microRNAs and Markers of Neutrophil Activation as Predictors of Early Incidental Post-Surgical Pulmonary Embolism in Patients with Intracranial Tumors

Abstract

Venous thromboembolism (VTE) is a common complication of cancer that severely increases morbidity and mortality. Patients with intracranial tumors are more likely to develop VTE than patients with cancers at other sites. Conversely, limited tools exist to identify patients with high thrombotic risk. Upon activation, neutrophils release their content through different mechanisms triggering thrombosis. We explored the ability of microRNAs (miRNAs) and plasma markers of neutrophil activation measured before surgery to predict the risk of early post-surgical pulmonary embolism (PE) in glioma and meningioma patients. We recruited and prospectively followed 50 patients with glioma and 50 with meningioma, 34% of whom in each group developed an early objectively-diagnosed post-surgical PE. We measured miRNA expression and neutrophil markers (cell-free DNA, nucleosomes, calprotectin and myeloperoxidase) before surgery. In glioma patients, we adjusted and validated a predictive model for post-surgical PE with 6 miRNAs: miR-363-3p, miR-93-3p, miR-22-5p, miR-451a, miR-222-3p and miR-140-3p (AUC = 0.78; 95% Confidence Interval (CI) [0.63, 0.94]) and another with cfDNA and myeloperoxidase as predictors (AUC = 0.71; 95% CI [0.52, 0.90]). Furthermore, we combined both types of markers and obtained a model with myeloperoxidase and miR-140-3p as predictors (AUC = 0.79; 95% CI [0.64, 0.94]). In meningioma patients we fitted and validated a predictive model with 6 miRNAs: miR-29a-3p, miR-660-5p, miR-331-3p, miR-126-5p, miR-23a-3p and miR-23b-3p (AUC = 0.69; 95% CI [0.52, 0.87]). All our models outperformed the Khorana score. This is the first study that analyzes the capability of plasma miRNAs and neutrophil activation markers to predict early post-surgical PE in glioma and meningioma patients. The estimation of the thrombotic risk before surgery may promote a tailored thromboprophylaxis in a selected group of high-risk patients, in order to minimize the incidence of PE and avoid bleedings.

Increase of Neutrophil Activation Markers in Venous Thrombosis—Contribution of Circulating Activated Protein C

“…The causes of thrombosis are both genetic and acquired; however, despite the large increase in the number of identified risk factors, still a substantial number of thrombotic events occur spontaneously without an apparent origin, which may reflect causes not yet discovered. Provided the interplay between immunity and thrombosis, where neutrophils play a predominant role; markers of neutrophil activation may allow identifying patients with high thrombotic risk, as we previously demonstrated in cancer patients [33,34]. Thus, we explored the relation of neutrophil activation markers and the risk of thrombosis.…”

“…cfDNA could be released into plasma by apoptotic or necrotic cells. Following the strategy addressed in previous studies [25][26][27][28][29]33,34,54,55], we evaluated whether the different markers of neutrophil activation measured in plasma had the same cellular origin by means of their correlation. We found a significant correlation between levels of cfDNA and calprotectin (r = 0.28; p < 0.0001), similar to that observed in previous plasma studies [27,33], and also between neutrophil count and calprotectin (Spearman r = 0.18; p = 0.003) indicating that they might have, to some extent, the same origin, probably an increased activation of neutrophils or NETosis.…”

“…Previous studies carried out to clarify the role of NETs in thrombosis have been mainly conducted in animal models [2,4,6,20,21]. However, there is already incipient evidence about the relationship between NETs and the risk of thrombosis in patients with various prothrombotic and inflammatory disorders [22][23][24][25][26][27][28][29][30][31][32][33][34]. In the particular scenario of VTE, in a case-control study with a very small number of samples, Díaz et al [26] observed a significant increase in plasma cell-free DNA (cfDNA) concentration in patients with acute DVT.…”

Management of Cancer-Associated Thrombosis: An Evolving Area

“…This Special Issue of Cancers is a collection of eight translational, clinical research, and review articles on recent advances in the management of CAT. The authors discuss the unmet needs of patients with CAT and address the limits of current therapeutic approaches by analyzing strengths and weaknesses of recent trials [ 13 ], as well as the management of incidental VTE [ 14 , 15 ], which account for 50% of VTE in cancer patients, and the need for individualized strategies for CAT prevention [ 16 , 17 , 18 , 19 , 20 ].…”

“…Likewise, Oto et al investigated the association among the expression of 179 microRNAs (miRNAs), neutrophil activation markers (including cell-free DNA, nucleosomes, calprotectin, and myeloperoxidase), and the risk of VTE in a cohort of 100 patients with primary brain tumors undergoing surgery. In their study, a model incorporating myeloperoxidase and miR-140-3p expression levels predicted post-surgical pulmonary embolism (PE) in glioma patients with both high sensitivity and high specificity (area under the Receiver Operator Curve = 0.79; 95% CI, 0.64–0.9]) [ 19 ], an improvement over available risk prediction scores. Together, these studies illustrate how the identification of new predictive biomarkers might help to refine VTE risk prediction.…”