Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism

Høiland, Ina Isabella; Liang, Robin Amanda; Brækkan, Sigrid Kufaas; Pettersen, Kristin; Ludviksen, Judith Krey; Latysheva, Nadezhda; Snir, Omri; Ueland, Thor; Hindberg, Kristian; Mollnes, Tom Eirik; Hansen, John‐Bjarne

doi:10.1111/jth.14438

Cited by 19 publications

(30 citation statements)

References 44 publications

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“…In addition, through in vivo C5aR1 antagonism, C3aR activation can potentially stimulate the increase on systemic levels of inflammatory mediators (4,11,(91)(92)(93) and promote pathological events, which can evolve to cause multiple organs dysfunction and death (53,(93)(94)(95). In addition, cobra venom also induces the formation of high amounts of sTCC, a complex with inflammatory and deleterious properties, which is a risk factor to multiple pathologies (17,53,(96)(97)(98)(99)(100). Thus, by using other pharmacological tools to inhibit additional steps of the complement cascade, in vivo, our results may be expanded.…”

Section: Discussionmentioning

confidence: 99%

C5a-C5aR1 Axis Activation Drives Envenomation Immunopathology by the Snake Naja annulifera

et al. 2021

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Systemic complement activation drives a plethora of pathological conditions, but its role in snake envenoming remains obscure. Here, we explored complement’s contribution to the physiopathogenesis of Naja annulifera envenomation. We found that N. annulifera venom promoted the generation of C3a, C4a, C5a, and the soluble Terminal Complement Complex (sTCC) mediated by the action of snake venom metalloproteinases. N. annulifera venom also induced the release of lipid mediators and chemokines in a human whole-blood model. This release was complement-mediated, since C3/C3b and C5a Receptor 1 (C5aR1) inhibition mitigated the effects. In an experimental BALB/c mouse model of envenomation, N. annulifera venom promoted lipid mediator and chemokine production, neutrophil influx, and swelling at the injection site in a C5a-C5aR1 axis-dependent manner. N. annulifera venom induced systemic complementopathy and increased interleukin and chemokine production, leukocytosis, and acute lung injury (ALI). Inhibition of C5aR1 with the cyclic peptide antagonist PMX205 rescued mice from these systemic reactions and abrogated ALI development. These data reveal hitherto unrecognized roles for complement in envenomation physiopathogenesis, making complement an interesting therapeutic target in envenomation by N. annulifera and possibly by other snake venoms.

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Section: Discussionmentioning

confidence: 99%

C5a-C5aR1 Axis Activation Drives Envenomation Immunopathology by the Snake Naja annulifera

et al. 2021

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“…Underscoring the relevance of C3 to venous thrombus development, C3 deficiency has caused prolonged bleeding and reduced thrombus incidence, thrombus size, fibrin and platelet deposition after ligature of inferior vena cava in mice (Subramaniam et al, 2017). Furthermore, high levels of plasma soluble terminal C5b‐9 complement complex were associated with VTE risk and unprovoked events in particular (Høiland et al, 2019). However, these studies do not provide evidence for a causative mechanism between complement activation and VTE.…”

Section: Implications For Disease Developmentmentioning

confidence: 99%

Complement, inflammation and thrombosis

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Sauter

Nording

et al. 2021

British J Pharmacology

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A mutual relationship exists between immune activation and mechanisms of thrombus formation. In particular, elements of the innate immune response such as the complement system can modulate platelet activation and subsequently thrombus formation. Several components of the complement system including C3 or the membrane attack complex have been reported to be associated with platelets and become functionally active in the micromilieu of platelet activation. The exact mechanisms how this interplay is regulated and its consequences for tissue inflammation, damage or recovery remain to be defined. This review addresses the current state of knowledge on this topic and puts it into context with diseases featuring both thrombosis and complement activation. Linked Articles This article is part of a themed issue on Canonical and non‐canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc

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“…Procedures for blood collection and storage of blood products have been previously described elsewhere. 29,30 In short, at inclusion in Tromsø 4 (1994/95), nonfasting blood was collected from an antecubital vein into 5-mL vacutainers (Becton Dickinson, Le Pont de Claix, France) containing ethylenediaminetetraacetic acid (EDTA) (K3-EDTA 40 μL, 0.37 mol/L per tube) as an anticoagulant. Platelet-poor plasma was prepared by centrifugation at 3,000 Â g for 10 minutes at room temperature, after which the supernatant was transferred into cryovials (Greiner Labortechnik, Nürtingen, Germany) in 1-mL aliquots and stored at -80°C until further use.…”

Section: Blood Sample Collection and Storage Of Blood Productsmentioning

confidence: 99%

Plasma Levels of Leptin and Risk of Future Incident Venous Thromboembolism

et al. 2021

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Background Circulating levels of leptin, an adipocyte-derived hormone, are frequently elevated in obesity. Leptin has been reported to upregulate prothrombotic hemostatic factors in vitro and could potentially mediate venous thromboembolism (VTE) risk in obesity. However, whether leptin is associated with VTE remains uncertain. Objective This article investigates the association between plasma leptin and risk of incident VTE, and the potential of leptin to mediate VTE risk in obesity. Methods A population-based nested case–control study with 416 VTE cases and 848 age- and sex-matched controls was derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across leptin quartiles. Analyses were performed separately in men and women using sex-specific quartile cut-offs determined in controls. Results In the age-adjusted model, the VTE risk increased across leptin quartiles, particularly in men. Compared with the lowest quartile, the ORs for VTE in the highest quartile were 1.70 (95% CI 1.04–2.79) in men and 1.36 (95% CI 0.85–2.17) in women. However, with additional adjustment for body mass index (BMI), risk estimates were markedly attenuated in men (OR 1.03, 95% CI 0.55–1.93) and women (OR 0.82, 95% CI 0.45–1.48). The ORs for VTE were increased in obese men and women (BMI ≥ 30 kg/m2) and were only marginally affected after adjustment for leptin. Conclusion Our results indicate that the apparent association between plasma leptin levels and VTE risk is confounded by BMI and that leptin is not a relevant mediator for VTE risk in obesity.

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Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism

Cited by 19 publications

References 44 publications

C5a-C5aR1 Axis Activation Drives Envenomation Immunopathology by the Snake Naja annulifera

C5a-C5aR1 Axis Activation Drives Envenomation Immunopathology by the Snake Naja annulifera

Complement, inflammation and thrombosis

Plasma Levels of Leptin and Risk of Future Incident Venous Thromboembolism

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