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: 2359

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

Diminished Protective Response to ROS leads to Coagulation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Diminished Protective Response to ROS

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Coagulation

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 Do not cite	Under Development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

ROS are oxygen-derived molecules that oxidize molecules or are converted into oxygen radicals (André-Lévigne D, et al., 2017). ROS have dual-effects which are cell damaging or beneficial roles (André-Lévigne D, et al., 2017, Beckman KB and Ames BN, 1998, Bedard K and KH Krause, 2007). ROS generated by NOX2, a NADPH oxidase, in macrophage play an important role in killing of phagocytosed microorganisms (Bedard K and KH Krause, 2007). The ROS accumulation cause mitochondrial dysfunction which leads to coagulopathy associated with inflammatory signaling pathways (Saleh J et al., 2020). Polymorphonuclear leucocytes, commonly referred to as neutrophils, generate large amounts of ROS via the NADPH oxidase complex (Barrett CD et al., 2018).

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" and "coagulation" in NCBI database. The references that have relevant insights in diminished protective response to ROS and coagulation were selected and cited.

Microsoft co-pilot was used to write the relationship between NRF2 inactivation and blood coagulation (as of January 19th, 2024).

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

The ROS released from the polymorphonuclear leucocytes following trauma and haemorrhagic shock led to lung injury and coagulopathy (Barrett CD et al., 2018). Serpin family A member 1 (SERPINA1/alpha-1-antitrypsin), a serine protease inhibitor, inhibits coagulation factor 2a (thrombin) (Cohen AB., 1973). SERPINA1 is a member of low-density lipoprotein (LDL) and involved in ROS network (Lubrano V, and Balzan S. 2020). ROS are required for release of granzyme B (GzmB), a cytotoxic lymphocyte protease, into the cytosol (Mangan MS et al., 2016). SERPINA1 is converted into a ROS-sensitive granzyme B (GzmB) inhibitor by replacing the P4-P3’ reactive center loop residues (Mangan MS et al., 2016). Thrombin activates NADPH oxidase and produces ROS, which leads to fibroblast proliferation (Zhou SY et al., 2010). Endothelial exposure of thrombin induces NOX-dependent superoxide superoxide anion and hydrogen peroxide (Pai WY et al., 2017, Holland JA et al., 1998).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The presence of ROS assists in the transformation of a circulating, non-oxidized, circular-shaped beta2-glycoprotein 1 into an oxidized J-shape, which binds to antiphospholipid antibodies such as anticardiolipin, lupus anticoagulant, and anti-beta2-GP1 antibodies (Janardhan et al., 2020). Domain V of beta2gP1 binds with the phospholipid layer of platelets or endothelial cells via Annexin (Janardhan et al., 2020).

Nrf2, a basic leucine zipper transcription factor, plays a crucial role in cellular defense against oxidative stress by inducing the expression of cytoprotective and detoxifying genes. Activation of Nrf2 has protective roles against cancer onset and progression, while persistent activation can lead to malignant progression, chemo/radio resistance, and poor prognosis Pouremamali, F., et al. (2022).

Nrf2’s involvement in inflammatory responses and erythrocyte homeostasis suggests a potential impact on blood coagulation. Additionally, the interaction between Nrf2 and NF-κB, and the increase in inflammatory factors due to Nrf2 deficiency, highlight the complex role of Nrf2 in cellular processes (Motohashi et al., 2021).

Keap1, a major regulator of Nrf2, ubiquitinates Nrf2 under basal conditions, targeting it for proteasomal degradation in the cytoplasm. This regulation is crucial for maintaining cellular homeostasis and responding to oxidative stress (Khodakarami et al., 2022).

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

Considering the effect of Nrf2 inactivation on blood coagulation, it is hypothesized that inactivation could lead to increased inflammatory responses, potentially promoting blood coagulation. However, this relationship requires further research for confirmation.

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

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

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

Fibrin may induce oxidative stress.

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

This KER is applied for human.

References

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

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.

Barrett CD et al., (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.

Beckman KB, BN Ames. (1998) The free radical theory of aging matures. Physiol Rev. 78(2):547-81.

Bedard K, KH Krause. (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 87(1):245-313.

Cohen AB. (1973) Mechanism of action of alpha-1-antitrypsin. J Biol Chem. 248(20):7055-9.

Holland JA, Meyer JW, Donnell RW, Johnson DK, Ziegler LM. (1998) Thrombin Stimulated Reactive Oxygen Species Production in Cultured Human Endothelial Cells. Endothelium. 6(2):113-121.

Janardhan, V., V. Janardhan and V. Kalousek. (2020) COVID-19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy. Journal of Neuroimaging 30(5): 555-561.

Khodakarami A. (2022) The molecular biology and therapeutic potential of Nrf2 in leukemia. Cancer Cell International. 22:241.

Lubrano V, S Balzan. (2020) Role of oxidative stress-related biomarkers in heart failure: galectin 3, α1-antitrypsin and LOX-1: new therapeutic perspective? Mol Cell Biochem. 464(1-2):143-152.

Mangan MS, Bird HS, Kaiserman D, Matthews AY, Hitchen C, et al. (2016) A Novel Serpin Regulatory Mechanism: SerpinB9 is reversibly inhibited by vicinal disulfide bond formation in the reactive center loop. J Biol Chem. 291(7):3626-38.

Motohashi H. (2021) NRF2によるストレス応答と硫黄代謝制御. Journal of Japanese Biochemical Society 93(5): 674-683 .

Pai WY, Lo WY, Hsu T, Peng CT, Wang Hj. (2017) Angiotensin-(1-7) Inhibits Thrombin-Induced Endothelial Phenotypic Changes and Reactive Oxygen Species Production via NADPH Oxidase 5 Downregulation. Front Physiol. 8:994.

Pouremamali F, et al. (2022) An update of Nrf2 activators and inhibitors in cancer prevention/promotion. Cell Communication and Signaling, 20, Article number: 100.

Saleh J, Peyssonaux, Singh KK, Edeas M. (2020) Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion. 54:1-7.

Zhou SY, Xiao W, Pan XJ, Zhu MX, Yang ZH, et al. (2010) Thrombin promotes human lung fibroblasts to proliferate via NADPH oxidase/reactive oxygen species/extracellular regulated kinase signaling pathway. Chin Med J (Engl). 123(17):2432-9.