Neutralization of heparin by histone and its subfractions

Pal, Pranab K.; Starr, Toby; Gertler, Menard M.

doi:10.1016/0049-3848(83)90008-7

Cited by 30 publications

(28 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upon interaction with histone H4, the fluorescence of prothrombin decreases 30% and produces binding curves with an apparent equilibrium dissociation constant K d,app ϭ 9 Ϯ 1 nM and a stoichiometry N ϭ 1.2 Ϯ 0.1 indicating binding to a single site. Binding of histone H4 is reversed completely by addition of heparin that is known to interact strongly with histones (30).…”

Section: Resultsmentioning

confidence: 94%

Histone H4 Promotes Prothrombin Autoactivation

Barranco-Medina¹,

Pozzi²,

Vogt

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 94%

Histone H4 Promotes Prothrombin Autoactivation

Barranco-Medina¹,

Pozzi²,

Vogt

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The effect of heparin was also observed in medium, indicating a direct interaction of heparin with the NETs (Movie S3). Heparin has high affinity for histones (17) and releases histones from chromatin (18). Consequently, incubation of NETs under static conditions with heparin or DNase alone released histones to the culture supernatant (Fig.…”

Section: Resultsmentioning

confidence: 99%

Extracellular DNA traps promote thrombosis

Fuchs

Brill

Duerschmied

et al. 2010

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

2,062

2,083

View full text Add to dashboard Cite

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

show abstract

“…Also histones, as basic proteins, can bind with high affinity to UFH and offset its antithrombin activity (Pal et al, 1983). However, evidence that histones affect the antithrombotic potential of anticoagulants other than UFH is limited to a report showing that nuclear material from cancer cells containing histones interferes with the activity of LMWHs (Morita et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Neutralization of heparin by histone and its subfractions

Cited by 30 publications

References 17 publications

Histone H4 Promotes Prothrombin Autoactivation

Histone H4 Promotes Prothrombin Autoactivation

Extracellular DNA traps promote thrombosis

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

Contact Info

Product

Resources

About