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While the association between coronavirus disease-19 (COVID-19) and neutrophils extracellular traps (NETs) is recognized, uncertainties remain regarding its precise onset, timing of resolution and target therapy. To assess changes in inflammatory and NET markers during the first week of COVID-19 hospitalization, and the association with disease severity. "In vitro" experiments investigated the effect of antiplatelets, anticoagulants, and cyclic nucleotide stimulators on NETs release. Prospective cohort study, changes in interleukin (IL)-6, IL-8, IL-17, TNF-α, RANTES, PF4, and citrullinated-H3 (citH3) levels within each outcome group was evaluated using ANOVA. Differences between moderately ill, critically ill, and non-survivors were determined using Kruskal-Wallis and logistic regression. Healthy neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) or COVID-19 sera and treated with unfractionated heparin (UFH), low molecular weight heparin (LMWH), aspirin (ASA), ticagrelor, cinaciguat, sildenafil, and milrinone. The proportion of NETosis was assessed using IncuCyte Cell Imager. Of the 125 patients, 40.8% had moderate COVID-19, 40.8% had critical COVID-19 but recovered, and 18.4% died. From admission to hospitalization day 8, IL-6 levels decreased in moderately and critically ill, but not in non-survivors, while citH3 levels increased in critically ill and non-survivors. IL-6, IL-8, and TNF-α levels were associated with critical and fatal COVID-19. The release of NETs by neutrophils stimulated with PMA or COVID-19 sera was decreased in the presence of ASA, UFH, LMWH and cyclic nucleotide stimulators in a dose-dependent manner. In the first week of hospitalization, NET markers rose later than inflammatory markers in severe COVID-19 cases. Cyclic nucleotide stimulators, ASA and heparin may emerge as treatment approaches as they may modulate NETosis., Competing Interests: Declarations Conflict of interest The authors declare no conflict of interest. Generative AI and AI-assisted technologies in the writing process During the preparation of this work the author(s) used https://www.deepl.com/ in order to correct grammatical errors in the text. After using this tool, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication. Informed consent The study was conducted in compliance with the Helsinki Declaration. A waiver of the Informed Consent was granted based on the emergence of the pandemic, the observational nature of the study, the utilization of data obtained from medical records, and the use of residual samples. The study ensured the deidentification of patient records. In addition, patients diagnosed with COVID-19 were isolated, and access to the patients and their relatives was restricted to healthcare personnel., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Declaration of competing interests The authors declare the following conflicts of interest (past 36 months): F.N.A.: member of the International Society on Thrombosis and Haemostasis (ISTH) Council and Vice-Chair of the ISTH Guideline and Guidance Committee; research funding (investigator-initiated studies, paid to university) from Bayer, Daiichi-Sankyo, and Sanofi; and consultancy fees (paid to university) from Boston Scientific. D.D.M.: member of the ISTH Council and consultant to the National Bleeding Disorders Foundation, the American Society of Hematology, and Believe Ltd on matters related to future research and workforce development in the areas of hematology and inherited bleeding disorders. A.C.: serves on the advisory board of Novo Nordisk and has received honoraria from Novo Nordisk, Grifols, Takeda, and Roche. E.V.D.P.: medical consultant for the area of the Brazilian Ministry of Health responsible for the national program of hereditary bleeding disorders. S.M.: member of the ISTH Council and reports participation in advisory or educational activities with AbbVie, Bayer, Astra Zeneca, Alveron (Advisory Board), Hemab, Norgine, Sanofi, Synapse, and Viatris; all honoraria are being paid to her institution. Y.F.-Y, T.S., and C.S. report no conflict of interest.

Coagulation activation in immunothrombosis involves various pathways distinct from classical hemostasis, offering potential therapeutic targets to control inflammation-induced hypercoagulability while potentially sparing hemostasis. The Angiopoietin/Tie2 pathway, previously linked to embryonic angiogenesis and sepsis-related endothelial barrier regulation, was recently associated with coagulation activation in sepsis and COVID-19. This study explores the connection between key mediators of the Angiopoietin/Tie2 pathway and coagulation activation. The study included COVID-19 patients with hypoxia and healthy controls. Blood samples were processed to obtain platelet-free plasma, and frozen until analysis. Extracellular vesicles (EVs) in plasma were characterized and quantified using flow cytometry, and their tissue factor (TF) procoagulant activity was measured using a kinetic chromogenic method. Several markers of hemostasis were assessed. Levels of ANGPT1, ANGPT2, and soluble Tie2 correlated with markers of coagulation and platelet activation. EVs from platelets and endothelial cells were increased in COVID-19 patients, and a significant increase in TF + EVs derived from endothelial cells was observed. In addition, ANGPT2 levels were associated with TF expression and activity in EVs. In conclusion, we provide further evidence for the involvement of the Angiopoietin/Tie2 pathway in the coagulopathy of COVID-19 mediated in part by release of EVs as a potential source of TF activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Barbosa, de Lima, Peachazepi Moraes, Borba-Junior, Huber, Santos, Bombassaro, Dertkigil, Ilich, Key, Annichino-Bizzacchi, Orsi, Mansour, Velloso and De Paula.)

SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Data on availability, affordability, and accessibility is key for the planning of global strategies to reduce the burden of venous thromboembolism (VTE)., Objectives: A survey was conducted for the 10th anniversary of World Thrombosis Day to assess the availability of VTE therapies worldwide and challenges in uniform implementation., Methods: We gathered information on the approval status, availability, utilization, occurrence of shortages, and spread of medical and interventional therapies for VTE. Furthermore, we collected information by accessing or contacting national or continental medicines agencies, manufacturers or distributors, and online drug repositories., Results: We obtained data from a total of 69 countries: 33 countries in Europe, 19 in Asia, 7 in the Americas, 9 in Africa, and 1 in Oceania. Unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists were available in almost all countries, but shortages were recorded in 13%, 19%, and 15% of them, respectively. Direct oral anticoagulants were available in approximately three-quarters of the surveyed countries. At least one parenteral medication for heparin-induced thrombocytopenia was available in 57% of countries and a shortage was reported in 9% of these. Shortage of thrombolytics was recorded in 50% of countries. Overall, at least one type of catheter-directed therapy system was approved for use in 77% of countries and available in 23% of surveyed institutions. Our findings revealed notable geographic disparities in the worldwide availability of VTE therapies, the access to which appeared to be limited by economic and geopolitical factors., Conclusion: We anticipate that this comprehensive information will play a pivotal role in highlighting the shortcomings of VTE therapies and the lack of homogeneous availability globally., Competing Interests: Declaration of competing interests C.A. received honoraria for lectures and participation in advisory boards from Bayer, BMS/Pfizer, Daiichi Sankyo, and Sanofi. L.A.C. research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma, and Servier. L.A.C. holds a Tier 2 research Chair in Thrombosis and Anticoagulation Safety from the University of Ottawa. S.B. received institutional grants from Sanofi, Concept Medical, Bayer, Medtronic, Boston Scientific, Bard, Novartis, and Daiichi Sankyo and honoraria for advisory boards or lectures from Boston Scientific, Penumbra, Viatris, Bayer, Sanofi. S.A.M., R.M.F., G.C.M., E.V.D.P., M.D., M.C.G.E., L.H., P.S., C.M.S., and M.T.S. report no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)