Targeting potential drivers of COVID-19: Neutrophil extracellular traps

Barnes, Betsy J.; Adrover, Jose M.; Baxter-Stoltzfus, Amelia; Borczuk, Alain; Cools-Lartigue, Jonathan; Crawford, James M.; Daßler-Plenker, Juliane; Guerci, Philippe; Huynh, Caroline; Knight, Jason S.; Loda, Massimo; Looney, Mark R.; McAllister, Florencia; Rayes, Roni; Renaud, Stephane; Rousseau, Simon; Salvatore, Steven; Schwartz, Robert E.; Spicer, Jonathan D.; Yost, Christian C.; Weber, Andrew; Zuo, Yu; Egeblad, Mikala

NETs and excessive thrombosis Acute cardiac and kidney injuries are common in patients with severe COVID-19 and contribute to the mortality of this disease (Bonow et al., 2020) . D-dimer (a fibrin degradation product indicative of hyperactive coagulation) has emerged as a reliable marker of severe COVID-19 . High blood levels of NETs may explain these findings: intravascular NETs have been shown to play a vital role in initiating and accreting thrombosis in arteries and veins . For example, in severe coronary artery disease, complexes of NETs are elevated, and NET levels positively associate with thrombin levels, which predict adverse cardiac events (Borissoff et al., 2013) . In addition, autopsy samples collected from septic patients show that NETs infiltrate microthrombi (Jiménez-Alcázar et al., 2017) . Thus, when NETs circulate at high levels in blood, they can trigger the occlusion of small vessels, leading to damage in the lungs, heart, and kidneys (Cedervall et al., 2015; Fuchs et al., 2010; Laridan et al., 2019; Martinod and Wagner, 2014) . In mouse models of septicemia, intravascular NETs form microthrombi that obstruct blood vessels and cause damage to the lungs, liver, and other organs (Jiménez-Alcázar et al., 2017) . Mechanistically, NETs activate the contact pathway of coagulation (also called the plasma kallikrein-kinin system) via electrostatic interactions between the NET histones and platelet phospholipids (Oehmcke et al., 2009) . Histones can also promote platelet activation by acting as ligands for the Toll-like receptors on platelets (Semeraro et al., 2011) . At the same time, NE (which is bound in its active form to NETs) likely also plays an important role by digesting the major coagulation inhibitors antithrombin III and tissue factor pathway inhibitor (Massberg et al., 2010) . Furthermore, there is almost surely a feedback loop whereby pro-coagulant activity (e.g., that of thrombin) leads to platelet activation, and activated platelets then further enhance NET formation (Caudrillier et al., 2012; Clark et al., 2007; Fuchs et al., 2010; Massberg et al., 2010; Sreeramkumar et al., 2014; von Brühl et al., 2012) . Dissolving NETs with DNase I restores normal perfusion of the heart and kidney microvasculature in animal models (Cedervall et al., 2015; Jansen et al., 2017; Nakazawa et al., 2017; Raup-Konsavage et al., 2018) . Based on the above findings, we argue that targeting intravascular NETs may similarly reduce thrombosis in patients with severe COVID-19.