ArticleThrombosis and haemostasis2021
Extracellular Histones Inhibit Fibrinolysis through Noncovalent and Covalent Interactions with Fibrin.
Article in Thrombosis and haemostasis, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.
- Neutrophil extracellular traps correlate with severity and prognosis in patients with ischemic stroke: a systematic review and meta-analysis.Acta neurologica Belgica · 2024Pooled it
- Thrombolytic resistance: an important factor leading to the failure of intravenous thrombolytic therapy.Journal of neurology · 2026Review
- Emerging biomodels to understand the pathophysiology of sepsis and evaluate new therapeutic strategies targeting extracellular histones.Materials today. Bio · 2026Review
- Monitoring anti-Xa levels and thromboelastography in puerperal venous thromboembolism: a prospective cohort study.Frontiers in medicine · 2026Article
- Sepsis-induced coagulopathy: recent insights on the role and clinical application of neutrophil extracellular trap formation.Scientific reports · 2025Article
- Thrombus Composition and the Evolving Role of Tenecteplase in Acute Ischemic Stroke.Journal of clinical medicine · 2025Article
- M1 protein from group ABlood vessels, thrombosis & hemostasis · 2025Article
- Kringle-Dependent Inhibition of Plasmin-Mediated Fibrinolysis by Native and Citrullinated Core Histones.International journal of molecular sciences · 2025Article
- Disseminated intravascular coagulation.Journal of intensive care · 2025Review
- Degradation rather than disassembly of necrotic debris is essential to enhance recovery after acute liver injury.Cellular and molecular life sciences : CMLS · 2025Article
- Systemic mechanisms of necrotic cell debris clearance.Cell death & disease · 2024Review
- Blood Clot Dynamics and Fibrinolysis Impairment in Cancer: The Role of Plasma Histones and DNA.Cancers · 2024Article
- Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review.Frontiers in immunology · 2024Review
- pH-Responsive Theranostic Colloidosome Drug Carriers Enable Real-Time Imaging of Targeted Thrombolytic Process with Near-Infrared-II for Deep Venous Thrombosis.Research (Washington, D.C.) · 2024Article
- Maintaining the balance: the critical role of plasmin activity in orthopedic surgery injury response.Journal of thrombosis and haemostasis : JTH · 2023Review
- Novel mechanisms of thrombo-inflammation during infection: spotlight on neutrophil extracellular trap-mediated platelet activation.Research and practice in thrombosis and haemostasis · 2023Article
- DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase.Frontiers in immunology · 2023Article
- Article
- Clot Morphology in Acute Ischemic Stroke Decision Making.International journal of molecular sciences · 2022Review
- The Applicability of Current Turbidimetric Approaches for Analyzing Fibrin Fibers and Other Filamentous Networks.Biomolecules · 2022Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.