FXIII Catalyses Histone-Fibrin Crosslinking to Inhibit Fibrinolysis

 

Histones and DNA released from activated immune cells in the form of extracellular traps play an important role in the response to infection by trapping and killing microbial pathogens. However, this may come at a cost, as histones cause significant collateral damage through their cytotoxic, pro-inflammatory, and procoagulant properties. Numerous studies have identified a link between high levels of circulating histones and poor prognosis in cerebrovascular and cardiovascular disease, and histones initiate and propagate venous and arterial thrombosis in animal models. High levels of histones have also been detected in the blood of COVID-19 patients, where they potentially contribute to microvascular thrombosis, organ failure, and death.

Histones bind fibrinogen and fibrin and have been identified in patient thrombi. In vitro studies have shown that histones increase clot stability and resistance to current thrombolytic therapies such as tissue plasminogen activator (tPA or alteplase), which work by dissolving fibrin networks. Matthew Locke, D.Phil., of the National Institute for Biological Standards and Control in the United Kingdom stated on Sunday during the Fibrinolysis and Proteolysis virtual session that his vision was to investigate this phenomenon further. Specifically, he wanted to determine the mechanisms behind the enhanced lytic stability of clots containing histones and investigate ways they can be broken down more efficiently by existing thrombolytics.

As he stated, histones delayed fibrinolysis by competitively inhibiting the key fibrinolytic enzyme plasmin to protect fibrin from degradation. This effect was enhanced by the covalent crosslinking of histones to the fibrin network by the transglutaminase FXIIIa, which has known roles in enhancing fibrin stability. Using FXIII-deficient plasma, FXIIIa inhibitors, and purified FXIII, it was shown that histones were less effective at delaying clot breakdown in the absence of FXIIIa activity. Excitingly, therapeutic doses of low molecular weight heparin, which binds histones with high affinity, prevented histone-fibrin crosslinking and rendered clots more susceptible to dissolution by tPA/alteplase.

Locke concluded that histones alter the structure and composition of fibrin to promote clot stability and fibrinolytic resistance, and that FXIIIa is responsible for mediating these effects by crosslinking histones to fibrin, where they inhibit plasmin. This suggests that targeting the FXIII-histone-fibrin axis with FXIIIa inhibitors and/or heparinoids could be an effective strategy to prevent thrombotic fibrin networks and thrombosis, which warrants further investigation.

Read the full abstract here.

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