Risk Factors For Perioperative Venous Thromboembolism in Patients With Gynecological Malignancies

Introduction(cid:0)Venous thromboembolism (VTE), is a frequent postoperative complication of gynecologic malignancies during perioperative period.Although a number of risk factors for perioperative VTE with gynecological malignancies have been reported, the ndings are diverse or even contradictory .In addition, most of the existing studies were retrospective case-control studies with small sample sizes .This study was a prospectively matched case-control study and aimed to specically explore the risk factors related to surgery for perioperativeVTE in gynecologic malignancies. Material and methods(cid:0)Overall,734 patients with gynecologic malignancies were enrolled in this study.54 patients who developed VTE were included as the case group. A total of 270 non-VTE patients matched in a ratio of 1:5 as a control group with the matched principle of the same ethnicity and similar date of surgery (difference ± 3 days). The demographic characteristics, clinical data, laboratory tests, surgical data, and data related to the occurrence of VTE were collected during the follow-up period. Conditional logistic regression models were used for univariate and multifactorial analyses. Factors related to surgical treatment, especially those could be intervened and prevented, were used as target factors, which were gradually corrected by demographic data, clinical data, laboratory tests and other factors related to surgery, and sensitivity analysis was performed. Results:The results of univariate analysis showed that age, place of residence, occupation, high-fat diet, menopause, comorbid chronic diseases, duration of upper extremity indwelling needle retention, disease diagnosis, sleep during hospitalization, admission albumin, surgical approach , duration of intensive care unit(ICU)admission, start of anticoagulant use, time to resume postoperative anal evacuation, duration of bed rest, duration of drinking abstinence, difference between postoperative and admission Caprini scores,duration of abdominal drainage tube retention, and intraoperative bleeding were risk factors for VTE in patients with perioperative gynecologic malignancies (P<0.05). Stepwise corrected multifactorial conditional logistic regression analysis showed that admission albumin<46.40 g/L and large difference between postoperative and admission Caprini scores were risk factors for the development of VTE in patients with gynecologic malignancies in the perioperative period, and the risk of VTE in patients with admission serum albumin<46.40 g/L was 4.885 times higher than that in patients with admission serum albumin ≥ 46.40 g/L; The larger difference between postoperative and admission Caprini scores, the higher the risk of VTE, and a 1-point increase in the difference between postoperative and admission Caprini scores was associated with a 2.174-fold increase in the risk of VTE (95% CI: 1.255 to 3.766, P= 0.006). Conclusions: The main risk factors for perioperative VTE in gynecologic malignancies are serum albumin lower than 46.40 g/L and large difference between postoperative and admission Caprini scores. More attention should be paid to the dynamic changes of serum albumin and Caprini scores of patients in the perioperative period and those factors should be targeted to intervene in order to reduce the perioperative VTE. compression stockings,intermittent pneumatic therapy,prophylactic anticoagulation,start of anticoagulant use, postoperative Caprini score,admission Caprini score, difference between postoperative and admission Caprini scores,duration of abdominal drainage tube retention,VTE type, site, DVT discovery time, PTE occurrence time, etc. Diagnoses were objectively conrmed by color Doppler ultrasound for DVT and a ventilation-perfusion scan or computed tomography pulmonary angiography scan for PTE. of ICU admission, start of anticoagulant use, time to resume postoperative anal evacuation, duration of bed rest, difference between postoperative and admission Caprini score, duration of abdominal drainage tube retention may be the risk factors for VTE in patients with perioperative gynecologic malignancies (P<0.05). But,the main purpose of our study was focusing on exploring the risk factors related to surgery for perioperative VTE in gynecologic malignancies. especially the reversible or preventable factors. Therefore, the following 11 objective factors were nally determined as target factors, including sleep during hospitalization, admission albumin, surgical approach, duration of ICU admission, the forbidden drink time,start of anticoagulant use, time to resume postoperative anal evacuation, duration of bed rest, difference


Introduction
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) is a common complication in patients with gynecologic malignancies, with an incidence ranging from 3-25%.The incidence of VTE is even higher in patients undergoing surgery for gynecological malignancy [1] . It has been reported that the incidence of postoperative DVT in patients with gynecological malignancies was 12-33% [2] and that of perioperative DVT was 19.6-38% [3] .VTE is the most common cause of death in patients with cancer after surgery within 30 days [4] .
There were many studies on the risk factors of perioperative VTE in patients with gynecological malignancies, however,the ndings of existing studies are diverse or even contradictory [5][6][7] . M Sakon found that female gender, operation site, age>60 years, and operation time were four risk factors found to be signi cant [5] .Qing Tian have pointed out that Age > 50 years, hypertension, D-dimer > 0.5 mg/L, duration of surgery≥60 min, intraoperative pneumoperitoneum pressure≥15mmHg, duration of days in bed > 3 days were the independent risk factors for DVT in patients undergone gynecological laparoscopic surgery [6] . In our previous meta-analysis study [7] , we found that the risk factors for perioperative VTE in patients with gynecological malignancy may include advanced age, BMI > 26 kg/m 2 , increased platelet count, elevated D-dimer level, long duration of surgery, long time in bed after surgery, long-term hospital stay, large amount of intraoperative blood loss, tumor differentiation (GREAD3), tumor staging(stage IV), and operative approach (laparotomy). Other studies have found that surgery is the main pathogenic factor of perioperative VTE [8] , including intraoperative posture, intraoperative peripheral vascular injury [9] , intraoperative hypothermia [10] and preoperative enema, diet prohibition time, postoperative recovery time of anal exhaust, etc. Consquently, surgical factors are the most important and most likely to be intervened factors for the occurrence of perioperative VTE .However, most of these studies were retrospective case-control studies with small sample sizes [11,12] .Therefore, there may be retrospective bias in the process of extracting patient medical records such as case selection bias, information bias and so on [13] .
As such, in this study, we conducted a macthed case-control study to prospectively collect perioperative surgery-related factors without knowing the patients' VTE outcomes, espically focusing on surgery-related factors and strictly adhering to inclusion and exclusion criteria. To control for bias in the case-control study design as much as possible, we also used a stepwise corrected multifactorial conditional logistic regression analysis with multiple models to gradually correct the confounding factors. To further validate the stability of the results, we performed the sensitivity analyses. So that to explore the risk factors related to surgery for perioperativeVTE in gynecologic malignancies and provide a basis for the prevention and clinical intervention, and provide a scienti c basis for further construction of risk assessment models of perioperative VTE in gynecologic malignancies.

Study design
This was a prospectively matched case-control study. Between December 2019 and February 2021, patients with gynecologic malignancies who were admitted to a tertiary women's and children's specialized hospital in Chengdu, Sichuan Province, undergoing surgical treatment were recruited for this study. We excluded subjects meeting one of the following criteria: (1) Combination of other primary malignant tumors (other than gynecologic malignancies) ; (2) Con rmed preoperative DVT by the vascular ultrasound ; (3) using anticoagulant drug within 1 week before surgery. Patients who developed VTE in the perioperative period were included as the case group, according to the matched principle of the same ethnicity and similar date of surgery (difference ± 3 days), we selected ve patients from this cohort to each case in a ratio of 1:5 as a control group.

Data collection
The demographic characteristics, clinical data, laboratory tests, surgery related data,and data related to the occurrence of VTE were collected during the follow-up period.The following data were collected for analysis: age, marriage, work type,Body Mass Index(BMI), education, living environment, diagnosis, tumor types/stages, lymph node metastasis, radiotherapy, chemotherapy, chronic disease , history of VTE, menopause, varicose veins, leg edema, duration of upper limb indwelling needle retention, disease diagnosis,whether to stay in the intensive care unit (ICU),duration of ICU admission,blood type, coagulation function and blood biochemistry,surgical approach, duration of bed rest, blood transfusion, prophylactic thrombosis-speci c compression stockings,intermittent pneumatic therapy,prophylactic anticoagulation,start of anticoagulant use, postoperative Caprini score,admission Caprini score, difference between postoperative and admission Caprini scores,duration of abdominal drainage tube retention,VTE type, site, DVT discovery time, PTE occurrence time, etc.
Diagnoses were objectively con rmed by color Doppler ultrasound for DVT and a ventilation-perfusion scan or computed tomography pulmonary angiography scan for PTE.

Ethical Approval
Written informed consent was obtained from each participant, and the study was approved by the Ethics Committee of West China Second University Hospital Sichuan University. All authors had full access to all the data in this study.

Statistical Analysis
Statistical analysis was performed using SPSS version 23.0 software. Continuous data were presented as mean ± standard deviation and median (interquartile range,IQR) for non-normally distributed data. Categorical variable was presented as number (percentage), risk ratio and 95% con dence interval (CI). A P-value of 0.05 was considered statistically signi cant.
Conditional logistic regression models were used for univariate and multifactorial analyses.Surgery related data, especially those could be intervened and prevented, were used as target factors, which were gradually corrected with demographic data, clinical data, laboratory tests and other factors related to surgery, and sensitivity analysis was performed.

Results
We enrolled 734 patients in this study. During the follow-up period, 54 patients who developed VTE were included as the case group. And according to the matched principle of the same ethnicity and similar date of surgery (difference ± 3 days), a total of 270 non-VTE patients matched in a ratio of 1:5 as a control group.
The age ranged from 15~81 years with a mean age of 50.46 ± 11.09 years. The case group (55.98 ± 9.45 years) was much older than the control group (49.36 ± 11.08 years). The admission BMI ranged from 16.94~40.27 kg/m 2 with a mean of 23.39±3.24 kg/m 2 . The mean admission BMI of the case group (23.55±2.83 kg/m2) was similar to that of the control group (23.35±3.33 kg/m 2 ). The characteristics of perioperative VTE in case group are shown in Table 1.
The characteristics of perioperative VTE in case group: Comparison of General demographic data Related to Perioperative DVT The General demographic data included age, BMI, work type, place of residence, sleep status during hospitalization,High-fat diet; Except BMI, there were signi cant differences between the VTE and non-VTE groups in the above-mentioned parameters (P < 0.05) as shown in Table 2.

Clinical Data Analyses
As shown in Table 3, comparison of clinical data related to perioperative VTE were made between the 2 groups, including menopause,chronic disease,duration of upper limb indwelling needle retention (h),disease diagnosis. All the parameters were different between the VTE and non-VTE groups (P <0.05).  Table 4, laboratory tests were compared between the VTE and the non-VTE groups. The admission serum albumin(Alb) level was found to be signi cantly different between the 2 groups (P =.005), while there were no differences in any of the other parameters (all P > 0.05).

Surgery related factors
The operative data included anal evacuation time(h),duration of bed rest(h),surgical approach,prophylactic thrombosis-speci c compression stockings,intermittent pneumatic therapy,prophylactic anticoagulation,start of anticoagulant use(h),blood transfusion,postoperative Caprini score,Caprini score post-admission,admission Caprini score,duration of ICU admission(h),duration of abdominal drainage tube retention; Anal evacuation time(h),duration of bed rest(h),surgical approach, prophylactic thrombosis-speci c compression stockings,start of anticoagulant use(h),postoperative Caprini score,difference between postoperative and admission Caprini scores,duration of ICU admission h ,duration of abdominal drainage tube retention were different between the VTE and non-VTE groups (P<0.05), while no signi cant differences were found between the VTE and non-VTE groups in the other parameters, including intermittent pneumatic therapy,prophylactic anticoagulation,blood transfusion,admission Caprini score, (all P >0 .05) as shown in Table 5. perioperative gynecologic malignancies (P<0.05). But,the main purpose of our study was focusing on exploring the risk factors related to surgery for perioperative VTE in gynecologic malignancies. especially the reversible or preventable factors. Therefore, the following 11 objective factors were nally determined as target factors, including sleep during hospitalization, admission albumin, surgical approach, duration of ICU admission, the forbidden drink time,start of anticoagulant use, time to resume postoperative anal evacuation, duration of bed rest, difference between postoperative and admission Caprini scores, duration of abdominal drainage tube retention and intraoperative blood loss. These above target factors were gradually corrected with demographic data, clinical data, laboratory tests and surgery related factors. Laboratory test results showed no statistical signi cance except for the serum albumin level, so no correction was required. Therefore, the nal corrected data include age, place of residence, work type, high-fat diet,menopause, chronic disease, duration of upper limb indwelling needle, disease diagnosis.
As shown in Table 6, Stepwise corrected multifactorial conditional logistic regression analysis results showed that admission albumin<46.40 g/L and large difference between postoperative and admission Caprini score were risk factors for the development of VTE in patients with gynecologic malignancies in the perioperative period, and the risk of VTE in patients with admission serum albumin<46.40 g/L was 4.885 times higher than that in patients with admission serum albumin≥46.40 g/L. The larger difference between postoperative and admission Caprini score, the higher the risk of VTE, and a 1-point increase in the difference between postoperative and admission Caprini scores was associated with a 2.174-fold increase in the risk of VTE (95% CI: 1.255 to 3.766, P= 0.006).

Discussion
VTE is a frequent complication of gynecologic malignancies during perioperative period. Reviews of the literature report the incidence of VTE in patients with gynecologic malignancies from 3% to 25% [14,15] . Given the high frequency of VTE and associated morbidity and mortality, ascertaining predictive factors might be warranted to identify the high risk patients who may potentially bene t from closer surveillance or pharmacological thromboprophylaxis.
In our study,a total of 54 patients developed VTE. Age strati cation was performed according to Caprini rating scale [16] , and it was found that 3.7% of the patients were ≤40 years old, 29.6% were ≥61 years old, and most of the patients (66.7%) were aged between 41 and 60 years old.
Univariate analysis showed that age was a risk factor for perioperative VTE in gynecological malignancies, and the older the age, the higher the risk of VTE. Compared with patients aged ≤40 years, the risk of VTE was signi cantly increased in patients older than 40 years, and the risk of VTE was signi cantly higher in patients aged ≥61 years than in patients aged 41-60 years.This may be related to age-related endothelial dysfunction and platelet function changes [17] , especially in elderly patients with tumors [18,19] . According to the results of this study and our previous studies, patients over 40 years , especially over 60 years , are at higher risk of VTE.Therefore, it is necessary to strengthen the dynamic assessment of the risk of perioperative VTE in these people and to take preventive measures in advance to reduce the incidence of VTE.
In our study, DVT accounted for 70.3%, PTE accounted for 16.7%, and DVT+PTE accounted for 13.0%, among which DVT occurred all in lower limbs: 28.9% DVT in left lower limbs, 33.3% DVT in right lower limbs, and 37.8% DVT in both lower limbs. This is consistent with the results of Nordstom et al. [20] , indicating that DVT of lower extremities is more likely to happen after surgery for gynecological malignancies.Previous studies have shown that the proportion of DVT in the left lower extremity is higher than that in the right extremity due to the anatomical characteristics of local veins [21,22] . However, no signi cant difference was found in the incidence of VTE between the left and right lower limbs.
This may be related to the simultaneous in uence of various factors that may lead to changes in vascular wall, platelet and hemodynamics [23] .
In the 54 cases of VTE ,94.4% of the patients occurred VTE in 2 ~ 8 days after surgery, while PTE occurred within 7 days after surgery, of which 62.5% occurred in 2 and 3 days after surgery. This is consistent with the results of existing relevant studies. Multiple studies have shown that perioperative VTE in patients with gynecological malignant tumors mostly occurs within 10 days after surgery [24,25] .Peedicayil et al. [26] also found that 75% of VTE in gynecological cancer patients occurred within 1 week after surgery.The occurrence time of postoperative VTE may be related to many factors, including the operation time, operation approach and duration of bed rest,etc.In our study, color Doppler ultrasound was arranged immediately when patients were with numbness, swelling, pain and changes in skin temperature and skin color of lower limbs.Other patients who were asymptomatic were examined only at admission or before discharge . Therefore, in this study, only the time when patients were detected with VTE could be known, the actual occurrence time of VTE maybe earlier than the inspection time. More large sample and multicenter studies are needed to provide evidence for the effective prevention of perioperative VTE in gynecological malignancies.
The results showed that the large difference between postoperation and admission Caprini scores was a risk factor for perioperative VTE in gynecological malignancies. The larger the difference, the higher the risk . Every point increased in the difference between Caprini score after operation and that at admission, the risk of postoperative VTE increased by 2.174 times (95%CI: 1.255 to 3.766). Therefore, it is very important to evaluate dynamic Caprini score timely and accurately in perioperative period.Caprini risk assessment model, as a widely used VTE risk assessment model in the world, has been extensively veri ed in different populations, including patients with cancer [27] .Studies have shown that the occurrence of VTE can be effectively reduced by taking targeted preventive measures after evaluating the risk of VTE in postoperative patients with gynecological tumors according to Caprini score [28] ,however, the application of Caprini risk assessment model in patients with gynecological malignant tumors still needs to be supplemented and improved [29] .
The results of this study showed that there was no statistical difference in Caprini score between the case group and the control group at admission (P=0.123), and it was unscienti c to evaluate the risk of perioperative VTE in patients with gynecological malignancies only by Caprini score once at admission.In addition to the traumatic stress response of the operation itself, which increases the risk of VTE in patients [30] , the injury of vascular endothelia and the in uence of surgical trauma on the coagulation system of the body promote the elements of VTE formation. Therefore, the evaluation of perioperative VTE should take into account the surgical approach, surgical duration, and other potential risk factors caused by surgery [31,32] .The risk of VTE is also changing in the perioperative period. It is reliable to evaluate the risk of VTE based on the difference value of Caprini score before and after surgery. In clinical practice, Caprini score should be evaluated dynamically and timely and more attention should be paid to the size and causes of the score difference, so as to take targeted measures to eliminate reversible risk factors and reduce the impact of irreversible risk factors as far as possible.
We found that serum albumin level was an in uential factor for perioperative VTE in gynecological malignancies, and high albumin was a protective factor.The risk of VTE in patients with serum albumin <46.40g/L was 4.885 times higher than that in patients with serum albumin ≥46.40g/L (P=0.004). This is similar to the conclusion of previous studies. Studies on malignant VTE in digestive system showed that the risk of VTE increased when albumin <30g/L (OR=2.980, P=0.002) [33] .A Meta-analysis results also showed that albumin <30g/L was a risk factor for VTE in lung cancer (OR =4.01, P<0.001) [34] . Studies on related factors of VTE in malignant solid tumors showed that high albumin was a protective factor (OR=0.863, P< 0.05), and it was suggested that patients with malignant solid tumors with VTE should maintain albumin above 35.505 (g/L) [35] .At present, there are few studies on the relationship between albumin and VTE, and the mechanism of action between VTE and albumin is still unclear [36] . It may be related to the physiological effects of serum albumin, including the protection of vascular endothelial integrity [37,38 ], the maintenance of the body's plasma colloid osmotic pressure, and the regulation of coagulation [39,40] . When serum albumin concentration is high, it promotes the above physiological effects and is not conducive to the formation of thrombosis.The results of this study and previous studies all suggest that low protein is a risk factor for VTE, so more attention should be paid to albumin and dynamic monitoring should be taken during perioperative period .
This study tried to control the effects of confounding factors by prospective data collection, matching cases, and stepwise correction regression. However, there were still some de ciencies : (1) Laboratory examination: this study is a real world study, clinical examination of some indicators, such as genetic thrombi, has not been carried out, which may affect the results of the study.(2)Sample: Due to the limitations of time, manpower and material resources, this study was only carried out in the gynecological ward of one third-grade Grade A specialized hospital for women and children in Sichuan Province. The sample size was small, and the hospital grade and patient population were limited, so bias was inevitable in the research results. Therefore, the representativeness and generalization of the research results need to be improved by further research.
Conclusion VTE in patients with gynecologic malignancies is affected by many factors, but the main risk factors for perioperative VTE are serum albumin lower than 46.40 g/L and large difference between postoperative and admission Caprini scores. Therefore, medical staff should pay more attention to the dynamic changes of serum albumin and Caprini scores of patients in the perioperative period, so as to identify the high-risk factors of VTE timely and actively take effective measures.
Patients with the following characteristics are at high risk of perioperative VTE: patients who are menopausal, serum albumin less than 46.40 g/L at admission, with a difference between postoperative and admission Caprini scores greater than 3; patients with a difference between postoperative and admission Caprini scores less than 3 but admission Caprini scores greater than 5. Patients at high risk of perioperative VTE can be screened quickly and easily by the above association rules, and then the possibility of VTE can be actively and dynamically assessed and individualized preventive measures can be taken.
Prevention of perioperative VTE in patients with gynecologic malignancies is crucial. Risk factors for VTE should be dynamically assessed based on basic patient data, clinical data, and treatment progress, and individualized preventive measures should be actively taken for the presence/potential or emerging high-risk factors to reduce the occurrence of postoperative VTE.