Antibodies and complement are key drivers of thrombosis

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.

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Publication Details

Journal
Immunity
Published
2024-09-01
DOI
https://doi.org/10.1016/j.immuni.2024.08.007
Citations
37
Primary Topic
Complement system in diseases
Type
article
Field-Weighted Citation Impact
8.90

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article

Antibodies and complement are key drivers of thrombosis

Florian Gaertner, Steffen Maßberg, Irene Schubert, Christian Dávid et al.
37 citations
Immunity
Complement system in diseases
8.90
article

Antibodies and complement are key drivers of thrombosis

Florian Gaertner, Steffen Maßberg, Irene Schubert, Christian Dávid, Admar Verschoor, Anja Lux, Philipp Mertins, Sue Chandraratne, Thomas Korff, Badr Kilani, Marieluise Kirchner, Alexander Leunig, Valeria Fumagalli, Johanna Busse, Konstantin Stark, Bernd Engelmann, Birgitta Heyman, Markus Moser, Kami Pekayvaz, Lukas P. Frenzel, Leo Nicolai, Markus Sperandio, Sven Stockhausen, Oliver Popp, Alexandra da Palma Guerreiro, Matteo Iannacone, Arthur Dopler, Falk Nimmerjahn, Julia Stermann, Martin B. Müller, Michael Lorenz, Martina Rudelius, Christoph Q. Schmidt, Felix Stephan, Marie-Luise von Brühl, Thuy-Duong Tran
article en
37 citations

Abstract

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.

ImmunityVol. 57(9)
Uppsala University (SE), Vita-Salute San Raffaele University (IT), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Universität Ulm (DE), Max Delbrück Center (DE), Heidelberg University (DE), TUM Klinikum (DE), LMU Klinikum (DE), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Centre of Experimental Medicine of the Slovak Academy of Sciences (SK), Max Planck Institute of Psychiatry (DE), Max Planck Institute of Biochemistry (DE), University Hospital Cologne (DE), Ludwig-Maximilians-Universität München (DE), University of Lübeck (DE)
Deutsches Zentrum für Herz-Kreislaufforschung, Imperial College London, University of Oxford, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Eidgenössische Technische Hochschule Zürich, Associazione Italiana per la Ricerca sul Cancro, Universität Zürich, Universität Duisburg-Essen, H2020 European Research Council
Zero hunger
Openalex Percentile: Top 2%
Complement system in diseases
8.90
DOIOpen Access PDFOpenAlex
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