scholarly journals Neutrophil Extracellular Traps in the Development of Sepsis-Induced Disseminated Intravascular Coagulation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1175-1175
Author(s):  
Nicholas Leo Jackson Chornenki ◽  
Dhruva J Dwivedi ◽  
Andrew C Kwong ◽  
Nasim Zamir ◽  
Alison E Fox-Robichaud ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Conflicts Of Interest ◽  
Early Recognition ◽  
Critical Role ◽  
Neutrophil Extracellular Traps ◽  
Trauma Patients ◽  
Intravascular Coagulation ◽  
Extracellular Traps ◽  
Inflammatory Stimuli ◽  
Endothelial Cell Death

Abstract Introduction: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation complicating many conditions including sepsis and traumatic injuries. Early recognition and treatment of DIC is of paramount importance. However, to date no useful markers have been identified that can differentiate "pre-DIC" (which is destined to lead to DIC) from "without-DIC" (in which the hypercoagulable state is transient and does not lead to DIC). Activation of neutrophils by inflammatory stimuli or microbes results in the release of neutrophil extracellular traps (NETs). NETs are web-like structures consisting of cell-free DNA (cfDNA), histones, myeloperoxidase (MPO), and anti-microbial proteins. Although NETs aid in the host response to infection by sequestering pathogens, excessive production of NETs can exert collateral damage to the host by activating coagulation, inhibiting fibrinolysis, and causing endothelial cell death. Recently, sepsis-induced DIC has been shown to correlate with circulating levels of DNA-associated MPO, suggesting that the release of NETs by neutrophils plays a critical role in the onset of DIC. Our objective was to attempt to identify a mechanistic role for NETosis in the development DIC in sepsis and use this information to identify 'pre-DIC' signatures. Methods: Clinical data and biological samples from 357 septic patients who were part of the DNA as a Prognostic Marker in ICU patient (DYNAMICS) study were used. Incidence of DIC was determined using the International Society on Thrombosis and Haemostasis (ISTH) scoring system on Day 1 and each subsequent day. We quantified levels of Citrullinated Histone H3 (H3Cit), a biomarker of NETosis, as well as levels of cfDNA. We also measured levels of Protein C (PC), a natural anticoagulant that prevents blood clotting in the microcirculation. Increased consumption of PC is a hallmark of sepsis and may lead to microvascular thrombosis and DIC. Results: Of the 357 patients included from the DYNAMICS study, 121 were classified as having DIC during the study period: 79 on Day 1 ('overt-DIC') and 42 on a subsequent day ('pre-DIC'). Baseline characteristics of patients are shown in Table 1. Those with DIC had significantly higher baseline APACHE II scores and were significantly more likely to be on vasopressors at admission or have a history of chronic liver disease. DIC was associated with significantly increased mortality (HR= 2.53; 95% CI = 1.62 - 3.93; p < 0.001) even when age and past medical history were controlled for. Levels of PC were significantly reduced in patients with DIC at all time points compared to those without DIC (p < 0.01). However, cfDNA levels did not differ between patients with and without DIC at any timepoint. As cfDNA may be released by multiple mechanisms and sources, H3 Cit was quantified on Day 1 as a marker of NETosis. Levels of H3 Cit on Day 1 were significantly higher in "pre-DIC" and "overt-DIC" patients compared to those 'without DIC' (p<0.05), non-septic, non-trauma ICU Controls (p<0.01), and healthy volunteers (p<0.001) (Figure 1). With respect to differentiating 'pre-DIC' from 'overt-DIC', using Day 1 H3 Cit provided an AUC of 0.66 (0.59-0.74). Higher H3 Cit levels were also correlated with lower PC levels in septic patients (r = -0.124; p = 0.02). In a comparison group of non-septic trauma patients also from the DYNAMICS study; (n=6) patients with DIC did not have significantly different Day 1 H3 Cit from (n=25) trauma patients without DIC (p=0.62) or ICU controls (p=0.99). Conclusion: In sepsis, DIC pathophysiology reflects a consumptive process as indicated by reduced PC levels. NETosis may contribute to this process by producing pro-coagulant stimuli and may prove useful in identifying patients who will develop DIC. As a regulated and targetable process investigations involving NETosis may yield therapies for early treatment of DIC in sepsis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhaoyuan Chen ◽  
Hao Zhang ◽  
Mengdi Qu ◽  
Ke Nan ◽  
Hanzhong Cao ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Clinical Evaluation ◽  
Disseminated Intravascular Coagulation ◽  
Early Recognition ◽  
Neutrophil Extracellular Traps ◽  
Intravascular Coagulation ◽  
Extracellular Traps ◽  
Coagulation Dysfunction ◽  
Septic Thrombosis

Patients with sepsis commonly suffer from coagulation dysfunction and lead to the formation of thrombus. During the development of sepsis, neutrophils migrate from the circulating blood to infected tissues and mediate the formation of neutrophil extracellular traps (NETs) that kill pathogens. However, the overactivation of neutrophils can promote the formation of immunothrombosis and even cause disseminated intravascular coagulation (DIC), which damages microcirculation. The outcome of sepsis depends on early recognition and intervention, so clinical evaluation of NETs function may be a valuable biomarker for early diagnosis of sepsis. The interaction of NETs with platelets, complement, and endothelium mediates the formation of immunothrombosis in sepsis. Inhibiting the formation of NETs is also considered to be one of the potential treatments for sepsis. In this review, we will discuss the key role of neutrophils and NETs in sepsis and septic thrombosis, in order to reveal new mechanisms for thrombosis treatment of sepsis.

scholarly journals Recent advances in pathophysiology of disseminated intravascular coagulation: the role of circulating histones and neutrophil extracellular traps

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2143 ◽  
Author(s):  
Yasir Alhamdi ◽  
Cheng-Hock Toh
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Cell Injury ◽  
Neutrophil Extracellular Traps ◽  
Intravascular Coagulation ◽  
Extracellular Traps ◽  
Complex Interactions ◽  
Recent Advances ◽  
Novel Biomarkers

Disseminated intravascular coagulation (DIC) is an acquired condition that develops as a complication of systemic and sustained cell injury in conditions such as sepsis and trauma. It represents major dysregulation and increased thrombin generationin vivo. A poor understanding and recognition of the complex interactions in the coagulation, fibrinolytic, inflammatory, and innate immune pathways have resulted in continued poor management and high mortality rates in DIC. This review focuses attention on significant recent advances in our understanding of DIC pathophysiology. In particular, circulating histones and neutrophil extracellular traps fulfil established criteria in DIC pathogenesis. Both are damaging to the vasculature and highly relevant to the cross talk between coagulation and inflammation processes, which can culminate in adverse clinical outcomes. These molecules have a strong potential to be novel biomarkers and therapeutic targets in DIC, which is still considered synonymous with ‘death is coming’.

scholarly journals A Novel Assay of Neutrophil Extracellular Traps (NETs) Formation Independently Predicts DIC and Identifies the Rationale for Anti-IL-8 Therapies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 440-440
Author(s):  
Simon Timothy Abrams ◽  
Ben Morton ◽  
Yasir Alhamdi ◽  
Mohmad Alsabani ◽  
Zhenxing Cheng ◽  
...  
Keyword(s):  
Organ Failure ◽  
Conflicts Of Interest ◽  
Clinical Care ◽  
Neutrophil Extracellular Traps ◽  
Protective Mechanism ◽  
Positive Staining ◽  
Icu Patients ◽  
Intravascular Coagulation ◽  
Icu Admission ◽  
Extracellular Traps

Background Neutrophils are the first line of defence against bacterial infection and formation of neutrophil extracellular traps (NETs) is an important protective mechanism. However, NETs can also cause harm by promoting intravascular coagulation and multi-organ failure (MOF) in animal models. Although increasingly considered as important therapeutic targets, there is currently no robust and specific measure of NETs formation to inform clinical care and enable precision medicine in patients on the intensive care unit (ICU). The aim of this study is to establish a novel assay for measuring NETs and assess its clinical significance. Methods A prospective cohort of 341 consecutive adult ICU patients was recruited, following written informed consent. The NETs-forming capacity of ICU admission blood samples was semi-quantified by directly incubating patient plasma with isolated healthy neutrophils ex vivo. The association of NETs-forming capacity with sequential organ failure assessment (SOFA) scores, disseminated intravascular coagulation (DIC) and 28-day mortality were analysed and compared with available NETs assays. Cytokine analysis together with inhibitor studies was performed to determine the driving factors of NETs patients. To determine the pathological relevance of NETs, complementary in vivo studies were performed in mice models of sepsis (caecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli), without or with anti-NETs therapy. Results We observed that NETs were directly induced by heterologous healthy neutrophils incubated with plasma taken from ICU patients, but not from healthy donors (unless incubated with 100 nM PMA). Using the novel assay, we could stratify ICU patients into 4 groups, those with absent (22.0%), mild (49.9%), moderate (14.4%) and strong (13.8%) NETs formation, respectively. Strong NETs formation was predominantly found in sepsis (P &lt;0.0001) and was associated with higher SOFA scores on admission and throughout the study duration (72 hours post-admission). Adjusted by APACHE II, multivariate regression showed that measuring the degree of NETs formation in ICU admission could independently predict DIC and mortality whereas other NETs assays, e.g. cell-free DNA, myeloperoxidase and myeloperoxidase-DNA complexes, could not. Interleukin (IL)-8 levels were found to be strongly associated with NETs formation and inhibiting IL-8 significantly attenuated NETosis. MAPK activation by IL-8 has been identified as a major pathway of NETs formation in patients. Using mice models of sepsis, we specifically observed NETs positive staining (cit-H3) in the lung tissue. This was associated with increases in lung injury scores, along with circulating markers of liver (BUN [CLP: P=0.005, E.coli: P&lt;0.001]), kidney (ALT [CLP: P=0.01, E.coli: P=0.002]) and cardiac injury (cTnI [(CLP: P&lt;0.001, E.coli: P&lt;0.001]). By targeting IL-8 we were able to significantly inhibit NETs formation, organ injury and also improved survival times in septic mice (P=0.004). Conclusions Our new NETs assay directly measures the NETs-forming capacity in patient plasma. This could guide clinical management and enable identification of NETs-inducing factors in individual patients for targeted treatment and personalised ICU medicine. We identify IL-8 as a major driving factor in sepsis, with anti-IL-8 therapy in septic mice significantly reducing NETs-induced organ damage and mortality. Disclosures No relevant conflicts of interest to declare.

scholarly journals Orchestration of Neutrophil Extracellular Traps (Nets), a Unique Innate Immune Function during Chronic Obstructive Pulmonary Disease (COPD) Development

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 53
Author(s):  
Anjali Trivedi ◽  
Meraj A. Khan ◽  
Geetanjali Bade ◽  
Anjana Talwar
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Chronic Obstructive ◽  
Tissue Destruction ◽  
Mucus Production ◽  
Obstructive Pulmonary Disease ◽  
Extracellular Traps ◽  
Endothelial Cell Death

Morbidity, mortality and economic burden caused by chronic obstructive pulmonary disease (COPD) is a significant global concern. Surprisingly, COPD is already the third leading cause of death worldwide, something that WHO had not predicted to occur until 2030. It is characterized by persistent respiratory symptoms and airway limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles of gases. Neutrophil is one of the key infiltrated innate immune cells in the lung during the pathogenesis of COPD. Neutrophils during pathogenic attack or injury decide to undergo for a suicidal death by releasing decondensed chromatin entangled with antimicrobial peptides to trap and ensnare pathogens. Casting neutrophil extracellular traps (NETs) has been widely demonstrated to be an effective mechanism against invading microorganisms thus controlling overwhelming infections. However, aberrant and massive NETs formation has been reported in several pulmonary diseases, including chronic obstructive pulmonary disease. Moreover, NETs can directly induce epithelial and endothelial cell death resulting in impairing pulmonary function and accelerating the progression of the disease. Therefore, understanding the regulatory mechanism of NET formation is the need of the hour in order to use NETs for beneficial purpose and controlling their involvement in disease exacerbation. For example, DNA neutralization of NET proteins using protease inhibitors and disintegration with recombinant human DNase would be helpful in controlling excess NETs. Targeting CXC chemokine receptor 2 (CXCR2) would also reduce neutrophilic inflammation, mucus production and neutrophil-proteinase mediated tissue destruction in lung. In this review, we discuss the interplay of NETs in the development and pathophysiology of COPD and how these NETs associated therapies could be leveraged to disrupt NETopathic inflammation as observed in COPD, for better management of the disease.

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