Antibodies and complement are key drivers of thrombosis

• DOI: 10.1016/j.immuni.2024.08.007
• Publication Date: 2024-09-02T14:36:49Z
• Authors: Konstantin Stark; Badr Kilani; Sven Stockhausen; Johanna Busse; Irene Schubert; Thuy-Duong Tran; Florian Gaertner; Alexander Leunig; Kami Pekayvaz; Leo Nicolai; Valeria Fumagalli; Julia Stermann; Felix Stephan; Christian David; Martin B. Müller; Birgitta Heyman; Anja Lux; Alexandra da Palm...; Lukas P. Frenzel; Christoph Q. Schmidt; Arthur Dopler; Markus Moser; Sue Chandraratne; Marie-Luise von B...; Michael Lorenz; Thomas Korff; Martina Rudelius; Oliver Popp; Marieluise Kirchner; Philipp Mertins; Falk Nimmerjahn; Matteo Iannacone; Markus Sperandio; Bernd Engelmann; Admar Verschoor; Steffen Massberg
• Keywords: Immunologi inom det medicinska området; Immunology in the medical area; Technology Platforms; Molecular Processes and Therapies [Topic 2]

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.