Abstract Number: OC 02.3
Meeting: ISTH 2020 Congress
Background: Histones released from activated or damaged and dying cells are associated with poor outcome in sepsis and cardiovascular and cerebrovascular disease. As major components of neutrophil extracellular traps (NETs), histones together with DNA are causally implicated in arterial, venous, and microvascular thrombosis by promoting coagulation and enhancing clot stability. Their presence in patient thrombi is a potential obstacle to effective thrombolytic therapy.
Aims: To determine the mechanisms behind the enhanced lytic stability of clots containing histones.
Methods: Fibrinolytic assays with purified components, plasma and whole blood (ROTEM®) were supported by kinetic and biochemical studies with FXIIIa inhibitors, recombinant proteins, and deficient plasmas.
Results: Although histones stimulated plasminogen activation by tPA in solution, they delayed fibrinolysis by competitively inhibiting plasmin to protect fibrin from degradation. Histones were noncovalently and covalently associated with fibrin isolated from clotted blood but not from FXIIIa-deficient plasma (Figure 1). Covalent interactions were abolished by FXIIIa inhibitors and restored by purified FXIII. All histones subtypes (H1, H2A, H2B, H3, and H4), expressed as recombinant his-tagged proteins, were directly crosslinked to fibrin by FXIIIa. The antifibrinolytic and clot-strengthening effects of histones were largely negated by FXIIIa inhibition (Figure 2). Therapeutic doses of low molecular weight heparin bound histones and prevented covalent but not noncovalent histone-fibrin interactions and neutralised their antifibrinolytic potency.
Conclusions: DNase is proposed to dismantle NETs and improve thrombolysis. However, histones remain and alter the structure and composition of fibrin to promote clot stability and fibrinolytic resistance. FXIIIa is responsible for mediating these effects by crosslinking histones to fibrin, where they inhibit plasmin. Our findings provide a rationale for targeting the FXIII-histone-fibrin axis with FXIIIa inhibitors and heparinoids to improve thrombolysis and prevent thrombosis. They also emphasise that thrombi are complex mixtures of cells and cell-derived factors, the electrostatic and covalent crosslinking of which are under-explored factors in clot stability.
To cite this abstract in AMA style:Locke M, Longstaff C. FXIII Catalyses Histone-Fibrin Crosslinking to Inhibit Fibrinolysis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/fxiii-catalyses-histone-fibrin-crosslinking-to-inhibit-fibrinolysis/. Accessed May 6, 2021.
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