Investigations of the effectiveness of heparin variants as inhibitors of histones

• Published in: Journal of thrombosis and haemostasis 2022-06, Vol.20 (6), p.1485-1495
• Main Authors: Sharma, Neha, Haggstrom, Lauren, Sohrabipour, Sahar, Dwivedi, Dhruva J., Liaw, Patricia C.
• Format: Article
• Language: English
• Subjects: Animal models; Anticoagulants; Antithrombin; Cell surface; Cytotoxicity; Endothelial cells; extracellular histones; fondaparinux; Heparin; Histones; low‐molecular‐weight heparin; Monocytes; Phosphatidylserine; Sepsis; Tissue factor; unfractionated heparin; Vascular diseases; Vasoflux
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.15706

Background Extracellular histones exert cytotoxic and procoagulant effects which contribute to immunothrombosis in vascular diseases such as sepsis. Heparin has been shown to neutralize the pathologic effects of histones in vitro and in animal models. Objectives To compare the effectiveness of unfractionated heparin (UFH), low‐molecularweight heparin (LMWH), Vasoflux (lacks anticoagulant activity), and fondaparinux in neutralizing the cytotoxic and procoagulant activities of histones Methods Binding affinities between heparin variants and histone subunits were determined by Bio‐layer Interferometry. The ability of heparin variants to diminish the cytotoxic and procoagulant effects of histones was studied by treating endothelial cells or monocytic THP‐1 cells with histones ± heparin variants. Results Unfractionated heparin, LMWH, and Vasoflux bind histone subunits with high affinities (Kd 1.7 kDa and is independent of the antithrombin‐binding pentasaccharide. In contrast, the ability of heparin to neutralize histone‐mediated impairment of APC generation is independent of size and anticoagulant activity. These findings suggest that heparin variants may have differential therapeutic potential in vascular diseases associated with elevated levels of histones.