Neutrophil extracellular trap formation is an independent risk factor for occult cancer in patients presenting with venous thromboembolism

Background: Venous thromboembolism (VTE), particularly unprovoked VTE, is associated with occult cancer. The optimal screening regimen remains controversial. Neutrophil extracellular traps (NETs) are implicated in cancer-associated thrombosis, and elevated biomarkers of NET formation are associated with poor prognosis.Objectives: To investigate the association between NET formation and occult cancer in patients with VTE.Methods: Blood biomarkers associated with NETs and neutrophil activation (nucleo-somal citrullinated histone H3 [H3Cit-DNA], cell-free DNA, and neutrophil elastase) were quantified in patients with VTE. The primary outcome was cancer diagnosed during a one-year follow-up.Results: This study included 460 patients with VTE, of which 221 (48%) had isolated deep vein thrombosis. Forty-three patients had active cancer at inclusion and were excluded from the primary analysis Cancer during follow-up was diagnosed in 29 of 417 (7.0%) patients. After adjustment for age and unprovoked VTE, the hazard ratio of cancer during follow-up per 500 ng/mL increase of H3Cit-DNA was 1.79 (95% CI, 1.03-3.10). Furthermore, patients with cancer-associated VTE (known active cancer or cancer diagnosed during follow-up) had higher levels of H3Cit-DNA than cancer-free patients with VTE after adjustment for age, hemoglobin, gender, chronic obstructive pulmonary disease, previous cancer, and start of anticoagulant treatment (odds ratio 2.06 per 500 ng/mL increase of H3Cit-DNA [95% CI, 1.35-3.13]).Conclusions: H3Cit-DNA is an independent predictor for occult cancer in patients with VTE and elevated in cancer-associated VTE, suggesting that H3Cit-DNA is potentially a useful diagnostic marker for cancer in patients with VTE and that elevated NET formation is a hallmark of cancer-associated VTE.