Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy

Nicolai, Leo; Leunig, Alexander; Brambs, Sophia; Kaiser, Rainer; Weinberger, Tobias; Weigand, Michael; Muenchhoff, Maximilian; Hellmuth, Johannes C.; Ledderose, Stephan; Schulz, Heiko; Scherer, Clemens; Rudelius, Martina; Zöller, Michael; Höchter, Dominik; Keppler, Oliver T.; Teupser, Daniel; Zwißler, Bernhard; Bergwelt‐Baildon, Michael von; Kääb, Stefan; Maßberg, Steffen; Pekayvaz, Kami; Stark, Konstantin

doi:10.1161/circulationaha.120.048488

Cited by 512 publications

(633 citation statements)

References 46 publications

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“…Consequently, platelet reprogramming could facilitate the transmission of SARS-CoV-2 and promote thrombo-inflammation. Indeed, thromboinflammation mediated by distinct patterns of platelet and neutrophil activations, neutrophil-platelet aggregate formation, and neutrophil extracellular traps has been reported in COVID-19 pneumonia (126).…”

Section: Coagulation Cascades and The Mechanisms Of Thrombosis In Covmentioning

confidence: 99%

Vascular Manifestations of COVID-19 – Thromboembolism and Microvascular Dysfunction

Roberts

Colley

Agbaedeng

et al. 2020

Front. Cardiovasc. Med.

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The coronavirus pandemic has reportedly infected over 31.5 million individuals and caused over 970,000 deaths worldwide (as of 22nd Sept 2020). This novel coronavirus, officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although primarily causes significant respiratory distress, can have significant deleterious effects on the cardiovascular system. Severe cases of the virus frequently result in respiratory distress requiring mechanical ventilation, often seen, but not confined to, individuals with pre-existing hypertension and cardiovascular disease, potentially due to the fact that the virus can enter the circulation via the lung alveoli. Here the virus can directly infect vascular tissues, via TMPRSS2 spike glycoprotein priming, thereby facilitating ACE-2-mediated viral entry. Clinical manifestations, such as vasculitis, have been detected in a number of vascular beds (e.g., lungs, heart, and kidneys), with thromboembolism being observed in patients suffering from severe coronavirus disease (COVID-19), suggesting the virus perturbs the vasculature, leading to vascular dysfunction. Activation of endothelial cells via the immune-mediated inflammatory response and viral infection of either endothelial cells or cells involved in endothelial homeostasis, are some of the multifaceted mechanisms potentially involved in the pathogenesis of vascular dysfunction within COVID-19 patients. In this review, we examine the evidence of vascular manifestations of SARS-CoV-2, the potential mechanism(s) of entry into vascular tissue and the contribution of endothelial cell dysfunction and cellular crosstalk in this vascular tropism of SARS-CoV-2. Moreover, we discuss the current evidence on hypercoagulability and how it relates to increased microvascular thromboembolic complications in COVID-19.

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Section: Coagulation Cascades and The Mechanisms Of Thrombosis In Covmentioning

confidence: 99%

Vascular Manifestations of COVID-19 – Thromboembolism and Microvascular Dysfunction

Roberts

Colley

Agbaedeng

et al. 2020

Front. Cardiovasc. Med.

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“…Several reports have also shown that NET-platelet aggregates favor vascular coagulation in COVID-19 patients. A recent report has shown microvascular thrombi associated with platelet-neutrophil aggregates in the lungs, kidney and the heart (224). Another study has shown NETs in the heart by electron microscopy (EM) in an autopsy sample from COVID-19 patient with MIS-C (210).…”

Section: Indirect Effect Of Sars-cov-2 Infection On Triggering Cardiomentioning

confidence: 99%

Immune Mechanisms in Cardiovascular Diseases Associated With Viral Infection

2020

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Influenza virus infection causes 3-5 million cases of severe illness and 250,000-500,000 deaths worldwide annually. Although pneumonia is the most common complication associated with influenza, there are several reports demonstrating increased risk for cardiovascular diseases. Several clinical case reports, as well as both prospective and retrospective studies, have shown that influenza can trigger cardiovascular events including myocardial infarction (MI), myocarditis, ventricular arrhythmia, and heart failure. A recent study has demonstrated that influenza-infected patients are at highest risk of having MI during the first seven days of diagnosis. Influenza virus infection induces a variety of pro-inflammatory cytokines and chemokines and recruitment of immune cells as part of the host immune response. Understanding the cellular and molecular mechanisms involved in influenza-associated cardiovascular diseases will help to improve treatment plans. This review discusses the direct and indirect effects of influenza virus infection on triggering cardiovascular events. Further, we discussed the similarities and differences in epidemiological and pathogenic mechanisms involved in cardiovascular events associated with coronavirus disease 2019 (COVID-19) compared to influenza infection.

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“…A further study proved that SARS-CoV-2 could directly trigger NET formation via an ACE2-serine protease TMPRSS2 dependent pathway and induce lung epithelial cell death in vitro (163). Nicolai et al demonstrated that in COVID-19 patients, inflammatory microvascular thrombi containing NETs were present in lung, kidney, and heart (164). Middleton et al also demonstrated that elevated levels of PF4 and RANTES, which were demonstrated to trigger NETosis, were detected in plasma from COVID-19 patients and COVID-19 plasma-induced NET formation was inhibited by neonatal NET-Inhibitory Factor (nNIF), indicating that NETs contributed to immunothrombosis in COVID-19 patients (165).…”

Section: Net-vwf Axis Is a Potential Therapeutic Target In Covid-19mentioning

confidence: 99%

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

Yang

Long

et al. 2020

Front. Immunol.

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Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

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Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy

Cited by 512 publications

References 46 publications

Vascular Manifestations of COVID-19 – Thromboembolism and Microvascular Dysfunction

Vascular Manifestations of COVID-19 – Thromboembolism and Microvascular Dysfunction

Immune Mechanisms in Cardiovascular Diseases Associated With Viral Infection

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

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