دورية أكاديمية
Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19.
| العنوان: | Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19. |
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| المؤلفون: | Eustes AS; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Ahmed A; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Swamy J; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Patil G; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Jensen M; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Wilson KM; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Kudchadkar S; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Wahab A; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Perepu U; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Miller FJ Jr; Department of Internal Medicine, Vanderbilt University Medical Center and VA Medical Center, Nashville, Tennessee, USA., Lentz SR; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA., Dayal S; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA; Iowa City VA Healthcare System, Iowa City, Iowa, USA. Electronic address: sanjana-dayal@uiowa.edu. |
| المصدر: | Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2024 Sep; Vol. 22 (9), pp. 2514-2530. Date of Electronic Publication: 2024 May 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: England NLM ID: 101170508 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7836 (Electronic) Linking ISSN: 15387836 NLM ISO Abbreviation: J Thromb Haemost Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2023- : [New York] : Elsevier Original Publication: Oxford : Blackwell Pub. |
| مواضيع طبية MeSH: | Blood Platelets*/metabolism , COVID-19*/blood , COVID-19*/complications , Extracellular Vesicles*/metabolism , Histones*/blood , Platelet Activation* , Thrombosis*/blood , Thrombosis*/etiology, Adult ; Animals ; Female ; Humans ; Male ; Mice ; Middle Aged ; Blood Coagulation ; Case-Control Studies ; Citrullination ; Mice, Inbred C57BL ; Nucleosomes/metabolism ; Thrombin/metabolism ; Clinical Trials, Phase IV as Topic |
| مستخلص: | Background: COVID-19 can cause profound inflammation and coagulopathy, and while many mechanisms have been proposed, there is no known common pathway leading to a prothrombotic state. Objectives: From the beginning of the COVID-19 pandemic, elevated levels of extracellular histones have been found in plasma of patients infected with SARS-CoV-2. We hypothesized that platelet activation triggered by extracellular histones might represent a unifying mechanism leading to increased thrombin generation and thrombosis. Methods: We utilized blood samples collected from an early clinical trial of hospitalized COVID-19 patients (NCT04360824) and recruited healthy subjects as controls. Using plasma samples, we measured the procoagulant and prothrombotic potential of circulating extracellular histones and extracellular vesicles (EVs). Platelet prothrombotic activity was assessed via thrombin generation potential and platelet thrombus growth. Circulating EVs were assessed for thrombin generation potential in vitro in plasma and enhancement of thrombotic susceptibility in vivo in mice. Results: Compared with controls, COVID-19 patients had elevated plasma levels of citrullinated histone H3, cell-free DNA, nucleosomes, and EVs. Plasma from COVID-19 patients promoted platelet activation, platelet-dependent thrombin generation, thrombus growth under venous shear stress, and release of platelet-derived EVs. These prothrombotic effects of COVID-19 plasma were inhibited by an RNA aptamer that neutralizes both free and DNA-bound histones. EVs isolated from COVID-19 plasma enhanced thrombin generation in vitro and potentiated venous thrombosis in mice in vivo. Conclusion: We conclude that extracellular histones and procoagulant EVs drive the prothrombotic state in COVID-19 and that histone-targeted therapy may prove beneficial. Competing Interests: Declaration of competing interests There are no competing interests to disclose. (Published by Elsevier Inc.) |
| معلومات مُعتمدة: | R01 AI162778 United States AI NIAID NIH HHS; T32 HL007344 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: COVID-19; extracellular vesicles; histones; thrombin generation; thrombosis |
| المشرفين على المادة: | 0 (Histones) 0 (Nucleosomes) EC 3.4.21.5 (Thrombin) |
| تواريخ الأحداث: | Date Created: 20240530 Date Completed: 20240822 Latest Revision: 20240823 |
| رمز التحديث: | 20240823 |
| DOI: | 10.1016/j.jtha.2024.05.019 |
| PMID: | 38815756 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7836 |
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| DOI: | 10.1016/j.jtha.2024.05.019 |