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• W3118607788 abstract "The coronavirus disease 2019 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) evokes an intricate global public health crisis. Scientists all over the world are trying to decipher the mechanisms by which SARS‐CoV‐2 induces a systemic response in severely affected individuals, which contributes to a high mortality rate. Hence, a clear understanding of the underlying pathology is warranted to allow for optimal treatment of patients, which—in the case of COVID‐19—seems diverse and complex. Recently, the pathogenesis of COVID‐19 was elegantly compared to four horsemen of a viral apocalypse, consisting of four intertwined loops, which include the viral loop, the hyperinflammatory loop, the noncanonical renin‐angiotensin system axis loop, and the hypercoagulation loop.1.Domingo P. Mur I. Pomar V. Corominas H. Casademont J. de Benito N. The four horsemen of a viral apocalypse: the pathogenesis of SARS‐CoV‐2 infection (COVID‐19).EBioMedicine. 2020; 58: 102887Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Of particular interest, the hypercoagulatory state induced by SARS‐CoV‐2 shows characteristics distinct from those seen in bacterial sepsis‐induced coagulopathy and disseminated intravascular coagulation.2.Iba T. Levy J.H. Connors J.M. Warkentin T.E. Thachil J. Levi M. The unique characteristics of COVID‐19 coagulopathy.Crit Care. 2020; 24: 360Crossref PubMed Scopus (272) Google Scholar The importance of COVID‐19–associated coagulopathy (CAC) is further underlined by an increased risk for thrombotic events in SARS‐CoV‐2–infected individuals, making prophylactic anticoagulation and vigilant monitoring for thrombotic complications a central task in management of patients with COVID‐19. However, there is a gap in understanding the underlying cause of CAC and its precise mechanism. Neither do we know why some patients are more prone to CAC compared to others and how adverse events should be treated and prevented. The new study in Research and Practice in Thrombosis and Haemostasis by von Meijenfeldt et al3.von Meijenfeldt F.A. Havervall S. Adelmeijer J. Rudberg A. Magnusson M. Mackman N. et al.Prothrombotic changes in COVID‐19 patients are associated with disease severity and mortality.Res Pract Thromb Haemost. 2020; : 1-10https://doi.org/10.1002/rth2.12462Google Scholar adds an important piece of knowledge to our understanding of the underlying pathology of CAC and the impact of anticoagulation. In a cohort of 102 hospitalized patients with COVID‐19, the authors extensively analyzed coagulation and fibrinolysis parameters. They found that patients with COVID‐19 on higher respiratory support had increased in vivo activation of coagulation (d‐dimers and thrombin‐antithrombin complexes), increased fibrinogen, factor VIII, and von Willebrand factor plasma levels, while ADAMTS‐13 levels were lower, compared to patients with less affected lung injury and healthy controls. In addition, in vivo activation of fibrinolysis, C‐reactive protein (CRP), and leukocyte counts increased with higher respiratory support (Figure 1). Further, and in line with previous reports, the authors found minimal abnormalities in prothrombin time and platelet count within the first days of admission.2.Iba T. Levy J.H. Connors J.M. Warkentin T.E. Thachil J. Levi M. The unique characteristics of COVID‐19 coagulopathy.Crit Care. 2020; 24: 360Crossref PubMed Scopus (272) Google Scholar, 3.von Meijenfeldt F.A. Havervall S. Adelmeijer J. Rudberg A. Magnusson M. Mackman N. et al.Prothrombotic changes in COVID‐19 patients are associated with disease severity and mortality.Res Pract Thromb Haemost. 2020; : 1-10https://doi.org/10.1002/rth2.12462Google Scholar Also, ex vivo thrombin generation was higher in these patients, while ex vivo fibrinolysis capacity was diminished. This is of special interest as the majority of patients were anticoagulated and patients on higher respiratory support even received higher doses of anticoagulants. So despite higher doses of anticoagulants, patients with COVID‐19 with higher respiratory support have increased procoagulatory activity, clearly indicating that current anticoagulation therapies in patients with COVID‐19 must be reevaluated. These data are supported by previous findings from the same group in another cohort of patients with COVID‐19 treated with low‐molecular‐weight heparin (LMWH), which showed no effect of this drug on in vivo coagulation activation and fibrinolysis.4.Blasi A. von Meijenfeldt F.A. Adelmeijer J. Calvo A. Ibañez C. Perdomo J. et al.In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID‐19 patients on anticoagulation.J Thromb Haemost. 2020; Abstract Full Text Full Text PDF Scopus (82) Google Scholar Intriguingly, in a large case series of over 4000 patients with COVID‐19, it was recently shown that anticoagulation is associated with improved survival.5.Nadkarni G.N. Lala A. Bagiella E. Chang H.L. Moreno P. Pujadas E. et al.Anticoagulation, mortality, bleeding and pathology among patients hospitalized with COVID‐19: a single health system study.J Am Coll Cardiol. 2020; Crossref Scopus (297) Google Scholar These observational data suggest that there is a benefit in anticoagulation therapy in these patients. Moreover, the authors found no difference in outcome between the types of anticoagulation therapy, LMWH or direct oral anticoagulants (DOACs). This could indicate that patients with COVID‐19 on anticoagulation do better, but there is still potential for improvement in patient treatment. Moreover, anticoagulants could bear beneficial effects beyond hemostasis in patients with COVID‐19. Endothelial dysfunction and loss of endothelial barrier function are common features of COVID‐19. Recently, the endothelial glycocalyx‐degrading enzyme heparanase, which contributes to vascular leakage and inflammation, has been shown to be elevated in patients with COVID‐19.6.Buijsers B. Yanginlar C. de Nooijer A. Grondman I. Maciej‐Hulme M.L. Jonkman I. et al.Increased plasma heparanase activity in COVID‐19 patients.Front Immunol. 2020; 11: 575047Crossref PubMed Scopus (69) Google Scholar LMWH is an inhibitor of heparanase and could therefore bear beneficial effects by preventing glycocalyx degradation.6.Buijsers B. Yanginlar C. de Nooijer A. Grondman I. Maciej‐Hulme M.L. Jonkman I. et al.Increased plasma heparanase activity in COVID‐19 patients.Front Immunol. 2020; 11: 575047Crossref PubMed Scopus (69) Google Scholar Moreover, heparin was recently found to bind SARS‐CoV‐2 with high affinity, thereby inhibiting virus binding on angiotensin‐converting enzyme 2–expressing cells in vitro.7.Kwon P.S. Oh H. Kwon S.J. Jin W. Zhang F. Fraser K. et al.Sulfated polysaccharides effectively inhibit SARS‐CoV‐2 in vitro.Cell Discov. 2020; 6: 50Crossref PubMed Scopus (181) Google Scholar There are multiple inflammatory and pathogenic mechanisms targeted by heparin8.Buijsers B. Yanginlar C. Maciej‐Hulme M.L. de Mast Q. van der Vlag J. Beneficial non‐anticoagulant mechanisms underlying heparin treatment of COVID‐19 patients.EBioMedicine. 2020; 59: 102969Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar; therefore, it is warranted to conduct clinical studies that evaluate therapeutic doses of these compounds in patients with COVID‐19. In clear contrast, little is known on the pathomechanistic effects of DOACs on COVID‐19 disease progression to this date, while an improvement in survival was seen for patients treated with DOACs. Importantly, alternatives to current therapeutic strategies need to be evaluated in the near future. Neutrophils, immunogenic platelets, and a dysregulated coagulation cascade cooperate to propagate immunothrombotic tissue injury in COVID‐19, revealing that immunothrombosis is not just a bystander in COVID‐19 but rather a link between systemic hypercoagulability and respiratory failure.9.Nicolai L. Leunig A. Brambs S. Kaiser R. Weinberger T. Weigand M. et al.Immunothrombotic dysregulation in COVID‐19 pneumonia is associated with respiratory failure and coagulopathy.Circulation. 2020; Crossref PubMed Scopus (291) Google Scholar Also in the study by von Meijenfeldt et al, d‐dimer levels were associated with increased CRP, indicating an interplay between inflammation and coagulation.3.von Meijenfeldt F.A. Havervall S. Adelmeijer J. Rudberg A. Magnusson M. Mackman N. et al.Prothrombotic changes in COVID‐19 patients are associated with disease severity and mortality.Res Pract Thromb Haemost. 2020; : 1-10https://doi.org/10.1002/rth2.12462Google Scholar Targeting immunothrombotic mechanisms could therefore provide a novel therapeutic strategy to prevent SARS‐CoV‐2 and other viral‐ or bacterial‐induced thromboinflammatory events but bears a number of yet unsolved challenges. Therapeutic intervention in NETosis for treating inflammatory and thrombotic diseases has a narrow therapeutic window as timing of neutrophil extracellular trap–degrading deoxyribonuclease (DNase) treatment seems crucial. Administration too early may result in harmful effects due to ineffective prevention of pathogen dissemination. Moreover, DNase cleavage may result in the liberation of unwanted cell‐free DNA and DNA‐binding proteins, which in turn may propagate inflammation.10.d'Alessandro E. Becker C. Bergmeier W. Bode C. Bourne J.H. Brown H. et al.Thrombo‐inflammation in cardiovascular disease: an expert consensus document from the Third Maastricht Consensus Conference on Thrombosis.Thromb Haemost. 2020; 120: 538-64Crossref PubMed Scopus (51) Google Scholar Therapeutic intervention of systemic inflammation and thrombosis via histone modification by peptidyl arginine deiminase 4 has been successful in mouse models but not yet translated to clinical settings.10.d'Alessandro E. Becker C. Bergmeier W. Bode C. Bourne J.H. Brown H. et al.Thrombo‐inflammation in cardiovascular disease: an expert consensus document from the Third Maastricht Consensus Conference on Thrombosis.Thromb Haemost. 2020; 120: 538-64Crossref PubMed Scopus (51) Google Scholar In summary, the optimal dose and type of anticoagulant intervention in hospitalized patients with COVID‐19 is unknown, and immediate answers from high‐quality randomized trials are urgently needed. Patients from all over the world would benefit from a collaborative effort to complete trials more quickly, conduct pooled analyses, and bring effective interventions to patients more quickly as recently suggested.11.Tritschler T. Mathieu M.E. Skeith L. Rodger M. Middeldorp S. Brighton T. et al.International Network of VTCRNI‐VTE. Anticoagulant interventions in hospitalized patients with COVID‐19: a scoping review of randomized controlled trials and call for international collaboration.J Thromb Haemost. 2020; Abstract Full Text Full Text PDF Scopus (72) Google Scholar On the other hand, novel interventions targeting pathomechanistic differences observed in severe and critical COVID‐19 cases need to be explored in detail. Studies like the one by von Meijenfeldt et al are important to decipher the precise pathological features of CAC to be able to define patients at risk for thrombotic complications and evaluate therapeutic strategies." @default.
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• W3118607788 title "COVID‐19–related prothrombotic changes increase with lung injury and remain unaffected by anticoagulation therapy" @default.
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