Plasminogen Degradation by Neutrophil Elastase in Pleural Infection, Not High Plasminogen Activator Inhibitor-1 (PAI-1), is the Cause of Intrapleural Lytic Failure.

BACKGROUND: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue-plasminogen activator(tPA) and deoxyribonuclease(DNase), 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 have 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 IRB approval from a randomized trial evaluating intrapleural fibrinolytics versus surgery for initial management of pleural space infections. Samples were collected pre-intervention, post-intervention day-1(PID1), PID2, and PID3. Activity assays, enzyme-linked immunosorbent assays, and western blot(WB) analysis were performed, and turbidometric measurements of fibrinolysis were performed on pleural fluid +/- exogenous plasminogen supplementation. Results are reported as median(Q1, Q3) or n(%) as appropriate, with alpha set at 0.05. RESULTS: Pleural fluid elastase activity was >4-fold higher(p=0.02) and plasminogen antigen levels >3-fold lower(p=0.04) than their corresponding plasma. Pleural fluid WB analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen-activator inhibitor-1(PAI-1), the native tPA inhibitor, had high antigen levels pre-intervention but the overwhelming majority of this PAI-1(82%) was not active(p=0.003), and all PAI-1 activity was lost by PID2 in patients receiving intrapleural tPA/DNase. Finally, using turbidity clot lysis assays we found that 9 of 10 patients' pleural fluid was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients. INTERPRETATION: Inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure.

Combination of aspirin and rosuvastatin for reduction of venous thromboembolism in severely injured patients: a double-blind, placebo-controlled, pragmatic randomized phase II clinical trial (The STAT Trial).

INTRODUCTION: Venous thromboembolism (VTE) remains a significant source of postinjury morbidity and mortality. Beta-hydroxy beta-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (rosuvastatin) significantly reduced pathologic clotting events in healthy populations in a prior trial. Furthermore, acetylsalicylic acid (ASA) has been shown to be noninferior to prophylactic heparinoids for VTE prevention following orthopedic surgery. We hypothesized that a combination of rosuvastatin/ASA, in addition to standard VTE chemoprophylaxis, would reduce VTE in critically ill trauma patients. METHODS: This was a double-blind, placebo-controlled, randomized trial, evaluating VTE rates in two groups: ASA + statin (Experimental) and identical placebos (Control). Injured adults, 18-65 years old, admitted to the surgical intensive care unit without contraindications for VTE prophylaxis were eligible. Upon initiation of routine VTE chemoprophylaxis (i.e. heparin/heparin-derivatives), they were randomized to the Experimental or Control group. VTE was the primary outcome. RESULTS: Of 112 potentially eligible patients, 33% (n = 37, median new injury severity scale = 27) were successfully randomized, of whom 11% had VTEs. The Experimental group had no VTEs, while the Control group had 6 VTEs (4 PEs and 2 DVTs) in 4 (22%) patients (P = 0.046). The Experimental treatment was not associated with any serious adverse events. Due to the COVID-19 pandemic, the study was interrupted at the second interim analysis at <10% of the planned enrollment, with significance declared at P < 0.012 at that stage. DISCUSSION: The combination of ASA and rosuvastatin with standard VTE prophylaxis showed a favorable trend toward reducing VTEs with no serious adverse events. An appropriately powered phase III multicenter trial is needed to further investigate this therapeutic approach. LEVEL OF EVIDENCE: Level II, Therapeutic.

Predicting metalwork following posterior fixation of thoracolumbar fractures.

OBJECTIVES: Surgical fusion through posterior instrumentation and pedicle screw placement is a long established method for stabilising traumatic spinal fractures. Post-surgical complications include infection and metal work failure, the most common aetiology of which is pedicle screw fracture. Metal work failure rates vary from 15% to 60%. Research relating to factors which predict metal work failure in post-traumatic thoracolumbar spinal fixation is lacking. This study aimed to identify potential risk factors for metalwork failure in patients who had posterior fixation for traumatic thoracolumbar spine fractures. METHODS: This retrospective cohort analysis was conducted by interrogating the hospital database for neurosurgical post-traumatic thoracolumbar fixation cases between 2015 and 2018 with at least 2 years follow up. Data was collected through electronic medical notes and PACS. Nineteen different patient factors (gender, age, mechanism of injury, presence of concomitant injury spinal or extra-spinal injury, pedicle cross-sectional area, pedicle cancellous bone density, pedicle total bone density, vertebral body bone density, erector spinae muscle density and lumbar spine subcutaneous fat thickness, Charlson comorbidity index, fracture location, surgical approach, long/short segment fixation, whether decompression was done, whether the index level was fixed, and presence of wound infection) were compared. RESULTS: We identified 92 patients with 97 operations, and 9 cases of metal work failure. Two factors were statistically significantly associated with metal work failure: Post-operative wound infection (p = 0.029) and lumbar spine fat thickness (p = 0.024). The relative risk calculated in patients with a wound infection was 3.76. Lumbar spine fat thickness was on average 11.9 mm greater than patients not experiencing metal work failure. CONCLUSIONS: This study has identified two factors associated with increased rates of metal work failure: Post-operative wound infection and lumbar spine fat thickness. When assessing surgical candidates these factors may be incorporated into surgical planning.

Multicenter experience with andexanet alfa for refractory pericardial bleeding during catheter ablation of atrial fibrillation.

INTRODUCTION: Pericardial bleeding is a rare but life-threatening complication of atrial fibrillation (AF) ablation. Patients taking uninterrupted oral anticoagulation (AC) may be at increased risk for refractory bleeding despite pericardiocentesis and administration of protamine. In such cases, andexanet alfa can be given to reverse rivaroxaban or apixaban. In this study, we aim to describe the rate of acute hemostasis and thromboembolic complications with andexanet for refractory pericardial bleeding during AF ablation. METHODS AND RESULTS: In this multicenter, case series, participating centers identified patients who received a dose of apixaban or rivaroxaban within 24 h of AF ablation, developed refractory pericardial bleeding during the procedure despite pericardiocentesis and administration of protamine and received andexanet. Eleven patients met inclusion criteria, with mean age of 73.5 ± 5.3 years and median CHA2 DS2 -VASc score 4 [3-5]. All patients received protamine and pericardiocentesis, and 9 (82%) received blood products. All patients received a bolus of andexanet followed, in all but one, by a 2-h infusion. Acute hemostasis was achieved in eight patients (73%) while three required emergent surgery. One patient (9%) experienced acute ST-elevation myocardial infarction after receiving andexanet. Therapeutic AC was restarted after a mean of 2.2 ± 1.9 days and oral AC was restarted after a mean of 2.9 ± 1.6 days, with no recurrent bleeding. CONCLUSION: In patients on uninterrupted apixaban or rivaroxaban, who develop refractory pericardial bleeding during AF ablation, andexanet can achieve hemostasis thereby avoiding the need for emergent surgery. However, there is a risk of thromboembolism following administration.

Association of Residual Ischemic Disease With Clinical Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Anatomical scoring systems have been used to assess completeness of revascularization but are challenging to apply to large real-world datasets. OBJECTIVES: The aim of this study was to assess the prevalence of complete revascularization and its association with longitudinal clinical outcomes in the U.S. Department of Veterans Affairs (VA) health care system using an automatically computed anatomic complexity score. METHODS: Patients undergoing percutaneous coronary intervention (PCI) between October 1, 2007, and September 30, 2020, were identified, and the burden of prerevascularization and postrevascularization ischemic disease was quantified using the VA SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score. The association between residual VA SYNTAX score and long-term major adverse cardiovascular events (MACE; death, myocardial infarction, repeat revascularization, and stroke) was assessed. RESULTS: A total of 57,476 veterans underwent PCI during the study period. After adjustment, the highest tertile of residual VA SYNTAX score was associated with increased hazard of MACE (HR: 2.06; 95% CI: 1.98-2.15) and death (HR: 1.50; 95% CI: 1.41-1.59) at 3 years compared to complete revascularization (residual VA SYNTAX score = 0). Hazard of 1- and 3-year MACE increased as a function of residual disease, regardless of baseline disease severity or initial presentation with acute or chronic coronary syndrome. CONCLUSIONS: Residual ischemic disease was strongly associated with long-term clinical outcomes in a contemporary national cohort of PCI patients. Automatically computed anatomic complexity scores can be used to assess the longitudinal risk for residual ischemic disease after PCI and may be implemented to improve interventional quality.

Advances in the Management of Coagulopathy in Trauma: The Role of Viscoelastic Hemostatic Assays across All Phases of Trauma Care.

Uncontrolled bleeding is the leading cause of preventable death following injury. Trauma-induced coagulopathy can manifest as diverse phenotypes ranging from hypocoagulability to hypercoagulability, which can change quickly during the acute phase of trauma care. The major advances in understanding coagulation over the past 25 years have resulted from the cell-based concept, emphasizing the key role of platelets and their interaction with the damaged endothelium. Consequently, conventional plasma-based coagulation testing is not accurate in predicting bleeding and does not provide an assessment of which blood products are indicated. Viscoelastic hemostatic assays (VHA), conducted in whole blood, have emerged as a superior method to guide goal-directed transfusion. The major change in resuscitation has been the shift from unbridled crystalloid loading to judicious balanced blood product administration. Furthermore, the recognition of the rapid changes from hypocoagulability to hypercoagulability has underscored the importance of ongoing surveillance beyond emergent surgery. While the benefits of VHA testing are maximized when used as early as possible, current technology limits use in the pre-hospital setting and the time to results compromises its utility in the emergency department. Thus, most of the reported experience with VHA in trauma is in the operating room and intensive care unit, where there is compelling data to support its value. This overview will address the current and potential role of VHA in the seriously injured patient, throughout the continuum of trauma management.

Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion.

Objective: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT. Methods: Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50mm (TEG-TIC), or clinical judgement (Clin-TIC) by the trauma surgeon. MT was defined as > 10 units of red blood cells in 24 hours or > 4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. Results: Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. Conclusion: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.

An Integrated Pharmacological, Structural, and Genetic Analysis of Extracellular Versus Intracellular ROS Production in Neutrophils.

The neutrophil NADPH oxidase produces both intracellular and extracellular reactive oxygen species (ROS). Although oxidase activity is essential for microbial killing, and ROS can act as signaling molecules in the inflammatory process, excessive extracellular ROS directly contributes to inflammatory tissue damage, as well as to cancer progression and immune dysregulation in the tumor microenvironment. How specific signaling pathways contribute to ROS localization is unclear. Here we used a systems pharmacology approach to identify the specific Class I PI3-K isoform p110ß, and PLD1, but not PLD2, as critical regulators of extracellular, but not intracellular ROS production in primary neutrophils. Combined crystallographic and molecular dynamics analysis of the PX domain of the oxidase component p47phox, which binds the lipid products of PI 3-K and PLD, was used to clarify the membrane-binding mechanism and guide the design of mutant mice whose p47phox is unable to bind 3-phosphorylated inositol phospholipids. Neutrophils from these K43A mutant animals were specifically deficient in extracellular, but not intracellular, ROS production, and showed increased dependency on signaling through the remaining PLD1 arm. These findings identify the PX domain of p47phox as a critical integrator of PLD1 and p110ß signaling for extracellular ROS production, and as a potential therapeutic target for modulating tissue damage and extracellular signaling during inflammation.

The morbidity of out-of-hours surgery for Cauda Equina Syndrome.

BACKGROUND: There is no literature specifically addressing the morbidity of out of hours surgery for Cauda Equina Syndrome (CES). Our paper rectifies this omission. This will assist the surgeon with real-time decision making with regards to timing of intervention in this rare but potentially disabling disease. METHODS: A retrospective case series analysis. Individual cases were identified using local electronic theatre management systems in the four neurosurgical centres in Scotland in 2017. "Out of hours" surgery was defined as starting outside the times 0900-1700 Monday to Friday. RESULTS: 86 patients underwent out of hours surgery for CES in Scotland in 2017. One patient sustained a nerve root injury without new deficit, giving an overall risk of 1.2%. Four patients had the intra-operative complication of CSF leak, giving an overall risk of 4.7%. Five patients underwent early revision surgery, equivalent to a re-operation risk of 5.8%. CONCLUSIONS: The morbidity of out of hours surgery for CES is comparable to that of elective microdiscectomy. Operating out of hours for CES does not appear to have an increased risk of complications. Since increased surgical risk is not borne out by our study, this should not be used as a justification to delay operative treatment.

Utility of Intracardiac Echocardiography for Guiding Ablation of Ventricular Tachycardia in Nonischemic Cardiomyopathy.

Intracardiac echocardiography (ICE) is a valuable tool in cardiac ablation procedures, especially in ablation of ventricular arrhythmias. The article details how ICE can aid in ablation of ventricular arrhythmias in nonischemic cardiomyopathy.

Forecasting influenza activity using machine-learned mobility map.

Human mobility is a primary driver of infectious disease spread. However, existing data is limited in availability, coverage, granularity, and timeliness. Data-driven forecasts of disease dynamics are crucial for decision-making by health officials and private citizens alike. In this work, we focus on a machine-learned anonymized mobility map (hereon referred to as AMM) aggregated over hundreds of millions of smartphones and evaluate its utility in forecasting epidemics. We factor AMM into a metapopulation model to retrospectively forecast influenza in the USA and Australia. We show that the AMM model performs on-par with those based on commuter surveys, which are sparsely available and expensive. We also compare it with gravity and radiation based models of mobility, and find that the radiation model's performance is quite similar to AMM and commuter flows. Additionally, we demonstrate our model's ability to predict disease spread even across state boundaries. Our work contributes towards developing timely infectious disease forecasting at a global scale using human mobility datasets expanding their applications in the area of infectious disease epidemiology.

Plasmin thrombelastography rapidly identifies trauma patients at risk for massive transfusion, mortality, and hyperfibrinolysis: A diagnostic tool to resolve an international debate on tranexamic acid?

BACKGROUND: Trauma patients with hyperfibrinolysis and depletion of fibrinolytic inhibitors (DFIs) measured by thrombelastography (TEG) gain clot strength with TXA, but TEG results take nearly an hour. We aimed to develop an assay, plasmin TEG (P-TEG), to more expeditiously stratify risk for massive transfusion (MT), mortality, and hyperfibrinolysis. METHODS: Trauma patients (N = 148) were assessed using TEG assays without exogenous additives (rapid/native), with exogenous plasmin (P-TEG) or tissue plasminogen activator (tPA TEG). The plasmin dose used does not effect healthy-control clot lysis 30 minutes after maximum amplitude (LY30) but causes shortened reaction time (R time) relative to native TEG (P-TEG R time < native TEG R time considered P-TEG negative). If P-TEG R time is greater than or equal to native TEG R time, the patient was considered P-TEG positive. Each assay's ability to predict MT, mortality, and (risk for) hyperfibrinolysis was determined. χ and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. Results were reported as median ± interquartile range or n (%). RESULTS: Plasmin TEG provided results faster than all other assays (4.7 ± 2.5-9.1 minutes), approximately 11-fold faster than rapid-TEG (rTEG) LY30 (54.2 ± 51.1-58.1 minutes; p < 0.001). Plasmin TEG-positive patients had greater than fourfold higher MT rate (30% vs. 7%; p = 0.0015) with an area under the receiver operating characteristic curve of 0.686 (p = 0.028), greater than fourfold higher 24-hour mortality (33.3% vs. 7.8%; p = 0.0177), greater than twofold higher 30-day mortality (35% vs. 16.4%; p = 0.0483), higher rates of DFI (55% vs. 18%; p < 0.001), and a trend toward elevated D-dimer (19.9 vs. 3.3 µg/mL; p = 0.14). Plasmin TEG was associated with hyperfibrinolysis on rTEG LY30 at the 7.6% threshold (p = 0.04) but not the 3% threshold (p = 0.40). Plasmin TEG performed best in relation to DFI, with a positive predictive value of 58% and negative predictive value of 81%. When combined with tPA TEG time to maximum amplitude, P-TEG outperformed rTEG LY30 for predicting MT (area under the receiver operating characteristic curve, 0.811 vs. 0.708). CONCLUSION: Within 5 minutes, P-TEG can stratify patients at highest risk for MT, mortality, and risk for hyperfibrinolysis. In composite with tPA TEG time to maximum amplitude, P-TEG outperforms rTEG LY30 for predicting MT and does so four times faster (12.7 vs. 54.1 minutes). The rapid results of P-TEG may be useful for those who practice selective TXA administration to maximize TXA's time-dependent efficacy. LEVEL OF EVIDENCE: Diagnostic test, level V.

Rescue therapy for severe COVID-19-associated acute respiratory distress syndrome with tissue plasminogen activator: A case series.

The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented stresses on modern medical systems, overwhelming the resource infrastructure in numerous countries while presenting a unique series of pathophysiologic clinical findings. Thrombotic coagulopathy is common in critically ill patients suffering from COVID-19, with associated high rates of respiratory failure requiring prolonged periods of mechanical ventilation. Here, we report a case series of five patients suffering from profound, medically refractory COVID-19-associated respiratory failure who were treated with fibrinolytic therapy using tissue plasminogen activator (tPA; alteplase). All five patients appeared to have an improved respiratory status following tPA administration: one patient had an initial marked improvement that partially regressed after several hours, one patient had transient improvements that were not sustained, and three patients had sustained clinical improvements following tPA administration. LEVEL OF EVIDENCE: Therapeutic, Level V.

Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation.

OBJECTIVES: The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience. BACKGROUND: Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis. METHODS: This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center. RESULTS: During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications. CONCLUSIONS: In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.

Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis.

BACKGROUND: COVID-19 threatens to quickly overwhelm our existing critical care infrastructure in the USA. Systemic tissue plasminogen activator (tPA) has been previously demonstrated to improve PaO2/FiO2 (mmHg) when given to critically ill patients with acute respiratory distress syndrome (ARDS). It is unclear to what extent tPA may impact population-based survival during the current US COVID-19 pandemic. METHODS: A decision analytic Markov state transition model was created to simulate the life critically ill COVID-19 patients as they transitioned to either recovery or death. Two patient groups were simulated (50,000 patients in each group); (1) Patients received tPA immediately upon diagnosis of ARDS and (2) patients received standard therapy for ARDS. Base case critically ill COVID-19 patients were defined as having a refractory PaO2/FiO2 of < 60 mmHg (salvage use criteria). Transition from severe to moderate to mild ARDS, recovery, and death were estimated. Markov model parameters were extracted from existing ARDS/COVID-19 literature. RESULTS: The use of tPA was associated with reduced mortality (47.6% [tTPA] vs. 71.0% [no tPA]) for base case patients. When extrapolated to the projected COVID-19 eligible for salvage use tPA in the USA, peak mortality (deaths/100,000 patients) was reduced for both optimal social distancing (70.5 [tPA] vs. 75.0 [no tPA]) and no social distancing (158.7 [tPA] vs. 168.8 [no tPA]) scenarios. CONCLUSIONS: Salvage use of tPA may improve recovery of ARDS patients, thereby reducing COVID-19-related mortality and ensuring sufficient resources to manage this pandemic.

Red Blood Cell Fragmentation Syndrome After Placement of MitraClip.

An 87-year-old woman with a history of trastuzumab-induced left ventricular dysfunction underwent the MitraClip (Abbott Vascular, Santa Clara, California) procedure for myxomatous mitral regurgitation. She presented a month later with severe intravascular hemolytic anemia, attributed to the MitraClip. She underwent surgical mitral valve replacement and had resolution of hemolysis. (Level of Difficulty: Advanced.).