Detection of procoagulant imbalance

2017 ◽  
Vol 117 (05) ◽  
pp. 830-836 ◽  
Author(s):  
Armando Tripodi
Keyword(s):  
Protein C ◽  
Neutrophil Extracellular Traps ◽  
Relative Strength ◽  
Feedback Mechanisms ◽  
Turn On ◽  
Extracellular Traps ◽  
Increased Risk ◽  
The Many ◽  
Clinical Conditions ◽  
Pro Inflammatory Cytokines

SummaryEach individual possesses his/her own endogenous-thrombin-potential (ETP) (i. e. the ability to generate thrombin) which depends on the relative strength of the pro- and anticoagulant drivers operating in plasma. This ability depends in turn on the clinical conditions in which the balance between the two drivers is variably affected. One of the major determinants of this balance is the factor (F)VIII-protein C(PC) axis and its effect can be conveniently explored by the thrombin generation procedures with results expressed as ETP ratio with/without thrombomodulin (TM) (ETP-TM ratio). Furthermore, owing to the many feedback mechanisms mediated by thrombin (e. g. activation of PC, FXI, FV, FVIII, platelets etc.) it is also possible that any perturbation of the balance between pro- and anticoagulants that may occur in plasma even outside the FVIII-PC axis could result in an increased ETPTM ratio and therefore may suggest a procoagulant imbalance. Indeed, other non-coagulation moieties (e. g. microparticles, neutrophil extracellular traps, pro-inflammatory cytokines and others) circulating in blood of patients with various clinical conditions may also contribute to the procoagulant imbalance even when FVIII and/or PC are apparently normal. It can be postulated that dual ETP measurements performed in the presence and absence of TM with results expressed as their ratio may be the candidate procedure to detect subtle procoagulant imbalance in many clinical conditions characterised by an increased risk of thromboembolism. This article aimed at reviewing the clinical conditions in which evidence for the value of the ETP-TM ratio has been provided.

scholarly journals Effects of Diabetes Mellitus on Fibrin Clot Structure and Mechanics in a Model of Acute Neutrophil Extracellular Traps (NETs) Formation

2020 ◽  
Vol 21 (19) ◽  
pp. 7107 ◽  
Author(s):  
Judith J. de Vries ◽  
Tamara Hoppenbrouwers ◽  
Cristina Martinez-Torres ◽  
Rezin Majied ◽  
Behiye Özcan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Mechanical Properties ◽  
Acute Phase ◽  
Structural Parameters ◽  
Neutrophil Extracellular Traps ◽  
Fibrin Clot ◽  
Branch Points ◽  
Extracellular Traps ◽  
Increased Risk ◽  
Clot Structure

Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by S. aureus bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subjects with DM had significantly thicker fibers and fewer pores and branch points than clots from subjects without DM. In addition, fibrinolysis was significantly slower, while mechanical properties were similar between both groups. In conclusion, in a model of acute NETs formation, DM plasma shows prothrombotic effects on fibrin clots.

scholarly journals The FcγRIII Engagement Augments PMA-Stimulated Neutrophil Extracellular Traps (NETs) Formation by Granulocytes Partially via Cross-Talk between Syk-ERK-NF-κB and PKC-ROS Signaling Pathways

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1127
Author(s):  
Cheng-Hsun Lu ◽  
Ko-Jen Li ◽  
Cheng-Han Wu ◽  
Chieh-Yu Shen ◽  
Yu-Min Kuo ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Cross Talk ◽  
Neutrophil Extracellular Traps ◽  
Ros Generation ◽  
Dependent Manner ◽  
Extracellular Traps ◽  
Tnf Α ◽  
The Impact ◽  
Pro Inflammatory Cytokines

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cell in the circulation capable of neutrophil extracellular traps (NETs) formation after stimulation. Both NADPH oxidase-dependent and -independent pathways are involved in NET formation. The IgG is the most abundant immunoglobulin in human serum. However, the impact of the circulating IgG on NET formation is totally unexplored. In this study, the all-trans retinoic acid (ATRA)-induced mature granulocytes (dHL-60) were pre-treated with monomeric human IgG, papain-digested Fab fragment, crystallizable IgG Fc portion, rituximab (a human IgG1), or IgG2. The NET formation of the dHL-60 in the presence/absence of phorbol 12-myristate 13-acetate (PMA) stimulation was then measured by the fluorescent area after SYTOX green nucleic acid stain. The intracellular reactive oxygen species (ROS) generation was measured by flow cytometry. Total and phosphorylated Syk, SHP-1, and ERK were detected by immunoblot. We found that human monomeric IgG and its subclasses IgG1 and IgG2 per se induced negligible NET formation of dHL-60, but the FcγRIII engagement by these IgG subclasses and Fc portion augment PMA-stimulated dHL-60 NET formation in a dose-dependent manner. Furthermore, we found that increased Syk and ERK phosphorylation, intracellular ROS generation, and pro-inflammatory cytokines, IL-8 and TNF-α, production could be induced after FcγRIII engagement. Blocking FcγRIII engagement by a specific antibody diminished the augmented NET formation. In conclusion, we discovered that cross-talk between FcγRIII engagement-induced Syk-ERK and PMA-induced PKC signaling pathways augment NET formation of dHL-60 via increased ROS generation and pro-inflammatory cytokines, IL-8 and TNF-α, production.

scholarly journals Flamethrowers: blood cells and cancer thrombosis risk

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 410-417 ◽  
Author(s):  
Ingrid Pabinger ◽  
Florian Posch
Keyword(s):  
Platelet Count ◽  
Cancer Patients ◽  
Blood Cells ◽  
Membrane Vesicles ◽  
Neutrophil Extracellular Traps ◽  
Activation Process ◽  
Clotting System ◽  
Extracellular Traps ◽  
Thrombosis Risk ◽  
Increased Risk

Abstract Cancer patients are at an increased risk of venous thromboembolism. The clotting system is activated in most cancer patients, which is reflected by specific parameters such as an increased thrombin generation and elevated D-dimer levels. Blood cells, especially WBCs and platelets, play an important role in this activation process. Neutrophils and monocytes are subpopulations of WBCs that increase the thrombotic potential by different mechanisms. Neutrophils are activated by tumor cells and can release DNA, generating highly thrombogenic neutrophil extracellular traps. Monocytes are able to synthesize and express significant quantities of procoagulant tissue factor on their surfaces upon activation. An increased risk of VTE has been found in patients with solid tumors and elevated platelet count and in those with high-grade gliomas and low platelet count. Small circulating membrane vesicles, also called microparticles (MPs), which largely derive from platelets, contribute to the procoagulant potential. Specifically, procoagulant MPs could play a role in tumor-associated thrombosis in pancreatic cancer. Interventional studies are under way that are investigating the benefits of thromboprophylaxis in patients identified to be at high risk of VTE through risk-scoring models that include blood count parameters. The “flames” thrown by blood cells, such as neutrophil extracellular traps and MPs, although exciting, still have to be investigated for their usefulness in the clinical setting.

scholarly journals Impaired Release of Neutrophil Extracellular Traps and Anemia-Associated T Cell Deficiency in Hereditary Hemorrhagic Telangiectasia

2020 ◽  
Vol 9 (3) ◽  
pp. 767
Author(s):  
Freya Droege ◽  
Ekaterina Pylaeva ◽  
Elena Siakaeva ◽  
Sharareh Bordbari ◽  
Ilona Spyra ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Bacterial Infections ◽  
Vascular Malformations ◽  
Multivariate Regression Analysis ◽  
Neutrophil Extracellular Traps ◽  
Healthy Individuals ◽  
Filamentous Actin ◽  
Extracellular Traps ◽  
Increased Risk

Hereditary hemorrhagic telangiectasia (HHT) is characterized by mucocutaneous telangiectases and visceral vascular malformations. Individuals suffering from HHT have a significantly increased risk of bacterial infections, but the mechanisms involved in this are not clear. White blood cell subpopulations were estimated with flow cytometry in 79 patients with HHT and 45 healthy individuals, and association with clinicopathological status was assessed. A prominent decrease in absolute numbers of T cells in HHT was revealed (0.7 (0.5–1.1) vs. 1.3 (0.8–1.6), 106/mL, p < 0.05), and in multivariate regression analysis, hemoglobin level was associated with lymphopenia (OR = 0.625, 95% CI: 0.417–0.937, p < 0.05). Although no changes in absolute numbers of neutrophils and monocytes were observed, we revealed a significant impairment of neutrophil antibacterial functions in HHT (n = 9), compared to healthy individuals (n = 7), in vitro. The release of neutrophil extracellular traps (NETs) against Pseudomonas aeruginosa MOI10 was significantly suppressed in HHT (mean area per cell, mm2: 76 (70–92) vs. 121 (97–128), p < 0.05), due to impaired filamentous actin organization (% of positive cells: 69 (59–77) vs. 92 (88–94), p < 0.05). To conclude, this study reveals the categories of patients with HHT that are prone to immunosuppression and require careful monitoring, and suggests a potential therapeutic strategy based on the functional activation of neutrophils.

scholarly journals Neutrophil Extracellular Traps and By-Products Play a Key Role in COVID-19: Pathogenesis, Risk Factors, and Therapy

2020 ◽  
Vol 9 (9) ◽  
pp. 2942 ◽  
Author(s):  
Alain R. Thierry ◽  
Benoit Roch
Keyword(s):  
Risk Factors ◽  
Rapid Evolution ◽  
Neutrophil Extracellular Traps ◽  
Biological Features ◽  
Extracellular Traps ◽  
Formation Function ◽  
Dna Release ◽  
Amplification Loop ◽  
Clinical Conditions ◽  
By Products

Understanding of the pathogenesis of the coronavirus disease-2019 (COVID-19) remains incomplete, particularly in respect to the multi-organ dysfunction it may cause. We were the first to report the analogous biological and physiological features of COVID-19 pathogenesis and the harmful amplification loop between inflammation and tissue damage induced by the dysregulation of neutrophil extracellular traps (NETs) formation. Given the rapid evolution of this disease, the nature of its symptoms, and its potential lethality, we hypothesize that COVID-19 progresses under just such an amplifier loop, leading to a massive, uncontrolled inflammation process. Here, we describe in-depth the correlations of COVID-19 symptoms and biological features with those where uncontrolled NET formation is implicated in various sterile or infectious diseases. General clinical conditions, as well as numerous pathological and biological features, are analogous with NETs deleterious effects. Among NETs by-products implicated in COVID-19 pathogenesis, one of the most significant appears to be elastase, in accelerating virus entry and inducing hypertension, thrombosis and vasculitis. We postulate that severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) may evade innate immune response, causing uncontrolled NETs formation and multi-organ failure. In addition, we point to indicators that NETS-associated diseases are COVID-19 risk factors. Acknowledging that neutrophils are the principal origin of extracellular and circulating DNA release, we nonetheless, explain why targeting NETs rather than neutrophils themselves may in practice be a better strategy. This paper also offers an in-depth review of NET formation, function and pathogenic dysregulation, as well as of current and prospective future therapies to control NETopathies. As such, it enables us also to suggest new therapeutic strategies to fight COVID-19. In combination with or independent of the latest tested approaches, we propose the evaluation, in the short term, of treatments with DNase-1, with the anti-diabetic Metformin, or with drugs targeting elastase (i.e., Silvelestat). With a longer perspective, we also advocate a significant increase in research on the development of toll-like receptors (TLR) and C-type lectin-like receptors (CLEC) inhibitors, NET-inhibitory peptides, and on anti-IL-26 therapies.

scholarly journals Release of potential pro-inflammatory peptides from SARS-CoV-2 spike glycoproteins in neutrophil-extracellular traps

2020 ◽  
Author(s):  
Aitor Blanco-Míguez ◽  
Borja Sánchez
Keyword(s):  
T Cell ◽  
Inflammatory Response ◽  
Pulmonary Inflammation ◽  
Neutrophil Extracellular Traps ◽  
List Type ◽  
Cell Recognition ◽  
Enzymatic Cleavage ◽  
T Cell Recognition ◽  
Extracellular Traps ◽  
Pro Inflammatory Cytokines

AbstractCOVID-2019 has progressed in around 10-15% of patients to an acute respiratory distress syndrome characterized by extensive pulmonary inflammation and elevated production of pro-inflammatory cytokines. Neutrophil activation seems to be crucial in the initiation and perpetuation of this exacerbated lung inflammation. However, the precise mechanisms by which this activation occurs remain yet elusive. To this end, this in silico study tried to identify potential proinflammatory inducing peptides (PIPs) produced by the action of the elastase released in neutrophil-extracellular traps over SARS-CoV-2 particles. We found nine potential PIPs exclusive from the SARS-CoV-2, showing homology against T cell recognition epitopes. Moreover, 78 percent of these exclusive PIPs were found produced by the enzymatic cleavage on the spike glycoproteins, suggesting that high PIP concentrations might be released following SARS-CoV-2 huge replication rate. Therefore, these PIPs might play a role in the exacerbated inflammatory response observed in some patients.HighlightsNine potential PIPs were predicted exclusive from the SARS-CoV-2.SARS-CoV-2 PIPs showed homology against T cell recognition epitopes.Most of PIPs were produced by enzymatic cleavage of the spike glycoproteins.The release of these PIPs might be related to the increased inflammatory response observed in the patients.Graphical abstract

scholarly journals The Role of Neutrophil Extracellular Traps in Cancer-Associated Arterial Thrombosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2508-2508
Author(s):  
Ella Grilz ◽  
Lisa-Marie Mauracher ◽  
Oliver Königsbrügge ◽  
Florian Posch ◽  
Irene Lang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Neutrophil Extracellular Traps ◽  
Categorical Variables ◽  
Study Cohort ◽  
Patients With Cancer ◽  
Extracellular Traps ◽  
Kaplan Meier ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Unit Increase

Abstract Introduction: Prior studies have indicated that Neutrophil extracellular traps (NETs) trigger arterial thromboembolism (ATE) and play a role in the pathogenesis of cancer-associated venous thrombosis. We investigated the association between NET biomarkers (citrullinated histone H3 [H3Cit], cell-free DNA [cfDNA], and nucleosomes) and the risk of ATE in patients with cancer. Methods: In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for objectively confirmed, symptomatic ATE and death. Fine&Gray competing-risk regression was used to model risk of ATE. Overall survival (OS) was analyzed with Kaplan-Meier estimators. Results: Nine-hundred and fifty-eight patients with cancer (median age: 61 years; 46.8% female; Table 1) were recruited. ATE occurred in 22 patients; the cumulative 6-, 12-, and 24-month risks of ATE were 1.1%, 1.8%, and 2.3%, respectively. The subdistribution hazard ratios (SHR) for ATE of H3Cit, cfDNA, and nucleosomes per unit increase were 1.0 (95% confidence interval [CI]: 1.0-1.0, p=.882), 1.0 (1.0-1.0, p=.639), and 1.1 (1.0-1.2, p=.246) respectively. The 6-, 12-, and 24-month ATE probability was 1.3%, 1.7%, and 2.6% in patients with a H3Cit level ≤ 75thpercentile, and 0.8%, 1.3%, and 1.7% in patients above this cut-off (SHR=0.7, 0.2-2.0, p=.460). The 6-, 12-, 24-month overall survival of the study cohort was 87.0% (95%CI: 84.6-89.0), 73.6% (70.6-76.3), and 57.6% (54.3-60.8), respectively. The hazard ratio (HR) for mortality of H3Cit, cfDNA, and nucleosomes per unit increase were 1.0 (1.0-1.0, p<.001), 1.0 (1.0-1.0, p<.001), and 1.0 (1.0-1.1, p=.181) respectively. For better illustration we defined two groups of patients with elevated or non-elevated NET biomarkers. Therefore, we set an empiric cut-off at the 75thpercentile of the study cohort. Elevated H3Cit (HR=1.7, 1.3-2.1, p<.001), and cfDNA levels (HR=1.4, 1.1-1.7, p=.008) were associated with an increased risk of mortality after adjusting for age, and sex (Figure 1A&B). No association was found between higher nucleosome levels and the risk of all-cause mortality in patients with cancer (HR=1.2, 1.0-1.5, p=.088, Figure 1C). Conclusion: There was no significant association between H3Cit, cfDNA, and nucleosomes and ATE occurrence in patients with cancer. However, elevated levels of H3Cit, and cfDNA, were independently associated with an increased risk of mortality in patients with cancer. Table 1. Baseline characteristics of the total study population. Continuous data is reported as medians with first and third quartiles. Categorical variables are given as absolute frequencies and percentages. Data on body mass index, and cancer stage are missing in 2, and 76 patients, respectively. aPatients with brain and hematologic cancer Figure 1. Kaplan-Meier estimated for overall survival probability of patients with cancer according to baseline H3Cit, cfDNA, and nucleosome levels. MoM = Multiple-of-the-mean (i.e. Nucleosome results were compared to pooled plasma from 5 young male healthy controls to obtain a multiple-of-the-median) Disclosures No relevant conflicts of interest to declare.

scholarly journals SARS-CoV2 may evade innate immune response, causing uncontrolled neutrophil extracellular traps formation and multi-organ failure

2020 ◽  
Vol 134 (12) ◽  
pp. 1295-1300 ◽  
Author(s):  
Alain R. Thierry ◽  
Benoit Roch
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Rapid Evolution ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Biological Features ◽  
Extracellular Traps ◽  
Clinical Conditions ◽  
By Products ◽  
New Strategies

Abstract We demonstrate that the general clinical conditions, risk factors and numerous pathological and biological features of COVID-19 are analogous with various disorders caused by the uncontrolled formation of neutrophil extracellular traps and their by-products. Given the rapid evolution of this disease’s symptoms and its lethality, we hypothesize that SARS-CoV2 evades innate immune response causing COVID-19 progresses under just such an amplifier loop, leading to a massive, uncontrolled inflammation process. This work allows us to propose new strategies for treating the pandemic.

scholarly journals β-Hydroxybutyrate Abrogates Formation of Bovine Neutrophil Extracellular Traps and Bactericidal Activity against Mammary Pathogenic Escherichia coli

2008 ◽  
Vol 76 (6) ◽  
pp. 2802-2807 ◽  
Author(s):  
Navit Grinberg ◽  
Sharon Elazar ◽  
Ilan Rosenshine ◽  
Nahum Y. Shpigel
Keyword(s):  
Escherichia Coli ◽  
Bactericidal Activity ◽  
Bacterial Species ◽  
Bovine Mastitis ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Function ◽  
E Coli ◽  
Extracellular Traps ◽  
Increased Risk ◽  
Bovine Neutrophils

ABSTRACT Escherichia coli is an important bacterial species isolated from bovine mastitis. The rate of neutrophil recruitment into the mammary gland and their bactericidal activity largely affect the severity and outcome of the disease. Ketosis is a common metabolic disease, and affected dairy cows are known to have increased risk for mastitis and other infectious conditions. The disease is associated with high blood and milk levels of β-hydroxybutyrate (BHBA), previously shown to negatively affect neutrophil function by unknown mechanisms. We show here that the mammary pathogenic E. coli strain P4 activates normal bovine neutrophils to form neutrophil extracellular traps (NETs), which are highly bactericidal against this organism. Preincubation of these neutrophils with increasing concentrations (0.1 to 8 mmol/liter) of BHBA caused a fivefold decrease of E. coli P4 phagocytosis, though intracellular killing was unaffected. Furthermore, BHBA caused a 10-fold decrease in the NETs formed by E. coli P4-activated neutrophils and a similar decrease in NET bactericidal activity against this organism. These negative effects of BHBA on bovine neutrophils might explain the increased susceptibility of ketotic cows to mastitis and other infectious conditions.

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