Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo

Müller, Felicitas; Mutch, Nicola J.; Schenk, Wolfdieter A.; Smith, Stephanie A.; Esterl, Lucie; Spronk, Henri M. H.; Schmidbauer, Stefan; Gahl, William A.; Morrissey, James H.; Renné, Thomas

doi:10.1016/j.cell.2009.11.001

Cited by 734 publications

(951 citation statements)

References 39 publications

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“…S4), and it is conceivable that NETs interact closely with fibrin strands in the thrombus, thus potentially influencing thrombus organization and stability. Given the procoagulant activity of nucleic acids (28) and polyphosphates (29), future studies should address whether NETs promote coagulation, how NETs affect the mechanical properties of fibrin (2), and the susceptibility of clots to thrombolysis.…”

Section: Discussionmentioning

confidence: 99%

Extracellular DNA traps promote thrombosis

Fuchs

Brill

Duerschmied

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

2,028

2,083

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Neutrophil extracellular traps (NETs) are part of the innate immune response to infections. NETs are a meshwork of DNA fibers comprising histones and antimicrobial proteins. Microbes are immobilized in NETs and encounter a locally high and lethal concentration of effector proteins. Recent studies show that NETs are formed inside the vasculature in infections and noninfectious diseases. Here we report that NETs provide a heretofore unrecognized scaffold and stimulus for thrombus formation. NETs perfused with blood caused platelet adhesion, activation, and aggregation. DNase or the anticoagulant heparin dismantled the NET scaffold and prevented thrombus formation. Stimulation of platelets with purified histones was sufficient for aggregation. NETs recruited red blood cells, promoted fibrin deposition, and induced a red thrombus, such as that found in veins. Markers of extracellular DNA traps were detected in a thrombus and plasma of baboons subjected to deep vein thrombosis, an example of inflammation-enhanced thrombosis. Our observations indicate that NETs are a previously unrecognized link between inflammation and thrombosis and may further explain the epidemiological association of infection with thrombosis.neutrophils | platelets | histones | red blood cells | chromatin

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Section: Discussionmentioning

confidence: 99%

Extracellular DNA traps promote thrombosis

Fuchs

Brill

Duerschmied

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

2,028

2,083

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“…Besides negatively charged artificial surfaces, several 'natural' surfaces have been proposed to activate FXII in vivo, such as amyloid aggregates (Yasuhara et al, 1994;Bergamaschini et al, 1998Bergamaschini et al, , 2001), polyphosphates (Smith et al, 2006;Mü ller et al, 2009), collagen (Meijden et al, 2009) and misfolded proteins (Maas, GoversRiemslag et al, 2008). Remarkably, not all of these surfaces result in activation of both the intrinsic coagulation pathway and the kallikrein-kinin system.…”

Section: Introductionmentioning

confidence: 99%

The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS

Beringer

Kroon-Batenburg

2013

Acta Cryst Sect F

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Coagulation factor XII (FXII) is a key protein in the intrinsic coagulation and kallikrein-kinin pathways. It has been found that negative surfaces and amyloids, such as A fibrils, can activate FXII. Additionally, it has been suggested that FXII simulates cells and that it plays an important role in thrombosis. To date, no structural data on FXII have been deposited, which makes it difficult to support any hypothesis on the mechanism of FXII function. The crystal structure of the FnI-EGF-like tandem domain of FXII presented here was solved using experimental phases. To determine the phases, a SIRAS approach was used with a native and a holmium chloride-soaked data set. The holmium cluster was coordinated by the C-terminal tails of two symmetryrelated molecules. Another observation was that the FnI domain was much more ordered than the EGF-like domain owing to crystal packing. Furthermore, the structure shows the same domain orientation as the homologous FnI-EGFlike tandem domain of tPA. The plausibility of several proposed interactions of these domains of FXII is discussed. Based on this FXII FnI-EGF-like structure, it could be possible that FXII binding to amyloid and negatively charged surfaces is mediated via this part of FXII.

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“…Polyphosphates can also inhibit the activity of tissue factor pathway inhibitor (TFPI) and accelerate the activity of thrombin-activatable fibrinolysis inhibitor (TAFI) (12,13). In the blood of hemophilia A and B patients and Hermansky-Pudlak syndrome patients, polyphosphates significantly reduce the clotting times (14). Moreover, platelet polyphosphates have also been reported to be proinflammatory and polyphosphate-factor XII binding results in the release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing (14).…”

mentioning

confidence: 99%

Nucleic acid scavengers inhibit thrombosis without increasing bleeding

Jain

Pitoc

Holl

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

102

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Development of effective, yet safe, antithrombotic agents has been challenging because such agents increase the propensity of patients to bleed. Recently, naturally occurring polyphosphates such as extracellular DNA, RNA, and inorganic polyphosphates have been shown to activate blood coagulation. In this report, we evaluate the anticoagulant and antithrombotic activity of nucleic acid-binding polymers in vitro and in vivo. Such polymers bind to DNA, RNA, and inorganic polyphosphate molecules with high affinity and inhibit RNA- and polyphosphate-induced clotting and the activation of the intrinsic pathway of coagulation in vitro. Moreover, [NH 2 (CH 2 ) 2 NH 2 ]∶(G = 3);dendri PAMAM(NH 2 ) 32 (PAMAM G-3) prevents thrombosis following carotid artery injury and pulmonary thromboembolism in mice without significantly increasing blood loss from surgically challenged animals. These studies indicate that nucleic acid-binding polymers are able to scavenge effectively prothrombotic nucleic acids and other polyphosphates in vivo and represent a new and potentially safer class of antithrombotic agents.

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Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo

Cited by 734 publications

References 39 publications

Extracellular DNA traps promote thrombosis

Extracellular DNA traps promote thrombosis

The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS

Nucleic acid scavengers inhibit thrombosis without increasing bleeding

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