ArticleJournal of thrombosis and haemostasis : JTH2011
Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation.
Article in Journal of thrombosis and haemostasis : JTH, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 208 papers, 1 of them a synthesis that pooled it.
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Who cites it
208 citing papers in PubMed, 1 synthesis or guideline pooled it, 378 citations in OpenAlex.
- The prognostic utility of protein C as a biomarker for adult sepsis: a systematic review and meta-analysis.Critical care (London, England) · 2022Pooled it
- Complement activation and fibrinolysis dysregulation drive contrast-induced acute kidney injury: a 4D proteomics rat study.Renal failure · 2026Article
- Microbial proteases and endothelial barrier disruption in sepsis: A neglected nexus.Virulence · 2026Review
- The Acute Respiratory Distress Syndrome (ARDS): epidemiology, etiology, molecular mechanisms, diagnosis and therapeutic strategies.Molecular biomedicine · 2026Review
- Review
- Emerging biomodels to understand the pathophysiology of sepsis and evaluate new therapeutic strategies targeting extracellular histones.Materials today. Bio · 2026Review
- Neutrophil extracellular traps: A central player in liver diseases.Hepatology communications · 2026Review
- Barrier breakdown: lung-brain crosstalk in systemic inflammation.Journal of neuroinflammation · 2026Review
- Endotheliopathy within the thromboinflammatory network of sepsis-induced coagulopathy.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Regulation of histones in thromboinflammation.Frontiers in immunology · 2026Review
- Neutrophil extracellular traps in atherosclerosis: current evidence and therapeutic potential of plant-derived metabolites.Frontiers in pharmacology · 2026Review
- Neutrophil extracellular traps in diabetic wound healing: mechanisms, pathological roles, and therapeutic implications.Burns & trauma · 2026Review
- The Role of Histone Modifications in Acute Lung Injury: Molecular Mechanisms and Potential of Traditional Chinese Medicine Treatment.Journal of inflammation research · 2026Review
- Neutrophil extracellular traps in the animal model of adenine-induced chronic kidney disease.PloS one · 2026Article
- Review
- Neutrophil extracellular traps-targeting therapy with deoxyribonuclease 1 reduces large vessel occlusion-induced downstream microvascular thromboinflammation in a rat model of stroke.Research and practice in thrombosis and haemostasis · 2025Article
- Article
- Unraveling NETs in Sepsis: From Cellular Mechanisms to Clinical Relevance.International journal of molecular sciences · 2025Review
- Role of platelets and NETs in arterial thrombosis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Kringle-Dependent Inhibition of Plasmin-Mediated Fibrinolysis by Native and Citrullinated Core Histones.International journal of molecular sciences · 2025Article
148 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHistones are basic proteins that contribute to cell injury and tissue damage when released into the extracellular space. They have been attributed a prothrombotic activity, because their injection into mice induces diffuse microvascular thrombosis. The protein C-thrombomodulin (TM) system is a fundamental regulator of coagulation, particularly in the microvasculature, and its activity can be differentially influenced by interaction with several cationic proteins.
objectiveTo evaluate the effect of histones on the protein C-TM system in a plasma thrombin generation assay and in purified systems.
methodsThe effect of histones on plasma thrombin generation in the presence or absence of TM was analyzed by calibrated automated thrombinography. Protein C activation in purified systems was evaluated by chromogenic substrate cleavage. The binding of TM and protein C to histones was evaluated by solid-phase binding assay.
resultsHistones dose-dependently increased plasma thrombin generation in the presence of TM, independently of its chondroitin sulfate moiety. This effect was not caused by inhibition of activated protein C activity, but by the impairment of TM-mediated protein C activation. Histones were able to bind to both protein C and TM, but the carboxyglutamic acid domain of protein C was required for their effect. Histones H4 and H3 displayed the highest activity. Importantly, unlike heparin, DNA did not inhibit the potentiating effect of histones on thrombin generation.
conclusionsHistones enhance plasma thrombin generation by reducing TM-dependent protein C activation. This mechanism might contribute to microvascular thrombosis induced by histones in vivo at sites of organ failure or severe inflammation.
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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.