Extracellular Vesicles and Citrullinated Histone H3 in Coronavirus Disease 2019 Patients

Ludwig Traby; Marietta Kollars; Manuel Kussmann; Matthias Karer; Hana Šinkovec; Elisabeth Lobmeyr; Alexander Hermann; Thomas Staudinger; Peter Schellongowski; Bernhard Rössler; Heinz Burgmann; Paul A. Kyrle; Sabine Eichinger

doi:10.1055/a-1522-4131

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2022; 122(01): 113-122
DOI: 10.1055/a-1522-4131

Blood Cells, Inflammation and Infection

Extracellular Vesicles and Citrullinated Histone H3 in Coronavirus Disease 2019 Patients

Ludwig Traby

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Marietta Kollars

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Manuel Kussmann

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Matthias Karer

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Hana Šinkovec

²Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria

,

Elisabeth Lobmeyr

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Alexander Hermann

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Thomas Staudinger

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Peter Schellongowski

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Bernhard Rössler

³Medical Simulation and Emergency Management Research Group, Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna, Austria

,

Heinz Burgmann

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Paul A. Kyrle

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

,

Sabine Eichinger

¹Department of Medicine I, Medical University of Vienna, Vienna, Austria

› Author Affiliations

Abstract

Objectives Pulmonary thrombus formation is a hallmark of coronavirus disease 2019 (COVID-19). A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear.

Methods We studied 41 adult COVID-19 patients with positive results on reverse-transcriptase polymerase-chain-reaction assays and 37 sex- and age-matched healthy controls. Number and surface characteristics of extracellular vesicles (EVs) and citrullinated histone H3 levels were determined in plasma upon inclusion by flow cytometry and immunoassay.

Results In total, 20 patients had severe and 21 nonsevere disease. The number of EV (median [25th, 75th percentile]) was significantly higher in patients compared with controls (658.8 [353.2, 876.6] vs. 435.5 [332.5, 585.3], geometric mean ratio [95% confidence intervals]: 2.6 [1.9, 3.6]; p < 0.001). Patients exhibited significantly higher numbers of EVs derived from platelets, endothelial cells, leukocytes, or neutrophils than controls. EVs from alveolar-macrophages and alveolar-epithelial cells were detectable in plasma and were significantly higher in patients. Intercellular adhesion molecule-1-positive EV levels were higher in patients, while no difference between tissue factor-positive and angiotensin-converting enzyme-positive EV was seen between both groups. Levels of EV did not differ between patients with severe and nonsevere COVID-19. Citrullinated histone H3 levels (ng/mL, median [25th, 75th percentile]) were higher in patients than in controls (1.42 [0.6, 3.4] vs. 0.31 [0.1, 0.6], geometric mean ratio: 4.44 [2.6, 7.7]; p < 0.001), and were significantly lower in patients with nonsevere disease compared with those with severe disease.

Conclusion EV and citrullinated histone H3 are associated with COVID-19 and could provide information regarding pathophysiology of the disease.

Keywords

COVID-19 - extracellular vesicles - NETs - coagulation activation - ARDS - immunothrombosis - citrullinated histone H 3

Full Text

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Supplementary Material

Supplementary Material