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Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19

Florian Tran, Danielle M.M. Harris, Alena Scharmacher, Hanna Graßhoff, Kristina Sterner, Susanne Schinke, Nadja Käding, Jens Y. Humrich, Otávio Cabral-Marques, Joana P. Bernardes, Neha Mishra, Thomas Bahmer, Jeanette Franzenburg, Bimba F. Hoyer, Andreas Glück, Martina Guggeis, Alexander Ossysek, Andre Küller, Derk Frank, Christoph Lange, Jan Rupp, Jan Heyckendorf, Karoline I. Gaede, Howard Amital, Philip Rosenstiel, Yehuda Shoenfeld, Gilad Halpert, Avi Z. Rosenberg, Kai Schulze-Forster, Harald Heidecke, Gabriela Riemekasten, Stefan Schreiber
ERJ Open Research 2022 8: 00379-2022; DOI: 10.1183/23120541.00379-2022
Florian Tran
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
2Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
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  • For correspondence: f.tran@ikmb.uni-kiel.de
Danielle M.M. Harris
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
3Institute for Human Nutrition and Food Science, University Medical Center Schleswig-Holstein, Kiel, Germany
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Alena Scharmacher
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Hanna Graßhoff
4Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein, Lübeck, Germany
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Kristina Sterner
4Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein, Lübeck, Germany
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Susanne Schinke
4Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein, Lübeck, Germany
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Nadja Käding
5Department of Infectious Diseases and Microbiology, University Medical Center Schleswig-Holstein, Lübeck, Germany
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Jens Y. Humrich
4Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein, Lübeck, Germany
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Otávio Cabral-Marques
6Department of Immunology, Instituto de Ciencias Biomedicas, Universidade de São Paulo, São Paulo, SP, Brazil
7Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
8Network of Immunity in Infection, Malignancy, and Autoimmunity, Universal Scientific Education and Research Network, Sao Paulo, SP, Brazil
9Department of Medicine, Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
10Laboratory of Medical Investigation 29, University of São Paulo School of Medicine, São Paulo, Brazil
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Joana P. Bernardes
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Neha Mishra
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Thomas Bahmer
2Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
11LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
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Jeanette Franzenburg
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
12Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Kiel, Germany
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Bimba F. Hoyer
13Section for Rheumatology, Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
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Andreas Glück
2Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
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Martina Guggeis
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
2Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
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Alexander Ossysek
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Andre Küller
14Department of Internal Medicine III, University Medical Center Schleswig-Holstein, Kiel, Germany
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Derk Frank
14Department of Internal Medicine III, University Medical Center Schleswig-Holstein, Kiel, Germany
15German Centre for Cardiovascular Research (DZHK), partner site Hamburg, Kiel, Lübeck, Germany
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Christoph Lange
16Research Center Borstel, Borstel, Germany
17German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Borstel, Germany
18Respiratory Medicine and International Health, University of Lübeck, Lübeck, Germany
19Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA
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Jan Rupp
5Department of Infectious Diseases and Microbiology, University Medical Center Schleswig-Holstein, Lübeck, Germany
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Jan Heyckendorf
2Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
16Research Center Borstel, Borstel, Germany
17German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Borstel, Germany
20Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany
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Karoline I. Gaede
16Research Center Borstel, Borstel, Germany
17German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Borstel, Germany
20Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany
21BioMaterialBank Nord, Borstel, Germany
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Howard Amital
22Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat-Gan, Israel
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Philip Rosenstiel
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Yehuda Shoenfeld
22Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat-Gan, Israel
23Ariel University, Ariel, Israel
24Laboratory of the Mosaic of Autoimmunity, Saint Petersburg State University, Saint-Petersburg, Russia
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Gilad Halpert
22Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat-Gan, Israel
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Avi Z. Rosenberg
25Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
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Kai Schulze-Forster
26CellTrend GmbH, Luckenwalde, Germany
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Harald Heidecke
26CellTrend GmbH, Luckenwalde, Germany
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Gabriela Riemekasten
3Institute for Human Nutrition and Food Science, University Medical Center Schleswig-Holstein, Kiel, Germany
27Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany
28These authors contributed equally
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Stefan Schreiber
1Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
2Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
28These authors contributed equally
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Abstract

In patients with severe #COVID19, increased levels of autoantibodies against PAR1 were found. These might serve as allosteric agonists of PAR1 on endothelial cells and platelets, and thus might contribute to the pathogenesis of microthrombosis in COVID-19. https://bit.ly/3pqM9Vv

To the Editor:

Immune perturbation is a hallmark of coronavirus disease 2019 (COVID-19), with ambiguous roles of various immune cell compartments. Plasma cells, responsible for antibody production, have a two-pronged response while mounting an immune defence with 1) physiological immune response producing neutralising antibodies against protein structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 2) potentially deleterious autoantibody generation. Growing evidence hints towards broad activation of plasma cells and the presence of pathological autoantibodies (abs) that mediate immune perturbation in acute COVID-19 [1]. Recently, a systematic screening for abs confirmed induction of diverse functional abs in SARS-CoV-2 infection, targeting several immunomodulatory proteins, including cytokines/chemokines and their respective G-protein coupled receptors (GPCR) [1]. Abs against GPCR act as agonistic and allosteric receptor modulators and are linked to chronic inflammatory diseases [2] and, as we demonstrated recently, disease severity in acute COVID-19 [3].

Immune-mediated thrombosis is a key pathogenic mechanism in COVID-19 linked to morbidity and mortality [4]. Peripheral blood megakaryocytes are potential biomarkers of severe COVID-19 [5], displaying prothrombogenic metabolic programmes and type I interferon signatures. Activated megakaryocytes and sequestering platelets might contribute to immune-mediated microthrombosis in COVID-19 [6]. Thrombin is another key factor in plasmatic coagulation, but it also induces platelet aggregation via GPCR protease-activated receptor 1 (PAR1), expressed on the plasma membrane of megakaryocytes, platelets and endothelial cells. Thrombin activation is linked to acute respiratory distress syndrome and fatal outcomes of COVID-19 [7], but it is (pre-)treatment with platelet inhibitors, not high-dose heparin therapy that reduces mortality and occurrence of thrombotic events in COVID-19 [8, 9]. Therefore, tackling platelet activation/PAR1-mediated coagulation could be a therapeutic target preventing microthrombotic complications in severe COVID-19 [10]. Additionally, thrombin mediates endothelial dysfunction in severe COVID-19 through PAR1 signalling [11]. Given these considerations, we hypothesised that anti-PAR1 abs are altered in COVID-19 and skew the coagulation system towards pro-thrombogenic states.

To investigate this, blood samples from 74 patients who tested positive for SARS-CoV-2 infection using reverse transcriptase-PCR detection (S gene) on nasopharyngeal swabs were collected after informed consent and ethical board review of the respective source studies from three hospitals (University Hospitals Schleswig-Holstein Kiel (identifier D466/20) and Lübeck (identifier 13-003) and Medical Clinic Research-Center-Borstel (identifier EK HL AZ 14-225)). 29 patients required intensive care unit (ICU) treatment and 14 died during hospital stay. Time of first sampling was within 48 h of hospital or ICU admission, while follow-up samples from 18 individuals were collected at random time points. In total, we collected 111 patient serum samples. Occurrence of thrombotic events within the COVID-19-related hospital stay was ascertained depending on the clinically suspected location of thrombosis by magnetic resonance imaging/computed tomography scanning with contrasting agents or duplex sonography. The most common manifestations in our cohort were lung embolism, stroke and intestinal embolic ischaemia. 29 single time point samples from healthy controls age-matched to the patients admitted to ICU were collected in Lübeck (identifier AZ16-199). All serum samples were subjected to duplicate quantification of anti-PAR1 abs by IgG-specific indirect sandwich ELISA (CellTrend, Luckenwalde, Germany) as described previously [12]. We use linear mixed models (LMMs) to evaluate differences between anti-PAR1 abs, disease severity and outcome (survival and thrombotic events), accounting for repeated measures via inclusion of patient-specific random intercepts. Lab analytes (including anti-PAR1 abs) were natural log transformed and residual plots visually inspected for deviations from normality or homoscedasticity. LMMs are reported with p-values (obtained using Satterthwaite's method) and 95% confidence intervals for log-transformed coefficient estimates. We assessed the power of anti-PAR1 abs in the prediction of survival and thrombotic events relative to established markers alone and in combination (D-dimers, C-reactive protein (CRP) and interleukin (IL)-6) using logistic regression, and evaluated the resultant models using receiver operating characteristic (ROC) analysis. Analyses were run in R (version 4.2.1; R Core Team, Vienna, Austria) with the base package stats and packages LmerTest and pROC (versions 3.1-3 and 1.18.0, respectively).

Disease severity varied within the cohort from hospitalised moderate-to-severe COVID-19 following World Health Organization criteria. The median age (63 years) was identical in the COVID-19 cohort (range 20–93 years) and the controls (range 19–90 years). Circulating anti-PAR1 abs were markedly increased in COVID-19 patients who required ICU treatment (95% CI 0.60–1.59; p=3.36×10−5 in LMM, ICU escalation as fixed effect) in comparison to age-matched controls, but not in hospitalised patients without ICU treatment (95% CI −0.06–0.84; p=0.092 in LMM) (figure 1a). Importantly, increased levels of anti-PAR1 abs within the ICU-treated subcohort were associated with fatal outcome (95% CI 0.12–1.71; p=0.0319 in LMM, mortality as fixed effect (figure 1b) and occurrence of thromboembolic events (95% CI 0.42–2.00; p=0.0062 in LMM, thrombotic events as fixed effect). Circulating anti-PAR1 abs correlated with D-dimers (95% CI 0.32–1.14; p=0.0010 in LMM, D-dimers as fixed effect (figure 1c), further underscoring that anti-PAR1 abs are linked to coagulation processes in acute COVID-19, while significant correlation was neither found with platelet counts nor inflammatory markers like IL-6 (p=0.3467 in LMM, data not shown). Anti-PAR1 abs and D-dimers have similar area under ROC curves (AUROCs) for ICU patients for the end-point survival (AUROC 0.7095 versus 0.7115), while anti-PAR1 abs performed better in discrimination of thromboembolism (AUROC 0.7692 versus 0.5992) (figure 1d). Combination of both markers further increased the AUROC for both end-point survival (AUROC 0.7846) and thromboembolism (AUROC 0.8347). Anti-PAR1 abs do not have better predictive value compared to IL-6 (AUROC 0.7652 and 0.7972 for the end-points thrombotic events and survival, respectively) and CRP (AUROC 0.8132 and 0.6619 for thrombotic events and survival, respectively); however, anti-PAR1 does improve the predictive power of IL-6 when the analytes are combined in logistic regression (anti-PAR1 abs+IL-6 AUROC 0.8485 and 0.8182 for thrombotic events and survival, respectively, the highest AUROC of all combined analyses of two analytes).

FIGURE 1
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FIGURE 1

Anti-protease-activated receptor 1 (PAR1) antibodies (abs) correlated with disease severity and survival. a) anti-PAR1 ab levels in serum samples from healthy controls (HC) (29 samples, 29 individuals) and patients with coronavirus disease 2019 (COVID-19), either hospitalised/non-intensive care unit (ICU) (59 samples, 45 individuals) or ICU treatment (52 samples, 29 individuals); linear mixed model (LMM) p=0.092 and 3.36×10−5, respectively; b) anti-PAR1 ab levels in serum samples from ICU-treated COVID-19 patients in the cohort (29 patients), stratified by the outcome thrombotic events and survival (LMM p=0.0062 and 0.0319, respectively); c) correlation analysis for anti-PAR1 abs in COVID-19 patients against D-dimers. The linear regression line with confidence interval is displayed; statistical analysis is based on LMM (p=0.0010); d) receiver operating characteristic (ROC) analysis of anti-PAR1 abs, D-dimers and combined (upper panels) as well as anti-PAR1 abs, interleukin (IL)-6 and combined (lower panels) for the clinical outcomes “thrombotic events” (left panels) and “survival” (right panels). Areas under the ROC curve (AUC) are indicated in the panels.

Our data reveal an association between ICU treatment in severe COVID-19 and generation of anti-PAR1 abs, which are associated with poor outcome. Intriguingly, we found no association between anti-PAR1 abs and systemic IL-6, despite the suggested agonistic role of anti-PAR1 abs on PAR1/p70S6K/ERK-dependent IL-6 expression in endothelial cells [13]. This suggests that endothelium-derived IL-6 does not impact systemic IL-6 levels. Indeed, monocytes have been described as the main source of IL-6 in COVID-19 [14], which may explain why endothelial cell and serum IL-6 appear to be uncoupled. This would explain not only the lack of correlation between serum IL-6 and anti-PAR1 abs, but also the improved predictive power that results from the combination of the two analytes. Additionally, increased PAR1-dependent platelet activation in COVID-19 leads to elevated aggregation of circulating cells and collagen [15]. We hypothesise that anti-PAR1 abs in combination with dysregulated coagulation proteases like activated protein C or matrix metalloprotease 1 could activate PAR1-dependent signals in endothelial cells and platelets, thus contributing to immune-mediated microthrombosis as suggested by the correlation of anti-PAR1 abs with D-dimers. Stimulating platelets and endothelial cells with isolated IgG from COVID-19 patients with PAR1 inhibitors (e.g. vorapaxar) could provide evidence of anti-PAR1 ab involvement in COVID-19-related coagulopathy.

Our study has several limitations. For most ICU patients, first sampling was upon ICU admission, making prediction of ICU necessity impossible. Although we did not observe sex effects on anti-PAR1 abs in either COVID-19 (p=0.60 in LMM, sex as fixed effect) or control cohorts (p=0.90 in t-test), the sex ratios in the cohorts were skewed.

Our data suggest an association of anti-PAR1 abs with thrombotic complications and fatal outcome in COVID-19, warranting verification in larger cohorts. Functional assessment of anti-PAR1 abs is important to understand their molecular properties and pathophysiological role in thrombosis and endothelial dysfunction in COVID-19.

Acknowledgements

We thank M. Rohm, M. Hansen and R. Möhring (Institute of Clinical Molecular Biology, University Medical Center Schleswig-Holstein, Kiel, Germany) for perfect technical assistance. We are indebted to the patients, their families and the hospital staff for support, without whom this study would not have been possible.

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Author contributions: F. Tran, H. Heidecke, T. Bahmer, P. Rosenstiel, K. Sterner, Y. Shoenfeld, G. Halpert, G. Riemekasten and S. Schreiber conceived study concept and design. F. Tran, D.M.M. Harris, A. Scharmacher, H. Graßhoff, T. Bahmer, A.Z. Rosenberg., P. Rosenstiel, H. Heidecke, G. Riemekasten and S. Schreiber contributed to literature search, data interpretation and writing the initial manuscript. All authors contributed to reviewing and editing of the manuscript. F. Tran, A. Scharmacher, H. Graßhoff, K. Sterner, S. Schinke, A. Glück, J. Franzenburg, M. Guggeis, A. Ossysek, A. Küller, D. Frank, C. Lange, G. Riemekasten, N. Käding, J. Rupp, J. Heyckendorf, H. Amital, G. Halpert, J.Y. Humrich, K.I. Gaede and K. Schulze-Forster participated in data and sample collection and processing. F. Tran, D.M.M. Harris, A. Scharmacher, H. Graßhoff, O. Cabral-Marques, J.P. Bernardes, N. Mishra, H. Heidecke and G. Riemekasten participated in data analysis. F. Tran, D.M.M. Harris, A. Scharmacher, H. Graßhoff, H. Heidecke and G. Riemekasten made figures and tables.

  • Support statement: This work was supported by COVID response grants from the State of Schleswig-Holstein, ExC 2167 Precision Medicine in Chronic Inflammation (RTF-VI), the research group miTARGET and the BMBF iTREAT project (to P. Rosenstiel), the IMI2 Project 3TR (P. Rosenstiel and S. Schreiber) and EU projects SYSCID (733100 to P. Rosenstiel). C. Lange is supported by the German Center for Infection Research (DZIF). The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North. The BioMaterialBank Nord is member of popgen 2.0 network. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Conflict of Interest: T. Bahmer reports grants from BMBF (unrestricted research grant for the German Center for Lung Research (DZL) and National Pandemic Cohort Network (NAPKON) – Coordinating Study Site for population-based cohort platform); lecture fees from Novartis, AstraZeneca, and Chiesi; support for attending the American Thoracic Society Conference from Chiesi; and advisory board participation with GlaxoSmithKline, Boehringer Ingelheim, Roche and AstraZeneca, outside the submitted work. D. Frank reports grants from DFG (467267736), BMBF and DZHK; consulting fees and support for attending meetings from Edwards Lifesciences and Medtronic; lecture honoraria from Edwards Lifesciences, Medtronic, Astra Zeneca, Pfizer, BMS, Novartis, Bayer and Abbott; and participation on advisory boards with BMS, Boehringer Ingelheim, Daiichi Sankyo, outside the submitted work. A.Z. Rosenberg reports grants from the NIH (NIDDK and NHLBI) outside the submitted work. CellTrend is owned by K. Schulze-Forster; CellTrend produces ELISA kits for the determination of antibodies against GPCR. G. Riemekasten reports consulting fees from CellTrend GmbH outside the submitted work. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk, outside the submitted work. All other authors have nothing to disclose.

  • Received August 1, 2022.
  • Accepted August 11, 2022.
  • Copyright ©The authors 2022
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Vol 8 Issue 4 Table of Contents
ERJ Open Research: 8 (4)
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Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19
Florian Tran, Danielle M.M. Harris, Alena Scharmacher, Hanna Graßhoff, Kristina Sterner, Susanne Schinke, Nadja Käding, Jens Y. Humrich, Otávio Cabral-Marques, Joana P. Bernardes, Neha Mishra, Thomas Bahmer, Jeanette Franzenburg, Bimba F. Hoyer, Andreas Glück, Martina Guggeis, Alexander Ossysek, Andre Küller, Derk Frank, Christoph Lange, Jan Rupp, Jan Heyckendorf, Karoline I. Gaede, Howard Amital, Philip Rosenstiel, Yehuda Shoenfeld, Gilad Halpert, Avi Z. Rosenberg, Kai Schulze-Forster, Harald Heidecke, Gabriela Riemekasten, Stefan Schreiber
ERJ Open Research Oct 2022, 8 (4) 00379-2022; DOI: 10.1183/23120541.00379-2022

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Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19
Florian Tran, Danielle M.M. Harris, Alena Scharmacher, Hanna Graßhoff, Kristina Sterner, Susanne Schinke, Nadja Käding, Jens Y. Humrich, Otávio Cabral-Marques, Joana P. Bernardes, Neha Mishra, Thomas Bahmer, Jeanette Franzenburg, Bimba F. Hoyer, Andreas Glück, Martina Guggeis, Alexander Ossysek, Andre Küller, Derk Frank, Christoph Lange, Jan Rupp, Jan Heyckendorf, Karoline I. Gaede, Howard Amital, Philip Rosenstiel, Yehuda Shoenfeld, Gilad Halpert, Avi Z. Rosenberg, Kai Schulze-Forster, Harald Heidecke, Gabriela Riemekasten, Stefan Schreiber
ERJ Open Research Oct 2022, 8 (4) 00379-2022; DOI: 10.1183/23120541.00379-2022
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