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Relationship: 2290

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 Thrombosis and DIC

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

Thrombosis and DIC

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	High	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 Do not cite	Under Development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
Homo sapiens	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

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

Many regulators are involved in coagulation system. Plasmin is one of the modulators required for dissolution of the fibrin clot. Plasmin is activated by tissue plasminogen activator (tPA) and urokinase plasminogen activation (uPA). SERPINs inhibit thrombin, plasmin and tPA. For example, SERPINE1 or plasminogen activator inhibitor-1 (PAI-1) inhibits tPA/uPA and results in hypofibrinolysis (Bernard I et al., 2021). In addition, SERPING1 inhibits FXII, and thus down-regulation of SERPING1 lifts suppression of FXII of the intrinsic coagulation cascade (Garvin et al., 2020). Protein C, protein S and thrombomodulin degrade FVa and FVIIIa. [Ref. IPA, Coagulation System, version60467501, release date: 2020-11-19]

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 “coagulation” and “thrombosis” in NCBI database. The fact that coagulation leads to thrombosis and disseminated intravascular coagulation (DIC) is known in general. The relationship between coagulation and thrombosis and DIC have been discussed in CIAO project as well in the scope of COVID-19.

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

Overexpression of procoagulant molecules, among which tissue factor is the most well studied, induces thrombosis. Thrombotic complications include disseminated intravascular coagulation (DIC) (Tsantes, Petrou et al. 2024).

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

Coagulation induced by activation of polymorphonuclear leucocytes leads to thrombosis and coagulopathy (Barrett, Hsu et al. 2018).

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

It is unclear how the balance between coagulation and hemolysis is involved in the induction of thrombosis and DIC.

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

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

Not well known

Response-response Relationship

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

Not well known

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

Not well known

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

Decreased fibrinolysis is involved in coagulation system. Coagulopathy induced by excess coagulation may be key for thrombosis and disseminated intravascular coagulation. (Mast AE et al., 2021, Garvin MR et al.,2020).

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 applies to Homo sapiens (Tsantes, Petrou et al. 2024).

References

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

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.

Bernard I, Limonta D, Mahal LK, Hobman TC. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses. 2021; 13(1):29. DOI: https://doi.org/10.3390/v13010029

Garvin et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020;9:e59177. DOI: https://doi.org/10.7554/eLife.59177

Mast AE, Wolberg AS, Gailani D, Garvin MR, Alvarez C, Miller JI, Aronow B, Jacobson D (2021) SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung. eLife 10:e64330. doi:10.7554/eLife.64330

Tsantes, A. G., E. Petrou, K. A. Tsante, R. Sokou, F. Frantzeskaki, A. Domouchtsidou, A. E. Chaldoupis, S. P. Fortis, D. Piovani, G. K. Nikolopoulos, N. Iacovidou, S. Bonovas, G. Samonis and A. E. Tsantes (2024). "Cancer-Associated Thrombosis: Pathophysiology, Laboratory Assessment, and Current Guidelines." Cancers (Basel) 16(11).