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dc.contributor.advisorMollnes, Tom Eirik
dc.contributor.authorStorm, Benjamin
dc.date.accessioned2022-08-03T08:28:11Z
dc.date.available2022-08-03T08:28:11Z
dc.date.issued2022-09-27
dc.description.abstract<p><i>Background:</i> Air embolism may complicate many medical procedures and cause vascular occlusion, organ infarctions, or death. In vitro, air triggers the alternative complement pathway and activates platelets. Previous studies of air emboli were conducted in serum, plasma, or heparin anticoagulated whole blood, with ambient air present in tubes, precluding detailed examination of thromboinflammation. The role of complement in air-induced thromboinflammation has not previously been examined in vivo in minimally anticoagulated large animal model. Thus, this project aimed to examine the effect of avoiding ambient air during in vitro blood incubations and to elucidate the air-induced thromboinflammation both in vitro and in vivo. <p><i>Methods:</i> In vitro, lepirudin anticoagulated human whole blood from 16 donors was either incubated for 180 minutes with air emboli and inhibitors of complement C3 and C5, C5a receptor 1, and the toll-like receptor co-receptor cluster of differentiation 14, or without air. Blood was analyzed for complement activation products, cytokines, tissue factor, β-thromboglobulin, and prothrombin fragment 1+2. In vivo, air was infused through an ear vein in 29 pigs for 300 minutes. Hemostasis was monitored using rotational thromboelastometry and thrombin-antithrombin complex. Blood and lung tissue were analyzed for complement activation products and cytokines. <p><i>Results:</i> In vitro and in vivo, air emboli triggered a C3-driven thromboinflammation without correlating terminal pathway activation. In vitro, C3 inhibition, and to a lesser degree, C5 inhibition attenuated cytokine release, and C3 and C5 inhibition equally reduced coagulation, but neither reduced the platelet activation. Avoiding ambient air during in vitro incubations reduced complement activation. In vivo, air embolism resulted in leukocytosis, hemostasis, increased proinflammatory cytokines and complement activation product C3a, but not TCC in the lung tissue. <p><i>Conclusion:</i> Air embolism triggered a complement C3-driven thromboinflammation in vitro and in vivo. During in vitro blood incubations, avoiding ambient air attenuated and C3 inhibition reduced thromboinflammation.en_US
dc.description.doctoraltypeph.d.en_US
dc.description.popularabstractAir bubbles entering the blood circulation may complicate medical procedures, potentially resulting in hemodynamic collapse, organ infarctions, or death. Air bubbles trigger inflammation and coagulation, mainly by activating a part of the immune system known as the complement system. However, the exact mechanisms are not fully elucidated, and no specific treatment for air-induced inflammation exists. This project examined the effect of ambient air and air bubbles on the thrombo-inflammatory system in human whole blood in test tubes and in pigs. We found that avoiding ambient air in test tubes during experiments significantly reduced “unavoidable” complement and coagulation background activation. Air activated a key complement molecule, C3, in a unique manner seldom seen in other inflammatory conditions. C3 inhibition attenuated both inflammation and coagulation but not platelet activation, pointing towards C3 inhibitions as a potential therapy in patients with air-induced inflammation.en_US
dc.description.sponsorshipHelse Nord RHFen_US
dc.identifier.urihttps://hdl.handle.net/10037/25922
dc.language.isoengen_US
dc.publisherUiT The Arctic University of Norwayen_US
dc.publisherUiT Norges arktiske universiteten_US
dc.relation.haspart<p>Paper I: Storm, B.S., Christiansen, D., Mollnes, T.E. & Nielsen, E.W. (2020). Avoiding ambient air in test tubes during incubations of human whole-blood minimizes complement background activation. <i>Journal of Immunological Methods, 487</i>, 112876. Also available in Munin at <a href=https://hdl.handle.net/10037/19898>https://hdl.handle.net/10037/19898</a>. <p>Paper II: Storm, B.S., Christiansen, D., Fure, H., Ludviksen, J.K., Lau, C., Lambris, J.D., … Mollnes, T.E. (2021). Air Bubbles Activate Complement and Trigger Hemostasis and C3-Dependent Cytokine Release Ex Vivo in Human Whole Blood. <i>Journal of Immunology, 207</i>(11), 2828-2840. Also available in Munin at <a href=https://hdl.handle.net/10037/23902>https://hdl.handle.net/10037/23902</a>. <p>Paper III: Storm, B.S., Ludviksen, J.K., Christiansen, D., Fure, H., Pettersen, K., Landsem, A., … Mollnes, T.E. (2022). Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs. <i>Frontiers in Immunology, 13</i>, 839632. Also available in Munin at <a href=https://hdl.handle.net/10037/25942>https://hdl.handle.net/10037/25942</a>.en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2022 The Author(s)
dc.subject.courseIDDOKTOR-003
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk immunologi: 716en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical immunology: 716en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Patofysiologi: 721en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Physiopathology: 721en_US
dc.subjectVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Anestesiologi: 765en_US
dc.subjectVDP::Medical disciplines: 700::Clinical medical disciplines: 750::Anesthesiology: 765en_US
dc.titleVenous Air Embolism and Complement-driven Thromboinflammation. In vitro human whole blood studies and in vivo porcine studies on the effect of air emboli on the complement system, cytokine network, and the hemostasisen_US
dc.typeDoctoral thesisen_US
dc.typeDoktorgradsavhandlingen_US


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