Venous 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 hemostasis
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
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. Journal of Immunological Methods, 487, 112876. Also available in Munin at https://hdl.handle.net/10037/19898.
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. Journal of Immunology, 207(11), 2828-2840. Also available in Munin at https://hdl.handle.net/10037/23902.
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. Frontiers in Immunology, 13, 839632. Also available in Munin at https://hdl.handle.net/10037/25942.
PublisherUiT The Arctic University of Norway
UiT Norges arktiske universitet
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