title: Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  The purpose of this study was to investigate the possible association between tumor necrosis factor-α (TNF-α) levels and defects in the activated protein C (APC) system as a determinant of venous thromboembolism (VTE) in metastatic colorectal cancer patients (mCRC) undergoing chemotherapy.
  
  
  METHODS
  TNF-α levels (measured by immunoassay) and abnormalities in the APC system [evaluated by an APC-dependent thrombin generation assay (ThromboPath-ThP)] were evaluated in 45 mCRC patients undergoing chemotherapy. VTE events were recorded during follow-up.
  
  
  RESULTS
  TNF-α levels were increased (p < 0.01), and APC functionality was decreased (p < 0.0001) in mCRC patients compared to age- and sex-matched controls. An inverse correlation was observed between TNF-α and APC impairment in mCRC (p < 0.0001). TNF-α was confirmed as an independent predictor (p = 0.007) for APC abnormalities at multivariate regression analysis. Nine (20 %) of 45 mCRC patients experienced VTE during chemotherapy. Bayesian analysis of combined ThP/TNF-α showed a positive predictive value of 0.67 in predicting VTE (p = 0.01). Cox proportional hazards survival analysis confirmed the predictive value of combined ThP/TNF-α determination in VTE risk assessment of mCRC patients (either negative vs. both positive: HR = 0.02; p = 0.001), and Kaplan-Meier analysis demonstrated that mCRC patients with either negative TNF-α or ThP values prior to chemotherapy were less likely to experience VTE (13 %) than patients with abnormalities of both markers (67 %, p = 0.002).
  
  
  CONCLUSIONS
  These results suggest that the host inflammatory response to cancer cells and/or tumor-derived cytokines could be responsible for an impairment of the APC system and a switch toward a pro-thrombotic state, which might predispose to the occurrence of VTE in mCRC patients undergoing chemotherapy.
authors.affiliation: Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Via della Pisana 235, 00163, Rome, Italy. patrizia.ferroni@sanraffaele.it
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferroni
authors.forename: Silvia
authors.initials: S
authors.lastname: Riondino
authors.forename: Ilaria
authors.initials: I
authors.lastname: Portarena
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Formica
authors.forename: Francesca
authors.initials: F
authors.lastname: La Farina
authors.forename: Francesca
authors.initials: F
authors.lastname: Martini
authors.forename: Gioia
authors.initials: G
authors.lastname: Massimiani
authors.forename: Raffaele
authors.initials: R
authors.lastname: Palmirotta
authors.forename: Fiorella
authors.initials: F
authors.lastname: Guadagni
authors.forename: Mario
authors.initials: M
authors.lastname: Roselli
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood* / Q000150:complications*; D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D015179:Colorectal Neoplasms / Q000097:blood* / Q000150:complications* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D012044:Regression Analysis; D013917:Thrombin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D054556:Venous Thromboembolism / Q000097:blood / Q000150:complications
chemical_list: D014409:Tumor Necrosis Factor-alpha; D013917:Thrombin