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Kardiologia Polska 2024Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation... (Review)
Review
Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation myocardial infarction (STEMI), have smaller infarcts and more favorable clinical outcomes than patients without spontaneous reperfusion. Understanding the mechanisms underlying spontaneous reperfusion is therefore important since this may identify possible novel therapeutic targets to improve outcomes in patients with STEMI. In this review, we discuss some of the possible determinants of spontaneous reperfusion including pro-thrombotic profile, endogenous fibrinolytic status, lipoprotein(a) (Lp[a]), inflammatory markers, and neutrophil extracellular traps (NETs). Effective (rapid) endogenous fibrinolysis, as assessed in whole blood in vitro, using a point-of-care technique assessment of global thrombotic status, has been strongly linked to spontaneous reperfusion. Lp(a), which has a high degree of homology to plasminogen, may impair fibrinolysis through competitive inhibition of tissue plasminogen activator-mediated plasminogen activation as well as tissue plasminogen activator-mediated clot lysis and contribute to pathogenic clot properties by decreasing fibrin clot permeation. NETs appear to negatively modulate clot lysis by increasing thrombin fiber diameter and inhibiting plasmin-driven lysis of plasma clots. There are limited data that oral anticoagulation may modulate endogenous fibrinolysis but antiplatelet agents currently appear to have no impact. Phase III trials involving subcutaneous P2Y12 or glycoprotein IIb/IIIa inhibitors, oral factor XIa inhibitors, interleukin-6 inhibitors, and apolipoprotein(a) antisense oligonucleotides in patients with cardiovascular disease are ongoing. Future studies will be needed to determine the impact of these novel antithrombotic, anti-inflammatory, and lipid-lowering therapies on endogenous fibrinolysis and spontaneous reperfusion.
Topics: Humans; ST Elevation Myocardial Infarction; Fibrinolysis; Extracellular Traps; Myocardial Reperfusion; Lipoprotein(a)
PubMed: 38493469
DOI: 10.33963/v.phj.99737 -
Research and Practice in Thrombosis and... Feb 2024Recently, we have shown alterations in the anticoagulant response to recombinant activated factor VII (rFVIIa)-induced coagulation activation in patients with...
BACKGROUND
Recently, we have shown alterations in the anticoagulant response to recombinant activated factor VII (rFVIIa)-induced coagulation activation in patients with thrombophilia.
OBJECTIVES
This study aimed to extend this model to fibrinolysis biomarkers.
METHODS
This interventional study included 56 patients with thrombophilia and previous venous thromboembolism (VTE+), 38 without VTE (VTE-), and 35 healthy controls. Plasma levels of D-dimer, plasmin-α2-antiplasmin (PAP) complex, and plasminogen activator inhibitor-1 (PAI-1) were monitored for over 8 hours after rFVIIa infusion (15 μg/kg) along with thrombin markers and activated protein C (APC).
RESULTS
Throughout cohorts, median PAP increased by 40% to 52% ( < 3.9 × 10) and PAI-1 decreased by 59% to 79% ( < 3.5 × 10). In contrast to thrombin-antithrombin (TAT) complex, which also increased temporarily (44% to 115%, < 3.6 × 10), changes in PAP and PAI-1 did not reverse during the observation period. The area under the measurement-time curves (AUCs) of PAP and TAT, which are measures of plasmin and thrombin formation, respectively, were each greater in the VTE+ cohort than in healthy controls (median PAP-AUC = 0.48 vs 0.27 ng·h/L [ = .003], TAT-AUC = 0.12 vs 0.03 nmol·h/L [ = 2.5 × 10]) and were correlated with one another ( = 0.554). As evidenced by the respective AUCs, asymptomatic factor (F)V Leiden carriers showed less PAP formation (0.22 vs 0.41 ng·h/L, = 9 × 10), more pronounced PAI-1 decline (0.10 vs 0.18 ng·h/L, = .01), and increased APC formation (28.7 vs 15.4 pmol·h/L, = .02) than those within the VTE+ group ( = 19 each).
CONCLUSION
rFVIIa-induced thrombin formation is associated with fibrinolysis parameter changes outlasting the concomitant anticoagulant response. Both correlate with thrombosis history in FV Leiden and might help explain its variable clinical expressivity.
PubMed: 38487678
DOI: 10.1016/j.rpth.2024.102351 -
Frontiers in Immunology 2024Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. species are... (Review)
Review
Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases.
Topics: Humans; Streptococcal Infections; Rheumatic Fever; Streptococcus pyogenes; Pharyngitis; Autoimmune Diseases
PubMed: 38464518
DOI: 10.3389/fimmu.2024.1361123 -
Frontiers in Cellular and Infection... 2024is an emerging zoonotic pathogen that can cause invasive disease commonly associated with meningitis in pigs and humans. To cause meningitis, must cross the...
is an emerging zoonotic pathogen that can cause invasive disease commonly associated with meningitis in pigs and humans. To cause meningitis, must cross the blood-brain barrier (BBB) comprising blood vessels that vascularize the central nervous system (CNS). The BBB is highly selective due to interactions with other cell types in the brain and the composition of the extracellular matrix (ECM). Purified streptococcal surface enolase, an essential enzyme participating in glycolysis, can bind human plasminogen (Plg) and plasmin (Pln). Plg has been proposed to increase bacterial traversal across the BBB via conversion to Pln, a protease which cleaves host proteins in the ECM and monocyte chemoattractant protein 1 (MCP1) to disrupt tight junctions. The essentiality of enolase has made it challenging to unequivocally demonstrate its role in binding Plg/Pln on the bacterial surface and confirm its predicted role in facilitating translocation of the BBB. Here, we report on the CRISPR/Cas9 engineering of enolase mutants , , , and possessing amino acid substitutions at predicted binding sites for Plg. As expected, amino acid substitutions in the predicted Plg binding sites reduced Plg and Pln binding to but did not affect bacterial growth compared to the wild-type strain. The binding of Plg to wild-type enhanced translocation across the human cerebral microvascular endothelial cell line hCMEC/D3 but not for the mutant strains tested. To our knowledge, this is the first study where predicted Plg-binding sites of enolase have been mutated to show altered Plg and Pln binding to the surface of and attenuation of translocation across an endothelial cell monolayer .
Topics: Animals; Humans; Swine; Plasminogen; Blood-Brain Barrier; Streptococcus suis; Bacterial Translocation; Fibrinolysin; Binding Sites; Phosphopyruvate Hydratase; Meningitis
PubMed: 38456079
DOI: 10.3389/fcimb.2024.1356628 -
American Journal of Kidney Diseases :... Mar 2024Glomerular disorders have a highly variable clinical course, and biomarkers that reflect the molecular mechanisms underlying their progression are needed. Based on our...
RATIONALE & OBJECTIVE
Glomerular disorders have a highly variable clinical course, and biomarkers that reflect the molecular mechanisms underlying their progression are needed. Based on our previous work identifying plasminogen as a direct cause of podocyte injury, we designed this study to test the association between urine plasmin(ogen) (ie, plasmin and its precursor plasminogen) and end-stage kidney disease (ESKD).
STUDY DESIGN
Multicenter cohort study.
SETTING & PARTICIPANTS
1,010 patients enrolled in the CureGN Cohort with biopsy-proven glomerular disease (focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A nephropathy).
PREDICTORS
The main predictor was urine plasmin(ogen) at baseline. Levels were measured by an electrochemiluminescent immunoassay developed de novo. Traditional clinical and analytical characteristics were used for adjustment. The ratio of urine plasmin(ogen)/expected plasmin(ogen) was evaluated as a predictor in a separate model.
OUTCOME
Progression to ESKD.
ANALYTICAL APPROACH
Cox regression was used to examine the association between urinary plasmin(ogen) and time to ESKD. Urinary markers were log transformed to approximate normal distribution and normalized to urinary creatinine (LoguPlasminogen/cr, Log urinary protein/cr [UPCR]). Expected plasmin(ogen) was calculated by multiple linear regression.
RESULTS
Adjusted LoguPlasminogen/cr was significantly associated with ESKD (HR per doubling Log uPlasminogen/cr 1.31 [95% CI, 1.22-1.40], P<0.001). Comparison of the predictive performance of the models including Log uPlasminogen/cr, Log UPCR, or both markers showed the plasmin(ogen) model superiority. The ratio of measured/expected urine plasmin(ogen) was independently associated with ESKD: HR, 0.41 (95% CI, 0.22-0.77) if ratio<0.8 and HR 2.42 (95% CI, 1.54-3.78) if ratio>1.1 (compared with ratio between 0.8 and 1.1).
LIMITATIONS
Single plasmin(ogen) determination does not allow for the study of changes over time. The use of a cohort of mostly white patients and the restriction to patients with 3 glomerular disorders limits the external validity of our analysis.
CONCLUSIONS
Urinary plasmin(ogen) and the ratio of measured/expected plasmin(ogen) are independently associated with ESKD in a cohort of patients with glomerular disease. Taken together with our previous experimental findings, urinary plasmin(ogen) could be a useful biomarker in prognostic decision making and a target for the development of novel therapies in patients with proteinuria and glomerular disease.
PLAIN-LANGUAGE SUMMARY
Glomerular diseases are an important cause of morbidity and mortality in patients of all ages. Knowing the individual risk of progression to dialysis or transplantation would help to plan the follow-up and treatment of these patients. Our work studies the usefulness of urinary plasminogen as a marker of progression in this context, since previous studies indicate that plasminogen may be involved in the mechanisms responsible for the progression of these disorders. Our work in a sample of 1,010 patients with glomerular disease demonstrates that urinary plasminogen (as well as the ratio of measured to expected plasminogen) is associated with the risk of progression to end-stage kidney disease. Urine plasminogen exhibited good performance and, if further validated, could enable risk stratification for timely interventions in patients with proteinuria and glomerular disease.
PubMed: 38452919
DOI: 10.1053/j.ajkd.2024.01.520 -
Scientific Reports Mar 2024Actinic lentigines (AL) or age spots, are skin hyperpigmented lesions associated with age and chronic sun exposure. To better understand the physiopathology of AL, we...
Actinic lentigines (AL) or age spots, are skin hyperpigmented lesions associated with age and chronic sun exposure. To better understand the physiopathology of AL, we have characterized the inflammation response in AL of European and Japanese volunteers. Gene expression profile showed that in both populations, 10% of the modulated genes in AL versus adjacent non lesional skin (NL), i.e. 31 genes, are associated with inflammation/immune process. A pro-inflammatory environment in AL is strongly suggested by the activation of the arachidonic acid cascade and the plasmin pathway leading to prostaglandin production, along with the decrease of anti-inflammatory cytokines and the identification of inflammatory upstream regulators. Furthermore, in line with the over-expression of genes associated with the recruitment and activation of immune cells, immunostaining on skin sections revealed a significant infiltration of CD68+ macrophages and CD4 T-cells in the dermis of AL. Strikingly, investigation of infiltrated macrophage subsets evidenced a significant increase of pro-inflammatory CD80+/CD68+ M1 macrophages in AL compared to NL. In conclusion, a chronic inflammation, sustained by pro-inflammatory mediators and infiltration of immune cells, particularly pro-inflammatory M1 macrophages, takes place in AL. This pro-inflammatory loop should be thus broken to normalize skin and improve the efficacy of age spot treatment.
Topics: Humans; Photosensitivity Disorders; Inflammation; Lentigo; Skin; Arachidonic Acid
PubMed: 38438410
DOI: 10.1038/s41598-024-53990-5 -
Heliyon Mar 2024Deep vein thrombosis (DVT) has been reported as an adverse event for patients receiving combined oral contraceptives. Norethindrone/ethinyl estradiol (NET/EE) and...
BACKGROUND
Deep vein thrombosis (DVT) has been reported as an adverse event for patients receiving combined oral contraceptives. Norethindrone/ethinyl estradiol (NET/EE) and drospirenone/ethinyl estradiol (DRSP/EE) are two commonly prescribed combined hormonal oral contraceptive agents used in the United States, differing in their progestin component.
OBJECTIVE
The purpose of this study was to determine the association between the progestin component of a combined oral contraceptive and the risk of DVT in patients taking oral contraceptives for birth control using data derived from the FDA Adverse Event Reporting System (FAERS).
METHODS
The risk of DVT was compared between patients that had taken NET/EE with those that had taken the DRSP/EE COC formulation for birth control. In addition, age was assessed as a possible confounder and the outcome severity for those diagnosed with DVT were compared between the two groups. Finally, association rule mining was utilized to identify possible drug-drug interactions that result in elevated DVT risk.
RESULTS
DVT was the fourth most commonly adverse event reported for patients taking DRSP/EE accounting for 8558 cases and the seventeenth most commonly reported adverse event for NET/EE accounting for 298 cases. Age was found to be a significant confounder for users of DRSP/EE with regards to DVT risk across all age groups assessed: 20
40 (ROR = 3.69, 95% CI 3.37-4.04) However, there was only a statistically significant elevated risk in patients over 40 years of age taking NET/EE (ROR = 1.98, 95% CI 1.36-2.88). Patients that had taken DRSP/EE and the corticosteroid prednisone simultaneously had an approximately 3-fold increase in DVT risk (ROR = 2.77, 95% CI 2.43-3.15) relative to individuals that had only taken DRSP/EE. CONCLUSION
Based on this analysis, there is a higher risk of developing DVT when taking DRSP/EE than when taking NET/EE as hormonal contraception. In addition, a possibly significant drug-drug interaction between different COC formulations and prednisone were identified. This interaction may result in elevated DVT risk due to a synergistic impairment of fibrinolysis and a decrease in plasmin production.
PubMed: 38434341
DOI: 10.1016/j.heliyon.2024.e26462 -
PLoS Pathogens Feb 2024Lyme disease (LD) caused by Borrelia burgdorferi is among the most important human vector borne diseases for which there is no effective prevention method....
Lyme disease (LD) caused by Borrelia burgdorferi is among the most important human vector borne diseases for which there is no effective prevention method. Identification of tick saliva transmission factors of the LD agent is needed before the highly advocated tick antigen-based vaccine could be developed. We previously reported the highly conserved Ixodes scapularis (Ixs) tick saliva serpin (S) 17 (IxsS17) was highly secreted by B. burgdorferi infected nymphs. Here, we show that IxsS17 promote tick feeding and enhances B. burgdorferi colonization of the host. We show that IxsS17 is not part of a redundant system, and its functional domain reactive center loop (RCL) is 100% conserved in all tick species. Yeast expressed recombinant (r) IxsS17 inhibits effector proteases of inflammation, blood clotting, and complement innate immune systems. Interestingly, differential precipitation analysis revealed novel functional insights that IxsS17 interacts with both effector proteases and regulatory protease inhibitors. For instance, rIxsS17 interacted with blood clotting proteases, fXII, fX, fXII, plasmin, and plasma kallikrein alongside blood clotting regulatory serpins (antithrombin III and heparin cofactor II). Similarly, rIxsS17 interacted with both complement system serine proteases, C1s, C2, and factor I and the regulatory serpin, plasma protease C1 inhibitor. Consistently, we validated that rIxsS17 dose dependently blocked deposition of the complement membrane attack complex via the lectin complement pathway and protected complement sensitive B. burgdorferi from complement-mediated killing. Likewise, co-inoculating C3H/HeN mice with rIxsS17 and B. burgdorferi significantly enhanced colonization of mouse heart and skin organs in a reverse dose dependent manner. Taken together, our data suggests an important role for IxsS17 in tick feeding and B. burgdorferi colonization of the host.
Topics: Mice; Animals; Humans; Serpins; Saliva; Peptide Hydrolases; Mice, Inbred C3H; Lyme Disease; Ixodes; Borrelia burgdorferi; Complement System Proteins; Endopeptidases; Immune System
PubMed: 38394332
DOI: 10.1371/journal.ppat.1012032 -
Marine Drugs Jan 2024Marine organisms are a rich source of enzymes that exhibit excellent biological activity and a wide range of applications. However, there has been limited research on...
Marine organisms are a rich source of enzymes that exhibit excellent biological activity and a wide range of applications. However, there has been limited research on the proteases found in marine mudflat organisms. Based on this background, the marine fibrinolytic enzyme FELP, which was isolated and purified from clamworm (), has exhibited excellent fibrinolytic activity. We demonstrated the FELP with a purification of 10.61-fold by precipitation with ammonium sulfate, ion-exchange chromatography, and gel-filtration chromatography. SDS-PAGE, fibrin plate method, and LC-MS/MS indicated that the molecular weight of FELP is 28.9 kDa and identified FELP as a fibrinolytic enzyme-like protease. FELP displayed the maximum fibrinolytic activity at pH 9 (407 ± 16 mm) and 50 °C (724 ± 27 mm) and had excellent stability at pH 7-11 (50%) or 30-60 °C (60%), respectively. The three-dimensional structure of some amino acid residues of FELP was predicted with the SWISS-MODEL. The fibrinolytic and fibrinogenolytic assays showed that the enzyme possessed direct fibrinolytic activity and indirect fibrinolysis via the activation of plasminogen; it could preferentially degrade Aα-chains of fibrinogen, followed by Bβ- and γ-chains. Overall, the fibrinolytic enzyme was successfully purified from a marine Annelida (phylum), with favorable stability that has strong fibrinolysis activity in vitro. Therefore, FELP appears to be a potent fibrinolytic enzyme with an application that deserves further investigation.
Topics: Animals; Fibrinolysin; Chromatography, Liquid; Hydrogen-Ion Concentration; Tandem Mass Spectrometry; Serine Proteases; Polychaeta; Fibrinolytic Agents; Temperature; Molecular Weight
PubMed: 38393039
DOI: 10.3390/md22020068 -
Journal of Cellular and Molecular... Feb 2024Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease...
Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease (AD). Since plasmin also regulates the synaptic activity, it is possible that altered PAI-1 is present in other neurodegenerative disorders. We investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty five FTLD patients (21 in mild cognitive impairment stage (MCI) and 14 in dementia stage) and 10 cognitively healthy controls were recruited. Serum tPA and PAI-1 protein levels were measured by anova. Correlation between biochemical and demographic data were explored by measuring Pearson correlation coefficient. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls. tPA serum levels and PAI-1/tPA ratio did not significantly differ among groups. There was a negative correlation between PAI-1 serum levels and disease severity measured by MMSE score. No correlations of tPA serum levels and PAI-1/tPA ratio with MMSE were found. Increased PAI-1 serum levels may serve as a marker of dementia in FTLD, suggesting that, besides Aβ pathway, the plasmin system may affect cognition through synaptic activity.
PubMed: 38386354
DOI: 10.1111/jcmm.18013