Venous Thromboembolism in Patients Undergoing Distal Cholangiocarcinoma Surgery: Prevalence, Risk Factors, and Outcome

doi:10.21203/rs.3.rs-2204201/v1

Background: To investigate venous thromboembolism (VTE) in patients undergoing distal cholangiocarcinoma (dCCA) surgery, we performed a single-center study to assess its prevalence, risk factors, prognosis.

Method: We studied a total of 177 patients undergoing dCCA surgery from January 2017 to April 2022. Demographic, clinical data, laboratory data (including lower extremity ultrasound findings), and outcome variables were obtained, and compared between VTE and non-VTE groups.

Results: Of the 177 patients undergoing dCCA surgery (aged 65.2±9.6years; 108 (61.0%) male), 64 patients developed VTE after surgery. Logistic multivariate analysis showed that, age, operation procedure, TNM stage, ventilator duration and preoperative D-dimer were independent risk factors. Based on these factors, we constructed the nomogram to predict VTE after dCCA for the first time. The areas under the receiver operating curve (ROC) of the nomogram were 0.80 (95% CI: 0.72-0.88) and 0.79 (95% CI: 0.73-0.89) in the training and validation groups, respectively. Patients developed VTE had a worse prognosis by Kaplan-Meier curve analysis (p = 0.001).

Conclusion: The prevalence of VTE is high and is associated with adverse outcomes in patients undergoing dCCA surgery. We developed a nomogram assessing VTE risk, which may help clinicians to screen out people at high risk for VTE and to undertake rational preventive measures.

venous thromboembolism

distal cholangiocarcinoma

surgery

nomogram

Cholangiocarcinoma (CCA), or biliary tract cancer (BTC), is a malignant tumor originating from the biliary epithelium (1). According to its anatomy, CCA is divided into intrahepatic (iCCA) or extrahepatic (eCCA). The latter can be further divided into perihilar (pCCA) and distal (dCCA) types. Distal (dCCA) accounts for 20–30% of CCA cases (2). The prognosis of CCA is poor because most cases are diagnosed at an advanced stage, lose the chance of surgery, and respond poorly to systemic therapy (1). Patients with CCA have a median survival of less than 2 years, with 90% of patients surviving no more than 5 years after their first diagnosis (2). Although early CCA can be completely resected by surgery, most patients will still experience tumor recurrence within 2 years (3, 4).

The relationship between coagulation and cancer was first described by Armand Trousseau in the 19th century (5). With the advancement of technology and the development of scientific research projects, the correlation between cancer and venous thromboembolism (VTE) has been widely recognized. On the one hand, cancer patients have a significantly higher risk of VTE (deep vein thrombosis (DVT) and pulmonary embolism (PE)) than non-cancer patients due to increased secretion of cancer-related procoagulant factors, and therapeutic interventions such as surgery and chemotherapy (6–10). On the other hand, VTE also promotes tumor progression and recurrence, leading to a worse prognosis in cancer patients (11–13). However, the prevalence, risk factors, prognosis, screening, and prevention strategies for VTE have not been investigated in patients undergoing dCCA surgery.

Therefore, we performed a single-center study to determine the prevalence, risk factors, and prognosis of VTE in a large cohort. In addition, we also tried to establish a nomogram for predicting VTE to provide a reference for clinicians to identify people at high risk of VTE.

Ethics approval and consent to participate:

All surgical procedures and therapies were consented by patients and their family members. Informed consent was obtained from all of the patients and/or their legal guardian(s). All procedures in this study involving human participants were performed in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and were approved by Ethnic Committee and Committee for Clinical Application of Medical Technology of Beijing ChaoYang Hospital, Capital Medical University (No. 2020-D-301).

Patients

We retrospectively analyzed the clinical data and follow-up data of patients that met inclusion criteria. Inclusion criteria: (1) Patients who were accepted and received surgery in Department of Hepatobiliary Surgery in Beijing Chaoyang Hospital from January 2017 to April 2022; (2) Age between 18 to 80, no limitation on gender; (3) Preoperative imaging examination confirmed dCCA; (4) Received pancreaticoduodenectomy (PD) or PD with allogeneic venous replacement; (5) Patients with tumors suffered no arterial invasion and distal metastasis. Exclusion criteria: (1) Patients with other systemic tumors; (2) Patients with hematologic diseases; (3) VTE on pre-operative examination; (4) Clinical data and follow-up data were incomplete.

Gradient compression stockings (GCS) were applied as mechanical prophylaxis in all patients perioperatively. Prophylactic anticoagulation was started in patients without significant bleeding risk after surgery and continued until discharge.

Clinical characteristics and follow-up

The following data were recorded through the electronic medical record system: patient-related information included age, sex, body mass index (BMI), comorbidities (diabetes, cerebrovascular diseases, etc.); tumor-related information included preoperative imaging examination, tumor diameter, venous invasion, lymph node metastasis, distant metastasis and TNM stage (14); treatment-related information included surgical approach, operation time, blood loss, transfusion; routine laboratory tests included WBC, neutrophil percentage, hemoglobin, platelet, albumin, total bilirubin, tumor markers (CA199, CEA, etc.), D-dimer.

The primary outcome of this study was the occurrence of VTE events in patients within 1 month after surgery. Secondary outcome is death from any cause. All patients underwent venous color Doppler ultrasonography of both lower limbs before and after surgery to identify the presence or absence of new VTE. If a patient has typical PE symptoms (chest pain, hemoptysis, dyspnea, or persistent hypoxemia) or newly diagnosed postoperative DVT, computed tomography pulmonary angiography (CTPA) should be performed to determine the presence of PE.

All patients were followed up by telephone, return visit, or inpatient observation, and the follow-up data were recorded until April 2022 or death.

Derivation and validation of the nomogram model

The patients were randomly divided into a training set and a validation set at a ratio of 7:3. In order to identify the risk factors for new VTE after dCCA, univariate analysis was performed first, and then variables with a significant p value of less than 0.2 were included in multivariate logistic regression analysis to screen for independent risk factors. Finally, nomogram models were developed using independent risk factors selected by multivariate logistic regression. A receiver operating characteristics curve (ROC) and the area under the curve (AUC) was assessed to evaluate discriminatory ability. Calibration curves were applied to describe the consistence between predicted and actual probabilities. The closer the two lines are, the closer the predicted and actual occurrence rates are, further indicating better consistency of the model. Finally, decision curve analysis (DCA) was used to evaluate the net benefit and clinical utility of patients by quantifying the net benefit at different threshold probabilities in the validation set.

Statistical Analysis

In this study, variables with more than 30% missing values were discarded and missing data were filled by a predictive average matching algorithm. Measurement data were presented as mean and standard deviation or median and interquartile range, and count data were presented as numbers (percentages). Measurement data were compared by two unpaired sample t-test, and count data were compared using chi-square test or Fisher's exact test. Kaplan-Meier curves were applied for survival analysis. Two-sided p<0.05 was considered as statistical significance. All the data were analyzed using SPSS (version 26.0) and R software (version 4.2.0).

1. Baseline and clinical characteristics of patients

A total of 177 consecutive patients were recruited in this study, and the incidence of VTE in the present study was 36.2% (64/177) (Figure 1). Included 108 males and 69 females with a mean age of 65.2±9.6 years. Clinical characteristics of total patients are shown in the Table 1. Patients were randomly divided into 124 patients (70%, 43 VTE patients and 81 non-VTE patients) in the training group and 53 patients (30%, 21 VTE patients and 32 non-VTE patients) in the validation group at a ratio of 7:3.

2. The risk factors associated with VTE of patients

Multivariate logistic analyses were performed in Table 2. Among them, age (OR: 1.056, 95% CI: 1.005-1.110, p=0.03), operation procedure (OR: 3.120, 95% CI: 1.037-9.386, p=0.04), TNM stage (OR: 2.572, 95% CI: 1.235-5.355, p=0.01), ventilator duration (OR: 1.019, 95% CI: 1.000-1.039, p=0.05) and pre-D-dimer (OR: 1.875, 95% CI: 1.053-3.340, p=0.03) were found to be independently associated with VTE in patients after dCCA surgery. Because there was multicollinearity between surgical approach and length of surgery, we only included surgical approach in the multivariate analysis. Other variables were not significantly different. To construct nomograms, a multivariate logistic regression was performed on the training set and similar results were obtained (Table 3).

3. Development and validation of nomogram model

A nomogram was constructed based on independent factors derived from multivariate logistic regression analysis of the training group (Figure 2). In this nomogram, each factor is assigned a score and the cumulative overall risk score is finally calculated. Then, drawing a straight line down can visually estimate the probability of VTE for each patient after dCCA surgery.

This nomogram was evaluated by ROC curves and calibration curves for the training and validation groups. The AUC values of the nomogram in the training group and validation group were 0.80 (95% CI: 0.72-0.88) and 0.79 (95% CI: 0.73-0.89), respectively (Figure 3A and B). According to the calibration curves, this nomogram performed well in both test datasets (Figure 4A and B). These results suggest that nomogram prediction models have good discriminatory power.

Finally, DCA was conducted to evaluate the clinical usefulness of the prediction nomogram. The nomogram added a net benefit over either the “treat all” or the “treat none” scheme in the decision curve (Figure 5).

4. Survival

Median overall survival (OS) for the whole cohort was 56.0 months (95% CI: 47.4-64.6). Median OS for patients diagnosed with VTE was 31.0 months (95% CI: 8.0-54.0) compared to 67.0 months (95% CI: 50.2-83.8) for patients without VTE. Kaplan-Meier survival curves stratified according to the diagnosis of VTE are shown in Figure 6. Patients who developed VTE after dCCA surgery had significantly worse survival than those who did not develop VTE (p = 0.001).

Surgery is an important treatment for early dCCA, while VTE is a common postoperative complication. The occurrence of VTE impacts the quality of life of patients, increases medical costs, and is also the second leading cause of postoperative death in cancer patients (15, 16).

In previous studies, VTE associated with CCA has rarely been reported, with an incidence of approximately 14.7-29.3% (17, 18). We investigated patients underwent dCCA surgery for the first time in this study, and the results showed that the prevalence of VTE after dCCA surgery was 36.2% (64/177). Further analysis showed that age, operation procedure, TNM stage, ventilator duration, and preoperative D-dimer were independent factors associated with postoperative VTE.

Risk factors for VTE mainly include patient-related factors, tumor-related factors, treatment-related factors, and biomarkers (19). This mainly includes age, BMI, tumor stage, tumor differentiation, vascular invasion, surgery, venous catheterization, D-dimer, and so on (20, 21). In this study, age (OR: 1.056, 95% CI: 1.005-1.110, p=0.03), operation procedure (OR: 3.120, 95% CI: 1.037-9.386, p=0.04), TNM stage (OR: 2.572, 95% CI: 1.235-5.355, p=0.01), ventilator duration (OR: 1.019, 95% CI: 1.000-1.039, p=0.05) and pre-D-dimer (OR: 1.875, 95% CI: 1.053-3.340, p=0.03) were found to be independently associated with VTE in patients after dCCA surgery.

Previous studies have shown that age is a risk factor for VTE, and elderly patients will experience activation of coagulation status, prompting blood to be in a hypercoagulable state (22-25). Advanced age is also associated with endothelial dysfunction, which tends to become more severe with increasing age (26). In addition, common chronic diseases in the elderly (hypertension, diabetes, hyperlipidemia, coronary heart disease, etc.) may also further induce VTE.

The operation procedure for dCCA in our center was PD. If portal venous system is severely invaded, PD with allogeneic vascular replacement is required. Studies have shown that when the complexity of cancer surgery increases, the incidence of postoperative complications such as VTE also increases (27). In our study, the prevalence of VTE was significantly higher in patients receiving allogeneic vascular replacement than in patients undergoing PD alone (59.3% VS 32.0%, p=0.02). PD with allogeneic vascular replacement often involves the blocking of blood vessels, inevitably causing local arteriovenous injury, and vascular endothelial injury will expose collagen and basement membrane, while releasing tissue factor (TF), promoting the coagulation of platelets, leading to thrombosis (28, 29); at the same time, vascular occlusion will also lead to arteriovenous pressure, blood flow rate and coagulation balance changes, promoting the formation of thrombosis. Static recumbency during surgery and prolonged bed rest after surgery may lead to weakened lower limb muscle pump reflux, lower limb venous dilatation in patients with venous return blocked, prone to thrombotic events. The complexity of PD with venous replacement surgery itself also means longer operation time, more blood loss and blood transfusion volume, which can lead to disruption of coagulation balance and hemodynamic changes, which increase the risk of VTE (30-33).

Compared with healthy people, tumor patients will continuously form thrombin and fibrin due to procoagulant factors secreted by tumor cells such as tissue factor (TF) (34-36). This causes blood to become hypercoagulable and contributes to VTE. Tumor cells also promote platelet activation, resulting in the release of particles of phosphatidylserine and promoting a hypercoagulable state (37). In cancer patients, tumor stage is also a determinant of cellular and plasma hypercoagulability (38).

Tumor stage had a significant impact on the concentration of the procoagulant platelet

derived microparticles (Pd-MP) and procoagulant phospholid dependent clotting time (PPL-ct). Patients with metastatic disease had significantly higher levels of Pd-MP and platelet-derived microparticles expressing phosphatidylserin (Pd-MP/PS+) compared to patients with regional stage (38). In this study, our findings are consistent with this. As tumors progress, the incidence of VTE also increases gradually. In addition, tumor stage has also been shown to be associated with recurrence of VTE (39).

Prolonged mechanical ventilation significantly increases the incidence of VTE (40-44). The prolonged duration of ventilator means that the patient remains immobile for a longer period of time, with slow venous blood flow in the lower extremities, which may lead to blood stasis and subsequent VTE (45). In addition, prolonged ventilator duration may be associated with disease severity and the development of postoperative complications, which may also be an important reason for the increased incidence of VTE. Our study also verified that ventilator duration was an independent risk factor for developing VTE after dCCA surgery.

D-dimer is a degradation product of cross-linked fibrin, indicating overall coagulation activation and fibrinolysis. As a common blood biomarker, D-dimer has been widely used in the prediction of VTE (46-48). D-dimer has a high sensitivity, but there is also a problem of poor specificity, because surgery, drugs and other factors can cause significant fluctuations in D-dimer. Therefore, in this study, we included preoperative D-dimer (pre-D-dimer) in the analysis, which we believe is more reflective of whether the patient is already in a hypercoagulable state. The results showed that pre-D-dimer was indeed an independent risk factor for postoperative VTE.

Based on the above independent risk factors, we constructed nomogram to predict the incidence of postoperative VTE. Because of the complexity of PD or PD with allogeneic venous replacement, there is a high risk of hemorrhage after surgery, which also poses some challenges for the use of prophylactic anticoagulants. Therefore, it is critical to identify people at true high risk of VTE, which may avoid hemorrhage from unnecessary anticoagulation. Compared with traditional risk assessment models, this nomogram may be more effective in VTE assessment in this population after dCCA surgery. Appropriate prophylactic anticoagulation helps to improve the prognosis of cancer patients (49).

Our study also has some limitations as follows. First, this was a single-center retrospective study and the study results required external validation. Second, the study sample size is small. A multicenter study with a large sample size is still needed to further explore in the future. Finally, this study included patients who underwent dCCA surgery, so whether the results could be applicable in other types of patients also needs to be confirmed by more studies.

Patients undergoing dCCA surgery have a high prevalence of VTE and are associated with long-term adverse outcomes. Age, operation procedure, TNM stage, ventilator duration, and pre-D-dimer were independently associated with VTE in patients after dCCA surgery. We developed a nomogram assessing the risk of VTE, which may help clinicians to screen out people at high risk of VTE for further anticoagulation.

Ethics approval

All surgical procedures and therapies were consented by patients and their family members. All allogeneic vessels (AGV) were obtained during organ procurement underwent by OPO and were approved by Ethnic Committee and Committee for Clinical Application of Medical Technology of our hospital (No. 2020-D-301). All procedures in this study involving human participants were performed in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration.

Consent for publication

Not applicable.

Availability of data and materials

The data used and analyzed in this study is included in the article or are available from the corresponding and first authors on reasonable request.

Competing interest

The authors declare that there has no conflict of interest.

Funding

None.

Authors’ contributions

Contributions: (I) Conception and design: Qing Chen, Songping Cui, Jincan Huang; (II)Administrative support: Shaocheng Lyu, Ren Lang; (III) Provision of study materials or patients: Shaocheng Lyu, Ren Lang; (IV) Collection and assembly of data: Jing Wang, Di Wang, Hanxuan Wang; (V) Data analysis and interpretation: Qing Chen, Songping Cui, Jincan Huang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work

Acknowledgment

None

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Table 1 Baseline characteristics of patients undergoing dCCA surgery

Variable	Total	Non-VTE(n=113)	VTE(n=64)	p value
Age, mean (SD), y	65.2(9.6)	64.1(9.4)	68.4(7.8)	＜0.01
Sex (n/%)				0.74
Male	108(61)	70(61.9)	38(59.4)
Female	69(39)	43(38.1)	26(40.6)
BMI, mean (SD), kg/m²	24.1(3.1)	23.9(3.2)	24.5(2.8)	0.22
Cerebrovascular diseases (n/%)	95(53.7)	56(49.6)	39(60.9)	0.14
Smoking (n/%)	53(29.9)	38(33.6)	15(23.4)	0.15
Diabetes (n/%)	49(27.7)	31(27.4)	18(28.1)	0.92
CA199, median (IQR), U/mL	66.5(278.5)	48.9(146.3)	135.4(881)	0.17
Biliary drainage (n/%)				0.83
PTBD	66(37.3)	38(33.6)	28(43.8)
ENBD	21(11.9)	15(13.3)	6(9.4)
OP procedure (n/%)				0.02
PD	150(84.7)	102(90.3)	48(75.0)
PD with allogeneic venous replacement	27(15.3)	11(9.7)	16(25.0)
Blood loss, median (IQR), mL	500(250)	500(200)	500(400)	＜0.01
Transfusion, median (IQR), mL	0(400)	0(400)	400(400)	＜0.01
OP time, mean (SD), h	10.1(2.3)	9.9(1.9)	10.6(2.8)	0.07
Grading of cancer (n/%)				0.36
Low	54(30.5)	31(27.4)	23(35.9)
Intermediate	91(51.4)	61(54.0)	30(46.9)
High	32(17.9)	21(18.6)	11(17.2)
TNM stage (n/%)				＜0.01
I	4(2.3)	4(3.5)	0(0)
II	143(80.8)	95(84.1)	48(75)
III	22(12.4)	13(11.5)	9(14.1)
IV	8(4.5)	1(0.9)	7(10.9)
Ventilator duration, median (IQR), h	14(6.5)	13(4)	16.5(17)	＜0.01
ICU, median (IQR), day	3(3)	2(3)	3(4.75)	＜0.01
Pre-D-dimmer, mean (SD), mg/L	0.8(0.7)	0.7(0.7)	1(0.6)	＜0.01

Abbreviations: dCCA, distal cholangiocarcinoma; VTE, venous thromboembolism; SD, standard deviation; BMI, Body Mass Index; CA199, carbohydrate antigen 199; IQR, interquartile range; PTBD, Percutaneous Transhepatic Biliary Drainage; ENBD, Endoscopic Nasobiliary Drainage; OP, operation; PD, pancreaticoduodenectomy; ICU, Intensive Care Unit; Pre-D-dimme, preoperative D-dimer.

Table 2 Factors associated with the VTE in patients undergoing dCCA surgery

Variable	OR	95% CI	p value
Age	1.056	1.005-1.110	0.03
Cerebrovascular diseases	0.941	0.431-2.057	0.88
Smoking	0.512	0.219-1.200	0.12
CA199	1.000	1.000-1.000	0.99
OP procedure	3.120	1.037-9.386	0.04
Blood loss	1.001	1.000-1.002	0.16
Transfusion	1.000	0.999-1.001	0.87
TNM stage	2.572	1.235-5.355	0.01
Ventilator duration	1.019	1.000-1.039	0.05
ICU	1.028	0.915-1.154	0.64
Pre-D-dimer	1.875	1.053-3.340	0.03

Abbreviations: VTE, venous thromboembolism; dCCA, distal cholangiocarcinoma; CA199, carbohydrate antigen 199; OP, operation; ICU, Intensive Care Unit; Pre-D-dimme, preoperative D-dimer.

Table 3 Factors associated with the VTE in the training group

Variable	Univariate analysis		Multivariate analysis
Variable	OR (95% CI)	p value	OR (95% CI)	p value
Age	1.055 (1.009-1.102)	0.02	1.055(1.007-1.106)	0.02
Sex	1.646 (0.774-3.499)	0.25
BMI	1.129 (0.973-1.309)	0.43
Cerebrovascular diseases	1.256 (0.595-2.653)	0.55
Smoking	0.631 (0.291-1.369)	0.63
Diabetes	1.011 (0.456-2.240)	0.98
CA199	1.000 (0.997-1.000)	0.26
Biliary drainage	1.143(0.687-1.903)	0.61
OP procedure	3.661(1.340-10.001)	0.01	3.025(1.090-8.397)	0.03
Blood loss	1.001(1.000-1.002)	0.01	1.001(1.000-1.003)	0.19
Transfusion	1.001(1.000-1.002)	0.01	1.000(0.999-1.001)	0.80
Grading of cancer	0.772(0.457-1.307)	0.34
TNM stage	2.103(1.029-4.297)	0.04	2.296(1.149-4.586)	0.02
Ventilator duration	1.024(1.003-1.045)	0.03	1.019(1.000-1.039)	0.04
ICU	1.164(1.033-1.312)	0.01	1.036(0.927-1.158)	0.53
Pre-D-dimmer	1.991(1.056-3.756)	0.03	1.829(1.036-3.231)	0.04

Abbreviations: VTE, venous thromboembolism; CA199, carbohydrate antigen 199; OP, operation; ICU, Intensive Care Unit; Pre-D-dimme, preoperative D-dimer.

No competing interests reported.

Venous Thromboembolism in Patients Undergoing Distal Cholangiocarcinoma Surgery: Prevalence, Risk Factors, and Outcome

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Abstract

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Introduction

Materials And Methods

Results

Discussion

Conclusion

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References

Tables

Additional Declarations

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