Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer

Patrizia Ferroni, Silvia Riondino, Ilaria Portarena, Vincenzo Formica, Francesca La Farina, Francesca Martini, Gioia Massimiani, Raffaele Palmirotta, Fiorella Guadagni, Mario Roselli

Research output: Contribution to journalArticle

Abstract

Purpose: 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.

Original languageEnglish
Pages (from-to)1561-1567
Number of pages7
JournalInternational Journal of Colorectal Disease
Volume27
Issue number12
DOIs
Publication statusPublished - 2012

Fingerprint

Activated Protein C Resistance
Colorectal Neoplasms
Tumor Necrosis Factor-alpha
Venous Thromboembolism
Protein C
Drug Therapy
Bayes Theorem
Kaplan-Meier Estimate
Survival Analysis

Keywords

  • Activated protein C
  • Metastatic colorectal cancer
  • Tumor necrosis factor alpha
  • Venous thromboembolism

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer. / Ferroni, Patrizia; Riondino, Silvia; Portarena, Ilaria; Formica, Vincenzo; La Farina, Francesca; Martini, Francesca; Massimiani, Gioia; Palmirotta, Raffaele; Guadagni, Fiorella; Roselli, Mario.

In: International Journal of Colorectal Disease, Vol. 27, No. 12, 2012, p. 1561-1567.

Research output: Contribution to journalArticle

Ferroni, Patrizia ; Riondino, Silvia ; Portarena, Ilaria ; Formica, Vincenzo ; La Farina, Francesca ; Martini, Francesca ; Massimiani, Gioia ; Palmirotta, Raffaele ; Guadagni, Fiorella ; Roselli, Mario. / Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer. In: International Journal of Colorectal Disease. 2012 ; Vol. 27, No. 12. pp. 1561-1567.
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abstract = "Purpose: 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.",
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T1 - Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer

AU - Ferroni, Patrizia

AU - Riondino, Silvia

AU - Portarena, Ilaria

AU - Formica, Vincenzo

AU - La Farina, Francesca

AU - Martini, Francesca

AU - Massimiani, Gioia

AU - Palmirotta, Raffaele

AU - Guadagni, Fiorella

AU - Roselli, Mario

PY - 2012

Y1 - 2012

N2 - Purpose: 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.

AB - Purpose: 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.

KW - Activated protein C

KW - Metastatic colorectal cancer

KW - Tumor necrosis factor alpha

KW - Venous thromboembolism

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