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Relationship: 2356

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

Hypofibrinolysis leads to Increased proinflammatory mediators

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

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 non-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 Do not cite Under Development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

Sex Applicability

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

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

Hypofibrinolysis is the process of a decreased fibrinolytic response, or decreasing the breakdown of fibrin in blood clots.  Hallmarks of a hypofibrinolysis state include elevated levels of TAFI and PAI-1 inhibitors, a dysregulated uPA/uPAR system, increased fibrinogen, and high levels of CRP (Bachler et al, 2021). These markers were found as a result of perturbation from SARS-COV-2 infection, although nanomaterial stressors can result in hypofibrinolysis as well. The results of hypofibrinolysis include an increase in coagulation levels and thrombosis(Hofman et al, 2016).

Hypofibrinolysis increases proinflammatory mediator levels through increase in PAI-1, a dysregulated uPA/uPAR system, and high levels of CRP. These markers of hypofibrinolysis increase proinflammatory mediators through endothelial cell dysfunction and activate pathways that lead to an increase in proinflammatory cytokines such as IL-2, TNF, and IL-6.

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 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 biological plausibility is high as there is a relationship that understands that the evidence that indicates hypofibrinolysis, such as PAI-1, increased proinflammatory mediators levels when tested as a stressor. The increase of proinflammatory mediators through hypofibrinolysis is what leads to hypercogulation.

 

The result of hypofibrinolysis is increased levels of PAI-1 inhibitor, dysregulated uPA/uPAR system, high levels of C-reactive protein (CRP), and increased fibrinogen ( Bachler et al, 2016.) Increased expression of proinflammatory mediators such as IL6, TNF-Alpha, and MCP-1 followed exposure of PAI-1 inhibitor in mice, where macrophage were activated through NFKB and TLR4 (Gupta et al, 2016). This same data was discovered in human small cell lung cancer patients as well (Zhu et al, 2017). In a postmortem study of COVID-19 patients, expression of proinflammatory mediators was found in blood vessels parallel to PAI-1 localization (D’Agnillio et al, 2014). CRP, a proinflammatory mediator, also has a significant correlation with hypofibrinolysis, as studied in sepsis patients (Boudjeltia et al, 2004). A dysregulated uPA/uPAR system can also cause the increase of proinflammatory mediators, as uPA activation of co-receptors vascular endothelial growth factor(VEGF) VEGF-A and VEGF-2 causes signaling leading to downstream activation of proinflammatory pathways like NFKB and STAT3. (Sproston et al, 2018,  D’Alonzo et al, 2020)).

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

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)

Chemicals

(weak evidence)

PFAS (PFOS)  PFOS activates NF-κB and significantly induces the production of TNF-α and IL-6 in Kupffer cells [1], in HAPI cells [2] and in microglial cells [3], as well as in the liver of zebrafish [4].

1) doi: 10.1016/j.chemosphere.2018.02.137

2) doi: 0.1016/j.intimp.2015.05.019

3) doi: 10.1002/jat.3119

4) doi: 10.1016/j.fsi.2019.05.018

Age Young/old people During the aging process, alterations of coagulation and fibrinolysis have been evidenced. Hypercoagulability with higher plasma concentrations of fibrinogen and factor VIII seems to be the basis of the increased thrombotic tendency occurring with age [1]. Hemostatic changes during aging have been described associated to plasma concentrations of some coagulation factors, such as fibrinogen, factor V, factor VII, factor VIII, factor IX, high molecular weight kininogen and prekallikrein increase in healthy humans in parallel with the physiological processes of aging. Fibrinogen levels increase in response to IL-6, which itself is strongly correlated with aging. Regarding anticoagulant proteins being modulated during aging, heparin co-factor II levels showed an age-related decrease, independently of sex [2]. The fibrinolytic system is also affected in aging and has previously been described as a systemic state of ‘‘thrombotic preparedness’’ with an acquired thrombophilia, characterized by heightened inflammation and impaired fibrinolytic capability [3]. To date, the implication of PAI-1 has been demonstrated in the process of cellular senescence. A null mutation in the PAI-1 gene was reported to increase aging in humans [4]. Increased PAI-1 production contributes to the multi-morbidity of aging. Both chronological and stress-induced accelerated aging are associated with cellular senescence and accompanied by marked increases in PAI-1 expression in tissues [5]. Furthermore, PAI-1 governs cellular senescence by regulating the extracellular proteolysis of the senescence-associated secretory phenotype (SASP). It has also been demonstrated that miR-146a negatively modulates PAI-1 in senescent cells, preventing an excessive increase in the production of inflammatory mediators and limiting some of the potentially deleterious effects of the SASP [6]. For this reason, PAI-1 is not only a key mediator of cellular senescence and aging but also of aging-related pathologies [5].

1) 10.1016/j.exger.2007.06.014

2) 10.1016/j.critrevonc.2006.06.004

3) 10.1007/s11239-009-0433-0

4) 10.1097/HS9.0000000000000570

5) 10.1161/ATVBAHA.117.309451

6) 10.1167/iovs.09-4874

Lipids Atherogenic dyslipidemia

Lipoproteins play an integral role in hemostasis and thrombosis. Apolipoprotein A1 (ApoA1), a component of HDL, is ubiquitously antithrombotic [1].

In COVID-19. Morelli et al. observed significantly increased odds for venous thrombosis with lower ApoA1 and ApoB levels in a large case-control study [2]. ApoA1 prevented thrombosis in mice by upregulating nitric oxide availability [3], while in vitro studies have demonstrated its potential at fostering the anticoagulant protein C pathway [4].

In correlation with other biomarkers, observational studies have shown that low levels of ApoA1 and low levels in ApoB/ApoA1 in COVID-19 patients would potentially be associated with an “anti-fibrinolytic state” [5], as ApoA1 negatively correlated with PAI-1 while ApoB/ApoA1 were positively associated with plasminogen, resulting in reduced fibrinolytic capacity. Thus, the low HDL precondition associated with atherogenic dyslipidemia observed in severe COVID-19 may contribute to coagulopathy via the loss of the antithrombotic effect provided by these lipoproteins.

1) doi: 10.1001/jama.2009.1619

2) doi:  10.1007/s10654-017-0251-1

3) doi: 10.1161/ATVBAHA.112.252130

4) doi:  10.1016/j.dsx.2021.04.011

5) doi:  10.1016/j.dsx.2021.04.011
Vitamin D (moderate evidence) Vitamin D deficiency

Low vitamin D status increases the risk of endothelial dysfunction with increased intracellular oxidative stress [1]. In endothelial cells, vitamin D regulates the synthesis of the vasodilator nitric oxide (NO) by mediating the activity of the endothelial NO synthase. High production of reactive oxygen species (ROS) increases NO degradation and impairs NO synthesis: impaired NO bioavailability is an early event toward the development of vascular damage. In this process, vitamin D acts as a protective agent against oxidative stress, by counteracting ROS production and enhancing the activity of anti-oxidative enzymes such as superoxide dismutase [1]. The antiphospholipid syndrome, a human autoimmune disease with thrombotic manifestations associated with low vitamin D serum levels, provides supportive evidence of the prothrombotic effect of vitamin D deficiency [2].

[1] doi: 10.3390/nu12020575

[2] doi: 10.1177/0961203318801520

genetic factors  

The blood group influences thrombogenesis. Factor-VIII vonWillebrand factor is lower in people with group 0 and higher blood levels of Factor VIII are associated with higher thrombotic risk [1]. Emerging evidence indicates that COVID-19 patients are at a high risk of developing coagulopathy and thrombosis, conditions that elevate levels of D-dimer [2]. It is believed that homocysteine, an amino acid that plays a crucial role in coagulation, may also contribute to these conditions. At present, multiple genes are implicated in the development of these disorders. For example, SNPs in FGG, FGA, and F5 mediate increases in D-dimer and SNPs in ABO, CBS, CPS1 and MTHFR mediate differences in homocysteine levels, and SNPs in TDAG8 associate with heparininduced thrombocytopenia. The gene–gene interaction network revealed three clusters that each contained hallmark genes for D-dimer/fibrinogen levels, homocysteine levels, and arterial/venous thromboembolism with F2 and F5 acting as connecting nodes [3].

[1] doi: 10.1046/j.1365-3148.2001.00315.x

[2] doi: 10.1016/j.hrtlng.2021.01.011

[3] doi: 10.3389/fphar.2020.587451

Therapeutic intervention against COVID-19. Heparin

Enhances the anticoagulant property of anti-thrombin, prevents fibrin formation and inhibits thrombin-induced

activation of platelets and other coagulation factors [1,2].

1) 10.3389/fmed.2021.615333

2) 10.1161/hq0701.093686

Diet (weak) Plant-based diets may improve fibrinolysis markers
  • A few studies in human populations found indications that plant-focused or plant-based diets improve fibrinolysis markers, including shorter ELT (euglobulin lysis test, an indicator of higher fibrinolytic activity), increased fibrinolytic activity, increased EFA (euglobulin fibrinolytic activity), and decreased PAI-1 [290,291].
  • Other studies found associations between high meat intake and PAI-1 and PAI-1ag levels, indicating lower fibrinolytic activity [292,293].
  • Some studies found no association between dietary patterns or dietary components and fibrinolytic activity [294]. 
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

Domain of Applicability

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References

List of the literature that was cited for this KER description. More help
  1.  Bachler, M. Impaired fibrinolysis in critically ill COVID-19 patients. British Journal of Anaesthesia Volume 126, Issue 3, March 2021, Pages 590-598. doi: https://doi.org/10.1016/j.bja.2020.12.010
  2. D'Alonzo D, De Fenza M, Pavone V. COVID-19 and pneumonia: a role for the uPA/uPAR system. Drug Discov Today. 2020;25(8):1528-1534. doi:10.1016/j.drudis.2020.06.013
  3. Gupta KK, Xu Z, Castellino FJ, Ploplis VA. Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4. Biochem Biophys Res Commun. 2016 Aug 26;477(3):503-8. doi: 10.1016/j.bbrc.2016.06.065. Epub 2016 Jun 15. PMID: 27317488

  4. Kwann, H. Lindholm, P. The Central Role of Fibrinolytic Response in COVID-19—A Hematologist’s Perspective. Int. J. Mol. Sci. 2021, 22(3), 1283; https://doi.org/10.3390/ijms22031283
  5. Hofman, Z., de Maat, S., Hack, C.E. et al. Bradykinin: Inflammatory Product of the Coagulation System. Clinic Rev Allerg Immunol 51, 152–161 (2016). https://doi.org/10.1007/s12016-016-8540-0

  6. . Sproston, N. Ashworth, J. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front. Immunol., 13 April 2018. doi: ttps://doi.org/10.3389/fimmu.2018.00754

  7. Zhu C, Shen H, Zhu L, Zhao F, Shu Y. Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage. Cell Physiol Biochem. 2017;44(6):2201-2211. doi: 10.1159/000486025. Epub 2017 Dec 13. PMID: 29253845.

  8.  Zouaoui Boudjeltia, K., Piagnerelli, M., Brohée, D. et al. Relationship between CRP and hypofibrinolysis: Is this a possible mechanism to explain the association between CRP and outcome in critically ill patients?. Thrombosis J 2, 7 (2004). https://doi.org/10.1186/1477-9560-2-7

9. Zuo, Y., Warnock, M., Harbaugh, A. et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci Rep 11, 1580 (2021). https://doi.org/10.1038/s41598-020-80010-z