Circulating Nucleosomes and Neutrophil Activation as Risk Factors for Deep Vein Thrombosis

Abstract

Objective-The formation of neutrophil extracellular traps and the exposure of nucleosomes on these neutrophil extracellular traps contribute to coagulation activation and the propagation of deep vein thrombosis (DVT) in animal models. However, no data are available on the role of neutrophil extracellular traps or nucleosomes in patients with thrombosis. Methods and Results-We conducted a case-control study, in which levels of circulating nucleosomes and neutrophil elastase-α1-antitrypsin complexes were assessed in plasma from 150 patients with objectified symptomatic DVT (cases) and compared with 195 patients with a clinical suspicion of DVT but in whom DVT was excluded (controls). We explored the association between both nucleosomes and elastase-α1-antitrypsin complexes, and the presence of DVT by calculating the odds ratio with corresponding 95% CIs. Elevated levels of both circulating nucleosomes and elastase-α1-antitrypsin complexes were associated with a 3-fold risk of DVT, and the associations remained similar after adjustment for potential confounders (malignancy, smoking, recent immobilization, recent hospitalization). The risk increased with higher nucleosome and elastase-α1-antitrypsin complex levels, suggesting a dose-dependent relationship among circulating nucleosomes, activated neutrophils, and DVT. Conclusion-Our study suggests an association among circulating nucleosomes, activated neutrophils, and presence of DVT in humans, which might have implications for treatment and prevention.

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

“…Complement activation attracts and activates neutrophils [31,32], and in turn may exacerbate NET release, initiating a positive feed-back loop. These observations are in line with the recent report on the association among circulating nucleosomes, activated neutrophils (as indicated by increased neutrophil elastase-α1-antitrypsin complexes), and presence of deep vein thrombosis [33]. Taken together, evolutionarily conserved innate mechanisms acting in concert may stimulate thrombosis, endothelial damage [34,35] and contribute to the precipitation of acute TTP.…”

Propagation of thrombosis by neutrophils and extracellular nucleosome networks

“…8,57 Recently, it has been described that NET and circulating nucleosomes are present in human thromboembolism, suggesting that extracellular nucleosomes may be of relevance to deep vein thrombosis in patients. 58,59 Apart from immobilization, cancer is another important risk factor for venous thrombosis and is associated with hypercoagulability, which could in part be explained by an increased activation of neutrophils and their enhanced ability to form NET in tumor-bearing mice. 60 …”

“…[5][6][7][8]41,53,58,59,[61][62][63] Since nucleosomes are not only externalized by neutrophils but also by apoptotic and necrotic cells, and since the plasma levels of nucleosomes have been shown to be increased under various pathological conditions (e.g. ischemia/reperfusion, cancer), the diagnostic evaluation of nucleosome-driven thrombosis requires the use of additional markers.…”

“…64 Additional markers might include, for example, plasma markers of neutrophil activation such as NE as well as Ddimer levels. 6,58 Inhibition of the prothrombotic functions of NET/extracellular nucleosomes by specific antibodies, such as anti-H2A/H2B-DNA antibody, or their degradation by DNase I robustly inhibits thrombosis in different vascular beds in animal models. 5,7,8 Inhibition of NET formation in PAD4-deficient mice does not change bleeding times.…”

La pêche miraculeuse des filets du neutrophile

“…De plus, la quantification des marqueurs de « nétose » circulants présente un intérêt pronostique, puisque le taux de nucléosomes circulants (issus de la dégradation des NET) est corrélé à la sévérité des microangiopathies thrombotiques [24] et des crises vaso-occlusives drépanocytaires [25]. Enfin, un taux élevé de nucléosomes circulants expose à un risque trois fois plus élevé de thrombose veineuse profonde, indépendamment de la présence d'autres facteurs de risque thrombotique [26].…”