The prognosis of pancreatic cancer patients stays dismal regardless of the rapid progression of surgical techniques and adjuvant therapies. Increasing evidence suggests that not only the intrinsic histopathologic features of the tumor but also the host-related factors are associated with long-term disease outcomes [17-19]. According to new clinical guidelines, considering the special biological behavior of pancreatic cancer, plasma biomarkers and conditional host-related factors are playing more important roles in the decision-making process . In malignancy, together with the host cell inflammatory, cancer cell-specific prothrombotic properties induce the hypercoagulation state . As a consequence, a subclinical activation of blood coagulation is prevalent in cancer patients, as demonstrated by abnormalities of coagulation biomarkers. As a stable fibrin degradation product, plasma D-dimer is a marker of hypercoagulation and is usually used for the assessment of suspected thrombosis or disseminated intravascular coagulation (DIC) in clinical practice. In the present study, preoperative plasma D-dimer was elevated in 30.9% of resectable PDAC patients, and the elevated levels were found to be significantly related to poor prognosis in patients following radical pancreatic surgery.
The D-dimer showed a reliable prognostic value in pancreatic cancer, regardless of age, NLR levels, obstructive jaundice, CA19-9 levels, pathologic staging, poor differentiation and adjuvant therapy. However, D-dimer is not an accurate prognostic indicator for patients with R1 resection. Several possible reasons might account for it. First, patients with R1 resection are more likely to develop local recurrence when compared to patients with R0 resection, which would negative affect the prognosis independently . Second, there are only 13.18% of patient with R1 resection, and no statistically significant association was found between D-dimer and R1 resection (p=0.383). More patients are needed to improve the statistical power.
Previous studies also demonstrated the utility of D-dimer as a prognostic marker in pancreatic cancer. It has been reported that patients with high levels of preoperative plasma D-dimer are at high risk for locally advanced disease or occult hepatic metastases . Subsequent studies have also reported that plasma D-dimer serves as a negative prognostic factor in pancreatic cancer, but the clinical significance remains controversial because of the small number of patients analyzed and the limited perioperative factors included in these studies [13, 22-24]. In addition, Cao et al.  examined the prognostic value of preoperative plasma D-dimer in operable pancreatic cancer patients, but the results in this study were not adjusted by other risk factors, and the scale of the study was limited. In a Japanese cohort, Watanabe et al.  found that the D-dimer was the only independent prognostic factor in resectable pancreatic cancer. Furthermore, Durczynski et al  found that the D-dimer levels in portal blood was related with poorer overall survival in pancreatic cancer.
However, the mechanism underlying the association between the plasm D-dimer and the prognosis of pancreatic cancer remains unclear. Recent studies have demonstrated the bidirectional association between coagulation and cancer, and cancer-related hypercoagulation is reported to be closely related to cancer progression [8, 27]. Multiple and interdependent processes between the tumor and the patient induce a hypercoagulable state, including tumor-procoagulant activity, host inflammatory responses, and cancer treatments . Tissue factor (TF) is the main initiator of the coagulation cascade, which is highly expressed due to cancer . In addition, in malignancy, TF is also overexpressed by host normal blood cells triggered by cancer-derived inflammatory stimuli . Our studies also found that D-dimer correlated with NLR, an inflammatory indicator, suggesting the relationship between host inflammatory responses and cancer-related hypercoagulation.
On the other hand, some evidence suggested that hypercoagulable state can contribute to cancer progression in turn . TF expression in cancer is related with a variety of pathologic processes, such as thrombosis, metastasis, tumor angiogenesis, and tumor growth . The mesh of fibrin, induced by TF surface expression, was found to envelop cancer cells preventing them from being recognized by NK cells. Furthermore, the formation of platelet-fibrin rich microemboli could help tumor cells escape NK-mediated immune recognition . In vitro experiments, inhibition of TF, FXa or thrombin has been shown to prevent the formation of metastasis in melanoma tumors . Besides that, a growing body of evidence has suggested that anticoagulants have antitumor effects and can increase the survival time in solid tumor patients [32-35]. Klerk et al. reported that combining low-molecular-weight heparin (LMWH) with other adjuvant therapies improved prognosis in patients with advanced malignancy . In advanced pancreatic cancer patients, the addition of LMWH to gemcitabine-based chemotherapy significantly improved the response and survival . These findings regarding coagulation and cancer supported a pathological role for procoagulant activity in cancer. However, further studies associated with the antitumor effects of anticoagulants are needed in the operable pancreatic cancer patients, especially in patients with elevated D-dimer levels.
Some limitations in this study also warrant emphasis. First, because this was a retrospective study, the use of postoperative prophylactic anticoagulant therapy was not available in the database. Second, patients with neoadjuvant therapy or preoperative anticoagulation treatment were excluded, which may limit the generalizability of this study. Third, some patients in this study failed to receive adjuvant treatment due to their age or postoperative complications.