Demystifying the prothrombotic role of NETs

Schulz, Christian; Maßberg, Steffen

doi:10.1182/blood-2017-01-757328

Cited by 16 publications

(12 citation statements)

References 10 publications

(10 reference statements)

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“…In addition to H3Cit levels, we also determined the levels of cfDNA and nucleosomes, which are essential components of NETs [2]. In recent studies, it was shown that such NET breakdown products rather than intact NETs induce coagulation [38,39]. However, elevated levels as such do not necessarily indicate increased NET formation, as apoptotic and necrotic cell death are other potential sources of cfDNA and nucleosome release [40].…”

Section: Discussionmentioning

confidence: 99%

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients

Mauracher

Posch

Martinod

et al. 2018

Journal of Thrombosis and Haemostasis

215

172

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Background Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients. Objectives To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell-free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients. Patients/Methods Nine-hundred and forty-six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3-month, 6-month, 12-month and 24-month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively. Results Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2-year risk of 14.5%) than patients with levels below this cut-off (2-year risk of 8.5%, n = 710). In a competing-risk regression analysis, a 100 ng mL increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04-1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D-dimer level, and soluble P-selectin level (SHR 1.13, 95% CI 1.04-1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time-dependent, with associations with a higher risk of VTE only during the first 3-6 months. Conclusion These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer-associated thrombosis.

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Section: Discussionmentioning

confidence: 99%

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients

Mauracher

Posch

Martinod

et al. 2018

Journal of Thrombosis and Haemostasis

215

172

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“…In this context, it has been observed that NETs can trigger platelet activation and that activated platelets can, in turn, promote NETosis [89,90]. Furthermore, it seems that intact NETs may not be required, but rather that isolated NETs components such as cell-free DNA, histones or liberated serine proteases may provide the crucial impetus [90,91]. Furthermore, it seems that intact NETs may not be required, but rather that isolated NETs components such as cell-free DNA, histones or liberated serine proteases may provide the crucial impetus [90,91].…”

Section: Pregnancy Nets and Thrombosismentioning

confidence: 99%

“…The mechanism whereby NETs promote coagulation is currently unclear, but may involve interaction with platelets [89]. In this context, it has been observed that NETs can trigger platelet activation and that activated platelets can, in turn, promote NETosis [89,90]. If left unchecked, this could provide the basis for autocatalytic loop with potentially disastrous consequences.…”

Section: Pregnancy Nets and Thrombosismentioning

confidence: 99%

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The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines

Hahn

Harmatz

Vokálová

et al. 2019

Clinical and Experimental Immunology

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Neutrophils are often exclusively considered as a first-line innate immune defence, able to rapidly kill or trap pathogens and causing in case of over-activation tissue damage. In the female reproductive tract, however, the presence and activity of neutrophils seems to be tightly regulated. Major players in orchestrating this regulation are cyclical steroid sex hormones present during the menstrual cycle and pregnancy. This review describes the role of sex hormones in regulating directly or indirectly the functionality of neutrophils, the role of neutrophils during fertilization and pregnancy and in controlling viral, fungal and bacterial infection. This review also discusses the consequence of overt neutrophil activation in pregnancy pathologies.Our intention in this review is to highlight new observations made during discrete stages of the reproductive cycle, focusing particularly on the role of sex hormones and cytokines in modulating neutrophil activity and their potential dysregulation in pathology.

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“…Several studies have reported on the procoagulant activity of NETs. cfDNA triggers thrombin generation via activation of the contact pathway and elevated levels of circulating cfDNA is a hallmark feature in patients with deep vein thrombosis and sepsis ( 4 – 7 ).…”

Section: Introductionmentioning

confidence: 99%

Cell-Free DNA Promotes Thrombin Autolysis and Generation of Thrombin-Derived C-Terminal Fragments

et al. 2021

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Cell-free DNA (cfDNA) is the major structural component of neutrophil extracellular traps (NETs), an innate immune response to infection. Antimicrobial proteins and peptides bound to cfDNA play a critical role in the bactericidal property of NETs. Recent studies have shown that NETs have procoagulant activity, wherein cfDNA triggers thrombin generation through activation of the intrinsic pathway of coagulation. We have recently shown that thrombin binds to NETs in vitro and consequently can alter the proteome of NETs. However, the effect of NETs on thrombin is still unknown. In this study, we report that DNA binding leads to thrombin autolysis and generation of multiple thrombin-derived C-terminal peptides (TCPs) in vitro. Employing a 25-residue prototypic TCP, GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), we show that TCPs bind NETs, thus conferring mutual protection against nuclease and protease degradation. Together, our results demonstrate the complex interplay between coagulation, NET formation, and thrombin cleavage and identify a previously undisclosed mechanism for formation of TCPs.

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Demystifying the prothrombotic role of NETs

Cited by 16 publications

References 10 publications

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients

The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines

Cell-Free DNA Promotes Thrombin Autolysis and Generation of Thrombin-Derived C-Terminal Fragments

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