To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:1866

Event: 1866

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Fibrinolysis, decreased

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Hypofibrinolysis

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
negative regulation of fibrinolysis increased
negative regulation of blood coagulation decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Dysregulated fibrinolysis/bradykinin leading to hyperinflammation MolecularInitiatingEvent Penny Nymark (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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 in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Human Not Specified

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Background

Fibrinolysis is an essential and highly regulated physiological process resulting in the enzymatic breakdown of intravascular fibrin in blood clots. The process prevents extensive fibrin deposition and  facilitates the degradation of thrombi and microthrombi in any affected organ. Fibrinolysis occurs both within the thrombi, where fibrin strands provide a surface for binding plasminogen (precursor of the primary fibrinolysin, plasmin), as well as on interaction with endothelial cell surfaces.  There are many known disorders of fibrinolysis, including congenital and acquired conditions which can result in inadequate or excessively active fibrinolytic pathways. Acquired disorders resulting in hypofibrinolysis include numerous acute and chronic conditions; malignancy, hypothyroidism, autoimmune disorders and alcoholic liver disease (10.1016/j.blre.2014.09.003). Hypoxia has also been demonstrated to promote hypofribrinolysis (10.1172/JCI307). Conversely, disseminated intravascular coagulation (DIC) is one of the better characterized hyperfibrinolytic disorders, associated with systemic inflammation (10.1016/j.blre.2014.09.003). Fibrinolytic pathways act in conjunction with processes regulating coagulation and platelet activity to regulate hemostasis.  An imbalance between coagulation and the fibrinolytic pathways leads to coagulopathy and may, if unresolved, lead to bleeding diatheses, thrombosis and inflammation (thromboinflammation).

How the KE works

In normal conditions fibrinolysis begins when tissue plasminogen activator (tPA, gene PLAT), bound to fibrin, and urokinase (uPA, gene PLAU), expressed on the endothelium, converts plasminogen to plasmin. Plasmin breaks down fibrin (which is formed during coagulation), and resolves the fibrin clot. This process results in an increase in the formation of circulating fibrin degradation products (FDP), some of which have been associated with immune activation (Chapin & Hajjar). In addition, D-Dimers, biomarkers for thrombosis, are generated when fibrin polymers get broken down. Fibrin clot formation, activation of coagulation factor XII (FXIIa, also known as the Hageman factor, gene F12) and increased levels of plasminogen, as well as the activation of the bradykinin system by FXIIa-stimulated increased levels of tPA/uPA. A number of endogenous molecules act to prevent excessive clot breakdown; tPA/uPA is inhibited by plasminogen activator inhibitor 1 (PAI-1, encoded by SERPINE1) and C1-inhibitor (C1-INH, encoded by SERPING1) inhibits plasmin (reviewed in 10.1007/s12016-016-8540-0). Other molecules involved in plasmin inhibition include Alpha 2 antiplasmin (encoded by SERPINF2) and alpha 2 macroglobulin (encoded by A2M), each of which contribute uniquely to the precise regulation of thrombus formation and lysis. A balance must be maintained between clot formation and clot breakdown by regulating tPA and uPA.

Fibrinolysis in various diseases, including COVID-19

Fibrinolysis is reported to be dysregulated in several pathologies, including cancer, pulmonary fibrosis, kidney disease, coronary artery disease, rheumatoid arthritis, systemic sclerosis, bone destructive disease, lupus erythematosus, Alzheimer's disease, psoriasis, endometriosis and COVID-19 (reviewed in 10.1016/j.drudis.2020.06.013). In particular, a hypofibrinolysis state has been reported in e.g. COVID-19 patients who have developed acute respiratory distress syndrome (ARDS), which is coupled to high levels of PAI-1 (10.1016/j.drudis.2020.06.013). In addition, reduced levels of transcripts encoding for uPA and the uPA receptor (uPAR) have been reported in the lung tissue of patients with severe COVID-19 (10.7554/eLife.64330).

In COVID-19, the increased levels of PAI-1 have been associated with down-regulated ACE2 activity, which leads to increased angiotensin II (Ang II), which in turn promotes activation of PAI-1 (reviewed in 10.3390/v13010029).

 In contrast, hyperfibrinolysis has also been reported in COVID-19 patients, based on high plasmaD-dimer (DDI) levels (10.3389/fphys.2020.596057). Thus, in some cases SARS-COV-2 promotes activation of the coagulation cascade via tissue factor, leading to high levels of fibrin and hyperactivated fibrinolysis with increased levels of plasmin. Plasmin breaks down fibrin and causes high plasma DDI levels which maintain the hyperfibrinolytic state. In acute respiratory distress syndrome (ARDS), plasminogen-plasmin activity has been found to be increased, and the fibrinolytic system is assumed to play a role due to partial inhibition of the tPA/uPA system. 

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

In vitro systems

Whole human blood model for testing the dysregulation of fibrinolysis. The same model system allows for analysis of any kind of cross talk between blood cells and plasma proteins as reflected in the cascade system (complement, contact, coagulation, fibrinolysis systems activation etc) parameters, other plasma protein alterations and cell phenotypes (flow cytometry, cyto/chemokine generation, protein release etc) (10.1016/j.biomaterials.2015.01.031 , 10.1016/j.nano.2017.12.008 , 10.1080/14686996.2019.1625721).

Near-patient systems

Devices for performing viscoelastic haemostatic assays (VHA) are available in most intensive care units as a near-patient method for evaluating thrombus formation under low shear stress. Outputs of such assays are primarily used in the setting of major haemorrhage to rapidly determine the need for replacement of specific blood products. Importantly, VHA can differentiate causes of coagulopathy, for example, coagulation factor deficiency vs thrombocytopenia vs excessive fibrinolysis. VHA are also able to indicate hypercoagulability; separate outputs demonstrate the contribution of fibrinogen with and without platelet activation (10:1111/bjh.15524).

In addition, transcription profiles of e.g. human bronchial alveolar lavage (BAL) samples can be measured, with targeted analyses focused on downregulation of genes transcribing for proteins involved in the fibrinolytic cascade, e.g. uPA (PLAU), uPAR (PLAUR) (10.7554/eLife.64330).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

SARS-COV

SERPINE1 is inactivated causing an imbalance between fibrinolysis and coagulation (urokinase pathway). Also genes associated with the induction of a procoagulant state (thrombin, F7a, F11a, F12a, PLAU, PLAUR, tissue factor F2R) and other fibrinolysin pathway components were altered by infection

nanoparticles

Several proteins of the coagulation system, including fibrinogen, HMWK, kallikrein, F12, F11, and C1-INH bind to TiO2 NPs, and induce clot formation triggered specifically by F12, as well as release of pro-inflammatory cytokines and chemokines (IL-8 [CXCL8], MIP-1α [CCL3], MIP-1β [CCL4] and MCP-1 [CCL2]).

SARS-COV-2

SERPING1 is downregulated in severe COVID-19 BAL samples lifting the suppression of F12

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

1. D´Alonzo et al. COVID-19 and pneumonia: a role for the uPA/uPAR system. Drug Discovery Today Volume 25, Issue 8, August 2020, Pages 1528-1534

2. Ekdahl, Kristina N et al. “A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity.” Science and technology of advanced materials vol. 20,1 688-698. 24 Jun. 2019, doi:10.1080/14686996.2019.1625721 

3. Bernard, I.; Limonta, D.; Mahal, L.K.; Hobman, T.C. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2021, 13, 29. https://doi.org/10.3390/v13010029 

4. Mast AE, Wolberg AS, Gailani D, Garvin MR, Alvarez C, Miller JI, Aronow B, Jacobson D. SARS-CoV-2 Suppresses Anticoagulant and Fibrinolytic Gene Expression in the Lung. eLife 2021;10:e64330 DOI: 10.7554/eLife.64330

5. Curry N.S, Davenport R, Pavord S, Mallett S.V, Kitchen D, Klein A.A, Maybury H, Collins P.W, Laffan M. The use of viscoelastic haemostatic assays in the management of major bleeding - A British Society for Haematology Guideline. British Journal of Haematology. 2018. doi: 10.1111/bjh.15524 

6. Chapin JC & Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015;29(1):17-24

7. Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P et al. Coordinated Induction of Plasminogen Activator Inhibitor-1 (PAI-1) and Inhibition of Plasminogen Activator Gene Expression by Hypoxia Promotes Pulmonary Vascular Fibrin Deposition. J Clin Invest. 1998;102(5):919-928

8. 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

9. Jacob et al. COVID-19-Associated Hyper-Fibrinolysis: Mechanism and Implementations. Front. Physiol., 16 December 2020 | https://doi.org/10.3389/fphys.2020.596057 

10. Lisa E. Gralinski, Armand Bankhead III, Sophia Jeng, Vineet D. Menachery, Sean Proll, Sarah E. Belisle, Melissa Matzke, Bobbie-Jo M. Webb-Robertson, Maria L. Luna, Anil K. Shukla, Martin T. Ferris, Meagan Bolles, Jean Chang, Lauri Aicher, Katrina M. Waters, Richard D. Smith, Thomas O. Metz, G. Lynn Law, Michael G. Katze, Shannon McWeeney, Ralph S. Baric. Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury. mBio Aug 2013, 4 (4) e00271-13; DOI: 10.1128/mBio.00271-13