Abstract
Background
The optimal duration for thromboprophylaxis after colorectal cancer surgery remains uncertain. We sought to compare the effectiveness and safety of long-term thromboprophylaxis to that of short-term thromboprophylaxis in preventing venous thromboembolism (VTE) after colorectal cancer surgery.
Methods
In our retrospective study, patients undergoing colorectal cancer surgery were divided into the short-term (< 7 days) and long-term (≥ 7 days) thromboprophylaxis groups based on the low molecular weight heparin prophylaxis regimen. Propensity score matching was performed for both groups, and comparative analysis of the incidence of asymptomatic or symptomatic VTE and bleeding complications was conducted. Multivariable logistic regression analysis was performed in the unmatched cohort to explore the association of potential risk factors with postoperative VTE.
Results
A total of 140 patients undergoing colorectal cancer surgery were included. After matching, there were 57 patients in each group. VTE occurred in 18 patients (15.8%) within 6 months after surgery, with 12 cases (21.1%) in the short-term thromboprophylaxis group and six cases (10.5%) in the long-term thromboprophylaxis group (P = 0.123). There were no significant differences in the incidence of bleeding complications between the two groups. Multivariable logistic regression analysis indicated that long-term thromboprophylaxis can reduce the risk of postoperative VTE (odds ratio 0.34, 95% confidence interval 0.12–0.95; P = 0.039).
Conclusions
Long-term thromboprophylaxis (≥ 7 days) demonstrated comparable effectiveness and safety to shorter regimens (< 7 days) in preventing postoperative VTE in patients with colorectal cancer, while suggesting potential sustained protective benefits during extended follow-up periods exceeding 6 months. Whether VTE prophylaxis should be extended to 28 days post-surgery requires further research.
Key Points
| For patients undergoing colorectal cancer surgery who are at high risk for venous thromboembolism (VTE), the choice of the duration of postoperative pharmacological thromboprophylaxis is crucial for preventing VTE while avoiding bleeding. Long-term thromboprophylaxis (≥ 7 days) demonstrated comparable effectiveness and safety to shorter regimens (< 7 days) in preventing postoperative VTE. |
| Considering the adherence to the continued use of low molecular weight heparin (LMWH) after discharge, as well as the length of postoperative hospital stay and treatment costs, using LMWH for short-term thromboprophylaxis during hospitalization may also prevent the development of postoperative VTE in clinical practice. |
Introduction
Venous thromboembolism (VTE) is one of the common and life-threatening complications in cancer patients [1], with a ninefold higher incidence compared to the general population [2]. Surgical interventions, particularly in colorectal cancer, further elevate VTE risk (8.1–24.3%) [3–6]. Thromboprophylaxis can significantly reduce the incidence of postoperative VTE [7].
The European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN) have recommended perioperative pharmacological thromboprophylaxis for a minimum of 7–10 days in patients undergoing major cancer surgeries [8–10]. Specifically, extended prophylaxis with low molecular weight heparin (LMWH) for 4 weeks is strongly advised for patients undergoing radical abdominal or pelvic cancer resections, given their elevated thrombotic risk profile [8–10]. Similarly, the American Society of Colon and Rectal Surgery (ASCRS) guidelines also recommend considering extended-duration pharmacological thromboprophylaxis for patients undergoing colorectal cancer resection [11]. Several randomized controlled trials showed that compared to a 1-week prevention regimen, extended thromboprophylaxis to 4 weeks can reduce the occurrence of postoperative VTE in colorectal cancer patients without increasing the risk of bleeding [12, 13].
Despite established guideline recommendations, significant gaps persist in implementing adequate thromboprophylaxis following colorectal cancer resections in real-world practice. A multicenter prospective study demonstrated that among patients at high risk of VTE, only 7.0% maintained prophylaxis beyond 7 days, with merely 0.5% completing the full 4-week course [14]. The optimal duration for thromboprophylaxis after colorectal cancer surgery has not yet been clarified. Our study aimed to explore whether long-term thromboprophylaxis can effectively reduce the incidence of VTE without increasing the risk of bleeding compared to short-term thromboprophylaxis.
Methods
Study Design and Population
Our study was a retrospective observational study. Data from patients who underwent colorectal cancer surgery from January 2019 to December 2023 were collected to evaluate the effectiveness and safety of different thromboprophylaxis regimens. Patients were eligible for inclusion in the study if they underwent radical surgery for colorectal cancer and received postoperative thromboprophylaxis with LMWH in addition to mechanical prophylaxis. Patients with diagnosis of VTE within 6 months prior to surgery, long-term use of anticoagulants or antiplatelet agents prior to surgery, severe liver or kidney dysfunction, no preoperative or postoperative lower extremity venous ultrasound, and no pharmacological prophylaxis (mechanical only or no prophylaxis) were excluded from the study cohort.
This study was approved by the ethics committee on 17 July 2023 (number: 2023-P2-177-01). Informed consent was waived because of the retrospective design of the study.
Patients receiving LMWH for a duration of ≥ 7 days were classified into the long-term thromboprophylaxis group, while those receiving it for < 7 days were classified into the short-term thromboprophylaxis group. All patients started using prophylactic dosages of LMWH during the perioperative period (enoxaparin 2000–4000 IU once daily [qd]; nadroparin 2850~4100 IU qd; dalteparin 2500–5000 IU qd).
Demographic and clinical characteristics of the patients, including body mass index (BMI), disease history, surgical-related information, neoadjuvant therapy, and site and stage of cancer, were included in the analysis. Additionally, individual risk factors listed in the Caprini score (age, BMI, coronary heart disease, chronic obstructive pulmonary disease [COPD], varicose veins of lower extremity, VTE history, and cerebral infarction) were collected as covariates for propensity score matching [15].
Study Outcomes
The primary effectiveness outcome was image-confirmed asymptomatic or symptomatic VTE (including proximal deep vein thrombosis [DVT], distal DVT, and acute symptomatic pulmonary embolism [PE]) occurring within 6 months after the operation. Proximal DVT was defined as thrombosis in the popliteal, femoral, or iliac veins, while distal DVT was confined to the calf veins (peroneal, posterior tibial, anterior tibial, or muscular veins). The diagnosis of DVT was confirmed by color ultrasound of lower extremity veins, with endovascular thrombosis. The diagnosis of PE was confirmed incidentally by computed tomography pulmonary angiography (CTPA) on follow-up, with filling defect of pulmonary artery and its branches. The primary safety outcome was bleeding complications, including major bleeding and clinically relevant non-major bleeding, defined according to the criteria of the International Society of Thrombosis and Haemostasis [16]. Secondary outcomes were the changes in laboratory indicators before and after medication, including D-dimer, fibrinogen, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL).
Statistical Analysis
Statistical analyses were performed using SPSS software, version 27.0 (IBM Corp, Armonk, NY, USA) and R statistical software, version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were presented as means ± standard deviation (SD) or medians with interquartile range (IQR), and categorical variables were reported as numbers and percentages. The inter-group comparison analysis was performed using the χ2 test or Fisher’s exact test for categorical variables, one-way analysis of variance (ANOVA) or one-way analysis of covariance (ANCOVA) for continuous variables with normal distribution, and Mann-Whitney U test for continuous variables with non-normal distribution.
Propensity score matching between the short-term thromboprophylaxis group and the long-term thromboprophylaxis group was performed using a logistic regression propensity score. Nearest neighbor matching was employed for one-to-one matching without replacement, with a caliper value of 0.2 [17]. Matching variables included individual risk factors listed in the Caprini score. When assessing the balance between the groups, a standardized mean difference (SMD) < 10% indicated good balance. To account for potential confounding effects of surgical factors (colectomy/rectal resection), risk-adjusted multivariable logistic regression was used to estimate the association between prophylaxis duration and postoperative VTE events.
In the unmatched cohort, univariate and multivariable logistic regression analyses were performed to evaluate the association of potential risk factors with postoperative VTE. Cumulative incidence curves of postoperative VTE between the short-term thromboprophylaxis group and the long-term thromboprophylaxis group were drawn and compared using the log-rank test. P values of < 0.05 were considered statistically significant.
Results
From January 2019 through December 2023, a total of 140 patients who underwent colorectal cancer surgery and received LMWH for thromboprophylaxis were included in the analysis (Fig. 1). Among them, 83 were in the short-term thromboprophylaxis group and 57 in the long-term thromboprophylaxis group. The baseline demographic and clinical characteristics of the patients are shown in Table 1. There were no significant differences in age, BMI, disease history, surgical information, and site and stage of cancer between the two groups. In the long-term thromboprophylaxis group, 44 patients (77.2%) were male, which was higher than that in the short-term thromboprophylaxis group (P = 0.009). Additionally, there were more patients with coronary heart disease in the long-term thromboprophylaxis group (38.6% vs 18.1%, P = 0.012).
Fig. 1.
Flow chart for patient inclusion/exclusion. LE lower extremity, VTE venous thromboembolism
Table 1.
Demographic and clinical characteristics of the patients at baseline
| Characteristics | All (n = 140) | Short-term thromboprophylaxis (n = 83) | Long-term thromboprophylaxis (n = 57) | P value |
|---|---|---|---|---|
| Age (years), median (IQR) | 68 (59–76) | 67 (59–74) | 69 (62–77) | 0.204 |
| Gender, n (%) | 0.009* | |||
| Male | 89 (63.6) | 45 (54.2) | 44 (77.2) | |
| Female | 51 (36.4) | 38 (45.8) | 13 (22.8) | |
| BMI (kg/m2), median (IQR) | 24.22 (21.73–26.42) | 24.03 (21.79–26.02) | 24.22 (20.31–26.56) | 0.847 |
| Smoking, n (%) | 36 (25.7) | 18 (21.7) | 18 (31.6) | 0.263 |
| Alcohol consumption, n (%) | 27 (19.3) | 14 (16.9) | 13 (22.8) | 0.511 |
| Disease history, n (%) | ||||
| Hypertension | 72 (51.4) | 40 (48.2) | 32 (56.1) | 0.452 |
| Diabetes | 39 (27.9) | 23 (27.7) | 16 (28.1) | 1.000 |
| Coronary heart disease | 37 (26.4) | 15 (18.1) | 22 (38.6) | 0.012* |
| Hyperlipidemia | 27 (19.3) | 15 (18.1) | 12 (21.1) | 0.825 |
| COPD | 3 (2.1) | 2 (2.4) | 1 (1.8) | 1.000 |
| Hepatic insufficiency | 13 (9.3) | 10 (12.0) | 3 (5.3) | 0.288 |
| Renal insufficiency | 9 (6.4) | 5 (6.0) | 4 (7.0) | 1.000 |
| Varicose veins of lower extremity | 2 (1.4) | 2 (2.4) | 0 (0.0) | 0.649 |
| VTE history | 3 (2.1) | 2 (2.4) | 1 (1.8) | 1.000 |
| Cerebral infarction | 16 (11.4) | 8 (9.6) | 8 (14.0) | 0.594 |
| Peripheral vascular disease | 15 (10.7) | 6 (7.2) | 9 (15.8) | 0.183 |
| Preoperative bowel obstruction, n (%) | 25 (17.9) | 15 (18.1) | 10 (17.5) | 1.000 |
| Preoperative bloody stool/tarry stool, n (%) | 60 (42.9) | 37 (44.6) | 23 (40.4) | 0.747 |
| Transfusion, n (%) | 5 (3.6) | 3 (3.6) | 2 (3.5) | 1.000 |
| Intraoperative bleeding (mL), median (IQR) | 50 (50–100) | 50 (50–50) | 50 (50–100) | 0.081 |
| Operation time (min), median (IQR) | 182 (150–245) | 185 (146–232) | 180 (150–255) | 0.497 |
| Anesthesia time (min), median (IQR) | 250 (200–300) | 250(202–298) | 255 (200–305) | 0.703 |
| Neoadjuvant therapy, n (%) | 31 (22.1) | 22 (26.5) | 9 (15.8) | 0.196 |
| Site of cancer, n (%) | 0.395 | |||
| Sigmoid colon/rectum | 111 (79.3) | 64 (77.1) | 47 (82.5) | |
| Right colon | 15 (10.7) | 9 (10.8) | 6 (10.5) | |
| Transverse colon | 6 (4.3) | 3 (3.6) | 3 (5.3) | |
| Left colon | 8 (5.7) | 7 (8.4) | 1 (1.8) | |
| Stage of cancer (TNM), n (%) | 0.391 | |||
| Stage 0 | 8 (5.7) | 6 (7.2) | 2 (3.5) | |
| Stage I | 20 (14.3) | 12 (14.5) | 8 (14.0) | |
| Stage II | 52 (37.1) | 26 (31.3) | 26 (45.6) | |
| Stage III | 54 (38.6) | 36 (43.4) | 18 (31.6) | |
| Stage IV | 6 (4.3) | 3 (3.6) | 3 (5.3) |
BMI body mass index, COPD chronic obstructive pulmonary disease, IQR interquartile range, VTE venous thromboembolism, TNM tumor node metastasis
*P < 0.05
After propensity score matching, the matched variables between the two groups (n = 57 each) were well balanced, with SMD < 10%, except for age, coronary heart disease, and COPD (Table 2). The median duration of LMWH prophylaxis was 4 days (IQR 3–5 days) in the short-term thromboprophylaxis group, and 10 days (IQR 8–13 days) in the long-term thromboprophylaxis group. In the matched cohort, 102 patients (89.5%) received 4100 IU of nadroparin, ten patients (8.8%) received 4000 IU of enoxaparin, and two patients (1.8%) received 5000 IU of dalteparin, with all medications administered once daily.
Table 2.
Summary of individual risk factors in the Caprini score before and after propensity score matching
| Variables | Unmatched | SMD | Matched | SMD | ||
|---|---|---|---|---|---|---|
| Short-term thromboprophylaxis (n = 83) | Long-term thromboprophylaxis (n = 57) | Short-term thromboprophylaxis (n = 57) | Long-term thromboprophylaxis (n = 57) | |||
| Age (years), n (%) | 0.315 | 0.198 | ||||
| ≤ 40 | 1 (1.2) | 0 (0.0) | 1 (1.8) | 0 (0.0) | ||
| 41–60 | 28 (33.7) | 13 (22.8) | 13 (22.8) | 13 (22.8) | ||
| 61–74 | 35 (42.2) | 26 (45.6) | 24 (42.1) | 26 (45.6) | ||
| ≥ 75 | 19 (22.9) | 18 (31.6) | 19 (33.3) | 18 (31.6) | ||
| BMI (kg/m2), mean (SD) | 24.15 (3.29) | 23.82 (4.27) | 0.088 | 23.57 (3.33) | 23.82 (4.27) | 0.063 |
| Coronary heart disease, n (%) | 15 (18.1) | 22 (38.6) | 0.468 | 15 (26.3) | 22 (38.6) | 0.265 |
| COPD, n (%) | 2 (2.4) | 1 (1.8) | 0.046 | 2 (3.5) | 1 (1.8) | 0.110 |
| Varicose veins of lower extremity, n (%) | 2 (2.4) | 0 (0.0) | 0.222 | 0 (0.0) | 0 (0.0) | < 0.001 |
| VTE history, n (%) | 2 (2.4) | 1 (1.8) | 0.046 | 1 (1.8) | 1 (1.8) | < 0.001 |
| Cerebral infarction, n (%) | 8 (9.6) | 8 (14.0) | 0.136 | 8 (14.0) | 8 (14.0) | < 0.001 |
BMI body mass index, COPD chronic obstructive pulmonary disease, SMD standardized mean difference, SD standard deviation, VTE venous thromboembolism
In the matched cohort, VTE occurred in 18 of 114 patients (15.8%) within 6 months after colorectal cancer surgery, with 12 cases (21.1%) in the short-term thromboprophylaxis group and six cases (10.5%) in the long-term thromboprophylaxis group (P = 0.123). Among these cases, 11 (9.6%) were symptomatic VTE, and seven (6.1%) were asymptomatic VTE. Most VTE events were DVT, and there was one case of DVT combined with PE (1.8%) in the short-term thromboprophylaxis group. Of 18 VTE events, 17 (94.4%) occurred within 28 days. Bleeding complications occurred in one patient (1.8%) in the short-term thromboprophylaxis group and no patients in the long-term thromboprophylaxis group. The proportion of patients in the long-term thromboprophylaxis group with a decrease in hemoglobin of > 20 g/L after medication was higher than that in the short-term thromboprophylaxis group, but the difference was not statistically significant (14.0% vs 5.3%, P = 0.113). There were no significant differences in laboratory indicators between the two groups before and after medication, including D-dimer (P = 0.056), hemoglobin (P = 0.726), fibrinogen (P = 0.064), platelet count (P = 0.080), ALT (P = 0.830), AST (P = 0.486), and TBIL (P = 0.114) (Table 3). After risk adjustment, long-term thromboprophylaxis (odds ratio 0.450, 95% confidence interval [CI] 0.155–1.303; P = 0.141) and rectal resection (odds ratio 0.615, 95% CI 0.221–1.714; P = 0.353) were not associated with postoperative VTE.
Table 3.
Clinical outcomes in the matched cohort of short-term thromboprophylaxis and long-term thromboprophylaxis group
| Outcomes | Short-term thromboprophylaxis (n = 57) | Long-term thromboprophylaxis (n = 57) | P value |
|---|---|---|---|
| VTE events | 12 (21.1%) | 6 (10.5%) | 0.123 |
| DVT | 11 (19.3%) | 6 (10.5%) | 0.189 |
| DVT+PE | 1 (1.8%) | 0 | 1.000 |
| Bleeding complications | 1 (1.8%) | 0 | 1.000 |
| △Hb > 20 g/L | 3 (5.3%) | 8 (14.0%) | 0.113 |
| D-dimer (mg/L) | 0.056 | ||
| Pre-medication | 2.52 (2.32) | 2.10 (2.47) | |
| Post-medication | 3.06 (3.94) | 1.85 (1.63) | |
| Hemoglobin (g/L) | 0.726 | ||
| Pre-medication | 116.46 (18.22) | 115.67 (19.22) | |
| Post-medication | 113.19 (18.61) | 113.49 (18.16) | |
| Fibrinogen (g/L) | 0.064 | ||
| Pre-medication | 3.77 (1.07) | 3.80 (1.23) | |
| Post-medication | 3.81 (1.60) | 3.34 (1.33) | |
| Platelet count (109/L) | 0.080 | ||
| Pre-medication | 180.19 (51.26) | 234.26 (107.21) | |
| Post-medication | 192.46 (60.99) | 255.47 (107.93) | |
| ALT (U/L) | 0.830 | ||
| Pre-medication | 13.67 (11.53) | 21.79 (61.96) | |
| Post-medication | 21.21 (23.86) | 22.81 (19.44) | |
| AST (U/L) | 0.486 | ||
| Pre-medication | 18.38 (7.56) | 26.41 (57.36) | |
| Post-medication | 25.77 (19.26) | 23.58 (15.79) | |
| TBIL (μmol/L) | 0.114 | ||
| Pre-medication | 16.80 (12.27) | 13.68 (7.56) | |
| Post-medication | 15.37 (8.81) | 16.52 (13.24) |
△Hb change (decrease) in hemoglobin, ALT alanine aminotransferase, AST aspartate aminotransferase, DVT deep vein thrombosis, PE pulmonary embolism, TBIL total bilirubin, VTE venous thromboembolism
Multivariable logistic regression analysis conducted in the pre-matching cohort indicated that long-term thromboprophylaxis can reduce the risk of postoperative VTE (odds ratio 0.34, 95% CI 0.12–0.95; P = 0.039). Age ≥ 69 years (odds ratio 4.99, 95% CI 1.83–13.64; P = 0.002), hyperlipidemia (odds ratio 2.95, 95% CI 1.02–8.50; P = 0.046), and preoperative bloody stool/tarry stool (odds ratio 3.31, 95% CI 1.28–8.57; P = 0.014) were also independent risk factors for postoperative VTE (Fig. 2). Figure 3 shows the cumulative incidence curves of postoperative VTE between the short-term thromboprophylaxis group and the long-term thromboprophylaxis group. Long-term thromboprophylaxis was associated with a nonsignificant reduction in VTE risk (log rank P = 0.063).
Fig. 2.
Forest plot summarizing the results of multivariable regression model. CI confidence interval, OR odds ratio
Fig. 3.
Cumulative incidence of venous thromboembolism (VTE) in the short-term thromboprophylaxis and long-term thromboprophylaxis group
Discussion
Our study showed that long-term thromboprophylaxis (≥ 7 days) was associated with a nonsignificant twofold reduction in incidence of VTE compared to short-term thromboprophylaxis (< 7 days). Both groups exhibited comparable safety profiles. However, multivariable-adjusted analysis revealed that long-term thromboprophylaxis may reduce postoperative VTE risk.
In our cohort, there was no significant difference in the incidence of VTE between the short-term thromboprophylaxis group and long-term thromboprophylaxis group. D-dimer levels, reflecting hypercoagulability [18], demonstrated a nonsignificantly greater reduction post-intervention in the prolonged prophylaxis group. Current guidelines recommend 7–10 days of thromboprophylaxis for major cancer surgeries and extended 4-week regimens for abdominal/pelvic procedures (e.g., colorectal cancer) [8–10]. However, only one patient in our study received the full 4-week regimen. Donahue et al. found that only 4.7% of patients received VTE prophylaxis after colorectal cancer surgery. Although the utilization rate of postoperative VTE prophylaxis has increased in recent years in large, specialized hospitals, significant limitations persist [19]. The patients were divided into two groups based on a 7-day threshold. The median durations of LMWH prophylaxis were 4 days (IQR 3–5 days) and 10 days (IQR 8–13 days) in the short-term and long-term thromboprophylaxis group, respectively. This indicated that a duration of less than 7 days may achieve comparable effectiveness to the guideline-recommended minimum duration (7–10 days). While meta-analyses support 4-week prophylaxis for abdominal/pelvic surgeries [20–22], optimal regimens for colorectal cancer patients remain undefined, with only two published randomized controlled trials available [12, 13]. The PERIOP-01 trial similarly found no significant VTE reduction with extended prophylaxis (2% vs 1%), which was consistent with the results of our study [23]. Corbin et al. also found that extended VTE prophylaxis was not associated with either postoperative VTE or bleeding events in colorectal cancer patients [24].
In terms of safety, LMWH has adverse drug reactions such as bleeding, liver function abnormalities, and heparin-induced thrombocytopenia (HIT). There was no significant difference in the incidence of bleeding complications and changes in hemoglobin levels between thromboprophylaxis groups. Hypofibrinogenemia (< 1 g/L), a recognized bleeding risk factor [25], was absent in our cohort. The fibrinogen levels in both groups were similar and within the normal range (2–4 g/L). HIT induced by LMWH is common in populations undergoing major surgical procedures, with an incidence rate of 0.8–1.2% [26]. Platelet counts of both groups in our study consistently stayed within the normal range, with no significant differences, and no one experienced HIT. Liver function assessment indicators, including ALT, AST, and TBIL, were also not significantly different between groups. During the prevention of VTE with LMWH, clinical pharmacists need to pay attention to whether patients experience bleeding events, as well as indicators such as hemoglobin, platelets counts, liver and kidney function, and coagulation function.
Based on the results of our study, there seemed to be no significant differences in effectiveness and safety between short-term thromboprophylaxis and long-term thromboprophylaxis. The median time for patients in our study to accept prophylactic anticoagulation after operation was 6 days (IQR 6–9 days). Considering the adherence to the continued use of LMWH after discharge, as well as the length of postoperative hospital stay and treatment costs, using LMWH for short-term thromboprophylaxis during hospitalization may also prevent the development of postoperative VTE.
Caprini score is the most commonly used VTE risk assessment model for general surgery, and it may have limitations in predicting postoperative VTE risk in colorectal cancer patients [5, 6, 14]. All patients included in our study had very high risk (≥ 5) Caprini scores, and risk factors in the Caprini score did not have characteristics specific to colorectal cancer patients. We found that preoperative bloody stool/tarry stool was also an independent risk factor for postoperative VTE in addition to advanced age and hyperlipidemia, which was similar to the results of a multicenter study [14]. A model specifically designed to predict the risk of postoperative VTE in colorectal cancer patients can effectively identify patients at high risk of VTE, allowing more patients to benefit from extended thromboprophylaxis.
The rate of VTE in the long-term thromboprophylaxis group remained high at 10.5%, which contrasts with lower VTE incidences in the literature (non-pharmacological thromboprophylaxis: 1.9% [27]; 7-day LMWH prophylaxis: 3.9% [12]). Possible reasons are as follows. Firstly, metastatic progression (documented in 42.9% stage III–IV patients in our study) elevates thrombogenic potential through tissue factor overexpression [28–30]. Secondly, retrospective design constraints resulted in incomplete lower extremity Doppler ultrasound implementation, potentially underestimating asymptomatic DVT prevalence, leading to data bias. Finally, the median duration of LMWH prophylaxis was 10 days (IQR 8–13 days) in the long-term thromboprophylaxis group, which may not have reached the optimal prophylactic duration. Postoperative activation of the coagulation system persists beyond the first 7–10 days after surgery [21], and one-third of postoperative VTE cases in colorectal cancer patients are identified after discharge [31]. Similarly, most patients experienced VTE within 28 days after operation in our cohort.
Our study has some limitations. Firstly, the single-center retrospective design with modest enrollment (n = 140) introduces potential selection bias and restricts extrapolation to diverse healthcare settings. Future large-scale, multicenter, prospective trials should be performed to explore the optimal regimen and duration of antithrombotic prophylaxis for patients undergoing colorectal cancer surgery. Secondly, the mechanical and pharmacological prophylaxis used for the included patients were not standardized, which may lead to heterogeneity. Thirdly, due to the retrospective study design, lower extremity ultrasound was not routinely performed for patients undergoing colorectal cancer surgery. The exclusion of patients without preoperative or postoperative lower extremity ultrasound may have introduced selection bias, which warrants further validation through prospective multicenter studies. Moreover, our study has several strengths. Firstly, as a real-world retrospective study, it accurately reflected the current status and challenges of postoperative VTE prophylaxis in colorectal cancer patients among the Chinese population, providing valuable insights for future practice improvement. Secondly, in addition to collecting data on VTE and bleeding events, we comprehensively accounted for potential adverse drug reactions associated with LMWH by systematically analyzing the changes in laboratory indicators before and after medication, including D-dimer, fibrinogen, ALT, AST, and TBIL.
Conclusions
Long-term thromboprophylaxis (≥ 7 days) demonstrated comparable effectiveness and safety to shorter regimens in preventing postoperative VTE, while suggesting potential sustained protective benefits during extended follow-up periods exceeding 6 months. Whether VTE prophylaxis should be extended to 28 days post-surgery requires further research.
Acknowledgements
The authors were involved at all stages of manuscript development.
Author Contributions
Y. Zhang and Y. Zhao are the guarantors of the entire manuscript; X.-Z. Zhou, Y. Wu, and S.-C. Chen contributed to the data acquisition and analysis; X.-L. Cui contributed to the important guidance for this study. All authors have read and approved the final submitted manuscript, and agree to be accountable for the work.
Funding
This study was supported by the Beijing Research Association for Chronic Diseases Control and Health Education 2024 Pharmacy Special Research Project (MBZX0082024001).
Availability of Data and Material
The datasets used and/or analyzed during the current study are available from the corresponding authors upon reasonable request.
Code Availability
Not applicable.
Declarations
Conflict of Interest
The authors have no conflicts of interest to declare.
Ethics Approval
This study was approved by the ethics committee on 17 July 2023 (number: 2023-P2-177-01). Informed consent was waived because of the retrospective design of the study.
Consent to Participate
Informed consent was waived because of the retrospective design of the study.
Consent for Publication
Not applicable.
Contributor Information
Xiangli Cui, Email: xianglicui@ccmu.edu.cn.
Ying Zhao, Email: yingzhao@ccmu.edu.cn.
References
- 1.Farge D, Frere C, Connors JM, et al. 2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19. Lancet Oncol. 2022;23(7):e334–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Mulder FI, Horváth-Puhó E, van Es N, et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood. 2021;137(14):1959–69. [DOI] [PubMed] [Google Scholar]
- 3.Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med. 2002;162(11):1245–8. [DOI] [PubMed] [Google Scholar]
- 4.Wu D, Gu H, Tang Y, et al. Predictive factors on postoperative venous thromboembolism after minimally invasive colorectal cancer surgery: a retrospective observational study. BMC Surg. 2023;23(1):85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lu X, Zeng W, Zhu L, et al. Application of the Caprini risk assessment model for deep vein thrombosis among patients undergoing laparoscopic surgery for colorectal cancer. Medicine (Baltimore). 2021;100(4): e24479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Yao J, Lang Y, Su H, et al. Construction of risk assessment model for venous thromboembolism after colorectal cancer surgery: a Chinese Single-Center Study. Clin Appl Thromb Hemost. 2022;28:10760296211073748. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kahale LA, Tsolakian IG, Hakoum MB, et al. Anticoagulation for people with cancer and central venous catheters. Cochrane Database Syst Rev. 2018;6(6):CD006468. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Streiff MB, Holmstrom B, Angelini D, et al. Cancer-associated venous thromboembolic disease, Version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(10):1181–201. [DOI] [PubMed] [Google Scholar]
- 9.Falanga A, Ay C, Di Nisio M, et al. Venous thromboembolism in cancer patients: ESMO clinical practice guideline. Ann Oncol. 2023;34(5):452–67. [DOI] [PubMed] [Google Scholar]
- 10.Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO guideline update. J Clin Oncol. 2023;41(16):3063–71. [DOI] [PubMed] [Google Scholar]
- 11.Patel SV, Liberman SA, Burgess PL, et al. The American Society of colon and rectal surgeons clinical practice guidelines for the reduction of venous thromboembolic disease in colorectal surgery. Dis Colon Rectum. 2023;66(9):1162–73. [DOI] [PubMed] [Google Scholar]
- 12.Becattini C, Pace U, Pirozzi F, et al. Rivaroxaban vs placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. Blood. 2022;140(8):900–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Vedovati MC, Becattini C, Rondelli F, et al. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Ann Surg. 2014;259(4):665–9. [DOI] [PubMed] [Google Scholar]
- 14.Wei Q, Wei ZQ, Jing CQ, et al. Incidence, prevention, risk factors, and prediction of venous thromboembolism in Chinese patients after colorectal cancer surgery: a prospective, multicenter cohort study. Int J Surg. 2023;109(10):3003–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon. 2005;51(2–3):70–8. [DOI] [PubMed] [Google Scholar]
- 16.Schulman S, Angeras U, Bergqvist D, et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8(1):202–4. [DOI] [PubMed] [Google Scholar]
- 17.Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46:399–424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Kim AS, Khorana AA, McCrae KR. Mechanisms and biomarkers of cancer-associated thrombosis. Transl Res. 2020;225:33–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Donahue CA, Brinton DL, Booth AT, et al. Guideline-concordant extended pharmacologic venous thromboembolism prophylaxis utilization after colorectal cancer resection is low regardless of patient factors or hospital characteristics. Dis Colon Rectum. 2025;68(4):417–25. [DOI] [PubMed] [Google Scholar]
- 20.Felder S, Rasmussen MS, King R, et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2019;3(3):CD004318. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Fagarasanu A, Alotaibi GS, Hrimiuc R, et al. Role of extended thromboprophylaxis after abdominal and pelvic surgery in cancer patients: a systematic review and meta-analysis. Ann Surg Oncol. 2016;23(5):1422–30. [DOI] [PubMed] [Google Scholar]
- 22.Bottaro FJ, Elizondo MC, Doti C, et al. Efficacy of extended thrombo-prophylaxis in major abdominal surgery: what does the evidence show? A meta-analysis. Thromb Haemost. 2008;99(6):1104–11. [DOI] [PubMed] [Google Scholar]
- 23.Auer RC, Ott M, Karanicolas P, et al. Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial. BMJ. 2022;378: e071375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Corbin SL, Harris L, Fuccello A, et al. Clinical outcomes of extended venous thromboembolism prophylaxis after oncologic colorectal surgery. J Gastrointest Surg. 2025;29(5): 102018. [DOI] [PubMed] [Google Scholar]
- 25.Stanworth SJ, Dowling K, Curry N, et al. Haematological management of major haemorrhage: a British Society for Haematology Guideline. Br J Haematol. 2022;198(4):654–67. [DOI] [PubMed] [Google Scholar]
- 26.Junqueira DR, Zorzela LM, Perini E. Unfractionated heparin versus low molecular weight heparins for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev. 2017;4(4):CD007557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Tan SJJ, Tan EK, Ng YYR, et al. Venous thromboembolism among Asian populations with localized colorectal cancer undergoing curative resection: is pharmacological thromboprophylaxis required? A systematic review and meta-analysis. Ann Coloproctol. 2024;40(3):200–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chen Y, Wang Y, Xie S, et al. A risk of venous thromboembolism algorithm as a predictor of venous thromboembolism in patients with colorectal cancer. Clin Appl Thromb Hemost. 2021;27:1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Cella CA, Di Minno G, Carlomagno C, et al. Preventing venous thromboembolism in ambulatory cancer patients: The ONKOTEV Study. Oncologist. 2017;22(5):601–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Gerotziafas GT, Taher A, Abdel-Razeq H, et al. A predictive score for thrombosis associated with breast, colorectal, lung, or ovarian cancer: the prospective COMPASS-Cancer-Associated Thrombosis Study. Oncologist. 2017;22(10):1222–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Reinke CE, Karakousis GC, Hadler RA, et al. Incidence of venous thromboembolism in patients undergoing surgical treatment for malignancy by type of neoplasm: an analysis of ACS-NSQIP data from 2005 to 2010. Surgery. 2012;152:186–92. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding authors upon reasonable request.
Not applicable.