Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs

Storm, Benjamin; Ludviksen, Judith Krey; Christiansen, Dorte; Fure, Hilde; Pettersen, Kristin; Landsem, Anne; Nilsen, Bent Aksel; Dybwik, Knut; Braaten, Tonje; Mollnes, Tom Eirik

doi:10.3389/fimmu.2022.839632

Cited by 10 publications

(15 citation statements)

References 39 publications

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“…Bubbles activate the hemostatic pathway initially through platelet activation and the complement pathway through C3 activation. Air emboli have been shown to cause the activation of platelets as well as the release of cytokines, including interleukins (ILs), chemokines, and growth factors (32), and this is central to the pathophysiology of air emboli (9,22,30,32,33,37,135,136). Air emboli also activate complement via the alternative complement pathway as determined by a lepirudin-anticoagulated human whole blood model, resulting in C3 convertase (C3bBbP) formation without simultaneous formation of C5 convertase (9,32,36).…”

Section: Thromboinflammation: Hydrodynamics Of Bubble Obstructionmentioning

confidence: 99%

“…This reduced disruption in the glycocalyx layer is reflected by the prolonged period during which HBOT may be effective following cerebral entry of air and incipient injury, as well as the need for frequent retreatments with HBOT in order to eliminate the cerebral circulation of remnant air emboli. The mediation of the thromboinflammation at the junction of the air embolus and the endothelium may be inhibited by C3a inhibitors and is associated with less elevation of HS and syndecan levels, as well as qualitative differences in cytokine release when compared to embolic blood clots (30,32,33,36,39,121,124,165).…”

Section: Thromboinflammation: Hydrodynamics Of Bubble Obstructionmentioning

confidence: 99%

“…Endothelial and pulmonary cellular injury and lung edema are the result of thromboinflammatory changes provoked by the release of damage-associated molecular patterns, normally not exposed to the innate immune system but recognized by the pattern recognition receptors when cell and tissue damage occur. Innate upstream systems like complement, toll-like receptors, and others induce downstream release (e.g., from the complement C5a-C5aR1 axis) of innumerable of inflammatory vasoactive mediators such as thromboxane, leukotrienes, cytokines, and coagulation factors with resultant increase in alveolocapillary permeability ( 1 , 3 , 12 , 30 , 35 – 37 , 79 , 80 ).…”

Section: Pathoanatomy and Importance Of Patient Positioningmentioning

confidence: 99%

“…The BBB may be disrupted because of activation and adhesion of polymorphonuclear leukocytes in the brain ( 104 ). Generation of immune mediators induced by complement and coagulation activation by bubbles can provoke resultant thromboinflammatory coagulopathies ( 32 , 35 , 44 , 104 – 109 ). A typical result of air embolism is the migration of air into small arteries with an average diameter range of 30–60 µm ( 2 , 52 ).…”

Section: Pathophysiology: the Immunothrombotic And Endothelial Respon...mentioning

confidence: 99%

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Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

Marsh,

Moore,

Moore

et al. 2023

Front. Immunol.

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Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition.

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Section: Thromboinflammation: Hydrodynamics Of Bubble Obstructionmentioning

confidence: 99%

Section: Thromboinflammation: Hydrodynamics Of Bubble Obstructionmentioning

confidence: 99%

Section: Pathoanatomy and Importance Of Patient Positioningmentioning

confidence: 99%

Section: Pathophysiology: the Immunothrombotic And Endothelial Respon...mentioning

confidence: 99%

See 2 more Smart Citations

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

Marsh,

Moore,

Moore

et al. 2023

Front. Immunol.

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“…Noteworthy, sC5b-9 levels in our experiments were generally lower than C3bc levels, and IONPs, when incubated alone with whole blood, did not lead to a significant increase in sC5b-9. Considering the surface deposition of C3b as a promoter for the complement convertases to switch substrate specificity from C3 to C5 ( 28 ), the limited capacity of small particles to offer a platform for C3b-deposition ( 26 ), similar to non-solid surfaces ( 29 ), could explain the more efficient C3- than C5-activation on IONPs.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model

et al. 2023

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Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility.

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Shedding light on the role of complement C4 activation in cancer

Cheung,

Hassan,

Huynh

et al. 2025

Human Immunology

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Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs

Cited by 10 publications

References 39 publications

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model

Shedding light on the role of complement C4 activation in cancer

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