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Event: 1866

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Fibrinolysis, decreased

Short name
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Hypofibrinolysis
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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. 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 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 KE.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

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Sex Applicability

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Key Event Description

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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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

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

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References

List of the literature that was cited for this KE description. 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