Antibodies and complement are key drivers of thrombosis

Stark, Konstantin ; Kilani, Badr ; Stockhausen, Sven; Busse, Johanna; Schubert, Irene; Tran, Thuy-Duong; Gaertner, Florian ; Leunig, Alexander ; Pekayvaz, Kami; Nicolai, Leo; Fumagalli, Valeria; Stermann, Julia; Stephan, Felix; David, Christian; Müller, Martin B.; Heyman, Birgitta; Lux, Anja; da Palma Guerreiro, Alexandra; Frenzel, Lukas P.; Schmidt, Christoph Q.; Dopler, Arthur; Moser, Markus; Chandraratne, Sue ; Brühl, Marie-Luise von; Lorenz, Michael; Korff, Thomas; Rudelius, Martina; Popp, Oliver; Kirchner, Marieluise; Mertins, Philipp ; Nimmerjahn, Falk; Iannacone, Matteo; Sperandio, Markus ; Engelmann, Bernd; Verschoor, Admar und Massberg, Steffen (10. September 2024): Antibodies and complement are key drivers of thrombosis. In: Immunity, Bd. 57, Nr. 9, 2140-2156e10

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.

• Dokumententyp: Zeitschriftenartikel
• EU Funded Grant Agreement Number: 947611
• EU-Projekte: Horizon 2020
• Fakultät: Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik I (Kardiologie)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 10747613
• Sprache: Englisch