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Relationship: 2356
Title
Hypofibrinolysis leads to Increased proinflammatory mediators
Upstream event
Downstream event
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 Do not cite | Under Development |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
Sex Applicability
Life Stage Applicability
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.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| 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
| 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 |
|
Due to the uncertain and ongoing nature of the COVID-19 pandemic, it is difficult to understand a dose response relationship as a result of the SARS-COV-2 stressor, however individuals hit harder by the virus (hospitalizations) find themselves with higher proinflammatory mediator levels as a result of hypofibrinolysis.