate mechanistic pathways and potential therapeutic modalities.

DOI: https://doi.org/10.1097/TA.0000000000003209
Ann Surg. 2021 Jun 16.

Early Prehospital Tranexamic Acid Following Injury is Associated with a 30-day Survival Benefit: A Secondary Analysis of a Randomized Clinical Trial.

Shimena R Li, Francis Guyette, Joshua Brown, Mazen Zenati, Katherine M Reitz, Brian Eastridge, Raminder Nirula, Gary A Vercruysse, Terence O'Keeffe, Bellal Joseph, Matthew D Neal, Brian S Zuckerbraun, Jason L Sperry.

OBJECTIVE: We sought to characterize the timing of administration of prehospital Tranexamic Acid (TXA) and associated outcome benefits.BACKGROUND: TXA has been shown to be safe in the prehospital setting post-injury.
METHODS: We performed a secondary analysis of a recent prehospital randomized TXA clinical trial in injured patients. Those who received prehospital TXA within 1hr (EARLY) from time of injury were compared to those who received prehospital TXA beyond 1hr (DELAYED). We included patients with a shock index of > 0.9. Primary outcome was 30-day mortality. Kaplan-Meier and Cox Hazard regression were utilized to characterize mortality relationships.
RESULTS: EARLY and DELAYED patients had similar demographics, injury characteristics and shock severity but DELAYED patients had greater prehospital resuscitation requirements and longer prehospital times. Stratified Kaplan-Meier analysis demonstrated significant separation for EARLY patients (N =238, log-rank chi-square test, 4.99; P = .03) with no separation for DELAYED patients (N=238, log-rank chi-square test, 0.04; P = .83). Stratified Cox Hazard regression verified, after controlling for confounders, that EARLY TXA was associated with a 65% lower independent hazard for 30-day mortality (HR 0.35, 95%CI 0.19-0.65, P = .001) with no independent survival benefit found in DELAYED patients (HR 1.00, 95%CI 0.63-1.59, P = .999). EARLY TXA patients had lower incidence of multiple organ failure and 6-hour and 24-hour transfusion requirements compared to placebo.
CONCLUSIONS: Administration of prehospital TXA within 1 hour from injury in patients at risk of hemorrhage is associated with 30-day survival benefit, lower incidence of multiple organ failure, and lower transfusion requirements.

DOI: https://doi.org/10.1097/SLA.0000000000005002
Front Immunol. 2021 ;12 674316

Suppression of Endoplasmic Reticulum Stress by 4-PBA Protects Against Hyperoxia-Induced Acute Lung Injury via Up-Regulating Claudin-4 Expression.

Hsin-Ping Pao, Wen-I Liao, Shih-En Tang, Shu-Yu Wu, Kun-Lun Huang, Shi-Jye Chu.

  Endoplasmic reticulum (ER) stress that disrupts ER function can occur in response to a wide variety of cellular stress factors leads to the accumulation of unfolded and misfolded proteins in the ER. Many studies have shown that ER stress amplified inflammatory reactions and was involved in various inflammatory diseases. However, little is known regarding the role of ER stress in hyperoxia-induced acute lung injury (HALI). This study investigated the influence of ER stress inhibitor, 4-phenyl butyric acid (4-PBA), in mice with HALI. Treatment with 4-PBA in the hyperoxia groups significantly prolonged the survival, decreased lung edema, and reduced the levels of inflammatory mediators, lactate dehydrogenase, and protein in bronchoalveolar lavage fluid, and increased claudin-4 protein expression in lung tissue. Moreover, 4-PBA reduced the ER stress-related protein expression, NF-κB activation, and apoptosis in the lung tissue. In in vitro study, 4-PBA also exerted a similar effect in hyperoxia-exposed mouse lung epithelial cells (MLE-12). However, when claudin-4 siRNA was administrated in mice and MLE-12 cells, the protective effect of 4-PBA was abrogated. These results suggested that 4-PBA protected against hyperoxia-induced ALI via enhancing claudin-4 expression.

Keywords:  4-phenyl butyric acid; acute lung injury; claudin-4; endoplasmic reticulum stress; hyperoxia; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2021.674316
Clin Chem Lab Med. 2021 Jun 18.

Novel severe traumatic brain injury blood outcome biomarkers identified with proximity extension assay.

Douglas D Fraser, Michelle Chen, Annie Ren, Michael R Miller, Claudio Martin, Mark Daley, Eleftherios P Diamandis, Ioannis Prassas.

  OBJECTIVES: Severe traumatic brain injury (sTBI) patients suffer high mortality. Accurate prognostic biomarkers have not been identified. In this exploratory study, we performed targeted proteomics on plasma obtained from sTBI patients to identify potential outcome biomarkers.METHODS: Blood sample was collected from patients admitted to the ICU suffering a sTBI, using standardized clinical and computerized tomography (CT) imaging criteria. Age- and sex-matched healthy control subjects and sTBI patients were enrolled. Targeted proteomics was performed on plasma with proximity extension assays (1,161 proteins).
RESULTS: Cohorts were well-balanced for age and sex. The majority of sTBI patients were injured in motor vehicle collisions and the most frequent head CT finding was subarachnoid hemorrhage. Mortality rate for sTBI patients was 40%. Feature selection identified the top performing 15 proteins for identifying sTBI patients from healthy control subjects with a classification accuracy of 100%. The sTBI proteome was dominated by markers of vascular pathology, immunity/inflammation, cell survival and macrophage/microglia activation. Receiver operating characteristic (ROC) curve analyses demonstrated areas-under-the-curves (AUC) for identifying sTBI that ranged from 0.870-1.000 (p≤0.005). When mortality was used as outcome, ROC curve analyses identified the top 3 proteins as vWF, WIF-1, and CSF-1. Combining vWF with either WIF-1 or CSF-1 resulted in excellent mortality prediction with AUC of 1.000 for both combinations (p=0.011).
CONCLUSIONS: Targeted proteomics with feature classification and selection distinguished sTBI patients from matched healthy control subjects. Two protein combinations were identified that accurately predicted sTBI patient mortality. Our exploratory findings require confirmation in larger sTBI patient populations.

Keywords:  biomarkers; intensive care unit; outcome; proteomics; traumatic brain injury

DOI:  https://doi.org/10.1515/cclm-2021-0103
J Surg Res. 2021 Jun 12. pii: S0022-4804(21)00296-1. [Epub ahead of print]267 63-70

Effects of lycopene in intestinal ischemia reperfusion injury via intestinal immunoglobulin A.

Özgür İkiz, Nurettin Kahramansoy, Hayri Erkol, Esra Koçoğlu, Tülin Fırat.

  BACKGROUND: Intestinal ischemia causes an inflammatory response that may become intense by reperfusion and result in bacterial translocation. Intestinal immunoglobulin A is known to be a barrier against bacterial translocation. Lycopene is a compound with antioxidant and anti-inflammatory properties. We hypothesized that lycopene has positive effects in ischemia-reperfusion of the intestine through the intestinal IgA.MATERIAL AND METHODS: Twenty-eight Wistar albino rats were separated into four groups: sham, control, lycopene-administered-before-ischemia (L-pre), and lycopene-administered-after-reperfusion groups. Histopathologic changes, intestinal immunoglobulin A levels, and bacterial translocation were evaluated after the ischemia-reperfusion period of 0.5-12 h.
RESULTS: Histopathologic changes, intestinal immunoglobulin A, and bacterial translocation levels in the L-pre group were similar to those in the sham group. Administration of the lycopene after reperfusion showed just a slight protective effect. However, the L-pre group had significantly fewer histopathologic changes when compared with changes in the control (P = 0.011). Intestinal immunoglobulin A level in the L-pre group was found to be higher than that in the control group (P = 0.014). Bacterial translocation levels in the blood and mesenteric lymph nodes, in the L-pre group, were lower than those in the control group (P = 0.0027 and P = 0.0097, respectively).
CONCLUSIONS: Lycopene limited intestinal damage, reduced loss of intestinal immunoglobulin A and decreased bacterial translocation when administered before the ischemia-reperfusion injury.

Keywords:  Bacterial translocation; Immunoglobulin A; Intestinal barrier; Intestinal ischemia reperfusion; Lycopene; Mesenteric ischemia

DOI:  https://doi.org/10.1016/j.jss.2021.04.039
Rev Esp Anestesiol Reanim (Engl Ed). 2021 May;pii: S2341-1929(21)00070-6. [Epub ahead of print]68(5): 301-303

Tranexamic acid use in severely injured patients, is it always appropriate?

P Duque, L Gonzalez-Zarco, R Martínez, S Gago, J A Varela.

  Recently, it has been suggested that tranexamic acid should be administered only in those patients with hyperfibrinolysis determined using viscoelastic assays, as severely injured patients may present with fibrinolytic shutdown. However the last European guidelines on management of major bleeding and coagulopathy following trauma endorse the use of tranexamic acid to the trauma patient who is bleeding or at risk of significant hemorrhage as soon as possible without waiting for viscoelastic results. We present a severely blunt trauma patient treated with on-scene administration of tranexamic acid that developed immediate pulmonary embolism.

Keywords:  Fibrinolysis shutdown; Fibrinólisis disminuida; Hiperfibrinólisis; Hyperfibrinolysis; Multiple trauma; Politraumatizado; Pulmonary embolism; Tranexamic acid; Tromboembolismo pulmonar; Ácido tranexámico

DOI:  https://doi.org/10.1016/j.redare.2020.06.016
N Engl J Med. 2021 06 17. 384(24): 2283-2294

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

Josef Dankiewicz, Tobias Cronberg, Gisela Lilja, Janus C Jakobsen, Helena Levin, Susann Ullén, Christian Rylander, Matt P Wise, Mauro Oddo, Alain Cariou, Jan Bělohlávek, Jan Hovdenes, Manoj Saxena, Hans Kirkegaard, Paul J Young, Paolo Pelosi, Christian Storm, Fabio S Taccone, Michael Joannidis, Clifton Callaway, Glenn M Eastwood, Matt P G Morgan, Per Nordberg, David Erlinge, Alistair D Nichol, Michelle S Chew, Jacob Hollenberg, Matthew Thomas, Jeremy Bewley, Katie Sweet, Anders M Grejs, Steffen Christensen, Matthias Haenggi, Anja Levis, Andreas Lundin, Joachim Düring, Simon Schmidbauer, Thomas R Keeble, Grigoris V Karamasis, Claudia Schrag, Edith Faessler, Ondrej Smid, Michal Otáhal, Marco Maggiorini, Pedro D Wendel Garcia, Paul Jaubert, Jade M Cole, Miroslav Solar, Ola Borgquist, Christoph Leithner, Samia Abed-Maillard, Leanlove Navarra, Martin Annborn, Johan Undén, Iole Brunetti, Akil Awad, Peter McGuigan, Roy Bjørkholt Olsen, Tiziano Cassina, Philippe Vignon, Halvor Langeland, Theis Lange, Hans Friberg, Niklas Nielsen, .

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty.METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device.
RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups.
CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

DOI: https://doi.org/10.1056/NEJMoa2100591
J Trauma Acute Care Surg. 2021 Jul 01. 91(1): 226-233

Effect of injury location and severity on opioid use after trauma.

Rachel C Baker, Craig S Brown, John R Montgomery, Charles A Mouch, Brooke C Kenney, Michael J Englesbe, Jennifer F Waljee, Mark R Hemmila.

OBJECTIVE: Recent data have suggested that persistent opioid use is prevalent following trauma. The effect of type of injury and total injury burden is not known. We sought to characterize the relationship between injury location and severity and risk of persistent opioid use.METHODS: We investigated postdischarge opioid utilization among patients who were admitted for trauma between January 2010 and June 2017 using the Optum Clinformatics Database. New persistent opioid use (NPOU) was defined as one of the following scenarios: (1) two separate opioid prescription fills between 0 and 14 days postdischarge and having 1+ fills in the 91 to 180 days following discharge or (2) filling a prescription in the 15 to 90 days following discharge in addition to a filling in the 91 to 180 day postdischarge period. Multivariable logistic regression was used to assess the relationship between injury type and severity with new persistent opioid use development.
RESULTS: A total of 26,437 opioid-naive patients were included in the analysis. Overall, 2,277 patients (8.6%) met the criteria for NPOU. After adjustment for confounding, NPOU was significantly more common for patients with injury to the extremities (adjusted odds ratio [aOR], 1.75; 95% confidence interval [CI], 1.57-1.94) or abdomen (adjusted odds ratio [aOR], 1.42; 95% CI, 1.22-1.64). Importantly, patients with maximum Abbreviated Injury Scale score of ≥2 for any body region had 1.49-fold odds of NPOU compared with patients with score of 1 (95% CI, 1.28-1.73), while no difference was seen across groupings of total injury burden based on Injury Severity Score.
CONCLUSION: New persistent opioid use is common among patients suffering from trauma. In addition, patients suffering from extremity and abdominal injuries are at highest risk. Maximum individual region injury severity predicts development of new persistent use, whereas total injury severity does not.
LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.

DOI: https://doi.org/10.1097/TA.0000000000003138
Haematologica. 2021 Jun 17.

The GPIbα intracellular tail - role in transducing VWF- and Collagen/GPVI-mediated signaling.

Adela Constantinescu-Bercu, Yuxiao A Wang, Kevin J Woollard, Pierre Mangin, Karen Vanhoorelbeke, James Tb Crawley, Isabelle I Salles-Crawley.

The GPIbT-VWF A1 domain interaction is essential for platelet tethering under high shear. Synergy between GPIbα and GPVI signaling machineries has been suggested previously, however its molecular mechanism remains unclear. We generated a novel GPIbα transgenic mouse (GpIbαΔsig/Δsig) by CRISPR-Cas9 technology to delete the last 24 residues of the GPIbα intracellular tail that harbors the 14-3-3 and phosphoinositide-3 kinase binding sites. GPIbαΔsig/Δsig platelets bound VWF normally under flow. However, they formed fewer filopodia on VWF/botrocetin in the presence of a oIIbI3 blocker, demonstrating that despite normal ligand binding, VWF-dependent signaling is diminished. Activation of GpIbαΔsig/Δsig platelets with ADP and thrombin was normal, but GpIbαΔsig/Δsig platelets stimulated with collagen-related-peptide (CRP) exhibited markedly decreased P-selectin exposure and eIIbI3 activation, suggesting a role for the GpIbaaintracellular tail in GPVI-mediated signaling. Consistent with this, while haemostasis was normal in GPIbαΔsig/Δsig mice, diminished tyrosine-phosphorylation, (particularly pSYK) was detected in CRP-stimulated GpIbαΔsig/Δsig platelets as well as reduced platelet spreading on CRP. Platelet responses to rhodocytin were also affected in GpIbαΔsig/Δsig platelets but to a lesser extent than those with CRP. GpIbαΔsig/Δsig platelets formed smaller aggregates than wild-type platelets on collagen-coated microchannels at low, medium and high shear. In response to both VWF and collagen binding, flow assays performed with plasma-free blood or in the presence of bIIbI3- or GPVI-blockers suggested reduced bIIbI3 activation contributes to the phenotype of the GpIbαΔsig/Δsig platelets. Together, these results reveal a new role for the intracellular tail of GPIbiiin transducing both VWF-GPIbGGand collagen-GPVI signaling events in platelets.

DOI: https://doi.org/10.3324/haematol.2020.278242
Eur J Trauma Emerg Surg. 2021 Jun 16.

Substitution of ROTEM FIBTEM A5 for A10 in trauma: an observational study building a case for more rapid analysis of coagulopathy.

Alexander Blayney, James McCullough, Elizabeth Wake, Kerin Walters, Don Campbell, Debbie Ho, Erick Chan, Aashish Chalasani, James Winearls.

  PURPOSE: Rotational thromboelastometry (ROTEM®) allows guided blood product resuscitation to correct trauma-induced coagulopathy in bleeding trauma patients. FIBTEM amplitude at 10 min (A10) has been widely used to identify hypofibrinogenaemia; locally a threshold of < 11 mm has guided fibrinogen replacement. Amplitude at 5 min (A5) carries an inherent time advantage. The primary aim was to explore the relationship between FIBTEM A5 and A10 in a trauma. Secondary aim was to investigate the use of A5 as a surrogate for A10 within a fibrinogen-replacement algorithm.METHODS: Retrospective observational cohort study of arrival ROTEM results from 1539 consecutive trauma patients at a Level 1 trauma centre in Australia. Consistency of agreement between FIBTEM A5 and A10 was assessed. A new fibrinogen replacement threshold was developed for A5 using the A5-A10 bias; this was clinically compared to the existing A10 threshold.
RESULTS: FIBTEM A5 displayed excellent consistency of agreement with A10. Intraclass correlation coefficient = 0.972 (95% confidence interval [CI] 0.969-0.974). Bias of A5 to A10 was - 1.49 (95% CI 1.43-1.56) mm. 19.34% patients met the original local threshold of A10 < 11 mm; 19.28% patients met the new, bias-adjusted threshold of A5 < 10 mm.
CONCLUSION: ROTEM FIBTEM A5 reliably predicts A10 in trauma. This further validates use of the A5 result over A10 allowing faster decision-making in time-critical resuscitation of trauma patients. A modification of -1 to the A10 threshold might be appropriate for use with the A5 value in trauma patients.

Keywords:  Coagulopathy; Fibrinogen; Haemorrhage; ROTEM; Resuscitation; Rotational thromboelastometry; Trauma

DOI:  https://doi.org/10.1007/s00068-021-01652-w
J Trauma Acute Care Surg. 2021 Jul 01. 91(1): 100-107

Trauma and nontrauma damage-control laparotomy: The difference is delirium (data from the Eastern Association for the Surgery of Trauma SLEEP-TIME multicenter trial).

Kaitlin McArthur, Cassandra Krause, Eugenia Kwon, Xian Luo-Owen, Meghan Cochran-Yu, Lourdes Swentek, Sigrid Burruss, David Turay, Chloe Krasnoff, Areg Grigorian, Jeffry Nahmias, Ahsan Butt, Adam Gutierrez, Aimee LaRiccia, Michelle Kincaid, Michele N Fiorentino, Nina Glass, Samantha Toscano, Eric Ley, Sarah R Lombardo, Oscar D Guillamondegui, James M Bardes, Connie DeLa'O, Salina M Wydo, Kyle Leneweaver, Nicholas T Duletzke, Jade Nunez, Simon Moradian, Joseph Posluszny, Leon Naar, Haytham Kaafarani, Heidi Kemmer, Mark J Lieser, Alexa Dorricott, Grace Chang, Zoltan Nemeth, Kaushik Mukherjee.

BACKGROUND: Damage-control laparotomy (DCL) has been used for traumatic and nontraumatic indications. We studied factors associated with delirium and outcome in this population.METHODS: We reviewed DCL patients at 15 centers for 2 years, including demographics, Charlson Comorbidity Index (CCI), diagnosis, operations, and outcomes. We compared 30-day mortality; renal failure requiring dialysis; number of takebacks; hospital, ventilator, and intensive care unit (ICU) days; and delirium-free and coma-free proportion of the first 30 ICU days (DF/CF-ICU-30) between trauma (T) and nontrauma (NT) patients. We performed linear regression for DF/CF-ICU-30, including age, sex, CCI, achievement of primary fascial closure (PFC), small and large bowel resection, bowel discontinuity, abdominal vascular procedures, and trauma as covariates. We performed one-way analysis of variance for DF/CF-ICU-30 against traumatic brain injury severity as measured by Abbreviated Injury Scale for the head.
RESULTS: Among 554 DCL patients (25.8% NT), NT patients were older (58.9 ± 15.8 vs. 39.7 ± 17.0 years, p < 0.001), more female (45.5% vs. 22.1%, p < 0.001), and had higher CCI (4.7 ± 3.3 vs. 1.1 ± 2.2, p < 0.001). The number of takebacks (1.7 ± 2.6 vs. 1.5 ± 1.2), time to first takeback (32.0 hours), duration of bowel discontinuity (47.0 hours), and time to PFC were similar (63.2 hours, achieved in 73.5%). Nontrauma and T patients had similar ventilator, ICU, and hospital days and mortality (31.0% NT, 29.8% T). Nontrauma patients had higher rates of renal failure requiring dialysis (36.6% vs. 14.1%, p < 0.001) and postoperative abdominal sepsis (40.1% vs. 17.1%, p < 0.001). Trauma and NT patients had similar number of hours of sedative (89.9 vs. 65.5 hours, p = 0.064) and opioid infusions (106.9 vs. 96.7 hours, p = 0.514), but T had lower DF/CF-ICU-30 (51.1% vs. 73.7%, p = 0.029), indicating more delirium. Linear regression analysis indicated that T was associated with a 32.1% decrease (95% CI, 14.6%-49.5%; p < 0.001) in DF/CF-ICU-30, while achieving PFC was associated with a 25.1% increase (95% CI, 10.2%-40.1%; p = 0.001) in DF/CFICU-30. Increasing Abbreviated Injury Scale for the head was associated with decreased DF/CF-ICU-30 by analysis of variance (p < 0.001).
CONCLUSION: Nontrauma patients had higher incidence of postoperative abdominal sepsis and need for dialysis, while T was independently associated with increased delirium, perhaps because of traumatic brain injury.
LEVEL OF EVIDENCE: Therapeutic study, level IV.

DOI: https://doi.org/10.1097/TA.0000000000003210
J Cell Mol Med. 2021 Jun 18.

NRF2 signalling pathway: New insights and progress in the field of wound healing.

Yang Liu, Xiaofan Yang, Yutian Liu, Tao Jiang, Sen Ren, Jing Chen, Hewei Xiong, Meng Yuan, Wenqing Li, Hans-Günther Machens, Zhenbing Chen.

  As one of the most common pathological processes in the clinic, wound healing has always been an important topic in medical research. Improving the wound healing environment, shortening the healing time and promoting fast and effective wound healing are hot and challenging issues in clinical practice. The nuclear factor-erythroid-related factor 2 (NFE2L2 or NRF2) signalling pathway reduces oxidative damage and participates in the regulation of anti-oxidative gene expression in the process of oxidative stress and thus improves the cell protection. Activation of the NRF2 signalling pathway increases the resistance of the cell to chemical carcinogens and inflammation. The signal transduction pathway regulates anti-inflammatory and antioxidant effects by regulating calcium ions, mitochondrial oxidative stress, autophagy, ferroptosis, pyroptosis and apoptosis. In this article, the role of the NRF2 signalling pathway in wound healing and its research progress in recent years are reviewed. In short, the NRF2 signalling pathway has crucial clinical significance in wound healing and is worthy of further study.

Keywords:  NRF2; ROS; oxidative stress; wound healing

DOI:  https://doi.org/10.1111/jcmm.16597