Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19

Alicia S. Eustes; Azaj Ahmed; Jagadish Swamy; Gokul Patil; Melissa Jensen; Katina M. Wilson; Shibani Kudchadkar; Abdul Wahab; Usha Perepu; Francis J. Miller; Steven R. Lentz; Sanjana Dayal

doi:10.1016/j.jtha.2024.05.019

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Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19

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Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19

Alicia S. Eustes, Azaj Ahmed, Jagadish Swamy, Gokul Patil, Melissa Jensen, Katina M. Wilson, Shibani Kudchadkar, Abdul Wahab, Usha Perepu, Francis J. Miller, …

Journal of thrombosis and haemostasis, Vol.22(9), pp.2514-2530

05/28/2024

DOI: 10.1016/j.jtha.2024.05.019

PMCID: PMC11343660

PMID: 38815756

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Abstract

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. 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. 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. Compared to 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. We conclude that extracellular histones and procoagulant EVs drive the prothrombotic state in COVID-19 and that histone-targeted therapy may prove beneficial.

and thrombosis

COVID-19

extracellular vesicles

histones

thrombin generation

Details

Title: Subtitle: Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19
Creators: Alicia S. Eustes - University of Iowa
Azaj Ahmed - University of Iowa
Jagadish Swamy - University of Iowa
Gokul Patil - University of Iowa
Melissa Jensen - University of Iowa
Katina M. Wilson - University of Iowa, Internal Medicine
Shibani Kudchadkar - Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
Abdul Wahab - Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
Usha Perepu - University of Iowa
Francis J. Miller - Vanderbilt University Medical Center
Steven R. Lentz - University of Iowa
Sanjana Dayal - University of Iowa
Resource Type: Journal article
Publication Details: Journal of thrombosis and haemostasis, Vol.22(9), pp.2514-2530
Publisher: Elsevier Inc
DOI: 10.1016/j.jtha.2024.05.019
PMID: 38815756
PMCID: PMC11343660
ISSN: 1538-7836
eISSN: 1538-7836
Grant note: National Institutes of Health awards: R01AI162778, R01 AG049784, T32HL007344 Department of Veterans Affairs grant: I01CX001932 American HeartAssociation awards: 19TPA34900002, 24POST1195019
This work was supported by funding from National Institutes of Health awards R01AI162778, R01 AG049784, and T32HL007344; Department of Veterans Affairsgrant I01CX001932; American HeartAssociation awards 19TPA34900002 and24POST1195019; and a pilot grant from the Roy J. Carver Charitable Trust. We acknowledge support from University of Iowa Flow Cytometry Facility, which is funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Iowa City Veteran's Administration Medical Center
Language: English
Electronic publication date: 05/28/2024
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984634258802771

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