Search

Abstract Background The coronavirus disease 2019 (COVID‐19) pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non–COVID‐19) demonstrated improvement in pulmonary function in patients ARDS using fibrinolytic therapy. A follow‐up trial using the widely available tissue‐type plasminogen activator (t‐PA) alteplase is now needed to assess optimal dosing and safety in this critically ill patient population. Objective To describe the design and rationale of a phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID‐19–induced ARDS. Patients/Methods A rapidly adaptive, pragmatic, open‐label, randomized, controlled, phase IIa clinical trial will be conducted with 3 groups: intravenous alteplase 50 mg, intravenous alteplase 100 mg, and control (standard‐of‐care). Inclusion criteria are known/suspected COVID‐19 infection with PaO2/FiO2 ratio 4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50 mg or 100 mg followed by heparin infusion for systemic anticoagulation, with alteplase redosing if there is a >20% PaO2/FiO2 improvement not sustained by 24 hours. Results The primary outcome is improvement in PaO2/FiO2 at 48 hours after randomization. Other outcomes include ventilator‐ and intensive care unit–free days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifty eligible patients will be enrolled in a rapidly adaptive, modified stepped‐wedge design with 4 looks at the data. Conclusion Findings will provide timely information on the safety, efficacy, and optimal dosing of t‐PA to treat moderate/severe COVID‐19–induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).

Abstract The coronavirus disease 2019 (COVID‐19) pandemic has caused respiratory failure and associated mortality in numbers that have overwhelmed global health systems. Thrombotic coagulopathy is present in nearly three quarters of patients with COVID‐19 admitted to the intensive care unit, and both the clinical picture and pathologic findings are consistent with microvascular occlusive phenomena being a major contributor to their unique form of respiratory failure. Numerous studies are ongoing focusing on anticytokine therapies, antibiotics, and antiviral agents, but none to date have focused on treating the underlying thrombotic coagulopathy in an effort to improve respiratory failure in COVID‐19. There are animal data and a previous human trial demonstrating a survival advantage with fibrinolytic therapy to treat acute respiratory distress syndrome. Here, we review the extant and emerging literature on the relationship between thrombotic coagulopathy and pulmonary failure in the context of COVID‐19 and present the scientific rationale for consideration of targeting the coagulation and fibrinolytic systems to improve pulmonary function in these patients.

Abstract Background Few therapies exist to treat severe COVID‐19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID‐19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID‐19 respiratory failure. Methods A multicenter, retrospective, observational study of patients with confirmed COVID‐19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy‐nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO2/FiO2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. Results tPA was associated with significant PaO2/FiO2 improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p

Abstract: Red blood cells (RBCs) are the most abundant host cell in the human body and play a critical role in oxygen transport and systemic metabolic homeostasis. Hypoxic metabolic reprogramming of RBCs in response to high-altitude hypoxia or anaerobic storage in the blood bank has been extensively described. However, little is known about the RBC metabolism following hemorrhagic shock (HS), the most common preventable cause of death in trauma, the global leading cause of total life-years lost. Metabolomics analyses were performed through ultra-high pressure liquid chromatography–mass spectrometry on RBCs from Sprague-Dawley rats undergoing HS (mean arterial pressure [MAP], 80 mm Hg). Steady-state measurements were accompanied by metabolic flux analysis upon tracing of in vivo–injected 13C15N-glutamine or inhibition of glutaminolysis using the anticancer drug CB-839. RBC metabolic phenotypes recapitulated the systemic metabolic reprogramming observed in plasma from the same rodent model. Results indicate that shock RBCs rely on glutamine to fuel glutathione (GSH) synthesis and pyruvate transamination, whereas abrogation of glutaminolysis conferred early mortality and exacerbated lactic acidosis and systemic accumulation of succinate, a predictor of mortality in the military and civilian critically ill populations. Glutamine is here identified as an essential amine group donor in HS RBCs, plasma, liver, and lungs, providing additional rationale for the central role glutaminolysis plays in metabolic reprogramming and survival following severe hemorrhage.

Although LDL is rendered proatherogenic by various experimental treatments (e.g., acetylation), the exact structural changes that drive LDL transformation in vivo remain enigmatic. Among the many hypothesized targets of oxidative modification are cholesterol esters (CE). This family of neutral lipids, which carries a highly unsaturated pool of fatty acyl groups, is the main component of both LDL particles and atherosclerotic plaques. Tandem mass spectrometry (MS/MS) was employed to reveal abundant and diverse oxidized CEs (oxCE), including novel oxidation products, within human peripheral vascular lesions. These oxCE species composed up to 40% of the total CE pool, with cholesteryl linoleate being oxidized to the greatest extent. Imaging mass spectrometry studies showed that oxCE was entirely confined within the plaque, along with unmodified CE and triacylglyceride (TAG). Interestingly, we found no evidence for TAG oxidation, although polyunsaturated species were abundant. Enzymatic oxidation of cholesteryl linoleate by 15-lipoxygenase (15-LO), an enzyme often invoked in CE oxidation, initially results in a regio- and stereospecific product. Analysis of intact cholesteryl hydroxyoctadecadienoate isomers in human atheromata revealed no regio- or stereospecificity, indicating 15-LO was either not a major source of oxCE or nonenzymatic processes had eroded any product specificity.

Background: Surgical stabilization of rib fractures (SSRF) is increasingly performed, however the outcome of patients undergoing SSRF while on pre-injury antithrombotic therapy remains unknown. We compared surgical variables and outcomes of patients who were and were not on antithrombotic therapy. We hypothesize pre-injury anticoagulation is associated with delay in SSRF and worse outcomes., Methods: For this retrospective cohort study, we queried the Chest Injury International Database, for patients undergoing SSRF between 08/2018 and 03/2022. Antithrombotic therapy was categorized into antiplatelet and anticoagulant use. Primary outcome was time from admission to SSRF. Secondary outcomes included SSRF duration and complications. Numerical data were presented as median (IQR), categorical data as number (%). Inverse probability weighting was used to control for confounding., Results: Two hundred and eighteen SSRF patients were included, 25 (11 %) were on antithrombotic therapy. These patients were older (72 years, (65-80) versus 57 years, (43-66); p < 0.001) with lower ISS (14, (10-20) versus 21, (14-30); p = 0.002). Time from admission to SSRF was comparable (2 days, (1-4) versus 2 days, (1-4); p = 0.37) as was operative time (154 mins, (120.0-212.0) versus 177 mins, (143.0-210.0); p = 0.34). Patients using antithrombotics had fewer ICU-free days (24 (22-26) versus 28 (23-28); p = 0.003) but more ventilator free days (28, (28-28) versus 27 (27-28); p < 0.008). After adjusting for confounding, pre-injury anticoagulation was not significantly associated with delayed SSRF (Relative Risk, RR=1.37, 95 % CI 0.30-6.24), operative time (RR=1.07, 95 % CI0.88-1.31), IFD <=28 (RR=2.05, 95 %CI:0.33-12.67), VFD<=27 (RR=0.71, 95 %CI:0.15-3.48) or complications (RR=0.55, 95 % CI0.06-5.01)., Conclusion: Pre-injury antithrombotic drug use neither delayed SSRF nor impacted operative time in patients requiring SSRF and was not associated with increased risk of complications. Our data suggest SSRF can be safely performed without delay in patients who use anticoagulation pre-injury., Level of Evidence: IV., Study Type: Therapeutic/care management., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation., Research Question: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure?, Study Design and Methods: We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of .05., Results: Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients., Interpretation: Our findings suggest that inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure., Trial Registry: ClinicalTrials.gov; No.: NCT03583931; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: C. D. B., H. B. M., E. E. M., and M. B. Y. have patents issued or pending related to coagulation or fibrinolysis diagnostics and previously received grant support from Genentech, Inc. C. D. B. has received grant support from Werfen and consulting fees from Atheneum Partners. H. B. M. and E. E. M. have received grant support from Haemonetics, Hemosonics, Stago Diagnostica, and Instrumentation Laboratories/Werfen. M. B. Y. owns stock options as a cofounder of Merrimack Pharmaceuticals. None declared (P. K. M., J. G. C., H. S., E. R. M., A. S., A. A. P.-C., K. B., J. W., C. D.-C., D. H., I. D., F. M. P.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI. In this study, we sought to delineate the dynamics of glycosaminoglycan alterations after TBI and discover the precise biologic processes responsible for observed glycosaminoglycan changes after injury. We performed state-of-the art mass spectrometry on brain tissues isolated from mice after TBI or craniotomy-alone. We observed dynamic changes in glycosaminoglycans at Day 1 and 7 post-TBI, with heparan sulfate, chondroitin sulfate, and hyaluronan remaining significantly increased after a week vis-à-vis craniotomy-alone tissues. We did not observe appreciable changes in circulating glycosaminoglycans in mice after experimental TBI compared to craniotomy-alone nor in patients with TBI and severe polytrauma compared to control patients with mild injuries, suggesting increases in injury site glycosaminoglycans are driven by local synthesis. We subsequently performed an unbiased whole genome transcriptomics analysis on mouse brain tissues 7 days post-TBI and discovered a significant induction of hyaluronan synthase 2, glypican-3, and decorin. The functional role of decorin after injury was further examined through multimodal behavioral testing comparing wild-type and Dcn -/- mice. We discovered that genetic ablation of Dcn led to an overall negative effect of TBI on function, exacerbating motor impairments after TBI. Collectively, our results provide a spatiotemporal characterization of post-TBI glycosaminoglycan alterations in the brain ECM and support an important adaptive role for decorin upregulation after TBI., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The pathophysiology after polytrauma represents a complex network of interactions. While it was thought for a long time that the direct and indirect effects of hypoperfusion are most relevant due to the endothelial permeability changes, it was discovered that the innate immune response to trauma is equally important in modifying the organ response. Recent multi center studies provided a "genetic storm" theory, according to which certain neutrophil changes are activated at the time of injury. However, a second hit phenomenon can be induced by activation of certain molecules by direct organ injury, or pathogens (damage associated molecular patterns, DAMPS - pathogen associated molecular patterns, PAMPS). The interactions between the four pathogenetic cycles (of shock, coagulopathy, temperature loss and soft tissue injuries) and cross-talk between coagulation and inflammation have also been identified as important modifiers of the clinical status. In a similar fashion, overzealous surgeries and their associated soft tissue injury and blood loss can induce secondary worsening of the patient condition. Therefore, staged surgeries in certain indications represent an important alternative, to allow for performing a "safe definitive surgery" strategy for major fractures. The current review summarizes all these situations in a detailed fashion., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Aortic occlusion (AO) to facilitate the acute resuscitation of trauma and acute care surgery patients in shock remains a controversial topic. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is an increasingly deployed method of AO. We hypothesized that in patients with non-compressible hemorrhage below the aortic bifurcation, the use of REBOA instead of open AO may be associated with a survival benefit., Methods: From the AAST Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA) registry, we identified 1494 patients requiring AO from 45 Level I and 4 Level II trauma centers. Presentation, intervention, and outcome variables were analyzed to compare REBOA vs open AO in patients with non-compressible hemorrhage below the aortic bifurcation., Results: From December 2014 to January 2019, 217 patients with Zone 3 REBOA or Open AO who required pelvic packing, pelvic fixation or pelvic angio-embolization were identified. Of these, 109 AO patients had injuries isolated to below the aortic bifurcation (REBOA, 84; open AO, 25). Patients with intra-abdominal or thoracic sources of bleeding, above deployment Zone 3 were excluded. Overall mortality was lower in the REBOA group (35.% vs 80%, p <.001). Excluding patients who arrived with CPR in progress, the REBOA group had lower mortality (33.33% vs. 68.75%, p = 0.012). Of the survivors, systemic complications were not significantly different between groups. In the REBOA group, 16 patients had complications secondary to vascular access. Intensive care lengths of stay and ventilator days were both significantly shorter in REBOA patients who survived to discharge., Conclusions: This study compared outcomes for patients with hemorrhage below the aortic bifurcation treated with REBOA to those treated with open AO. Survival was significantly higher in REBOA patients compared to open AO patients, while complications in survivors were not different. Given the higher survival in REBOA patients, we conclude that REBOA should be used for patients with hemorrhagic shock secondary to pelvic trauma instead of open AO., Level Iii Evidence: Therapeutic., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to report. No financial support was received for the conduct of this study., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Skeletal muscle myosin (SkM) molecules are procoagulant both in vitro and in vivo. The association of plasma SkM isoforms with blood coagulability and hemostatic capacity has not been defined., Objectives: We hypothesized that coagulopathy in acutely injured patients is associated with procoagulant plasma SkM heavy chain levels., Methods: To test this hypothesis, citrated whole blood and plasma from 104 trauma patients were collected and studied to obtain data for rapid thrombelastography, international normalized ratios, and plasma SkM levels. Coagulability parameters were dichotomized by the threshold for the hypercoagulable trauma-induced coagulopathy., Results: Lower plasma full-length SkM heavy chain (full-SkM) levels were associated with higher international normalized ratio values (>1.3) (p = .03). The full-SkM levels were also associated with a lower rate of clot propagation (thrombelastography angle <65°) (p = .004), and plasma full-SkM levels were positively correlated with the thrombelastography angle (r 2  = .32, p = .0007). The trauma patient group with the lower plasma full-SkM levels showed an association with lower clot strength (maximum amplitude <55 mm) (p = .002), and plasma full-SkM levels positively correlated with maximum amplitude (r 2  = .27, p = .005). Hyperfibrinolysis was associated with significantly decreased full-SkM levels (p = .03). Trauma patients who required red blood cells and fresh frozen plasma transfusions had lower plasma full-SkM levels compared with those without transfusions (p = .04 and .02, respectively)., Conclusions: In acutely injured trauma patients, lower levels of plasma full-SkM levels are linked to hypocoagulability in trauma-induced coagulopathy, implying that SkM plays a role in the hemostatic capacity in trauma patients and may contribute to trauma-induced coagulopathy., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Few therapies exist to treat severe COVID-19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID-19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID-19 respiratory failure., Methods: A multicenter, retrospective, observational study of patients with confirmed COVID-19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy-nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO 2 /FiO 2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis., Results: tPA was associated with significant PaO 2 /FiO 2 improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p  < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p  = 0.00). D-dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO 2 /FiO 2 ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration., Conclusions: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID-19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients., Research Question: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe?, Study Design and Methods: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao 2 to Fio 2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao 2 to Fio 2 ratio improvement of > 50% or Pao 2 to Fio 2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality., Results: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao 2 to Fio 2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao 2 to Fio 2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit., Interpretation: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality., Trial Registry: ClinicalTrials.gov; No.: NCT04357730; URL: www., Clinicaltrials: gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non-COVID-19) demonstrated improvement in pulmonary function in patients ARDS using fibrinolytic therapy. A follow-up trial using the widely available tissue-type plasminogen activator (t-PA) alteplase is now needed to assess optimal dosing and safety in this critically ill patient population., Objective: To describe the design and rationale of a phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID-19-induced ARDS., Patients/methods: A rapidly adaptive, pragmatic, open-label, randomized, controlled, phase IIa clinical trial will be conducted with 3 groups: intravenous alteplase 50 mg, intravenous alteplase 100 mg, and control (standard-of-care). Inclusion criteria are known/suspected COVID-19 infection with PaO 2 /FiO 2 ratio <150 mm Hg for > 4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50 mg or 100 mg followed by heparin infusion for systemic anticoagulation, with alteplase redosing if there is a >20% PaO 2 /FiO 2 improvement not sustained by 24 hours., Results: The primary outcome is improvement in PaO 2 /FiO 2 at 48 hours after randomization. Other outcomes include ventilator- and intensive care unit-free days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifty eligible patients will be enrolled in a rapidly adaptive, modified stepped-wedge design with 4 looks at the data., Conclusion: Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634)., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)