Thromb Haemost 2021; 121(04): 464-476
DOI: 10.1055/s-0040-1718760
Coagulation and Fibrinolysis

Extracellular Histones Inhibit Fibrinolysis through Noncovalent and Covalent Interactions with Fibrin

1  Biotherapeutics Division, National Institute for Biological Standards and Control, South Mimms, Hertfordshire, United Kingdom
,
Colin Longstaff
1  Biotherapeutics Division, National Institute for Biological Standards and Control, South Mimms, Hertfordshire, United Kingdom
› Author Affiliations

Abstract

Histones released into circulation as neutrophil extracellular traps are causally implicated in the pathogenesis of arterial, venous, and microvascular thrombosis by promoting coagulation and enhancing clot stability. Histones induce structural changes in fibrin rendering it stronger and resistant to fibrinolysis. The current study extends these observations by defining the antifibrinolytic mechanisms of histones in purified, plasma, and whole blood systems. Although histones stimulated plasminogen activation in solution, they inhibited plasmin as competitive substrates. Protection of fibrin from plasmin digestion is enhanced by covalent incorporation of histones into fibrin, catalyzed by activated transglutaminase, coagulation factor FXIII (FXIIIa). All histone subtypes (H1, H2A, H2B, H3, and H4) were crosslinked to fibrin. A distinct, noncovalent mechanism explains histone-accelerated lateral aggregation of fibrin protofibrils, resulting in thicker fibers with higher mass-to-length ratios and in turn hampered fibrinolysis. However, histones were less effective at delaying fibrinolysis in the absence of FXIIIa activity. Therapeutic doses of low-molecular-weight heparin (LMWH) prevented covalent but not noncovalent histone–fibrin interactions and neutralized the effects of histones on fibrinolysis. This suggests an additional antithrombotic mechanism for LMWH beyond anticoagulation. In conclusion, for the first time we report that histones are crosslinked to fibrin by FXIIIa and promote fibrinolytic resistance which can be overcome by FXIIIa inhibitors and histone-binding heparinoids. These findings provide a rationale for targeting the FXIII–histone–fibrin axis to destabilize fibrin and prevent potentially thrombotic fibrin networks.

Supplementary Material



Publication History

Received: 25 April 2020

Accepted: 15 September 2020

Publication Date:
01 November 2020 (online)

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