PB0595 - Factor XII activation by NET accumulation aggravates COVID-19-associated pulmonary thrombo-inflammation

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Hanna Englert, MSc

PhD Candidate
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany

Co-Author(s)

CR

Chandini Rangaswamy

Postdoc
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
Carsten Deppermann, PhD

Assistant Professor
University Medical Centre Mainz
Mainz, Rheinland-Pfalz, Germany
JS

Jan-Peter Sperhake

MD
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
CK

Christoph Krisp

Postdoc
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
DS

Danny Schreier

Technician
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
EG

Emma Gordon

Senior Scientist
Institute for Molecular Bioscience, Division of Cell and Developmental Biology, The University of Queensland
Brisbane, Queensland, Australia
Sandra Konrath, MSc

PhD Candidate
University Medical Center Hamburg-Eppendorf
Hamburg, Hamburg, Germany
MH

Munif Haddad

Attending physician
Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrum für Diagnostik, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
Giordano Pula, PhD

Group Leader for Platelet Signalling and Vascular Disease
University Medical Center Eppendorf Hamburg (UKE)
Hamburg, Hamburg, Germany
RM

Reiner K. Mailer

PI
University Medical Center Hamburg-Eppendorf
Hamburg, Hamburg, Germany
HS

Hartmut Schlüter

Head of Mass Spectrometry Unit
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
SK

Stefan Kluge

MD
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
FL

Florian Langer

Medical Specialist in Internal Medicine
Universitätsklinikum Eppendorf, II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum, Universitäres Cancer Center Hamburg (UCCH), Hamburg, Germany
Hamburg, Hamburg, Germany
KP

Klaus Püschel

Head of Department for Legal Medicine
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
KP

Kosta Panousis

Senior Director - Head of Molecular Biology
CSL Behring
Melbourne, Victoria, Australia
ES

Evi Stavrou

Assistant Professor
Case Western Reserve University
Cleveland, Ohio, United States
Coen Maas, PhD

Associate Professor
Department of CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Utrecht, Utrecht, Netherlands
TR

Thomas Renné

Head of Department
Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrum für Diagnostik, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
MF

Maike Frye

PI
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany

Background: Coagulopathy and inflammation are hallmarks of COVID-19 and are associated with increased mortality. Clinical and experimental data have revealed a role for neutrophil extracellular traps (NETs) in COVID-19. Mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood.

Aims: In this study, we aimed to investigate a possible role of NETs-driven coagulation factor XII (FXII) activation in COVID-19-related thrombo-inflammation.

Methods: We performed comprehensive proteomics and immunostaining of postmortem lung tissues from COVID-19 patients and patients with other lung pathologies. We compared FXII and DNase1 activities in plasma samples from COVID-19 patients and healthy control donors and determined NET-induced FXII activation using a chromogenic substrate assay.

Results: FXII expression and activity were increased in the lung parenchyma, within the pulmonary vasculature and in fibrin-rich alveolar spaces of postmortem lung tissues from COVID-19 patients over controls. Active FXII (FXIIa) was increased in plasma of COVID-19 patients. Furthermore, FXIIa colocalized with NETs in COVID-19 lung tissue indicating that NETs accumulation leads to FXII activation in COVID-19. Accumulation of NETs in COVID-19 was at least in parts due to impaired DNA clearance by extracellular DNases. In plasma from COVID-19 patients, DNase1 substitution improved NET dissolution and reduced FXII activation in vitro.

Conclusion(s): Collectively, our study shows that the NETs/FXIIa axis contributes to procoagulant and proinflammatory reactions in COVID-19. Targeting NETs and FXIIa may offer a potential therapeutic strategy for interfering with the COVID-19 lung pathology.