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Relationship: 2355

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

Bradykinin, activated leads to Hypofibrinolysis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Bradykinin, activated
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Hypofibrinolysis

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
Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation adjacent Cataia Ives (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 Do not cite Under Development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 High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female High

Life Stage Applicability

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

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

Bradykinin (BK) plays an important role in the kinin-kallikrein system (KKS) as a regulator of blood pressure and can induce vasodilation, increase blood flow, as well as hypotension. BK is also an important part of the inflammatory process after injury, inducing pain stimulation. Activation of the BK system is associated with vasodilation and vascular leakage, allowing for infiltration of proinflammatory cells such as IL6 ((Hofman et al, 2016).

During SARS-CoV-2 infection, increased activity of kallikrein activates the bradykinin system. Bradykinin is known to stimulate tissue plasminogen activator (tPA), a protein that increases fibrinolysis. However, ACE2 downregulation from SARS-COV-2 infection increases Angiotensin 1 and II (ANG 1 and ANGII), which increases Plasminogen activator inhibitor (PAI-1) levels and decreases tPA levels (Mogielnicki et al, 2014). PAI-1 inhibits the protective effects of tPA/uPA in fibrinolysis, decreasing fibrinolysis. Data shows that both Bradykinin, and subsequently tPA levels and PAI-1 levels increase in COVID-19 patients, but PAI-1 increases at a higher rate than tPA, leading to hypofibrinolysis(Zuo et al, 2021).

Bradykinin, as a result of its role as a vasodilator, increases vascular permeability, which increases levels of proinflammatory mediators such as IL6 (Sprague et al, 2009). These proinflammatory mediators have been found to increase PAI-1 levels, which ultimately leads to hypofibrinolysis(Kang et al, 2020. Rega et al, 2020).

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

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

While the evidence connecting bradykinin activation and fibrinolysis decrease is evident, a direct relationship where bradykinin activation leads to fibrinolysis decrease is harder to establish. One of the outcomes of bradykinin runs opposite to fibrinolysis decrease, as bradykinin increases tPA levels where hypofibrinolysis decreases tPA levels as a result of PAI-1 increase. Without a stressor that affects PAI-1 levels more drastically than bradykinin affects tPA levels, such as SARS-COV-2, this relationship would not be possible.

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

SARS-COV-2 is shown to be a modulating factor as Bradykinin activation normally causes increased tPA/uPA, which would cause fibrinolysis, not hypofibrinolysis.

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