Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

Fletcher‐Sandersjöö, Alexander; Maegele, Marc; Bellander, Bo‐Michael

doi:10.3390/ijms21051596

Cited by 21 publications

(17 citation statements)

References 104 publications

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“…In addition to complement activation, COVID-19 patients also suffer from excessive coagulation, leading to thrombotic complications and poor clinical outcome [3]. In non-CoV cohorts, there is evidence of interactions between the complement and coagulation systems, resulting in an amplification of their otherwise targeted responses [4,5,[14][15][16][17][18][19][20][21][22][23]6,[24][25][26][27][28][29][30][7][8][9][10][11][12][13]. However, it is not known whether this process occurs and could explain the thrombotic complications in COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review

Fletcher‐Sandersjöö

Bellander

2020

Thrombosis Research

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118

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Severe acute respiratory syndrome coronavirus 2 is responsible for the current COVID-19 pandemic resulting in an escalating number of cases and fatalities worldwide. Preliminary evidence from these patients, as well as past coronavirus epidemics, indicates that those infected suffer from disproportionate complement activation as well as excessive coagulation, leading to thrombotic complications and poor outcome. In non-coronavirus cohorts, evidence has accumulated of an interaction between the complement and coagulation systems, with one amplifying activation of the other. A pressing question is therefore if COVID-19 associated thrombosis could be caused by overactivation of the complement cascade? In this review, we summarize the literature on thrombotic complications in COVID-19, complement activation in coronavirus infections, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system is able to activate the coagulation cascade and platelets, inhibit fibrinolysis and stimulate endothelial cells. We also describe how these interactions see clinical relevance in several disorders where overactive complement results in a prothrombotic clinical presentation, and how it could be clinically relevant in COVID-19. membrane attack complex (MAC, also known as the terminal complement complex C5b-9) [34]. This activation generally follows three pathways, each triggered by different agents, which converge in the formation of C3 convertase. C3 convertase then cleaves C3 into C3b, a potent opsonin, and C3a, an anaphylatoxin [34]. Further propagation of C3b also results in the generation of C5 convertase, which cleaves C5 to C5a and C5b. C5b forms a complex with other complement proteins that make up the C5b-9 membrane attack complex (MAC). Deposition of MAC on cell membranes leads to calcium influx and cell lysis, but can also activate intracellular signaling at lower doses [34]. The complement system is also regulated by complement control proteins, including C1-inhibitor (CI-INH), decay-accelerating factor (DAF), C4binding protein (C4BP), factor H and other [34,35].

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Section: Introductionmentioning

confidence: 99%

Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review

Fletcher‐Sandersjöö

Bellander

2020

Thrombosis Research

Self Cite

118

137

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“…The initial injury is often followed by hemostatic disturbance, which is present in up to two-thirds of patients with severe TBI and associated with increased mortality [2,3]. While it is still unclear exactly how TBI affects the coagulation system, the primary drivers appear to be platelet dysfunction, endothelial activation, disturbed fibrinolysis, endogenous anticoagulation, and inflammation [2,[4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Time Course of Hemostatic Disruptions After Traumatic Brain Injury: A Systematic Review of the Literature

et al. 2020

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Almost two-thirds of patients with severe traumatic brain injury (TBI) develop some form of hemostatic disturbance, which contributes to poor outcome. While the initial head injury often leads to impaired clot formation, TBI is also associated with an increased risk of thrombosis. Most likely there is a progression from early bleeding to a later prothrombotic state. In this paper, we systematically review the literature on the time course of hemostatic disruptions following TBI. A MEDLINE search was performed for TBI studies reporting the trajectory of hemostatic assays over time. The search yielded 5,049 articles, of which 4,910 were excluded following duplicate removal as well as title and abstract review. Full-text assessment of the remaining articles yielded 33 studies that were included in the final review. We found that the first hours after TBI are characterized by coagulation cascade dysfunction and hyperfibrinolysis, both of which likely contribute to lesion progression. This is then followed by platelet dysfunction and decreased platelet count, the clinical implication of which remains unclear. Later, a poorly defined prothrombotic state emerges, partly due to fibrinolysis shutdown and hyperactive platelets. In the clinical setting, early administration of the antifibrinolytic agent tranexamic acid has proved effective in reducing head-injury-related mortality in a subgroup of TBI patients. Further studies evaluating the time course of hemostatic disruptions after TBI are warranted in order to identify windows of opportunity for potential treatment options.

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“…After TBI, HIF-1 has a two-way regulatory effect. HIF-1 can not only promote red blood cell proliferation and angiogenesis by inducing VEGF expression and increase nerve cell tolerance [30] but also mediate cell apoptosis and in ammation, leading to nerve cell death [31] . Studies have found that resveratrol can affect the permeability of the blood-brain barrier by regulating the expression of HIF-1, further verifying the reliability of the predictions made in this study [32] .…”

Section: Discussionmentioning

confidence: 99%

Tittle Exploring the Mechanism of Resveratrol on Traumatic Brain Injury by Network Pharmacology and Molecular Docking

Liu¹,

Li-jun²,

Li³

et al. 2020

Preprint

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[Background] Resveratrol is a polyphenol present abundantly in lots of traditional Chinese medicines, which has been shown to have beneficial effects on neurological diseases. However, the molecular mechanisms of resveratrol on traumatic brain injury have not been systematically studied yet. In this study, we elucidated the pharmacological mechanisms of resveratrol in treating traumatic brain injury by using a network pharmacology method. [Methods] The pharmacokinetics properties of resveratrol were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). The putative targets of resveratrol were obtained from TCMSP, BATMAN-TCM, SuperPred, PharmMapper, SwissTargetPrediction, DrugBank, and a literature search. The targets related to traumatic brain injury were obtained from TTD, DrugBank, CTD, GeneCards, OMIM, MalaCards, and a literature search. The STRING database and the Cytoscape 3.8.0 software were used to build the protein-protein interaction (PPI) network. The Metascape database was used to obtain the gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment information. Finally, The AutoDockTools 1.5.6 and PyMOL 2.4.0 software were employed for molecular docking analyses, and Discovery Studio 2020 was used for interaction analyses. [Results] A total of 165 overlapping targets involved in resveratrol intervention in traumatic brain injury were determined. The GO function analysis indicated that the targets are including the positive regulation of transferase activity, the positive regulation of cell migration, reactive oxygen species metabolism, the wound response, and so on. The KEGG pathway analysis identified the following enriched pathways: the AGE-RAGE signalling pathway, the FoxO signalling pathway, insulin resistance, complement and coagulation cascades, the HIF-1 signalling pathway, and so on. According to the PPI network analysis, INS, IGF1, TNF, TP53, ALB, IL6, SRC, STAT3, VEGFA, and MMP9 were identified as hub target genes, in which IL6, MMP9, INS, and SRC showed a good binding affinity with resveratrol in molecular docking. [Conclusions] Resveratrol may target multiple genes and multiple pathways to reduce brain damage after traumatic brain injury.

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Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

Cited by 21 publications

References 104 publications

Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review

Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review

Time Course of Hemostatic Disruptions After Traumatic Brain Injury: A Systematic Review of the Literature

Tittle Exploring the Mechanism of Resveratrol on Traumatic Brain Injury by Network Pharmacology and Molecular Docking

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