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Relationship: 2360
Title
Coagulation leads to Diminished Protective Response to ROS
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation | adjacent | Moderate | Not Specified | Shihori Tanabe (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
human | Homo sapiens | Moderate | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | Moderate |
Key Event Relationship Description
Blood coagulation through activation and recruitment of platelets following vessel-wall injury induces formation of thrombin through coagulation cascade, which induces reactive oxygen species generation by NOX enzymes in vascular cells (André-Lévigne D et al., 2017). Coagulation is a complex process that involves the formation of blood clots to prevent excessive bleeding. During injury or infection, tissue damage activates the coagulation cascade. Coagulation factors, such as tissue factor (TF), initiate clot formation by converting fibrinogen to fibrin. Simultaneously, inflammation is triggered, involving immune cells, cytokines, and chemokines. Reactive oxygen species (ROS) are produced during cell metabolism. ROS include radicals (e.g., superoxide anion, hydroxyl radical, nitric oxide) and non-radicals (e.g., hydrogen peroxide) and play dual roles: harmful (e.g., cell death pathways) and beneficial (e.g., microbial killing). Neutrophils and macrophages use ROS to kill engulfed pathogens. Chronic granulomatous disease (CGD), caused by NADPH oxidase deficiency, impairs ROS-dependent pathogen killing. ROS contribute to inflammation, signal transduction, cell migration, and gene expression. Hydrogen peroxide (H₂O₂) modulates gene expression via redox-based epigenetic modifications and transcriptional regulation. ROS are essential for immune system function. Coagulation and ROS intersect in immune responses, impacting both protective immunity and potential harm.
Evidence Collection Strategy
The references were searched with terms "ROS" or "reactive oxygen species" and "coagulation" in NCBI database. The references that have relevant insights where coagulation leads to diminished protective response to ROS were selected and cited.
Copilot GPT was input with a question "Please write Key Event Relationship starts from coagulation leading to diminished protective response to reactive oxygen species" on June 7th 2024 (ChatGPT4). The answers of Co-pilot were modified to fit the AOP-Wiki.
Evidence Supporting this KER
Biological Plausibility
Coagulation induces extracellular ROS production in a C5a-dependent manner that contributes to organ injury (Barrett, Hsu et al. 2018). Coagulation balance that refers to the interaction between the procoagulant pathways specific for clot formation and hose mechanisms included in the fibrinolysis system influences dysregulation of homeostasis maintenance, which lead sot oxidative stress (Robea, Balmus et al. 2023).
Empirical Evidence
Inhibition of activated protein C, an anti-coagulant involved in the interactions between the coagulation and immune systems, induces decreases in peripheral CD4+ T cells, which induces immune suppression (Alabanza, Esmon et al. 2013).
Uncertainties and Inconsistencies
Relationship between coagulation and diminished protective oxidative stress response is both directions and the amplification of the magnitude may be involved in feedback loop. There is uncertainty in terms of the relations in amount of the coagulation factors and reactive oxygen species.
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Thrombin (50 mU/ml, 2 min) induced ROS production (Balykina, Naida et al. 2024). The flavonoid aglycones (100 uM, 30 min) such as luteolin, myricetin, quecetin, eriodictyol, kaempferol, and apigenin inhibited thrombin-induced ROS formation (Panth, Paudel et al. 2016, Jomova, Raptova et al. 2023).
Time-scale
Thrombin treatment for 2 min induced ROS production in human platelets (Balykina, Naida et al. 2024).
Known Feedforward/Feedback loops influencing this KER
Increased ROS caused by diminished response to ROS causes oxidative stress and coagulation (Gutmann, Siow et al. 2020).
Increased oxidative stress has been reported in various cardiovascular-related diagnoses (Panth, Paudel et al. 2016, Ranneh, Ali et al. 2017, Jomova, Raptova et al. 2023).
Domain of Applicability
The KER applies to Homo sapiens (Robea, Balmus et al. 2023), Mus musculus (Alabanza, Esmon et al. 2013).
References
Alabanza, L. M., N. L. Esmon, C. T. Esmon and M. S. Bynoe (2013). "Inhibition of endogenous activated protein C attenuates experimental autoimmune encephalomyelitis by inducing myeloid-derived suppressor cells." J Immunol 191(7): 3764-3777.
André-Lévigne D, Modarressi A, Pepper MS, Cuenod BP. (2017) Reactive Oxygen Species and NOX Enzymes Are Emerging as Key Players in Cutaneous Wound Repair. Int J Mol Sci. 18(10):2149.
Balykina, A., L. Naida, K. Kirkgöz, V. O. Nikolaev, E. Fock, M. Belyakov, A. Whaley, A. Whaley, V. Shpakova, N. Rukoyatkina and S. Gambaryan (2024). "Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases." Int J Mol Sci 25(9).
Barrett, C. D., A. T. Hsu, C. D. Ellson, Y. M. B, Y. W. Kong, J. D. Greenwood, S. Dhara, M. D. Neal, J. L. Sperry, M. S. Park, M. J. Cohen, B. S. Zuckerbraun and M. B. Yaffe (2018). "Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy." Clin Exp Immunol 194(1): 103-117.
Bassoy, E.Y.; Walch, M.; Martinvalet, D. Reactive Oxygen Species: Do They Play a Role in Adaptive Immunity? Frontiers in Immunology 2021, 12, doi:10.3389/fimmu.2021.755856.
Gutmann, C.; Siow, R.; Gwozdz, A.M.; Saha, P.; Smith, A. Reactive Oxygen Species in Venous Thrombosis. International Journal of Molecular Sciences 2020, 21, 1918.
Jomova, K.; Raptova, R.; Alomar, S.Y.; Alwasel, S.H.; Nepovimova, E.; Kuca, K.; Valko, M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Archives of Toxicology 2023, 97, 2499-2574, doi:10.1007/s00204-023-03562-9.
Martinvalet, D.; Walch, M. Editorial: The Role of Reactive Oxygen Species in Protective Immunity. Frontiers in Immunology 2022, 12, doi:10.3389/fimmu.2021.832946.
Panth, N.; Paudel, K.R.; Parajuli, K. Reactive Oxygen Species: A Key Hallmark of Cardiovascular Disease. Advances in Medicine 2016, 2016, 9152732, doi:https://doi.org/10.1155/2016/9152732.
Ranneh, Y.; Ali, F.; Akim, A.M.; Hamid, H.A.; Khazaai, H.; Fadel, A. Crosstalk between reactive oxygen species and pro-inflammatory markers in developing various chronic diseases: a review. Applied Biological Chemistry 2017, 60, 327-338, doi:10.1007/s13765-017-0285-9.
Robea, M. A., I.-M. Balmus, I. Girleanu, L. Huiban, C. Muzica, A. Ciobica, C. Stanciu, C. D. Cimpoesu and A. Trifan (2023). "Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease—Oxidative Stress and Inflammation Relevance." Medicina 59(9): 1614.