The complement lectin pathway after cardiac arrest

Haugaard, Simon; Jeppesen, Anni Nørgaard; Troldborg, Anne; Kirkegaard, Hans; Thiel, Steffen; Hvas, Anne‐Mette

doi:10.1111/sji.12680

Cited by 5 publications

(6 citation statements)

References 34 publications

(82 reference statements)

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“…14 This might be due to release of damage associated molecular patterns (DAMPs) from injured cells followed by a chain of injurious events 15 leading to activation of complement signalling pathways, in particular the lectin pathway. 16 While the aforementioned study showed no relation of lectin pathway activation and outcome, this study confirms that the end-product of complement system activation sC5b-9 is associated with poor outcome. TTM33 treatment of OHCA patients leads to suppression of complement activation with return to levels above reference limit after rewarming 17 while one study reports that TTM33 lead to reduction of the regulatory protein Map19 of the complement lectin pathway compared to TTM36.…”

Section: Complement Activationsupporting

confidence: 46%

Complement activation is associated with poor outcome after out-of-hospital cardiac arrest

et al. 2021

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Background: Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death.Methods: Outcome was assessed at six months and defined by cerebral performance category scale (1À2; good outcome, 3À5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule.Results: Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p < 0.001 for both) and in patients with poor compared to good outcome (p = 0.03 and p < 0.001, respectively). Unadjusted, higher sC5b-9 at admission was associated with poor outcome (odds ratio 1.08 (95% CI 1.01À1.14), p = 0.024). Adjusted, sC5b-9 was still associated with outcome, but the association became non-significant when time to return-of-spontaneous-circulation above 25 min was included as a covariate. Endothelial cell activation markers increased from admission to day three, but only sE-selectin and thrombomodulin were significantly higher in patients with poor versus good outcome (p = 0.004 and p = 0.03, respectively) and correlated to sCD14 and sC5b-9/C3bc, respectively.

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Section: Complement Activationsupporting

confidence: 46%

Complement activation is associated with poor outcome after out-of-hospital cardiac arrest

et al. 2021

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“…MASP-2 and MAp19 are splice variants from the same gene but the lack of MAp19 in OHCA patients does not coincide with deficiency of MASP-2. 8 Thus, low MAp19 levels is presumably not a result of lacking transcription from the gene, but, rather, a specific influence on the splicing process leading to generation of MAp19 protein, or an increased usage or binding of MAp19 already present in the systemic circulation. Notably, our finding of non-detectable levels of MAp19 in the early phase after OHCA is novel and, to the best of our knowledge, this may be unique for post-arrest patients.…”

Section: Discussionmentioning

confidence: 99%

“…4,7 Prior work has demonstrated that the lectin pathway may be activated in post-cardiac arrest patients and furthermore that MASP-2 proteins levels were higher compared with healthy controls. 8 The gene MASP2 encodes two proteins: MASP-2, which is an enzyme activating complement factor C4 and C2 in the lectin pathway, and the smaller protein mannan-binding associated protein of 19 kilo Dalton (MAp19). 9 The two proteins share domain structures that interact with the pattern recognition molecules.…”

Section: Introductionmentioning

confidence: 99%

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The complement lectin pathway protein MAp19 and out-of-hospital cardiac arrest: Insights from two randomized clinical trials

Bro-Jeppesen

Jeppesen

Haugaard

et al. 2020

European Heart Journal. Acute Cardiovascular Care

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Aim: Activation of the complement system is known to be a potent inducer of systemic inflammation, which is an important component of post-cardiac arrest syndrome. Mannan-binding-lectin associated protein of 19 kDa (MAp19) is suggested to be a regulatory component of the lectin pathway of complement activation. The aims of this study were to describe serial levels of MAp19 protein in comatose survivors of out-of-hospital cardiac arrest (OHCA), to evaluate the effect of two different regimes of targeted temperature management and to investigate the possible association between levels of MAp19 and mortality. Methods: In this post-hoc study, we analysed data from two large randomized controlled studies: ‘Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest’ (TTM) and ‘Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest’ (TTH). We measured serial levels of MAp19 in 240 patients within 72 h after OHCA and in 82 healthy controls. The effect of targeted temperature management on MAp19 levels was analysed according to temperature allocation in main trials. Results: MAp19 levels were significantly lower in OHCA patients within 48 h after OHCA ( p-values <0.001) compared with healthy controls. A target temperature at 33°C compared with 36°C for 24 h was associated with significantly lower levels of MAp19 (–57 ng/mL (95% confidence interval (CI): –97 to −16 mg/mL), p=0.006). Target temperature at 33°C for 48 h compared with 24 h was not associated with a difference in MAp19 levels (–31 ng/mL (95% CI: –120 to 60 mg/mL), p=0.57). Low MAp19 levels at admission were associated with higher 30-day mortality (12% vs. 38%, plog-rank =0.0008), also in adjusted analysis (two-fold higher, hazard ratio =0.48 (95% CI: 0.31 to 0.75), p=0.001). Analysis of MAp19 levels at 24–72 h showed they were not associated with 30-day mortality. Conclusion: Survivors after OHCA have lower levels of MAp19 protein compared with healthy controls. A targeted temperature management at 33°C compared with 36°C was associated with significantly lower MAp19 levels, whereas target temperature at 33°C for 48 h compared with 24 h did not influence MAp19 protein levels. Low MAp19 levels at admission were independently associated with increased mortality.

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“…• Coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases • Thrombin efficiently cleaved C5 at a newly identified, highly conserved R947 site, generating previously undescribed intermediates C5(T) and C5b(T) • C5b(T)-9 membrane attack complex has significantly more lytic activity than with C5b-9 • Complement activation in the presence of thrombin leads to assembly of C5bT • Lectin pathway inhibitors may be beneficial in patients with coagulation abnormalities/bleeding and incomplete response to C5 blockade • This can be extended to DIC mediated TMA as dysregulated coagulation cascade triggers secondary complement activation and some genetic mutations have been isolated in DIC linking to alternative pathway dysfunction and coagulation cascade mutations Cardiac/vascular emergencies [83][84][85][86] :…”

Section: Complement Blocker With Potential Benefit Reasoning For Pote...mentioning

confidence: 99%

Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat

Jodele

Sabulski

2023

American J Hematol

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Over the last decade there have been numerous advances in both the diagnosis and treatment of transplant-associated thrombotic microangiopathy (TA-TMA). These are largely the result of an improved understanding of complement activation in TA-TMA and the ability to prevent end organ injury and death with timely initiation of complementblocking therapies. In this article, we review our current understanding of the pathophysiology of TA-TMA, particularly as it pertains to complement activation, endothelial injury, and clinical management. We then review novel complement-blocking therapies that are currently under investigation for use in TA-TMA, as well as discuss special considerations for complement-blocking therapy in hematopoietic stem cell transplant recipients. Through these reviews we aim to answer or at least provide an educated discussion on the most commonly posed TA-TMA management questions and dilemmas.

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The complement lectin pathway after cardiac arrest

Cited by 5 publications

References 34 publications

Complement activation is associated with poor outcome after out-of-hospital cardiac arrest

Complement activation is associated with poor outcome after out-of-hospital cardiac arrest

The complement lectin pathway protein MAp19 and out-of-hospital cardiac arrest: Insights from two randomized clinical trials

Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat

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