Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke

Ducroux, Célina; Meglio, Lucas Di; Loyau, Stéphane; Delbosc, Sandrine; Boisseau, William; Deschildre, Catherine; Maacha, Malek Ben; Blanc, Raphaël; Redjem, Hocine; Cicciò, Gabriele; Smajda, Stanislas; Fahed, Robert; Michel, Jean‐Baptiste; Piotin, Michel; Salomon, Laurence; Mazighi, Mikaël; Ho‐Tin‐Noé, Benoît; Desilles, Jean‐Philippe

doi:10.1161/strokeaha.117.019896

Cited by 258 publications

(298 citation statements)

References 12 publications

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“…Our previous in vitro [15] and a recent ex vivo [16] study provided evidence that NET components (DNA, histones) modify the structure of fibrin, increase its mechanical stability and render clots less sensitive to lysis with tissue-type plasminogen activator/plasminogen. In line with the recently reported findings in ischemic stroke thrombi [16,17], our present work confirms the presence of NET components in AIS thrombi, but we also demonstrate that extracellular DNA content -the major meshwork-forming constituent of NETs -of AIS (median FD50 of 0.208) thrombi is similar to CAD and 2.5-fold lower than in PAD thrombi (median FD50 of 0.082, p=0.0013, Figure 1). Thus, compared to other artery locations, in AIS the NET meshwork impedes the least the fibrinolytic therapeutic approach to restore the patency of occluded vessels, a fact that deserves attention when making therapeutic decisions in stroke.…”

Section: Extracellular Dna and Ch3supporting

confidence: 93%

“…Strong evidence supports the role of NETs in both deep venous [7][8][9][10][11] and arterial thrombi [12][13][14], and they are now regarded as an additional scaffold of thrombus formation tightly intertwined with the fibrin matrix. In a previous study, we demonstrated massive presence of extracellular DNA and histones in thrombi removed with surgery from patients with PAD [15] and recent studies showed the presence of NETs in ischemic stroke thrombi [16,17].…”

Section: Introductionmentioning

confidence: 77%

“…These facts justify the growing interest in investigating thrombus composition [22,23], but very few data are available concerning the fibrin structure in relation to the cellular and NET content of thrombi in the clinical setting of AIS. In view of the expanding application of mechanical thrombectomy to treat large vessel occlusions causing AIS, elaborate characterization of NET components in the culprit clot composition could refine the need for new therapeutics targeting the NETs [17], whereas associations of clot composition and routinely available clinical data, as well as comparisons with thrombi from other therapeutic interventions (CAD, PAD) could help the identification of etiology-and localization-specific predictors for optimal post-interventional treatment to prevent re-occlusion.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil extracellular traps in thrombi retrieved during interventional treatment of ischemic arterial diseases

Farkas

Szabó

et al. 2019

Thrombosis Research

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Highlights-Neutrophil extracellular traps (NETs) modify the structure and stability of fibrin.-NET content of thrombi varies at different locations (brain, heart, peripheral arteries).-DNA and histones in thrombi correlate with age and systemic inflammatory markers.-The amount of fibrin is similar at all examined arterial locations.-Thicker fibrin fibers are formed in coronaries than in brain and peripheral arteries. 3 Abstract Introduction-The ultrastructure and cellular composition of thrombi has a profound effect on the outcome of acute ischemic stroke (AIS), coronary (CAD) and peripheral artery disease (PAD). Activated neutrophils release a web-like structure composed mainly of DNA and citrullinated histones, called neutrophil extracellular traps (NET) that modify the stability and lysability of fibrin. Here, we investigated the NET-related structural features of thrombi retrieved from different arterial localizations and their interrelations with routinely available clinical data. Patients and methods-Thrombi extracted from AIS (n=78), CAD (n=66) or PAD (n=64) patients were processed for scanning electron microscopy, (immune)stained for fibrin, citrullinated histone H3 (cH3) and extracellular DNA. Fibrin fiber diameter, cellular components, DNA and cH3 were measured and analyzed in relation to clinical parameters. Results-DNA was least present in AIS thrombi showing a 2.5-fold lower DNA/fibrin ratio than PAD, whereas cH3 antigen was unvaryingly present at all locations. The NET content of thrombi correlated parabolically with systemic inflammatory markers and positively with patients' age. The median platelet content was lower in PAD (2.2%) than in either AIS (3.9%) or CAD (3.1%) and thrombi from smokers contained less platelets than non-smokers. Fibrin fibers were significantly thicker in male patients with CAD (median fiber diameter 76.3 nm) compared to AIS (64.1 nm) or PAD (62.1 nm) and their diameter correlated parabolically with systemic inflammatory markers.Conclusions-The observed NET-related variations in thrombus structure shed light on novel determinants of thrombus stability that eventually affect both the spontaneous progress and therapeutic outcome of ischemic arterial diseases.

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Section: Extracellular Dna and Ch3supporting

confidence: 93%

Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Neutrophil extracellular traps in thrombi retrieved during interventional treatment of ischemic arterial diseases

Farkas

Szabó

et al. 2019

Thrombosis Research

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“…Scale, 10 µm tissue-type plasminogen activator-induced thrombolysis of these thrombi ex vivo (61,62), which again indicates that thrombo-inflammatory clots require breakage of their nucleic acid component to achieve resolution.…”

mentioning

confidence: 99%

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

2018

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Peptidylarginine deiminase 4 (PAD4) is a nuclear citrullinating enzyme that is critically involved in the release of decondensed chromatin from neutrophils as neutrophil extracellular traps (NETs). NETs, together with fibrin, are implicated in host defense against pathogens; however, the formation of NETs (NETosis) has injurious effects that may outweigh their protective role. For example, PAD4 activity produces citrullinated neoantigens that promote autoimmune diseases, such as rheumatoid arthritis, to which PAD4 is genetically linked and where NETosis is prominent. NETs are also generated in basic sterile inflammatory responses that are induced by many inflammatory stimuli, including cytokines, hypoxia, and activated platelets. Mice that lack PAD4-deficient in NETosis-serve as an excellent tool with which to study the importance of NETs in disease models. In recent years, animal and human studies have demonstrated that NETs contribute to the etiology and propagation of many common noninfectious diseases, the focus of our review. We will discuss the role of NETs in thrombotic and cardiovascular disease, the induction of NETs by cancers and its implications for cancer progression and cancer-associated thrombosis, and elevated NETosis in diabetes and its negative impact on wound healing, and will propose a link between PAD4/NETs and age-related organ fibrosis. We identify unresolved issues and new research directions.-Wong, S. L., Wagner, D. D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging.

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“…Some of the most recent work has made it clear that combining PA encapsulation with magnetic localization, ultrasound, and hyperthermia may produce lysis rates up to an order of magnitude faster than those achievable using free PA. Engineered particles also allow for the delivery of two or more agents, which could be exploited to couple PA with other emerging thrombolytics targeted to von Willebrand factor, neutrophil extracellular traps, and thrombin‐activatable fibrinolysis inhibitor and PAI‐1; alternatively, PA could be delivered alongside adjuvants that enhance PA activity, PAI‐1 inhibitors, or FXIIIa inhibitors to accelerate thrombolysis …”

Section: Discussionmentioning

confidence: 99%

Engineered microparticles and nanoparticles for fibrinolysis

Disharoon

Marr

Neeves

2019

Journal of Thrombosis and Haemostasis

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Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the decades since their introduction into clinical practice, several limitations of have been identified in terms of both efficacy and bleeding risk associated with these agents. Engineered nanoparticles and microparticles address some of these limitations by improving circulation time, reducing inhibition and degradation in circulation, accelerating recanalization, improving targeting to thrombotic occlusions, and reducing off‐target effects; however, many particle‐based approaches have only been used in preclinical studies to date. This review covers four advances in coupling fibrinolytic agents with engineered particles: (a) modifications of plasminogen activators with macromolecules, (b) encapsulation of plasminogen activators and plasmin in polymer and liposomal particles, (c) triggered release of encapsulated fibrinolytic agents and mechanical disruption of clots with ultrasound, and (d) enhancing targeting with magnetic particles and magnetic fields. Technical challenges for the translation of these approaches to the clinic are discussed.

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Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke

Abstract: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02907736.

Cited by 258 publications

References 12 publications

Neutrophil extracellular traps in thrombi retrieved during interventional treatment of ischemic arterial diseases

Neutrophil extracellular traps in thrombi retrieved during interventional treatment of ischemic arterial diseases

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

Engineered microparticles and nanoparticles for fibrinolysis

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