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Decreased DNase activity in severe COVID-19 correlates with increased circulating NET burden

1KU Leuven, Leuven, Vlaams-Brabant, Belgium, 2Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 3Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Vlaams-Brabant, Belgium, 4Center for Molecular and Vascular Biology, University of Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 5Laboratory for Clinical Infectious and Inflammatory Disorders, UZ Leuven, Leuven, Vlaams-Brabant, Belgium, 6Laboratory of Clinical Microbiology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Vlaams-Brabant, Belgium, 7Department of Pneumology, UZ Leuven; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Vlaams-Brabant, Belgium, 8Invasive Cardiology, University Hospital Basel; Department of Cardiology and Angiology I, University Heart Center, Freiburg-Bad Krozingen; Faculty of Medicine, University of Freiburg, Freiburg, Germany, Freiburg, Baden-Wurttemberg, Germany, 9Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Vascular Medicine and Hemostasis, University Hospitals Leuven, Leuven, Belgium, Leuven, Vlaams-Brabant, Belgium, 10Medical Intensive Care Unit, Department of Internal Medicine, UZ Leuven; Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Vlaams-Brabant, Belgium

Abstract Number: OC 57.4

Meeting: ISTH 2022 Congress

Theme: COVID and Coagulation » COVID and Coagulation, Clinical

Background: COVID-19 represents a “perfect storm” for release of neutrophil extracellular traps (NETs) and resultant pathology from immunothrombosis. Levels of NETs in circulation are regulated by endogenous plasma DNases, which have been shown to be reduced in various diseases including myocardial infarction and sepsis. We previously reported elevated NET biomarkers in admission samples from our first wave study cohort.

Aims: To characterize DNase activity and biomarkers of released NETs in the context of COVID-19 immunothrombosis.

Methods: With ethical permission and informed consent, we prospectively collected citrated platelet-poor plasma samples from patients admitted to the COVID ward (55 patients) or intensive care unit (216 patients) from March 2020-December 2021 as part of the COntAGIouS trial at UZ Leuven in Belgium (NCT04327750), with special attention paid to sample preparation and storage to preserve NET fragments and DNase activity. Consecutive samples were obtained within 48 hours of admission, between days 6-8, and upon hospital or ICU discharge. Analysis was batch-performed for MPO, MPO-DNA, PF4, sP-selectin, citrullinated histones, DNase activity, VWF:Ag, and FVIII:Ag levels.

Results: In ICU patients, MPO, VWF, sP-selectin, and NET biomarkers were elevated throughout hospitalization, peaking at day 6-8 after admission, whereas PF4 and FVIII remained highly elevated through the time of ICU discharge. DNase activity was decreased in admission samples, normalized at day 6-8, and strongly increased at the time of discharge, indicating a potential compensatory mechanism. DNase activity was negatively correlated with MPO-DNA values (r = -0.29, P=0.0013). sPselectin and NET levels were significantly higher in admission samples for patients who experienced a thrombotic event in the period during hospitalization, including pulmonary embolism, DVT, myocardial infarction, and/or stroke.

Conclusion(s): Elevated NET levels and decreased DNase activity in plasma are correlated in severe COVID-19, together with elevated markers of thrombotic risk. Approaches to restore DNase activity in plasma may be beneficial in COVID-19-associated immunothrombosis.

To cite this abstract in AMA style:

Martens C, Kraisin S, Velásquez Pereira L, Lavend'homme R, Jacobs C, Vanderbeke L, Wauters E, Verhamme P, Witsch T, Jacquemin M, Wauters J, Martinod K. Decreased DNase activity in severe COVID-19 correlates with increased circulating NET burden [abstract]. https://abstracts.isth.org/abstract/decreased-dnase-activity-in-severe-covid-19-correlates-with-increased-circulating-net-burden/. Accessed October 1, 2023.

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