Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

Bonaventura, Aldo; Vecchiè, Alessandra; Dagna, Lorenzo; Martinod, Kimberly; Dixon, Dave L.; Tassell, Benjamin Van; Dentali, Francesco; Montecucco, Fabrizio; Maßberg, Steffen; Levi, Marcel; Abbate, Antonio

doi:10.1038/s41577-021-00536-9

Cited by 639 publications

(637 citation statements)

References 183 publications

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“…In accordance with previous studies (1, 49) we documented pulmonary emboli in 58.8% of the patients included in our investigation. It has been suggested that procoagulant and inflammatory responses ("thromboinflammation") are involved herein (16,50). Whilst we found limited differences in plasma and BALF biomarkers between patients with and without pulmonary embolism, our investigation was not designed or powered to detect such differences.…”

Section: Discussionmentioning

confidence: 68%

“…Autopsy studies have shown extensive alveolar damage accompanied by widespread inflammation and pulmonary in situ thrombosis in patients who succumbed to COVID-19 (2,15). Recently, it was proposed that SARS-CoV-2 infection induces a process termed immunothrombosis, in which activated leukocytes interact with platelets and coagulation factors, leading to intravascular clot formation and microthrombotic complications in lungs and other organs (16).…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary Procoagulant and Innate Immune Responses in Critically Ill COVID-19 Patients

et al. 2021

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RationaleSystemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited.ObjectivesTo evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome.MethodsPaired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured.Measurements and Main ResultsIn all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined.ConclusionsCritically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory “storm” in severe COVID-19.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Pulmonary Procoagulant and Innate Immune Responses in Critically Ill COVID-19 Patients

et al. 2021

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“…3, Table 3). This is, of course, very relevant to COVID-19 due to extensive clotting pathologies and stroke associated with COVID-19 (Bonaventura et al, 2021), as well as microvascular clotting and the apparent shut-down of fibrinolysis (Wright et al, 2020). Extensive blood coagulation of COVID-19 patients can even lead to clogging of dialysis equipment (Rabb, 2020).…”

Section: C1 the Ace2 Core Reciprocal Rank (Crr) Networkmentioning

confidence: 99%

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

Cheng

Werren

2021

Preprint

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Angiotensin-converting enzyme 2 (ACE2) is the human cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken a different approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that "coevolve" with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact directly with ACE2, while additional predicted novel interactors with ACE2 are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as coagulation factor V and fibrinogen components FGG, FGB, and FGA, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). Additionally, ACE2 has connections to proteins involved in cytokine signaling and immune response (e.g. IFNAR2, XCR1, and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has also elucidated possible functions for previously uncharacterized proteins and possible additional functions for well-characterized ones. Suggested validation approaches for ERC predicted ACE2 interacting proteins are discussed. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

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“…Since an acute cardiac involvement of COVID-19 infection [1] was observed, it has been hypothesized a direct effect of the virus on the myocardium and heart vessels [2,3]. There are many reports about the role on COVID-19 in spurring a diffuse endothelial inflammation [2,4,5] as a result of virus tropism for ACE2. This enzyme is expressed by type II pneumocytes [6], which is anatomically close to the lung vascular network and is typically described to be hyperplasic in samples from COVID-19 patients [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular Imaging Evaluation in COVID-19 Heart and Vascular Non-Ischaemic Involvement

Cicco¹,

Vacca²,

Cariddi³

et al. 2021

Preprint

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Coronavirus Disease 2019 (COVID-19) is the pandemic challenge of the last year. Cardiovascular involvement is one of the main characteristics of this disease. Due to endothelial damage, consequent phlogosis may increase a thrombosis risk. Cardiac injury may occur in different ways. However, an ischemic involvement of the cardiovascular system is rarely implied. In this regard, direct and indirect effects of COVID-19 are described. Nonetheless, the possible evaluation of the cardiovascular system may require different modalities. The cardiovascular evaluation may be different in emergency compared to critical care, requiring different tools for each setting. The aim of this review is to explore these modalities according to the different involvement of the cardiovascular system..

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Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

Cited by 639 publications

References 183 publications

Pulmonary Procoagulant and Innate Immune Responses in Critically Ill COVID-19 Patients

Pulmonary Procoagulant and Innate Immune Responses in Critically Ill COVID-19 Patients

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

Cardiovascular Imaging Evaluation in COVID-19 Heart and Vascular Non-Ischaemic Involvement

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