Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19

Busch, Matthias; Timmermans, Sjoerd A.M.E.G.; Nagy, Magdolna; Visser, Mayken; Huckriede, Joram; Aendekerk, Joop P.; Vries, Femke de; Potjewijd, Judith; Jallah, Borefore; Ysermans, Renee; Lashof, Astrid M. L. Oude; Breedveld, Paul; Poll, Marcel C.G. van de; Horst, Iwan C. C. van der; Bussel, Bas C.T. van; Theunissen, Ruud; Spronk, Henri M. H.; Damoiseaux, Jan; Cate, Hugo Ten; Nicolaes, Gerry A. F.; Reutelingsperger, Chris; Paassen, Pieter van

doi:10.1161/circulationaha.120.050656

Cited by 94 publications

(123 citation statements)

References 5 publications

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“… 4 Emerging data now suggest a role of NETs also in COVID-19 pathophysiology: (1) neutrophilia and neutrophil-to-lymphocyte ratio are linked to COVID-19 disease severity, 5 , 6 (2) NETs have been demonstrated in pulmonary microvessels of patients with COVID-19, 7 – 11 (3) neutrophils from patients with COVID-19 are prone to spontaneously form NETs, 7 , 8 , 10 (4) plasma from patients with COVID-19 induce the release of NETs by healthy neutrophils, 7 , 12 , 13 and (5) circulating markers of NET formation are correlated to COVID-19 disease severity. 7 , 8 , 13 , 14 Here, we show that circulating markers of NET formation are prognostic in a well-phenotyped, prospective study of 106 patients, and that they are associated with an inflammatory and prothrombotic state, suggesting the implication of NETs in COVID-19-related immunothrombosis.…”

mentioning

confidence: 66%

Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19

Havervall

Rosell

et al. 2021

ATVB

174

183

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Objective: The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy. The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression. Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis. Approach and Results: One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months. Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase). We found that plasma levels of NET markers were all elevated in patients with COVID-19 relative to healthy controls, were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection. Levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage. Conclusions: Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state. Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04402944, NCT04541979, NCT04445285, NCT04432987, NCT04402970.

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mentioning

confidence: 66%

Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19

Havervall

Rosell

et al. 2021

ATVB

174

183

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“…Ongoing randomized controlled trials will determine whether higher intensity than standard pharmacotherapeutic thromboprophylaxis regimes will ultimately improve the prognosis of COVID-19 patients by preventing more thrombotic complications without giving too much bleeding. A final explanation could involve a direct SARS-CoV-2-specific procoagulant effect also involving recruitment of the contact system, that is not mitigated by the current COVID-19 targeted treatment regimens, including LMWH that had little impact on contact coagulation activation markers, contributing to local thrombosis in the affected lung segments [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both occurred foremost in ventilated patients admitted to the Intensive Care Unit (ICU) and were associated with increased probability of death [ 6 ]. Several mechanisms involving hypercoagulability and inflammation interact resulting in thrombotic phenomena both in the microvasculature and in the larger, mostly pulmonary blood vessels [ [2] , [3] , [4] , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave

Coalition

Kaptein

Stals

et al. 2021

Thrombosis Research

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“…The results of studies by other authors unequivocally confirm that hypercoagulability and thrombotic events are driven by NETosis, contact pathways of blood coagulation activation and complement, and their repeatedly amplified feedback loops. Researchers are proposing C5a blockers, plasma kallikrein and FXIa inhibitors, and NETs-derived histone neutralizing agents as new therapeutic directions [ 61 ].…”

Section: Nets and Covid-19 Progression In People With Concurrent Dmentioning

confidence: 99%

Significance of NETs Formation in COVID-19

Janiuk

Jabłońska

Garley

2021

Cells

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Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), with the simultaneous involvement of human trans-membrane protease, serine 2 (TMPRSS2). Many scientific reports stress the importance of elevated recruitment and activity of neutrophils, which can form extracellular neutrophil traps (NETs) playing a significant role in the mechanism of combating pathogens, in the pathogenesis of COVID-19. Excessive generation of NETs during prolonged periods of inflammation predisposes for the occurrence of undesirable reactions including thromboembolic complications and damage to surrounding tissues and organs. Within the present manuscript, we draw attention to the impact of NET generation on the severe course of COVID-19 in patients with concurrent cardiovascular and metabolic diseases. Additionally, we indicate the necessity to explore not only the cellular but also the molecular bases of COVID-19 pathogenesis, which may aid the development of dedicated therapies meant to improve chances for the successful treatment of patients. We also present new directions of research into medications that display NETs formation regulatory properties as potential significant therapeutic strategies in the progress of COVID-19.

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Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19

Cited by 94 publications

References 5 publications

Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19

Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave

Significance of NETs Formation in COVID-19

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