Special Article
Neutrophils as instigators of thrombosis: Beyond antimicrobial protection
Neutrófilos como instigadores de trombosis: más allá de la protección antimicrobiana
J.A. Páramo
Corresponding author
Servicio de Hematología, CUN. Laboratorio Aterotrombosis, CIMA. Universidad de Navarra, IdiSNA, CIBERCV, Pamplona, Spain
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"apellidos" => "Rubal Bran" ] 2 => array:1 [ "colaborador" => "For the Shared Care and Consultations Working Group of the Spanish Society of Internal Medicine" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256520301363" "doi" => "10.1016/j.rce.2020.05.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256520301363?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887420301235?idApp=WRCEE" "url" => "/22548874/0000022000000009/v1_202012131457/S2254887420301235/v1_202012131457/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special Article</span>" "titulo" => "Neutrophils as instigators of thrombosis: Beyond antimicrobial protection" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "583" "paginaFinal" => "586" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J.A. Páramo" "autores" => array:1 [ 0 => array:4 [ "nombre" => "J.A." "apellidos" => "Páramo" "email" => array:1 [ 0 => "japaramo@unav.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Hematología, CUN. Laboratorio Aterotrombosis, CIMA. Universidad de Navarra, IdiSNA, CIBERCV, Pamplona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Neutrófilos como instigadores de trombosis: más allá de la protección antimicrobiana" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Neutrophils are the most abundant population of circulating leukocytes, and recent studies have shown that neutrophils play a key role in venous and arterial thrombosis. Historically, neutrophils have been associated with the first-line antimicrobial defense, as elements of innate immunity; however, we now know that neutrophils also participate in regulating the inflammatory response, repairing tissues, and promoting angiogenesis, among other processes. When certain stimuli are applied, neutrophils release network structures known as neutrophil extracellular traps (NETs), which have acquired a considerable interest in the field of research into thrombosis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Excessive NET production has been associated with inflammation, postischemic reperfusion damage, and the growth and progression of cancer.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">NETs were first described by Brinkmann et al. in 2004 who reported how DNA matrices, histones and other granular proteins capture, and destroy bacteria, which represented a new mechanism of antimicrobial protection.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">NETosis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Two forms of NETosis have been described in the literature: lytic or “suicidal” NETosis, which entails the death of the neutrophil, and “vital” NETosis, in which the formation of NETs and their release are performed without breaking the nuclear and cytoplasmic membrane, thereby preserving the neutrophil’s functions.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Suicidal NETosis occurs after stimulation with phorbol esters through protein kinase <span class="elsevierStyleSmallCaps">c</span> activation and the collaboration of nicotinamide adenine dinucleotide phosphate oxidases. Neutrophil stimulation not only by phorbol acetate but also by extracellular pathogens, hyperglycemia, hypoxia, cholesterol crystals, and complement causes the disintegration of the nuclear membrane and expulsion of chromatin in the cytosol. After hours of stimulation, the plasma membrane ruptures, releasing structures composed of DNA, histones, and granular proteins, such as myeloperoxidase and elastase. This process is considered a beneficial mechanism of the immune response against pathogens, while neutrophils lose their phagocytic and chemotactic functions.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Chromatin decondensation is a requirement for NET formation, the latter process is mediated by a calcium-dependent enzyme known as peptidylarginine deiminase 4 (PAD4), which mediates the posttranslational citrullination of arginine residues in histones, although there can be other forms of chromatin decondensation and, consequently, other NETosis pathways independent of PAD4.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Nevertheless, PAD4 plays a key role, given that mutations in the gene impede NET formation, as happens in PAD4-deficient mice.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5–7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In contrast, “vital” NETosis is produced by direct microbial exposure or the presence of lipopolysaccharides via Toll-like receptors. NETosis entails the release of NETs through the export of nuclear content, and the formation of vesicles containing NETs but with membrane integrity and therefore without cell lysis, allowing the neutrophils to continue developing the functions of pathogen detection, capture and destruction.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The formation of these extracellular traps can be measured in real-time using intravital microscopy and visualized through electron microscopy. However, the most widely used method in practice for detecting this formation is conventional microscopy with immunodetection of DNA, and histones in various tissues.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> At the circulating level, there are immunoenzymatic techniques that enable the quantification of NET components, such as elastase, myeloperoxidase and citrullinated histone H3.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Nevertheless, most of these methods require improvements in standardization, as well as validation of their sensitivity and specificity.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Prothrombotic effects of neutrophil extracellular traps</span><p id="par0030" class="elsevierStylePara elsevierViewall">Numerous studies, most of them <span class="elsevierStyleItalic">in vitro</span>, have reported that intact NETs and those separately produced by their components can promote thrombosis through various mechanisms. Initial studies have shown that these structures capture platelets, promoting their activation and aggregation.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Subsequent studies have shown that these structures facilitate the generation of thrombin by providing a matrix to which red blood cells, fibrinogen, von Willebrand factor, fibronectin and factor <span class="elsevierStyleSmallCaps">xii,</span> and tissue factor can adhere.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10–13</span></a> In the presence of DNA complexes and histones, clots are produced with thicker fibrin meshes that are more resistant to thrombolysis, while the administration of DNases reduces the quantity of fibrin and, consequently, the thrombotic occlusion of the vessel.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> Lastly, studies have observed that the various components of NETs can change the natural inhibiting pathways of coagulation. Thus, the elastase and cathepsin G of neutrophils degrade the tissue factor pathway inhibitor,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and the histones impair the activation of thrombomodulin-dependent protein <span class="elsevierStyleSmallCaps">C</span>.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">With the available evidence, it is easy to consider that NETs play a key role in immunothrombosis, a term that describes the relationship between the immune response and coagulation.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Neutrophil extracellular traps in venous and arterial thrombosis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Venous thrombosis is intimately related to inflammation because neutrophils combined with platelets and monocytes contribute to the onset and propagation of the process.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">NETs have been observed in human venous thrombi, preferentially located in those in the organizational phase.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> A study compared thrombi from patients with venous thrombosis with thrombi obtained after myocardial infarction and found that the venous thrombi contained fewer NETs, a finding that could be due to a slowing of the generation of venous thrombi compared with the arterial, which would have contributed to their degradation.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The levels of circulating NETs and released products have been measured in patients with symptomatic deep vein thrombosis (DVT), as well as in patients with clinical suspicion and exclusion of DVT. The presence of NETs was associated with a significant risk of DVT. These data were confirmed in another study that observed an increase in circulating DNA and myeloperoxidase levels in patients with symptomatic DVT, compared with a patient group with suggestive symptoms but no confirmation of DVT.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21,22</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Considering that atherosclerosis, the primary pathophysiological substrate of arterial thrombosis, is a chronic inflammatory process of the arterial wall, numerous studies have studied the role of NETs in vascular arterial diseases.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Several studies on humans have observed the presence of NETs in atherosclerotic lesions, especially in atheromatous plaques with superficial erosion, more than with the rupture of the plaques.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24–26</span></a> NETs have been detected in the core of coronary thrombi, correlating the number of NETs with the size of the infarction.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,27</span></a> NETs have also been detected in coronary stent thrombi<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and thrombi obtained from patients with ischemic stroke,<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29,30</span></a> although studies have not been able to confirm that cardioembolic stroke is associated with a greater quantity of NETs in cerebral thrombi.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Lastly, some authors have proposed using particular NET components as predictors of severity in coronary artery disease and ischemic stroke. For example, circulating levels of nucleosomes and myeloperoxidase-DNA complexes have been associated with increased histological and symptom severity in patients with coronary artery disease.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Other studies have observed that plasma levels of extracellular DNA, nucleosomes, and citrullinated histone H3 correlate with symptom severity and the prognosis of patients with ischemic stroke.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Neutrophil extracellular traps in cancer-associated thrombosis</span><p id="par0055" class="elsevierStylePara elsevierViewall">It has been suggested that NETs can play an important role in tumor progression, the formation of metastases, and contributing to cancer-associated thrombosis. For example, it has been observed that various tumor cell lines induce the NET formation and that these NETs intervene in the thrombosis observed in certain tumors, such as pancreatic cancer and other types of adenocarcinoma.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> The presence of NETs in arterial and venous thrombi obtained from patients with cancer has also been demonstrated,<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34,35</span></a> as well as high plasma levels of citrullinated histone H3, primarily in patients with pancreatic and lung cancer.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> These studies indicate that circulating markers of NETs can be useful in predicting venous thromboembolism in patients with various types of cancer.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In summary, activated neutrophils release structures (NETs) composed of DNA, histones, and granular proteins that provide an ideal matrix for platelet activation and coagulation mechanisms, thereby contributing to the pathogenesis of thrombosis in venous and arterial territories. This fact, in addition to representing a change in paradigm in the pathogenic theory of thrombosis, could be the basis for developing new diagnostic markers for thrombosis and designing antithrombotic strategies without hemorrhagic risk, using NETs as the therapeutic target.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The author declares that he has no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1432564" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1307719" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1432563" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1307720" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "NETosis" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Prothrombotic effects of neutrophil extracellular traps" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Neutrophil extracellular traps in venous and arterial thrombosis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Neutrophil extracellular traps in cancer-associated thrombosis" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-09-25" "fechaAceptado" => "2019-11-06" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1307719" "palabras" => array:4 [ 0 => "Leukocytes" 1 => "NETs" 2 => "Thrombosis" 3 => "Inflammation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1307720" "palabras" => array:4 [ 0 => "Leucocitos" 1 => "NETs" 2 => "Trombosis" 3 => "Inflamación" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">When activated, neutrophils release structures (NETs) composed of DNA, histones and granular proteins that provide an ideal matrix for platelet activation and coagulation mechanisms, thereby contributing to the pathogenesis of thrombosis in venous and arterial territories, as well as cancer-associated thrombosis. NETs play a key role in immunothrombosis, a term that describes the relationship between the immune response and coagulation.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los neutrófilos, cuando son activados, liberan estructuras (NETs) compuestas por ADN, histonas y proteínas granulares que proporcionan una matriz idónea para la activación plaquetaria y de los mecanismos de coagulación, contribuyendo así a la patogenia de la trombosis en los territorios venoso y arterial, así como a la trombosis asociada al cáncer. Los NETs juegan un papel clave en la inmunotrombosis, término que describe la relación entre la respuesta inmune y la coagulación.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Páramo JA. 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