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Key Event Title
Key Event Components
|negative regulation of fibrinolysis||increased|
|negative regulation of blood coagulation||decreased|
Key Event Overview
AOPs Including This Key Event
|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 Do not cite|
Key Event Description
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
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).
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
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
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
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]).
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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
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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