Mechanical Stability and Fibrinolytic Resistance of Clots Containing Fibrin, DNA, and Histones

Longstaff, Colin; Varjú, Imre; Sótonyi, Péter; Szabó, László; Krumrey, Michael; Hoell, Armin; Bóta, Attila; Varga, Zoltán; Komorowicz, Erzsébet; Kolev, Krasimir

doi:10.1074/jbc.m112.404301

Cited by 227 publications

(285 citation statements)

References 36 publications

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“…Therefore, it was important to assess whether DNA modulates their effects. When complexed with DNA to resemble nucleosomes, histones maintained the inhibitory activity toward UFH and enoxaparin, although it was slightly less pronounced, probably because DNA was displaced by heparins (Longstaff et al, 2013). On the contrary, in the case of fondaparinux, histone-DNA complexes behaved differently from histones alone as they inhibited the anticoagulant and, even more, the profibrinolytic activity of the drug.…”

Section: Discussionmentioning

confidence: 96%

“…All the effects of histones, DNA, and histone-DNA on anticoagulants might occur in vivo, because histones and DNA, both circulating and resident in the thrombus scaffold, can exist either in complex or naked (Fuchs et al, 2010;Abrams et al, 2013;Longstaff et al, 2013), most probably as a result of a selective degradation by proteases and DNases.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of these new mediators is further confirmed by the abundance of extracellular histones and DNA in animal (Fuchs et al, 2010) and human (Savchenko et al, 2014) venous thrombi. Moreover, they have also been detected in human arterial thrombi (Longstaff et al, 2013), providing new clues for the pathogenesis of arterial thrombosis.…”

Section: Introductionmentioning

confidence: 94%

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Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran

Ammollo

Semeraro

Carratù

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator-mediated clot lysis by turbidimetry, and thrombinactivatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparins.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran

Ammollo

Semeraro

Carratù

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…130 During clot formation, NETs colocalize with fibrin and von Willebrand factor, 135 where they provide a scaffold for thrombi that are resistant to fibrinolysis. 136,137 They bind to platelets and endothelial cells, inducing their activation, which in turn escalates further NETosis. Histones are a major constituent of NETs, enhancing activation of coagulation.…”

Section: Neutrophil Extracellular Trapsmentioning

confidence: 99%

Cross Talk Pathways Between Coagulation and Inflammation

Foley

Conway

2016

Circulation Research

426

376

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Anatomic pathology studies performed over 150 years ago revealed that excessive activation of coagulation occurs in the setting of inflammation. However, it has taken over a century since these seminal observations were made to delineate the molecular mechanisms by which these systems interact and the extent to which they participate in the pathogenesis of multiple diseases. There is, in fact, extensive cross talk between coagulation and inflammation, whereby activation of one system may amplify activation of the other, a situation that, if unopposed, may result in tissue damage or even multiorgan failure. Characterizing the common triggers and pathways are key for the strategic design of effective therapeutic interventions. In this review, we highlight some of the key molecular interactions, some of which are already showing promise as therapeutic targets for inflammatory and thrombotic disorders. (Circ Res.

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“…At 18 h of clot lysis, the D-dimer concentration significantly increased in the control groups compared to IL-1β groups, which was in accordance with the loose and thicker clot network observed in the control groups under SEM and CM. This is further evidenced by the literature, which shows that fibrinolysis occurs much faster on a loose and thicker fibrin network rather than on a tight and thinner one (Longstaff et al, 2013;.…”

Section: Discussionmentioning

confidence: 58%

Manipulating fibrin structure of hematomas enhances large bone defects healing

Wang¹

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Mechanical Stability and Fibrinolytic Resistance of Clots Containing Fibrin, DNA, and Histones

Cited by 227 publications

References 36 publications

Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran

Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran

Cross Talk Pathways Between Coagulation and Inflammation

Manipulating fibrin structure of hematomas enhances large bone defects healing

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