The impact of pharmacological thromboprophylaxis and disease-stage on postoperative bleeding following colorectal cancer surgery

Since venous thromboembolism (VTE) can result in fatal outcomes due to pulmonary thromboembolism, it is important to prevent VTE for patients undergoing abdominal surgery [1]. Recent guidelines recommended using physiological therapies such as intermittent pneumatic compression (IPC) and elastic stockings on the lower legs or pharmacological thromboprophylaxis according to patient risk level following abdominal major surgery [2]. There is a growing body of evidence supporting a symbiotic relationship between the clotting system and the biology of cancer. Colorectal cancer (CRC) leads to increased activation of the clotting system which manifests VTE; therefore, pharmacological thromboprophylaxis after CRC surgery is internationally recommended for VTE prevention [3, 4]. Two anticoagulants, fondaparinux (a synthetic Xa inhibitor) [5] and enoxaparin (a low molecular weight heparin) [6‐9], are available for use in the clinical setting for such patients in Japan. A recent systematic review demonstrated that there was no difference between perioperative thromboprophylaxis with enoxaparin compared with fondaparinux in their effects on mortality, thromboembolic outcomes, major bleeding, or minor bleeding in people with cancer [10]; however, the risk factors associated with postoperative bleeding in patients with pharmacological thromboprophylaxis following CRC surgery remain unknown. Therefore, we retrospectively evaluated the risk factors of postoperative bleeding after elective surgery for patients with primary CRC receiving perioperative pharmacological thromboprophylaxis comparing perioperative D-dimer levels.

The importance of VTE prevention is widely recognized in clinical medicine, since VTE can result in severe outcomes such as pulmonary embolism. In addition, the incidence of postoperative VTE following abdominal surgery in Japan has been increasing in recent years due to the change in lifestyle to a more sedentary Western lifestyle and improvements in the diagnostic accuracy of VTE [22, 23]. Both fondaparinux and enoxaparin demonstrate efficacy and safety for the prevention of VTE after abdominal surgery for malignancies [24]. A recent systematic review concluded that the risk of VTE in Asian general surgery patients is likely to be low [25]. These studies included patients with and without in-hospital anticoagulant administration. Kim et al. reported that the incidence of VTE was 3.7% (31/840 patients) in patients undergoing colorectal cancer surgery without perioperative anticoagulant prophylaxis [26]. The incidence of symptomatic VTE in patients with enoxaparin prophylaxis reportedly ranged from 0.43 to 1.4% [13, 27, 28] and 0 to 23.3% in patients with fondaparinux prophylaxis [16, 21, 29, 30] following abdominal surgery. One case (0.46%) of VTE was observed during our observational period. Thus, our findings were almost similar to the incidences of symptomatic VTE found in previous studies. However, the number of patients enrolled in this study seemed to be too small to compare the efficacy of the two anticoagulants prophylaxis in this study.

The latest meta-analysis demonstrated that fondaparinux was significantly more effective in preventing VTE after total hip replacement therapy when compared to enoxaparin, although this effectiveness was accompanied with an increased risk of major postoperative bleeding [31]. Only a few studies have compared the efficacy and safety between fondaparinux and enoxaparin in the same study cohorts following abdominal surgery. In those studies, postoperative bleeding events were reported as 21.2 % in the enoxaparin group and 37.6% in the fondaparinux group after major hepatobiliary-pancreatic surgery in Japanese patients [32]. Total postoperative bleeding was also observed at 11.5 % in the enoxaparin group and 22.2% in the fondaparinux group among the adult cancer population [19]. The postoperative transfusions for major postoperative bleeding increased by 0.9% in the fondaparinux group compared to 0.2% in the enoxaparin group following thoracic surgery [27]. According to previous comparison studies, postoperative bleeding after surgery was likely to be more frequent in the fondaparinux group than in the enoxaparin group. The incidence of postoperative bleeding following colorectal surgery in previous studies ranged from 4.6 to 11.5% in patients with enoxaparin prophylaxis [17‐20, 33] and 9.4 to 22.2% in patients with fondaparinux prophylaxis [16, 19, 21]. Our findings of major and minor bleeding in fondaparinux (10.4%) and enoxaparin (2.6%) prophylaxis are comparable to results from previous studies.

A recent study demonstrated the risk factors of postoperative bleeding in CRC patients administrated fondaparinux as thromboprophylaxis after surgery. They have shown that, in multivariate analysis, male gender, intraoperative blood loss of less than 25 mL, and a preoperative platelet count below 15 × 10⁴/μL were found to be independent risk factors for postoperative bleeding in the laparoscopic surgery group. Only the preoperative platelet count was an independent risk factor in the open surgery group [34]. We could not evaluate risk factors of postoperative bleeding differently between open and laparoscopic surgery due to the small number of patients in the present study. Moreover, they interestingly showed intraoperative blood loss as a negative impact for postoperative bleeding complication; however, we could not also find that intraoperative blood loss was significantly associated with negative risk for postoperative bleeding in univariate analysis.

The abnormalities of coagulation and fibrinolysis are frequently observed in cancer patients. A recent meta-analysis suggested that plasma D-dimer and fibrinogen levels were correlated with tumor stage and prognosis in digestive cancer patients [35‐37]. High pretreatment plasma D-dimer was reported to predict poor survival of colorectal cancer [38, 39]. We also observed the elevation in preoperative and postoperative D-dimer levels as the increase in disease stage in our patients. Previous clinical studies have suggested that preoperative D-dimer may also predict the development of postoperative VTE [40, 41]. Therefore, advanced CRC patients with elevated levels of D-dimer have a high risk of VTE following colorectal surgery. On the contrary, we did not observe such hypercoagulation status in early disease-stage CRC patients in their clinical course. Our findings revealed that early disease-stage CRC was one of the risk factors for postoperative bleeding by univariate analysis. The hypercoagulation status accompanied with progression of CRC appeared to be related to postoperative bleeding following CRC surgery in patients with pharmacological thromboprophylaxis.

We acknowledge several limitations of the current study that was a retrospective, non-randomized, and small-number cohort study. First, generally, the number of events per variable (EPV) analyzed in logistic regression analysis is recommended as 10 or greater in the previous studies [14, 15]. The statistical power appeared to be relatively weak, since EPV in the present study (11 events per two variables) was lower than 10 in multiple logistic regression analysis. However, recent research has reported the possibility of relaxing the rule of 10 EPV in logistic and Cox regression analysis. Moreover, power calculation (1-β err prob) of multiple regression in this study was 0.8439 (effect size f2 0.05, α err prob 0.05, sample size 218, number of predictors 2), which was analyzed by G3*Power 3.1 [42]. Therefore, we believe that logistic regression analysis with 5-9 EPV in the present study was acceptable. Second, we found the significant difference in the incidence of postoperative bleeding between the two anticoagulants. We adapted enoxaparin as a pharmacological thromboprophylaxis for high-risk patients following CRC surgery in 2010. We switched enoxaparin to fondaparinux from June 2012 to April 2013, because enoxaparin must be administrated twice injection daily in contrast to once injection daily of fondaparinux in Japan. However, we often observed minor bleeding complications with the administration of fondaparinux. Therefore, we reinstated enoxaparin prophylaxis and found that the incidence of minor hemorrhagic complications with the enoxaparin was similar to the first term of enoxaparin administration. We could not continuously use fondaparinux for patients ethically after our finding the significant risk of bleeding events in patients administrated fondaparinux until the achievement in enough statistical power between two drugs. Although fondaparinux prophylaxis was identified as independent risk factors for postoperative bleeding in our study, additional prospective studies are needed to clarify the significant and true risk factors for bleeding complications between the two drugs.

Fondaparinux administration and early disease-stage CRC appeared to be risk factors for postoperative bleeding in patients with pharmacological thromboprophylaxis undergoing surgical treatment for CRC. The coagulation status might be related to the occurrence of postoperative bleeding in patients with early disease-stage CRC according to perioperative D-dimer levels.