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

Abstract

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.

Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

“…Additionally, we investigated the association of NETs and the risk of mortality in patients with cancer. In conformity with previous studies we quantified NETs by measuring plasma levels of biomarkers reflecting NET formation, H3Cit, cfDNA and nucleosomes (Demers et al , ; Martinod et al , ; Thålin et al , ; Mauracher et al , ).…”

“…Experimental studies suggest that tumours pre‐dispose neutrophils to release NETs, which then induce a prothrombotic state (Engelmann & Massberg, ; Martinod & Wagner, ; Laridan et al , ; Pertiwi et al , ). The first evidence of a role of NETs for cancer‐associated VTE was reported recently in a study by Mauracher et al (), which found a 13% relative increase in VTE risk per 100 ng/ml increase in H3Cit level. In contrast, we did not observe an association of H3Cit with ATE in patients with cancer in our present study.…”

“…NETs have been detected in venous (VTE) and arterial thromboembolism (ATE) (Fuchs et al , , ; Brill et al , ; von Brühl et al , ; Mangold et al , ; Vallés et al , ). A recent study published showed that elevated NET markers are associated with a higher risk of VTE in patients with cancer (Mauracher et al , ). Furthermore, prior studies have shown that patients with cancer have elevated levels of NET markers compared to healthy controls, and indicate that biomarkers of NET formation are associated with poor survival in patients with cancer (Yang et al , ; Richardson et al , ; Thålin et al , ).…”

Prothrombotic fibrin clot properties associated with increased endogenous thrombin potential and soluble P‐selectin predict occult cancer after unprovoked venous thromboembolism

“…Of note, we found that K s and CLT, as well as thrombin, generation were associated with H3Cit measured in vivo, a finding that supports several prothrombotic effects of NET formation among others observed after addition of DNA and histones to plasma and expands them by showing association between NET formation and prothrombotic fibrin clot structure and lysability after VTE. The current study provides new insights into association of NET formation with a hypercoagulable state that can be observed not only in cancer‐associated thrombosis but also in VTE patients with no clinically evident malignancy at the time of VTE. A diagnostic value of H3Cit in VTE patients in the context of cancer deserves further investigation.…”

Mouse models of cancer-associated thrombosis

“…Indeed, mouse studies demonstrated that NETs contribute to thrombosis in the IVC stenosis model [33, 60]. In terms of cancer-associated thrombosis, plasma citrullinated histone H3, a marker of NETs, is associated with venous thrombosis in cancer patients [61]. Further, mouse studies sought to determine the role of NETs in cancer-associated thrombosis.…”