Background Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. Methods In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d -dimer level. Results The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d -dimer cohort, 92.9% in the low d -dimer cohort, and 97.3% in the unknown d -dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. Conclusions In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589 , NCT04505774 , NCT04359277 , and NCT02735707 .)

Injury is the fourth leading cause of mortality worldwide, accounting for 9% of deaths globally (4.9 million people) in 2016 (ref. 1 ). Moreover, the burden is highest in individuals <50 years of age, among whom injury as a cause of death is second only to infectious diseases. Early preventable deaths after injury in civilian 2 and military 3 settings are primarily attributable to uncontrolled haemorrhage 2-8 , whereas later preventable deaths are typically due to hypercoagulability 9 . Consequently, there is intense interest worldwide in the pathogenesis of trauma-induced coagulopathy (TIC) to attenuate its adverse effects on the outcomes of seriously injured patients.Impaired coagulation following sudden death from injury has been observed for centuries 10 and, in the 1960s, the first clinical laboratory documentation of the temporal changes in coagulation following severe injury were documented 11 . However, early endogenous drivers of coagulopathy were not specifically investigated until 1982, when a case series of patients with major abdominal vascular injuries highlighted TIC as a common direct cause of early post-injury mortality: 89% of the deaths were bleeding-related, yet half occurred after mechanical control of bleeding sites -in other words, they were due to coagulopathy 12 . The remaining ongoing quagmire is the inability to distinguish between patients with exsanguinating injuries whose TIC is the result of metabolic failure (that is, who are bleeding because they are dying) from patients whose TIC is the cause of the ongoing blood loss (that is, who are dying because they are bleeding) 13 . Furthermore, not all patients with abnormalities in laboratory coagulation tests are bleeding 14 .Despite the long-term fascination with changes in coagulation resulting from shock and tissue injury 15 , there is no standard definition of TIC, which refers to abnormal coagulation capacity attributable to trauma. The term TIC was established during the Trans-Agency Consortium for Trauma Induced Coagulopathy Workshop conducted by the National Institutes of Health in April 2010 to describe the variety of phenomena that characterize this condition. TIC can manifest as a spectrum of phenotypes from hypocoagulation to hypercoagulation (fig. 1), as a function of several interactive factors, including (but not limited to) tissue injury, presence of shock and, in particular, time from injury (fig. 2).

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.

Trauma remains a leading cause of death worldwide, and most early preventable deaths in both the civilian and military settings are due to uncontrolled hemorrhage, despite paradigm advances in modern trauma care. Combined tissue injury and shock result in hemostatic failure, which has been identified as a multidimensional molecular, physiologic and clinical disorder termed trauma-induced coagulopathy (TIC).Understanding the biology of TIC is of utmost importance, as it is often responsible for uncontrolled bleeding, organ failure, thromboembolic complications, and death.Investigations have shown that TIC is characterized by multiple phenotypes of impaired hemostasis due to altered biology in clot formation and breakdown. These coagulopathies are attributable to tissue injury and shock, and encompass underlying endothelial, immune and inflammatory perturbations. Despite the recognition and identification of multiple mechanisms and mediators of TIC, and the development of targeted treatments, the mortality rates and associated morbidities due to hemorrhage after injury remain high. The purpose of this review is to examine the past and present understanding of the multiple distinct but highly integrated pathways implicated in TIC, in order to highlight the current knowledge gaps and future needs in this evolving field, with the aim of reducing morbidity and mortality after injury. K E Y W O R D Sblood coagulation disorders, exsanguination, hemorrhagic shock, hemostasis, trauma | 853 KORNBLITH eT aL.

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Given the evidence for a hyperactive platelet phenotype in COVID-19, we investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). Integration of EC and platelet RNA sequencing revealed that plateletreleased factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. We identified S100A8 and S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2. Consistent with increased gene expression, the heterodimer protein product of S100A8/A9, myeloidrelated protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls. We demonstrate that platelet-derived MRP8/14 activates ECs, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to poor clinical outcomes in COVID-19 patients. Last, we present evidence that targeting platelet P2Y 12 represents a promising candidate to reduce proinflammatory platelet-endothelial interactions. Together, these findings demonstrate a previously unappreciated role for platelets and their activationinduced endotheliopathy in COVID-19.

BACKGROUND:Outcomes following pancreatic trauma have not improved significantly over the past two decades. A 2013 Western Trauma Association algorithm highlighted emerging data that might improve the diagnosis and management of high-grade pancreatic injuries (HGPIs; grades III-V). We hypothesized that the use of magnetic resonance cholangiopancreatography, pancreatic duct stenting, operative drainage versus resection, and nonoperative management of HGPIs increased over time. METHODS:Multicenter retrospective review of diagnosis, management, and outcomes of adult pancreatic injuries from 2010 to 2018 was performed. Data were analyzed by grade and time period (PRE, 2010(PRE, -2013 POST, 2014 POST, -2018 using various statistical tests where appropriate. RESULTS:Thirty-two centers reported data on 515 HGPI patients. A total of 270 (53%) had penetrating trauma, and 58% went directly to the operating room without imaging. Eighty-nine (17%) died within 24 hours. Management and outcomes of 426 24-hour survivors were evaluated. Agreement between computed tomography and operating room grading was 38%. Magnetic resonance cholangiopancreatography use doubled in grade IV/V injuries over time but was still low.Overall HGPI treatment and outcomes did not change over time. Resection was performed in 78% of grade III injuries and remained stable over time, while resection of grade IV/V injuries trended downward (56% to 39%, p = 0.11). Pancreas-related complications (PRCs) occurred more frequently in grade IV/V injuries managed with drainage versus resection (61% vs. 32%, p = 0.0051), but there was no difference in PRCs for grade III injuries between resection and drainage.Pancreatectomy closure had no impact on PRCs. Pancreatic duct stenting increased over time in grade IV/V injuries, with 76% used to treat PRCs. CONCLUSION:Intraoperative and computed tomography grading are different in the majority of HGPI cases. Resection is still used for most patients with grade III injuries; however, drainage may be a noninferior alternative. Drainage trended upward for grade IV/V injuries, but the higher rate of PRCs calls for caution in this practice.

Introduction: Historically, hemorrhage has been attributed as the leading cause (40%) of early death. However, a rigorous, real-time classification of the cause of death (COD) has not been performed. This study sought to prospectively adjudicate and classify COD to determine the epidemiology of trauma mortality. Methods: 18 trauma centers prospectively enrolled all adult trauma patients at the time of death during 12/2015-8/2017. Immediately following death, attending providers adjudicated the primary and contributing secondary COD using standardized definitions. Data were confirmed by autopsies, if performed. Results: 1536 patients were enrolled with a median age of 55 (IQR 32-75). 74.5% were male. Penetrating mechanism (n=412) patients were younger (32 vs 64, p<0.0001) and more likely male (86.7% vs. 69.9%, p<0.0001). Falls were the most common mechanism of injury (26.6%), with GSWs second (24.3%). The most common overall primary COD was TBI (45%), followed by exsanguination (23%). TBI was non-survivable in 82.2% of cases. Blunt patients were more likely to have TBI (47.8% vs. 37.4%, p<0.0001) and penetrating patients exsanguination (51.7% vs 12.5%, p<0.0001) as the primary COD. Exsanguination was the predominant prehospital (44.7%) and early COD (39.1%) with TBI most common later. Penetrating mechanism patients died earlier with 80.1% on day 0 (vs. 38.5%, p<0.0001). Most deaths were deemed disease related (69.3%), rather than by limitation of further aggressive care (30.7%). Hemorrhage was a contributing cause to 38.8% of deaths that occurred due to withdrawal of care. Conclusions: Exsanguination remains the predominant early primary COD with TBI accounting for most deaths at later time points. Timing and primary COD vary significantly by mechanism. Contemporaneous adjudication of COD is essential to elucidate the true understanding of patient outcome, center performance, and future research.