Abstract Number: OC 71.4
Meeting: ISTH 2021 Congress
Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors
Background: Neutrophil extracellular traps (NETs) contribute to coagulation and endothelial injury in vascular diseases such as thrombosis and sepsis. NETs consist of DNA, histones, and antimicrobial peptides, which aid in host defense by killing pathogens. However, histones can also exert harmful effects. Histones are cytotoxic to cells and can impair the protein C (PC) anticoagulant pathway. Furthermore, histones induce a procoagulant phenotype in monocytes through the expression of tissue factor (TF) and phosphatidylserine (PS).
Aims: To explore the effectiveness of glycosaminoglycans (GAGs) in neutralizing the procoagulant and cytotoxic activities of histones.
Methods: The GAGs used were unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), Vasoflux (lacks the antithrombin-binding pentasaccharide), and fondaparinux. Binding affinities between GAGs and histones were determined by Bio-layer Interferometry. The ability of GAGs to diminish the procoagulant effect of histones was studied by treating monocytes with histones +/- GAGs. TF, PS, and propidium iodide (PI) was measured via flow cytometry. Histone-mediated impairment of APC generation was studied by incubating TM- and EPCR-expressing HEK293 cells with histones +/- GAGs, and quantifying APC.
Results: UFH, LMWH, and Vasoflux bound histones with high affinities (KD < 1×10-3 nM to 86 nM), whereas fondaparinux exhibited a low affinity (KD > 8 mM). Treatment of monocytes with histones resulted in increased levels of TF, PS, and PI. These effects were attenuated with UFH, LMWH, or Vasoflux. Treatment of TM- and EPCR-expressing cells with histones resulted in reduced conversion of PC to APC. The addition of UFH, LMWH, or Vasoflux neutralized these effects. In contrast, fondaparinux had no protective effects against histones.
Conclusions: The ability of GAGs to reduce the procoagulant and cytotoxic effects of histones is size-dependent but independent of its anticoagulant activity. Our findings suggest that GAGs (UFH, LMWH, and Vasoflux) may have therapeutic potential in neutralizing the adverse effects of histones in vascular diseases.
To cite this abstract in AMA style:
Sharma N, Sohrabipour S, Dwivedi D, Liaw P. Modulation of the Procoagulant and Cytotoxic Effects of Histones by Glycosaminoglycans [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/modulation-of-the-procoagulant-and-cytotoxic-effects-of-histones-by-glycosaminoglycans/. Accessed March 22, 2024.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/modulation-of-the-procoagulant-and-cytotoxic-effects-of-histones-by-glycosaminoglycans/