Size‐ and charge‐dependent modulation of the lytic susceptibility and mechanical stability of fibrin‐histone clots by heparin and polyphosphate variants
| Autor: | László Szabó, Anna Tanka-Salamon, Attila Bóta, Nóra Balázs, Zoltán Varga, Colin Longstaff, Erzsébet Komorowicz, Krasimir Kolev |
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| Rok vydání: | 2021 |
| Předmět: |
Lysis
Plasmin medicine.medical_treatment 030204 cardiovascular system & hematology Tissue plasminogen activator Fibrin Histones 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Polyphosphates Fibrinolysis medicine Humans biology Heparin Polyphosphate Thrombosis Hematology Neutrophil extracellular traps Heparin Low-Molecular-Weight chemistry Tissue Plasminogen Activator biology.protein Biophysics medicine.drug |
| Zdroj: | Journal of Thrombosis and Haemostasis. 19:1307-1318 |
| ISSN: | 1538-7836 |
| DOI: | 10.1111/jth.15258 |
| Popis: | Background Neutrophil extracellular traps (NETs) containing DNA and histones are expelled from neutrophils in infection and thrombosis. Heparins, anticoagulant polyanions, can neutralize histones with a potential therapeutic advantage in sepsis. Polyphosphates, procoagulant polyanions, are released by platelets and microorganisms. Objectives To characterize the combined effects of NET components and polyanions on clot structure, mechanical properties and lytic susceptibility. Methods Scanning electron microscopy, pressure-driven permeation, turbidimetry, and oscillation rheometry were used for the characterization of the structure, viscoelasticity, and kinetics of formation and lysis of fibrin and plasma clots containing histones+/-DNA in combination with unfractionated heparin, its desulfated derivatives, low molecular weight heparin (LMWH), pentasaccharide, and polyphosphates of different sizes. Results Histones and DNA inhibited fibrin lysis by plasmin, but this behavior was not neutralized by negatively charged heparins or short polyphosphates. Rather, fibrin lysis was further inhibited by added polyanions. Histones inhibited plasma clot lysis by tissue plasminogen activator and the response to added heparin was size dependent. Unfractionated heparin, LMWH, and pentasaccharide had no effect, exacerbated, or reversed histone inhibition, respectively. Histones increased the mechanical strength of fibrin, which was exacerbated by smaller heparin and polyphosphate molecules. Histones increased fibrin diameter and pore size of fibrin clots and this effect was neutralized by all heparin variants but enhanced by polyphosphates. Conclusions Despite their common polyanionic character, heparins and polyphosphates exert distinct effects on fibrin mechanical and fibrinolytic stability. Anti-fibrinolytic effects of histones were more often enhanced by polyanions not counteracted. Careful selection of anti-histone strategies is required if they are to be combined with thrombolytic therapy. |
| Databáze: | OpenAIRE |
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