Networks that stop the flow: A fresh look at fibrin and neutrophil extracellular traps

Varjú, Imre; Kolev, Krasimir

doi:10.1016/j.thromres.2019.08.003

Cited by 41 publications

(52 citation statements)

References 184 publications

(247 reference statements)

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“…The insolubility of fibrin may increase the likelihood of it being citrullinated in circulation. As we could not stain specifically for citrullinated residues in fibrin only, detected fluorescence could also have originated from citrullinated histone derived from neutrophil extracellular traps (135). Nevertheless, binding of ACPAs to fibrin could render it less degradable, by decreasing available binding surface to plasmin (136).…”

Section: Discussionmentioning

confidence: 93%

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

Bezuidenhout

Venter

Roberts

et al. 2020

Preprint

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Objective. The risk of cardiovascular events in patients with RA is disproportionately heightened as a result of systemic inflammation. The relative effect of autoimmuneassociated citrullination on the structure and thrombotic potential of fibrin(ogen) remains unknown. We therefore compared indices of vascular function, inflammation, coagulation and fibrin clot composition in RA patients with healthy controls and evaluated inter-parameter relationships. Methods. Blood samples were collected from 30 RA patients and 25 age-and gender-matched healthy volunteers.Levels of SAA, CRP, ICAM-1 and VCAM-1 was measured using a sandwich immunoassay. Whole blood coagulation was assessed using Thromboelastography. Fibrin clot networks and fiber structure was investigated using Scanning Electron Microscopy. The detection and quantification of citrullination in formed fibrin clots were performed using a fluorescently labeled Citrulline monoclonal antibody with Confocal Microscopy. Results. Concentrations of SAA, CRP and ICAM-1 were significantly elevated in RA patients compared to controls. TEG parameters relating to coagulation initiation (R and K), rate of fibrin cross-linking (α-Angle), and time to reach maximum thrombus generation (TMRTG) were attenuated in RA patients. Parameters relating to clot strength (MA, MRTG, TGG) did not statistically differ between RA and controls. Logistic regression modelling revealed stronger association between acute phase reactants (CRP, SAA) with TEG parameters than endothelial function markers. Microscopic analysis revealed denser networks of thicker fibrin fibers in RA patients compared to controls [median (interquartile range) 214 (170-285) vs 120 (100-144) nm respectively, p<0.0001, Odds ratio=22.7). Detection of multiple citrullinated regions within fibrin clot structures in RA patients, which was less prevalent in control samples (p<0.05, OR=2.2). Conclusion.Patients with active RA display a coagulation profile that is dissimilar to general findings associated with other inflammatory conditions. The alteration of protein structures by autoimmune linked citrullination could play a role in determining the structure of fibrin and the potential of conferring a heightened thrombotic risk in RA patients.

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Section: Discussionmentioning

confidence: 93%

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

Bezuidenhout

Venter

Roberts

et al. 2020

Preprint

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“…After being activated by thrombin, fibrinogen converts to fibrin, a key mediator in blood coagulation and inflammatory response that could increase the procoagulant effect [ 86 , 87 ]. Also, fibrin and NETs interact to form a composite network within thrombi [ 88 ].…”

Section: Molecular Pathogenesis Of Covid-19mentioning

confidence: 99%

“…In fact, the interconnection of mechanisms such as inflammation and oxidative stress seems to be extremely important in determining the severity of COVID-19. For example, IL-6 overexpression and oxidative stress lead to increased fibrinogen processing and fibrin levels which, in turn, interacts with NET’s facilitating coagulation phenotypes, contributing to the COVID-19-associated coagulopathy [ 88 , 91 , 92 ] and shock [ 4 ]. Some patients also suffer neutrophilia, which results in increasing NET production and correlates with severe COVID-19 phenotypes and poor outcomes [ 72 , 73 , 74 , 75 , 76 , 93 ].…”

Section: Critically Ill Covid-19 Patients Show Clinical Manifestatmentioning

confidence: 99%

Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression

et al. 2020

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Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak emerged, countless efforts are being made worldwide to understand the molecular mechanisms underlying the coronavirus disease 2019 (COVID-19) in an attempt to identify the specific clinical characteristics of critically ill COVID-19 patients involved in its pathogenesis and provide therapeutic alternatives to minimize COVID-19 severity. Recently, COVID-19 has been closely related to sepsis, which suggests that most deceases in intensive care units (ICU) may be a direct consequence of SARS-CoV-2 infection-induced sepsis. Understanding oxidative stress and the molecular inflammation mechanisms contributing to COVID-19 progression to severe phenotypes such as sepsis is a current clinical need in the effort to improve therapies in SARS-CoV-2 infected patients. This article aims to review the molecular pathogenesis of SARS-CoV-2 and its relationship with oxidative stress and inflammation, which can contribute to sepsis progression. We also provide an overview of potential antioxidant therapies and active clinical trials that might prevent disease progression or reduce its severity.

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“…205 NETs along with their individual components (DNA and histones) have also been shown to possess significant prothrombotic and antifibrinolytic properties, and have been discussed at length in a recent review by Varjú and Kolev. 206 NETs provide a platform for the accumulation of integral hemostatic components such as platelets, erythrocytes, von Willebrand factor, and fibrinogen. 207 Histones promote fibrin deposition through its ability to bind to and inactivate antithrombin.…”

Section: Neutrophils and Netosismentioning

confidence: 99%

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

Bezuidenhout

Pretorius

2020

Semin Thromb Hemost

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Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of RA and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly RA-specific autoantibodies, known as anti-citrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deiminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore results in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary cardiovascular disease risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

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Networks that stop the flow: A fresh look at fibrin and neutrophil extracellular traps

Cited by 41 publications

References 184 publications

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

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