Abstract

Background: This study aims to identify risk factors of venous thromboembolism in the patients undergoing thoracic surgery.

Methods: A total of 167 patients (107 males, 60 females; mean age 56.7±16.8 years; range 16 to 81 years) who underwent thoracic surgery between September 2015 and December 2016 were included in this study. D-dimer and C-reactive protein values were analyzed and clinical data recorded. The patients received color Doppler ultrasound and thoracic computed tomography before and after surgery. The risk factors for venous thromboembolism were analyzed.

Results: Of the patients, 57 (34.1%) developed venous thromboembolism after thoracic surgery, among whom two patients developed pulmonary embolism and another 55 developed deep vein thrombosis. Age, D-dimer, operation time, and body mass index of venous thromboembolism patients were significantly higher than non-venous thromboembolism patients. There was no significant difference in the C-reactive protein values between the two patient groups. Age, smoking history, operation time, and body mass index were found to be the risk factors of venous thromboembolism. There was a significant difference in the incidence of venous thromboembolism among different surgeries. The patients who underwent esophagectomy had the highest incidence of thrombosis.

Conclusion: Age, smoking history, operation time and body mass index are independent risk factors for venous thromboembolism. A special attention should be given to the patients undergoing esophagectomy to prevent the development of venous thromboembolism.

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a fatal disease which is associated with significant morbidity and mortality. A recent study have shown that the overall incidence of VTE among 100,000 individuals is around 422 cases, and approximately 26 cases increase per 100,000 every year.[1] Studies have demonstrated that surgical procedures, including neurosurgery, major orthopedic surgery of the leg, thoracic surgery, abdominal surgery, renal transplantation, and cardiovascular surgery are all risk factors for VTE.[2] Therefore, prevention and treatment of VTE in patients undergoing surgery is particularly urgent.

Thoracic surgeries are mainly composed of open chest surgeries, which are associated with more postoperative complications, take longer time, and bring more surgical trauma to patients. Postoperative VTE is one of common and serious complications in patients undergoing thoracic surgery. In the autopsy cases of thoracic surgery, the incidence of VTE was found to be as high as 6.6%.[3] The success of thoracic surgery refers to not only the operation itself, but also the effective prevention of postoperative complications, including VTE.

In the present study, we aims to identify risk factors of VTE in the patients undergoing thoracic surgery to provide theoretical data for the prevention of VTE following thoracic surgery.

Methods

This prospective study was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University. A written informed consent was obtained from each patient. The study was conducted in accordance with the principles of the Declaration of Helsinki.

A total of 167 patients (107 males, 60 females; mean age 56.7±16.8 years; range 16 to 81 years) who underwent thoracic surgery in the Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University between September 2015 and December 2016 were included in this study. Blood samples of all the patients were taken to analyze D-dimer (DD) and C-reactive protein (CRP) at the time of admission, and all the patients underwent color Doppler ultrasound (CDU) and thoracic computed tomography (CT) before operation to identify the occurrence of VTE. Patients who had VTE before surgery were excluded from the study. Those who had cardiovascular and cerebral vascular diseases, diabetes and other documented inflammatory, hemorrhagic, and thrombotic diseases within the past six months were also excluded. Pregnant and lactating women and women using oral contraceptives were also ruled out.

All patients were instructed to wear compression stockings on the night before surgery and took off stockings until they were able to walk. Lowmolecular- weight heparin (LMWH) was allowed to be administered (5,000 IU, once daily) from the first day after surgery and discontinued until hospital discharge. After surgery, on the day thoracic drainage was ended, the patients underwent repeated CDU and thoracic CT to evaluate the development of VTE. The CDU and CT examination were performed by three professional physicians from the ultrasonography department and imaging department, respectively to ensure the accuracy of the results, and all physicians had at least five-year clinical experience. Deep vein thrombosis refers to the occurrence of new blood clot or thrombus within the venous system, and PE refers to the occurrence of new blood clot in a pulmonary artery with a subsequent obstruction of blood supply to the lung parenchyma. The patients who developed either DVT or PE or both were accepted as VTE. Data including age, gender, smoking history, body mass index (BMI), operation time, and type of surgery were collected from the medical records or electronic database.

Statistical analysis
Statistical analysis was performed using the IBM SPSS version 22.0 software (IBM Corp., Armonk, NY, USA). Continuous variables were presented in mean ± standard deviation (SD) and median (minmax) and compared using the Student’s t-test, while categorical variables were presented in frequency and percentage and compared using the chi-square test. Multivariate logistic regression analysis was used to obtain the odds ratio (OR) and corresponding 95% confidence interval (CI) to analyze the risk factors. Continuous variables were modeled linearly per unit and categorical measures were modeled with the use of indicator variables for each level compared to the lowest level. A p value of <0.05 was considered statistically significant.

Results

A total of 75 patients (44.9%) had smoking history. Among all patients, 61 (36.5%) received pulmonary lobectomy, 44 (26.3%) received esophagectomy, and pulmonary wedge resection was applied to 42 (25.1%). Fourteen patients (8.4%) underwent mediastinal-pericardial resection, while six patients (3.6%) underwent other surgeries, such as open chest exploration, and resection of the chest wall tumor. Baseline demographic and clinical characteristics of the patients are shown in Table 1.

Table 1: Demographic and clinical characteristics of patients

Postoperatively, the mean drainage duration was 5.3+3.6 (range, 3 to 9) days. Among 167 patients, 57 (34.1%) had VTE (positive group) and 110 (65.9%) had no VTE (negative group) on the day thoracic drainage was discontinued. In the positive group, two patients (3.5%) developed PE and 55 patients (96.5%) developed DVT. No complications of thromboprophylaxis such as severe bleeding and hypotension were found. Age (p<0.001), DD (p=0.009), operation time (p<0.001), and BMI (p<0.001) of the positive group were higher than the negative group, indicating a significant difference between the two groups. However, there was no significant difference in the CRP values (p=0.477) between the two groups. The analysis results are shown in Table 2.

Table 2: Analysis results of patients

Among 167 patients who underwent surgery in thoracic department, 61 received pulmonary lobectomy, among whom 21 (34.4%) had VTE after surgery. A total of 44 patients received esophagectomy and, of these, 25 (56.8%) developed VTE. A total of 42 patients accepted pulmonary wedge resection, among whom four (9.5%) developed VTE. Of 14 patients who underwent mediastinal-pericardial resection, five (35.7%) had VTE after surgery. Among other six surgeries, only two patients (33.3%) had VTE after surgery (Figure 1). There was a significant difference in the incidence of VTE among different operations.

Figure 1: Rate of venous thromboembolism in different surgical groups.
A: Pulmonary lobectomy; B: Esophagectomy; C: Pulmonary wedge resection; D: Mediastinal-pericardial resection; E: Other surgeries.

Multivariate logistic regression analysis showed that age (OR:1.065, 95% CI:1.031-1.101, p<0.001), smoking history (OR:1.005, 95% CI:1.001-1.010, p=0.044), operation time (OR:2.205. 95% CI:1.022- 4.756, p=0.016), and BMI (OR:2.220, 95% CI:0.953- 5.169, p=0.034) were found to be related with the incidence of VTE, suggesting that they were significant predictors of the development of VTE after thoracic surgery (Table 3).

Table 3: Results of multivariate logistic regression analysis

Discussion

Venous thromboembolism, including DVT and pulmonary embolism, refers to the abnormal coagulation of the blood in venous, blocking the vessels and inducing a series of clinical symptoms and complications. In the United States, VTE affects 350,000 to 600,000 individuals every year and more than 100,000 individuals die annually.[4] Previous studies considered VTE as a rare disease in Asia.[5,6] However, many recent studies found that the incidence of VTE was not as low as previously thought, on the contrary, incidence of VTE may be increasing in recent years.[7] As listed at the beginning, lots of surgeries are risk factors for VTE,[2] and the risk for thrombosis would persist over several months post-surgery;[8] therefore, it is quite significant to do the prevention of VTE in patients postoperative.

It is widely known that VTE is predominantly a disease of older age, and studies have also demonstrated that VTE is rare in children younger than 15 years.[9,10] In our study, age was also a risk factor for VTE, and the mean age of the positive group (65.3±10.1 years) was almost 13 years older than the negative group (52.3±17.8 years). We also found that none of the patients under 33 years had VTE after surgery. Therefore, our study also demonstrated that the incidence of VTE increased with age, which is consistent with previous findings.[11,12]

Several studies showed that male patients had a higher risk than females for the development of VTE.[13] A population-based cohort study also found that incidence of VTE was 1.3 per 1,000 personyears in men and 1.1 per 1,000 person-years in women respectively.[14] A mong 1 67 p atients i n o ur study, 38/107 men (35.5%) and 19/60 women (31.7%) developed VTE after surgery, which is consistent with previous findings.

Among various coagulation and inflammatory factors, more attention has been paid to DD and CRP. The former is a degradation product of cross-linked fibrin, which reflects the fibrinolytic activity and coagulation function in vivo. It has long been regarded as a sensitive indicator of ruling out VTE,[15] which means, if the DD level is negative, thromboembolic disease can be excluded. The latter is a type of acute inflammatory reaction protein, and higher levels of CRP indicate the activation of the inflammatory reaction mechanism.[16] Evidences show that CRP levels are higher during the acute and subacute phases of VTE, and remain higher in VTE patients even months or years later.[17,18] A study showed that patients with high values of CRP were at two-fold risk for VTE, compared to those with low values.[19] I n o ur s tudy, w e f ound t hat D D o f p ositive group (1.6±2.6 mg/L) was significantly higher than the negative group (0.9±0.6 mg/L), while there was no significant difference in the CRP values between the two groups. However, multivariate regression analysis revealed that neither DD nor CRP were the risk factors for VTE, although this can be attributed to the small sample size.

In our study, we found that operation time of the positive group (225.1±82.2 min) was significantly higher than the negative group (170.5±88.9 min). Saluja and Gilling[20] s ummarized t he r isk f actors f or V TE within the urological population and found the risk was further aggravated, if patients underwent an operative procedure, particularly when the time of operation was more than two hours. It is easier to understand that longer operation can cause blood flow slowly and requires more hemostatic agents in the process of anesthesia. Longer operation also brings more harm to the blood vessel wall, and injury of vessel wall disrupts the endothelial barrier. Longer operations may also prolong the time stay in bed after surgery. All these results of conger operation can thereby cause thrombus formation and increase the risk of postoperative VTE. Previous studies also have shown that obesity, assessed by BMI, is an independent risk factor for predicting VTE.[21] I t h as b een a p referable anthropometric measure of obesity for decades.[22] The results of our study showed that BMI of positive group (23.3±1.8 kg/m2) was significantly higher than the negative group (21.3±1.9 kg/m2), and regression analysis also indicated that BMI was a risk factor of VTE.

Our study also indicated that significant difference of the incidence of VTE was found among these different operation groups, and patients received esophagectomy had the highest incidence of VTE after surgery. This may be mainly due to the longer operation time of esophagectomy, which may be different due to surgeon’s surgical level and the complexity of the operation. Pulmonary wedge resection group had the lowest incidence of VTE, the reason may be that many patients were young and the operation time was short. Therefore, our study suggests that more attention should be given to the patients undergoing esophagectomy to prevent VTE among different thoracic surgeries.

The latest guideline of the American College of Chest Physicians (ACCP) recommends that routine thromboprophylaxis should be implemented in thoracic surgery.[23] I n o ur s tudy, a ll p atients r eceived LMWH from the first day after surgery to the day of discharge, and no complications such as bleeding were found among all these patients. However, previous studies revealed that in-patient VTE prophylaxis did not reduce the risk of post-discharge VTE,[24] and a recently meta-analysis revealed that benefit of thromboprophylaxis was unclear;[25] therefore, further studies should be carried out to evaluate the efficacy of thromboprophylaxis.

Nonetheless, there are some limitations to this study. First, unlike studies based on several medical centers which had large samples, our study was based on a single center and had a relatively small size. Therefore, the results may have little representation to some extent and may not be applied to other hospitals. Second, the diagnosis of VTE in our study mainly was based on the use of CDU and thoracic CT scan. Although these examinations were performed by three professional physicians, subjective error may be inevitable. In order to avoid missed diagnosis, non-VTE patients may be diagnosed as VTE patients, which may lead to the high incidence of VTE in our study. Another issue should be noted is that to prevent excessive bleeding, hemostatic drugs were used on the day of surgery, which may also affect the incidence of thrombosis in our study.

In conclusion, our study results suggest that age, smoking history, operation time, and Body Mass Index are independent risk factors for the occurrence of venous thromboembolism. Among all the thoracic surgeries, a special attention should be given to the patients undergoing esophagectomy to prevent the development of venous thromboembolism. To prevent venous thromboembolism, thromboprophylaxis should be implemented in the thoracic department and further well-designed, multi-center, large-scale studies should be carried out in the future.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
This work was supported by the Beijing science and technology development fund project of traditional Chinese medicine (JJ2015-09).

References

1) Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol 2011;86:217-20.

2) White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost 2003;90:446-55.

3) Rastan AJ, Gummert JF, Lachmann N, Walther T, Schmitt DV, Falk V, et al. Significant value of autopsy for quality management in cardiac surgery. J Thorac Cardiovasc Surg 2005;129:1292-300.

4) Lau BD, Shaffer DL, Hobson DB, Yenokyan G, Wang J, Sugar EA, et al. Effectiveness of two distinct web-based education tools for bedside nurses on medication administration practice for venous thromboembolism prevention: A randomized clinical trial. PLoS One 2017;12:e0181664.

5) Hwang WS. The rarity of pulmonary thromboembolism in asians. Singapore Med J 1968;9:276-9.

6) Yeo DX, Junnarkar S, Balasubramaniam S, Tan YP, Low JK, Woon W, et al. Incidence of venous thromboembolism and its pharmacological prophylaxis in Asian general surgery patients: a systematic review. World J Surg 2015;39:150-7.

7) Sakon M, Kakkar AK, Ikeda M, Sekimoto M, Nakamori S, Yano M, et al. Current status of pulmonary embolism in general surgery in Japan. Surg Today 2004;34:805-10.

8) Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet 2005;365:1163-74.

9) Heit JA, Silverstein MD, Mohr DN, Petterson TM, Lohse CM, O’Fallon WM, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001;86:452-63.

10) Stein PD, Patel KC, Kalra NK, El Baage TY, Savarapu P, Silbergleit A, et al. Deep venous thrombosis in a general hospital. Chest 2002;122:960-2.

11) De Martino RR, Goodney PP, Spangler EL, Wallaert JB, Corriere MA, Rzucidlo EM, et al. Variation in thromboembolic complications among patients undergoing commonly performed cancer operations. J Vasc Surg 2012;55:1035-40.

12) Oger E. Incidence of venous thromboembolism: a communitybased study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000;83:657-60.

13) Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008;28:370-2.

14) Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004;117:19-25.

15) Kelly J, Hunt BJ. A clinical probability assessment and D-dimer measurement should be the initial step in the investigation of suspected venous thromboembolism. Chest 2003;124:1116-9.

16) Auer J, Berent R, Lassnig E, Eber B. C-reactive protein and coronary artery disease. Jpn Heart J 2002;43:607-19.

17) Krieger E, van Der Loo B, Amann-Vesti BR, Rousson V, Koppensteiner R. C-reactive protein and red cell aggregation correlate with late venous function after acute deep venous thrombosis. J Vasc Surg 2004;40:644-9.

18) Bakirci EM, Topcu S, Kalkan K, Tanboga IH, Borekci A, Sevimli S, et al. The role of the nonspecific inflammatory markers in determining the anatomic extent of venous thromboembolism. Clin Appl Thromb Hemost 2015;21:181-5.

19) Zacho J, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein and risk of venous thromboembolism in the general population. Arterioscler Thromb Vasc Biol 2010;30:1672-8.

20) Saluja M, Gilling P. Venous thromboembolism prophylaxis in urology: A review. Int J Urol 2017;24:589-93.

21) Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002;162:1182-9.

22) Ay C, Tengler T, Vormittag R, Simanek R, Dorda W, Vukovich T, et al. Venous thromboembolism--a manifestation of the metabolic syndrome. Haematologica 2007;92:374-80.

23) Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:381-453.

24) Mahan CE, Fisher MD, Mills RM, Fields LE, Stephenson JJ, Fu AC, et al. Thromboprophylaxis patterns, risk factors, and outcomes of care in the medically ill patient population. Thromb Res 2013;132:520-6.

25) Carrier M, Khorana AA, Moretto P, Le Gal G, Karp R, Zwicker JI. Lack of evidence to support thromboprophylaxis in hospitalized medical patients with cancer. Am J Med 2014;127:82-6.