Clinical analysis of preoperative deep vein thrombosis risk factors in patients with colorectal cancer: Retrospective observational study

Abstract Aim Deep vein thrombosis (DVT) is a major complication of cancer. The postoperative prevalence of DVT in colorectal cancer (CRC) surgery is high, but the preoperative prevalence and the risk factors have not been clarified in detail. The objective of this retrospective study was to investigate the preoperative prevalence and risk factors of DVT in patients admitted to hospital for CRC surgery. Methods From January 2013 to March 2017, 1006 patients admitted for CRC surgery were deemed eligible for this retrospective study. Diagnosis of preoperative DVT was confirmed by compression ultrasonography. Prevalence of silent DVT in lower limbs in patients before CRC surgery was assessed, and the risk factors for preoperative DVT were investigated regarding the correlation of DVT with the patient's background. Results Preoperative DVT and asymptomatic pulmonary thromboembolism were diagnosed in 136 (13.5%) and in 10 (1.0%) of 1006 patients overall, respectively. Multivariate analysis showed that increased age (≥75 years), female gender, and an elevated d‐dimer level (>1.0 μg/mL) were independent risk factors for preoperative DVT in this study. Notably, the prevalence of preoperative DVT exceeded 50% in patients with all three predictors. Conclusions A high prevalence (13.5%) of preoperative DVT was found in patients admitted to the hospital for CRC surgery. The present results suggest that instrumental screening should be encouraged, at least in subgroups at a higher risk of preoperative DVT.

A prospective observational study in 2373 patients undergoing general, urological, or gynecological surgery reported that 50 patients (2.1%) were judged as affected by clinically overt VTE, and 12 events occurred within 5 days of surgery. 4 Another report of the Japanese Society of Anesthesiologists in Japanese patients showed that postoperative VTE tended to occur on the first postoperative day in patients who had risk factors, such as malignant disease or obesity [5].
Fatal PE is known to primarily occur when getting out of bed for the first time after surgery. DVT causing such fatal PE may have already occurred before surgery, making postoperative anticoagulant therapy relatively ineffective in preventing such early fatal PE. Therefore, it is important to carry out preoperative screening for DVT.
There have been several reports of a high prevalence of DVT after abdominal cancer surgery in general. 6,7 Among patients with colorectal cancer, the estimated prevalence of DVT after surgery is 20%. 8 However, the preoperative prevalence and the risk factors have not been clarified in detail. Only a few studies have focused on patients with gastroenterological cancer, although it is the most common risk factor for PE. [9][10][11] To our knowledge, only one study with a small number of patients has been carried out in patients with colorectal cancer, 9 and the covariates used to identify the independent risk factors were limited. In addition, the detailed anatomical distribution of DVT has not been reported.
Recently, lower-extremity venous ultrasonography has been considered a useful method of diagnosing DVT because it is easily accessible, noninvasive, and has a high sensitivity (93%-96%) and specificity (98%-99%). [12][13][14] The aim of the present study was to clarify the prevalence, anatomical distribution, and the risk factors for DVT of the lower extremities in patients with colorectal cancer before surgery.

| Patients
The study protocol was approved by the Ethical Advisory Committee To diagnose preoperative staging, contrast-enhanced helical computed tomography (CT) was usually carried out if an iodine contrast agent was available. At the same time, we checked whether asymptomatic PE was present incidentally.

| d-Dimer assay
Blood samples for the d-dimer analysis were obtained preoperatively. The samples were analyzed by the Nanopia d-dimer assay (Sekisui Medical, Tokyo, Japan), which is the standard assay at Yokohama City University Medical Center. The Auto Dimer assay is a quantitative latex test for cross-linked fibrin degradation products.
All samples were handled according to the manufacturer's instructions. The samples were analyzed using an Automated Coagulation Analyzer CP3000 (Sekisui Medical). The technologists analyzing the samples were unaware of the CUS findings. Because the optimal cutoff value of d-dimer was unknown in preoperative DVT screening, the Yokohama City University Medical Center standard cut-off level of 1.0 μg/mL was used.

| Thromboprophylaxis
According to the Japanese Guidelines for Prevention of Venous Thromboembolism, 17 most patients with colorectal cancer are classified in the high-risk group for postoperative DVT. For high-risk patients, physical treatments, such as intermittent pneumatic compression (IPC) or anticoagulant therapy, are recommended in the guidelines. Therefore, for patients in whom preoperative DVT was not detected, graduated compression stockings and IPC or anticoagulant therapy were carried out at the surgeon's discretion from the morning of surgery until the patient was able to walk adequately.
Patients with distal DVT were generally given anticoagulant therapy using low-molecular-weight heparin (LMWH). For patients with proximal DVT, a temporary inferior vena cava filter (IVCF) was placed before surgery at the cardiologist's discretion.

| Diagnosis of postoperative PE
When patients complained of symptoms such as dyspnea postoperatively, contrast-enhanced helical CT was given to diagnose PE. Only those cases of PE that required some medical intervention (Common Terminology Criteria for Adverse Events grade 3 or higher 18 ) were counted. Patients with asymptomatic postoperative PE were excluded from this study.

| Statistical analyses
Continuous variables were presented as median (range) and compared using the Mann-Whitney U test, whereas categorical variables were expressed as the absolute and relative frequencies and compared using the chi-squared test.
Clinicopathological risk factors for preoperative DVT were primarily evaluated using univariate analyses. Variables that had relevant associations with preoperative DVT on these analyses (P < 0.05) were included in a multivariate model. A multivariate analysis was carried out using logistic regression analysis. Backward elimination was used to select variable factors. Statistical significance was defined as P < 0.05. Analyses were done using the software package SPSS 22 (SPSS Inc., Chicago, IL, USA).

| D ISCUSS I ON
We analyzed a total of 1006 patients who underwent elective colorectal resection. Preoperative DVT was diagnosed in 136 patients They carried out lower-extremity ultrasonography in patients with a positive d-dimer assay result. In the present study, the prevalence of DVT was higher than that in the study of Wada et al, possibly as a result of differences in the study design and in the characteristics of patients.
We showed that older age (≥75 years) was an independent risk factor for preoperative DVT. Several authors have reported that the prevalence of VTE is greater in older patients than in younger ones. 10,19,20 In Japan, Wakabayashi et al. analyzed 505 patients who underwent total hip arthroplasty and investigated the risk factors for preoperative VTE. One of the factors significantly related to preoperative VTE was increased age. 21 Furthermore, Tanizawa et al. 10 analyzed 1140 patients who underwent gastric cancer surgery and showed that age ≥80 years was an independent risk factor for preoperative DVT. Consistent with previous reports, in the present study, the DVT-positive patients were significantly older than the DVT-negative patients.
In the present study, we also showed that elevated d-dimer levels (>1.0 μg/mL) were an independent risk factor for preoperative DVT. d-Dimer is a degradation product of crosslinked fibrin that appears in the blood after a blood clot is degraded by fibrinolysis. 22 Elevated d-dimer levels in the blood predict increased secondary fibrinolytic activity and are a principal marker of hypercoagulation and thrombosis. 23 conditions that activate the coagulation system are present. 27,28 The d-dimer assay is a safe and useful tool with a high sensitivity (97%-100%) for excluding acute DVT and a high negative predictive value (96%-100%). 29,30 Therefore, our finding that elevated d-dimer levels (>1.0 μg/mL) were an independent risk factor for preoperative DVT was an expected result.
Lower-extremity venous ultrasonography has a high sensitivity (93%-96%) as well as high specificity (98%-99%) for the diagnosis of DVT. [12][13][14] However, ultrasonography in all preoperative patients as a screening tool is considered to represent overuse of this tool. 31,32 The appropriate use of the d-dimer assay can limit the overuse and added cost of ultrasonography without any negative impact. 31  In conclusion, a high prevalence (13.5%) of preoperative DVT was found in patients admitted to hospital for colorectal cancer surgery.
The present results suggest that instrumental screening should be encouraged at least in subgroups at an increased risk of preoperative DVT.