ORIGINAL ARTICLE
Clinical and Prognostic Significance of Coagulation Assays in Pancreatic Cancer Patients With Absence of Venous Thromboembolism Wei Sun, MSc,* He Ren, PhD,* Chun-Tao Gao, PhD,* Wei-Dong Ma, PhD,* Lin Luo, MSc,w Yan Liu, MSc,w Peng Jin, MSc,* and Ji-Hui Hao, MD, PhD*
Objectives: Activation of coagulation and fibrinolysis is frequently observed in patients with cancer, even with absence of thrombosis. Furthermore, plasma coagulation parameters were associated with tumor progression, metastasis, and prognosis. Few studies have investigated these associations in pancreatic cancer (PA). This study aimed to investigate the clinical and prognostic significance of various plasma coagulation tests in PA patients with absence of venous thromboembolism (VTE). Materials and Methods: A total of 139 PA patients with the absence of VTE were included in the analysis. Patients were followed up for at least 12 months until death. Pretreatment coagulation parameters including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (F), antithrombin-III (AT-III), protein C (PC), factor-VIII (F-VIII), and D-dimer (DD) were evaluated. A total of 40 age-matched and sex-matched healthy individuals without coagulation disorder were enrolled as the control group. Results: Patients were inclined to have higher levels of PT, INR, APTT, F, F-VIII, and DD and lower levels of AT-III and PC than the control group (P < 0.01 for all, except P = 0.022 for INR and P = 0.015 for AT-III). Patients with advanced tumor stages were likely to have higher median DD levels and lower AT-III levels than the control group (P = 0.005 and P < 0.001, respectively). DD levels were higher in patients with advanced pathology grade (P < 0.001). Plasma DD levels (hazards ratio = 1.71; 95% confidence interval, 1.07-2.73; P = 0.025) were identified as the significantly independent prognostic predictors. Conclusions: PA patients are susceptible to activation of hemostasis system. Pretreatment plasma DD level was a potential predictor of prognosis in PA patients without VTE. Key Words: pancreatic cancer, venous thromboembolism, coagulation, D-dimer, prognosis
(Am J Clin Oncol 2015;38:550–556)
From the *Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy; and wTianjin Heping Obstetric and Gynecology Hospital, Tianjin, China. Supported by National Natural Science Foundation of China (Grant No. 81302082, 81272685, 31301151, 81172355); Doctoral Fund of Ministry of Education of China (Grant No. 20101202110002; Key program of Natural Science Foundation of Tianjin (Grant No.09JCZDJC17100, 11JCZDJC18400); major anticancer Technologies R & D Program of Tianjin (Grant No. 12ZCDZSY16700); project of Tianjin Educational Commission (Grant No. 20100123). The authors declare no conflicts of interest. Reprints: Ji-Hui Hao, MD, PhD, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. E-mail: [email protected]. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/3806-0550 DOI: 10.1097/01.coc.0000436088.69084.22
T
he association between cancer and the hemostatic system has been well known since Trousseau’s study in the 19th century, and almost all types of cancer are associated with activation of the hemostatic system.1–4 Importantly, rather than being merely a trigger of increased thromboembolic events, cancer-induced hemostatic activity has been shown to promote tumor progression and dissemination, inflammatory cell response regulation, tumor angiogenesis, and metastasis.5,6 Thrombin leads to the formation of fibrin, which accumulates in the cancer tissue and acts as a protective barrier against inflammatory cells.7 Plasminogen activators produce plasmin, which takes part in tumor invasion and in the penetration of tumor cells into the circulatory system.8 Thus, clinical consequences of hypercoagulation can be serious with a negative impact on the course of disease, increasing morbidity and mortality. Actually, abnormal coagulation parameters that represent active coagulation and fibrinolytic systems such as international normalized ratio (INR), fibrinogen (F), protein C (PC), and d-dimer (DD) have been associated with tumor progression and decreased overall survival (OS).9–11 Pancreatic cancer (PA) is one of the most malignant tumors with a 5-year survival of
Clinical and Prognostic Significance of Coagulation Assays in Pancreatic Cancer Patients With Absence of Venous Thromboembolism Wei Sun, MSc,* He Ren, PhD,* Chun-Tao Gao, PhD,* Wei-Dong Ma, PhD,* Lin Luo, MSc,w Yan Liu, MSc,w Peng Jin, MSc,* and Ji-Hui Hao, MD, PhD*
Objectives: Activation of coagulation and fibrinolysis is frequently observed in patients with cancer, even with absence of thrombosis. Furthermore, plasma coagulation parameters were associated with tumor progression, metastasis, and prognosis. Few studies have investigated these associations in pancreatic cancer (PA). This study aimed to investigate the clinical and prognostic significance of various plasma coagulation tests in PA patients with absence of venous thromboembolism (VTE). Materials and Methods: A total of 139 PA patients with the absence of VTE were included in the analysis. Patients were followed up for at least 12 months until death. Pretreatment coagulation parameters including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (F), antithrombin-III (AT-III), protein C (PC), factor-VIII (F-VIII), and D-dimer (DD) were evaluated. A total of 40 age-matched and sex-matched healthy individuals without coagulation disorder were enrolled as the control group. Results: Patients were inclined to have higher levels of PT, INR, APTT, F, F-VIII, and DD and lower levels of AT-III and PC than the control group (P < 0.01 for all, except P = 0.022 for INR and P = 0.015 for AT-III). Patients with advanced tumor stages were likely to have higher median DD levels and lower AT-III levels than the control group (P = 0.005 and P < 0.001, respectively). DD levels were higher in patients with advanced pathology grade (P < 0.001). Plasma DD levels (hazards ratio = 1.71; 95% confidence interval, 1.07-2.73; P = 0.025) were identified as the significantly independent prognostic predictors. Conclusions: PA patients are susceptible to activation of hemostasis system. Pretreatment plasma DD level was a potential predictor of prognosis in PA patients without VTE. Key Words: pancreatic cancer, venous thromboembolism, coagulation, D-dimer, prognosis
(Am J Clin Oncol 2015;38:550–556)
From the *Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy; and wTianjin Heping Obstetric and Gynecology Hospital, Tianjin, China. Supported by National Natural Science Foundation of China (Grant No. 81302082, 81272685, 31301151, 81172355); Doctoral Fund of Ministry of Education of China (Grant No. 20101202110002; Key program of Natural Science Foundation of Tianjin (Grant No.09JCZDJC17100, 11JCZDJC18400); major anticancer Technologies R & D Program of Tianjin (Grant No. 12ZCDZSY16700); project of Tianjin Educational Commission (Grant No. 20100123). The authors declare no conflicts of interest. Reprints: Ji-Hui Hao, MD, PhD, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. E-mail: [email protected]. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/3806-0550 DOI: 10.1097/01.coc.0000436088.69084.22
T
he association between cancer and the hemostatic system has been well known since Trousseau’s study in the 19th century, and almost all types of cancer are associated with activation of the hemostatic system.1–4 Importantly, rather than being merely a trigger of increased thromboembolic events, cancer-induced hemostatic activity has been shown to promote tumor progression and dissemination, inflammatory cell response regulation, tumor angiogenesis, and metastasis.5,6 Thrombin leads to the formation of fibrin, which accumulates in the cancer tissue and acts as a protective barrier against inflammatory cells.7 Plasminogen activators produce plasmin, which takes part in tumor invasion and in the penetration of tumor cells into the circulatory system.8 Thus, clinical consequences of hypercoagulation can be serious with a negative impact on the course of disease, increasing morbidity and mortality. Actually, abnormal coagulation parameters that represent active coagulation and fibrinolytic systems such as international normalized ratio (INR), fibrinogen (F), protein C (PC), and d-dimer (DD) have been associated with tumor progression and decreased overall survival (OS).9–11 Pancreatic cancer (PA) is one of the most malignant tumors with a 5-year survival of
