API

This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2360

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Coagulation leads to Diminished Protective Response to ROS

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Coagulation
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Diminished Protective Response to ROS

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Do not cite Under Development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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

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

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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).  

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

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
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Thrombin treatment for 2 min induced ROS production in human platelets (Balykina, Naida et al. 2024).

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The KER applies to Homo sapiens (Robea, Balmus et al. 2023), Mus musculus (Alabanza, Esmon et al. 2013).

References

List of the literature that was cited for this KER description. More help

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.