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AOP: 379

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
SARS-CoV2 to thrombosis and DIC
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Shihori Tanabe1, Youngjun Kim2, Sally Mayasich3, Maria João Amorim4, Nikolaos Parissis5, Penny Nymark6, Marvin Martens7, Dan Jacobson8, Felicity N. E. Gavins9, Luigi Margiotta-Casaluci10, Sabina Halappanavar11, Natàlia Garcia-Reyero12, Julija Filipovska13, Stephen W. Edwards14‚ Rebecca Ram15, Adrienne Layton16, Brigitte Landesmann5, Hasmik Yepiskoposyan17, Jukka Sund18, Clemens Wittwehr5, Laure-Alix Clerbaux5

1Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan　

2KIST Europe Forschungsgesellschaft mbH, Saarbrücken, Germany

3University of Wisconsin-Madison at U.S. Environmental Protection Agency, Duluth, Minnesota, United States

4Instituto Gulbenkian de Ciência – Fundação Calouste Gulbenkian, Oeiras, Portugal

5European Commission, Joint Research Centre (JRC), Ispra, Italy

6Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

7Maastricht University, Maastricht, Netherlands

8Oak Ridge National Laboratory, Oak Ridge, United States

9Brunel University London, London, United Kingdom

10King’s College London, London, United Kingdom

11Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada

12U.S. Army Engineer Research and Development Center (ERDC), Vicksburg, United States

13Independent Scientist & Consultant, North Macedonia

14GenOmics, Bioinformatics, and Translational Research Center, RTI International, Washington DC, United States

15Safer Medicines Trust, Kingsbridge, United Kingdom

16U.S. Consumer Product Safety Commission, Bethesda, United States

17Philip Morris International, Neuchatel, Switzerland

18Finnish Safety and Chemicals Agency, Finland

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Shihori Tanabe
  • Arthur Author

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

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OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
1.96 Under Development
This AOP was last modified on September 25, 2023 16:27

Revision dates for related pages

Page Revision Date/Time
Coagulation November 25, 2022 01:36
Thrombosis and Disseminated Intravascular Coagulation November 25, 2022 01:38
Increased SARS-CoV-2 production June 14, 2022 08:49
SARS-CoV-2 cell entry April 04, 2023 07:39
Diminished protective oxidative stress response March 09, 2023 20:49
Binding to ACE2 April 03, 2023 04:03
Interferon-I antiviral response, antagonized by SARS-CoV-2 April 03, 2023 15:20
Binding to ACE2 leads to SARS-CoV-2 cell entry February 07, 2023 23:24
SARS-CoV-2 cell entry leads to IFN-I response, antagonized April 03, 2023 15:49
IFN-I response, antagonized leads to SARS-CoV-2 production October 24, 2021 17:11
SARS-CoV-2 production leads to Diminished Protective Response to ROS July 25, 2023 00:18
Diminished Protective Response to ROS leads to Coagulation July 21, 2023 03:42
Coagulation leads to Diminished Protective Response to ROS April 20, 2021 03:50
Coagulation leads to Thrombosis and DIC February 05, 2023 20:49
Stressor:624 SARS-CoV-2 April 20, 2021 03:40

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Coronavirus disease-19 (COVID-19) is circulating all over the world. To understand and find a way of the COVID-19 treatment, the signaling pathway and therapeutic mechanism of COVID-19 should be investigated. The pathogenesis of COVID-19 includes molecular networks such as the binding of the membrane proteins, signaling pathways, and RNA replication. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a new type of coronavirus causing COVID-19, infects the cells via the binding of the membrane proteins of human cells and is internalized by the cells. The viral genome is replicated by RNA-dependent RNA polymerase (RdRp), followed by the packaging and releasing of the viral particles. These steps can be the main targets for the therapeutics of COVID-19. The AOP379 "Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation" consists of the molecular initiating event (MIE) as “Binding to ACE2” (KE1739), key events (KEs) as “SARS-CoV-2 cell entry” (KE1738), “Interferon-I antiviral response, antagonized by SARS-CoV-2” (KE1901), "Increased SARS-CoV-2 production" (KE1847), “Diminished protective oxidative stress response" (KE1869) and "Coagulation" (KE1845), and adverse outcome (AO) as "Thrombosis and Disseminated Intravascular Coagulation" (KE1846).

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

This AOP379 has been developed in the collaboration of Modelling the Pathogenesis of COVID-19 using the AOP framework (CIAO) international consortium (Clerbaux et al., 2022). Extensive efforts in discussion and literature search of the group crystalized into many AOPs related to coronavirus pathogenesis and coronavirus infectious disease 2019 (COVID-19), where the AOP379 focuses on the thrombosis and disseminated intravascular coagulation as adverse outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through reactive oxygen species-induced oxidative stress response (Tanabe et al., 2022).

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1739 Binding to ACE2 Binding to ACE2
KE 1738 SARS-CoV-2 cell entry SARS-CoV-2 cell entry
KE 1901 Interferon-I antiviral response, antagonized by SARS-CoV-2 IFN-I response, antagonized
KE 1847 Increased SARS-CoV-2 production SARS-CoV-2 production
KE 1869 Diminished protective oxidative stress response Diminished Protective Response to ROS
KE 1845 Coagulation Coagulation
AO 1846 Thrombosis and Disseminated Intravascular Coagulation Thrombosis and DIC

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding
Binding to ACE2 leads to SARS-CoV-2 cell entry adjacent High Moderate
SARS-CoV-2 cell entry leads to IFN-I response, antagonized adjacent Moderate Moderate
IFN-I response, antagonized leads to SARS-CoV-2 production adjacent Moderate Moderate
SARS-CoV-2 production leads to Diminished Protective Response to ROS adjacent Moderate Not Specified
Diminished Protective Response to ROS leads to Coagulation adjacent Moderate Not Specified
Coagulation leads to Diminished Protective Response to ROS adjacent Moderate Not Specified
Coagulation leads to Thrombosis and DIC adjacent High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help
Name
Stressor:624 SARS-CoV-2

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

This AOP is applicable to all sexes in Homo sapiens.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

The AOP379 focuses on the coronavirus-induced thrombosis and disseminated intravascular coagulation, which may contribute to the development of therapeutics of COVID-19 and long COVID syndrome. The understanding of the mechanism of the coronavirus-induced vascular adverse outcome may predict adverse responses of COVID-19 vaccines.

References

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

Blanco Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 181;(5):1036-1045.

Chen B, Tian EK, He B, Tian L, Han R, Wang S, et al. Overview of lethal human Coronaviruses. Signal Transduction and Targeted Therapy, 2020;5(1):89.

Clerbaux, L.-A., Amigó, N., Amorim, M. J., Bal-Price, A., Batista Leite, S., Beronius, A., Bezemer, G. F. G., Bostroem, A.-C., Carusi, A., Coecke, S., Concha, R., Daskalopoulos, E. P., De Bernardi, F., Edrosa, E., Edwards, S. W., Filipovska, J., Garcia-Reyero, N., Gavins, F. N. E., Halappanavar, S., Hargreaves, A. J., Hogberg, H. T., Huynh, M. T., Jacobson, D., Josephs-Spaulding, J., Kim, Y. J., Kong, H. J., Krebs, C. E., Lam, A., Landesmann, B., Layton, A., Lee, Y. O., Macmillan, D. S., Mantovani, A., Margiotta-Casaluci, L., Martens, M., Masereeuw, R., Mayasich, S. A., Mei, L. M., Mortensen, H., Munoz Pineiro, A., Nymark, P., Ohayon, E., Ojasi, J., Paini, A., Parissis, N., Parvatam, S., Pistollato, F., Sachana, M., Sørli, J. B., Sullivan, K. M., Sund, J., Tanabe, S., Tsaioun, K., Vinken, M., Viviani, L., Waspe, J., Willett, C. and Wittwehr, C. (2022) “COVID-19 through adverse outcome pathways: Building networks to better understand the disease – 3rd CIAO AOP Design Workshop”, ALTEX - Alternatives to animal experimentation, 39(2), pp. 322–335. doi: 10.14573/altex.2112161.

Cui J, Li F, Shi ZL. Origin and evolution of pathogenic Coronaviruses. Nature Reviews Microbiology. 2019;17(3):181-192.

Florindo HF, Kleiner R, Vaskovich-Koubi D, Acúrcio RC, Carreira B, Yeini,E, et al. Immune-mediated approaches against COVID-19. Nature Nanotechnology. 2020:15(8):630-45.

Kowalewski J, Ray A. Predicting novel drugs for SARS-CoV-2 using machine learning from a & g 10 million chemical space. Heliyon. 2020;6(8).

Pizzorno A, Padey B, Julien T, Trouillet-Assant S, Traversier A, Errazuriz-Cerda E, et al. Characterization and Treatment of SARS-CoV-2 in Nasal and Bronchial Human Airway Epithelia. Cell Reports Medicine. 2020:1(4). 

Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature. 2020.

Tanabe S (2020a). Cellular Internalization and RNA Regulation of RNA virus. Adv Clin Med Res. 2020;1(1):1-3. https://www.genesispub.org/cellular-internalization-and-rna-regulation-of-rna-virus

Tanabe S (2020b). The Therapeutic Mechanism of COVID-19. J Clin Med Res. 2020;2(5):1-3. DOI: https://doi.org/10.37191/Mapsci-2582-4333-2(5)-048

Tanabe, S., Beaton, D., Chauhan, V., Choi, I., Danielsen, P. H., Delrue, N., Esterhuizen, M., Filipovska, J., FitzGerald, R., Fritsche, E., Gant, T., Garcia-Reyero, N., Helm, J., Huliganga, E., Jacobsen, N., Kay, J. E., Kim, Y.-J., Klose, J., La Rocca, C., Luettich, K., Mally, A., O’Brien, J., Poulsen, S. S., Rudel, R. A., Sovadinova, I., Tollefsen, K. E., Vogel, U., Yepiskoposyan, H. and Yauk, C. (2022) “Report of the 1st and 2nd Mystery of Reactive Oxygen Species Conferences”, ALTEX - Alternatives to animal experimentation, 39(2), pp. 336–338. doi: 10.14573/altex.2203011.