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Implantation of a continuous-flow left ventricular assist device is associated with a significant but transient acute thromboinflammatory response
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.ORCID iD: 0000-0002-6194-6903
Oslo University Hospital, Norway.
Oslo University Hospital, Norway.
Oslo University Hospital, Norway;University of Oslo, Norway.
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology Cardiology and Cardiovascular Disease
Research subject
Biomedical Sciences, Immunology
Identifiers
URN: urn:nbn:se:lnu:diva-118764OAI: oai:DiVA.org:lnu-118764DiVA, id: diva2:1731356
Available from: 2023-01-26 Created: 2023-01-26 Last updated: 2025-02-10Bibliographically approved
In thesis
1. The role of the thromboinflammatory response under hemolytic conditions: pathophysiological mechanisms and therapeutic inhibition
Open this publication in new window or tab >>The role of the thromboinflammatory response under hemolytic conditions: pathophysiological mechanisms and therapeutic inhibition
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In blood circulation, the complement and the coagulation cascades, together with platelets and endothelial cells form a complex network of crosstalk. When dysregulated, these interactions can lead to inflammation in combination with thrombosis (thromboinflammation) and the manifestation of pathophysiological complications. As complement activation and thromboinflammation are often associated with intravascular hemolysis, e.g., sickle cell disease (SCD), we aimed to study these reactions in relation to heme, a product of hemolysis. Furthermore, our goal was to evaluate whether exposure to biomaterials results in hemolysis-induced thromboinflammation, and to examine the potential of complement inhibition.

Our findings show that heme could lead to a significant thromboinflammatory response in our in vitro whole blood model, as seen by complement-, cell- and coagulation- activation, as well as increased cytokine secretion. Inflammation, including complement activation, was also linked with increased heme concentrations in vivo in hemolytic disease in SCD patients. The mechanism of action was attributed to uncontrolled alternative pathway (AP) activation, as heme was shown to bind and inhibit the main AP regulator, factor I, resulting in increased concentrations of fluid phase and surface-bound C3b.

Moreover, administration of iron oxide nanoparticles (IONPs) in vitro and implantation of left ventricular assist device (LVAD) in vivo were monitored and correlated with increased hemolytic, e.g., heme, and thromboinflammatory markers, e.g., complement-, endothelial cell- and platelet- activation. Targeting complement components C5 and C3 in vitro was shown overall beneficial in the presence of heme or IONPs respectively. In our settings, the majority of the thromboinflammatory markers measured were successfully attenuated, indicating that complement fuels this response.

In conclusion, the results in this thesis stress that heme-induced complement activation is an important player in thromboinflammation. In addition, we propose that complement inhibition can be used as a therapeutic approach in hemolytic conditions and as a strategy to enhance biomaterials’ biocompatibility.

Place, publisher, year, edition, pages
Linnaeus University Press, 2023. p. 55
Series
Linnaeus University Dissertations ; 481
Keywords
Hemolysis, heme, thromboinflammation, biomaterials, complement inhibition, LVAD, IONPs
National Category
Immunology
Research subject
Natural Science, Biomedical Sciences; Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-118762 (URN)10.15626/LUD.481.2023 (DOI)9789189709928 (ISBN)9789189709928 (ISBN)
Public defence
2023-02-24, Kalmar, 09:30 (English)
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Supervisors
Available from: 2023-01-30 Created: 2023-01-29 Last updated: 2024-03-13Bibliographically approved

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Gerogianni, AlexandraSjöström, Dick J.Mohlin, CamillaNilsson, Per H.

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