Publication

Complement inhibition can decrease the haemostatic response in a microvascular bleeding model at multiple levels

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  • 06/25/2025
Type of Material
Authors
    Murielle Golomingi, University of BernJessie Kohler, University of BernChristina Lamers, University of BaselRichard B Pouw, University of BaselDaniel Ricklin, University of BaselJózsef Dobó, Hungarian Research Centre for Natural SciencesPéter Gál, Hungarian Research Centre for Natural SciencesGábor Pál, Eötvös Loránd UniversityBence Kiss, Eötvös Loránd UniversityArthur Dopler, University of UlmChristoph Q Schmidt, University of UlmElaissa Trybus Hardy, Emory UniversityWilbur Lam, Emory UniversityVerena Schroeder, University of Bern
Language
  • English
Date
  • 2023-09-13
Publisher
  • Frontiers Media SA
Publication Version
Copyright Statement
  • © 2023 Golomingi, Kohler, Lamers, Pouw, Ricklin, Dobó, Gál, Pál, Kiss, Dopler, Schmidt, Hardy, Lam and Schroeder
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Final Published Version (URL)
Title of Journal or Parent Work
Volume
  • 14
Start Page
  • 1226832
Grant/Funding Information
  • This project was funded by grants awarded to VS by the OPO Foundation (Zurich, Switzerland), Novartis Foundation for Medical-Biological Research (Basel, Switzerland), and Gottfried & Julia Bangerter-Rhyner Foundation (Bern, Switzerland). RP was supported by grants from the Swiss National Science Foundation (CRSK- 3_196744; Bern, Switzerland) and the University of Basel (3PH1062; Basel, Switzerland). DR was supported by the Swiss National Science Foundation (grants 205321_204607 and 31003A_176104). PG was supported by Eötvös Loránd Research Network (ELKH) grant KEP-5/2021, while GP and PG were both supported by Project no. RRF-2.3.1-21-2022-00015, which has been implemented with the support provided by the European Union; by project no. 2018-1.2.1-NKP-2018-00005 implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the 2018-1.2.1-NKP funding scheme and by the National Research, Development and Innovation Office (Hungarian Scientific Research Fund) grant K135289.
Supplemental Material (URL)
Abstract
  • Background: Haemostasis is a crucial process by which the body stops bleeding. It is achieved by the formation of a platelet plug, which is strengthened by formation of a fibrin mesh mediated by the coagulation cascade. In proinflammatory and prothrombotic conditions, multiple interactions of the complement system and the coagulation cascade are known to aggravate thromboinflammatory processes and increase the risk of arterial and venous thrombosis. Whether those interactions also play a relevant role during the physiological process of haemostasis is not yet completely understood. The aim of this study was to investigate the potential role of complement components and activation during the haemostatic response to mechanical vessel injury. Methods: We used a microvascular bleeding model that simulates a blood vessel, featuring human endothelial cells, perfusion with fresh human whole blood, and an inducible mechanical injury to the vessel. We studied the effects of complement inhibitors against components of the lectin (MASP-1, MASP-2), classical (C1s), alternative (FD) and common pathways (C3, C5), as well as a novel triple fusion inhibitor of all three complement pathways (TriFu). Effects on clot formation were analysed by recording of fibrin deposition and the platelet activation marker CD62P at the injury site in real time using a confocal microscope. Results: With the inhibitors targeting MASP-2 or C1s, no significant reduction of fibrin formation was observed, while platelet activation was significantly reduced in the presence of the FD inhibitor. Both common pathway inhibitors targeting C3 or C5, respectively, were associated with a substantial reduction of fibrin formation, and platelet activation was also reduced in the presence of the C3 inhibitor. Triple inhibition of all three activation pathways at the C3-convertase level by TriFu reduced both fibrin formation and platelet activation. When several complement inhibitors were directly compared in two individual donors, TriFu and the inhibitors of MASP-1 and C3 had the strongest effects on clot formation. Conclusion: The observed impact of complement inhibition on reducing fibrin clot formation and platelet activation suggests a role of the complement system in haemostasis, with modulators of complement initiation, amplification or effector functions showing distinct profiles. While the interactions between complement and coagulation might have evolved to support haemostasis and protect against bleeding in case of vessel injury, they can turn harmful in pathological conditions when aggravating thromboinflammation and promoting thrombosis.
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Keywords
Research Categories
  • Health Sciences, Medicine and Surgery
  • Health Sciences, Immunology
  • Biology, Cell

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