A retrospective analysis of risk factors associated with catheter-related thrombosis: a single-center study

Background: Catheter-related thrombosis may lead to catheter infections and failure, further deep venous thrombosis, and pulmonary embolism. Recognizing the risk factors for catheter-related thrombosis is extremely important to inform the development of catheter care guidelines. Methods: Data were collected from a total of 1,532 patients who had undergone venous catheterization, including indwelling catheterization from 19 March 2019 to 30 March 2019 in the Sun Yat-sen Memorial Hospital. The factors for which data were to be collected included the patients’ physical characteristics, catheter-related factors, and catheter care-related factors. Logistic regression analysis, the chi-squared test, Fisher’s exact test, and the t-test were used to analyze the data. Results: Of the 1,532 patients studied, 28 developed intraductal thrombi, and of the factors analyzed, malignancy, a catheterization history, a history of thrombophilia, surgery during the week before catheterization, the catheterization duration, and anticoagulant therapy were significant risk factors associated with catheter-related thrombosis (all p < 0.05). There were no significant associations between the catheter brand, the number of lumens, the insertion direction, or the factors associated with catheter care and catheter-related thrombosis (all p > 0.05). Conclusion: Our study incorporated clear and systematic risk factors associated with catheter-related thrombosis. Malignancy, history of thrombophilia, history of catheterization, surgery during the week before catheterization, and catheterization duration were associated with increased risks of catheter-related thrombosis. Prophylactic anticoagulation was effective for preventing and treating catheter-related thrombosis.

damage to the vein, fibrin is deposited onto the surface of the catheter, and a large number of smooth muscles and endothelial cells quickly become embedded within the fibrin. The continuous movement of the catheter in the vein erodes the endothelial cells, which enter the catheter cavity, and this may trigger mural thrombus formation, catheter infections, deep venous thrombosis (DVT), and persistent vascular damage if they are not detected and treated promptly. 3 Patients with CRT may develop persistent vascular occlusion many years after catheter removal, thereby increasing their risk of post-thrombotic syndrome and recurrent thrombosis. 4 Furthermore, CRT may lead to pulmonary embolism (PE) which may cause death. 5 Therefore, the presence of and possible harm caused by CRT should be considered, and the risk factors associated with CRT should be determined and mitigated.
While present findings indicate that many risk factors may be associated with CRT, they are yet to be clearly defined. 1 The risk factors associated with CRT can be categorized into three groups, including patients' physical characteristics, catheter-related factors, and catheter care-related factors. 1,3 Patients' physical factors include the presence of malignancy, embolism history, and infectious disease history. [6][7][8][9][10][11] Catheter-related factors include the type of catheter implanted, catheter placement location, catheter insertion location, and the catheterization duration. [12][13][14][15] Catheter care-related factors include the infusion order and the composition of the liquid because intraductal thrombosis may be caused by drug and parenteral nutrition preparations. 16,17 However, clear and systematic descriptions of the risk factors that may be associated with CRT and its prevention do not exist. Therefore, we collected data describing the baseline characteristics of patients who had CVCs inserted, catheter-related factors, and catheter care-related factors to analyze a variety of potential risk factors that may contribute to CRT. This study aimed to identify the main hospital-based risk factors for CRT and to provide benchmarks for the clinical prevention and treatment of adverse events, including infections, catheter failure, catheter-related DVT and its sequelae, and PE, which are caused by CRT.

Data sources
The data were collected from departments that used CVCs from 19 March 2019 until 30 March 2019 at the Sun Yat-sen Memorial Hospital of Sun Yat-sen University for this retrospective analysis. The study was approved by the hospital ethics committee. We distributed questionnaires to the critical care and pediatric intensive care units, and the biliary and pancreatic surgery, pediatric, otorhinolaryngology, gynecological oncology, hepatobiliary surgery, orthopedic, respiratory, emergency, rehabilitation, stomatology, urology, thoracic surgery, general medicine, cardiovascular surgery, cardiothoracic surgery, cardiothoracic surgery, neurorheumatology, neurosurgery, nephrology, gastrointestinal surgery, gastroenterology, hematology, ophthalmology, plastic surgery, oncology, and intensive care departments, and we collected data describing pertinent factors to analyze their association with CRT.

Patient's inclusion and exclusion criteria
The inclusion criteria were patients aged <75 years who had received CVCs implantation in the aforementioned departments, including patients who received systemic malignancy treatment. The exclusion criteria were patients with CRT that were detected two weeks before their inclusion in the study, and patients with primary brain malignancy. The patients' baseline data are presented in Table 1.

CRT risk factors
The catheter-related risk factors for CRT included the catheter brand, number of catheter lumens, catheter insertion approaches, and the catheterization duration. The catheter care-related risk factors for CRT included a comparison of prefilled saline delivery devices with syringes used to draw saline. In addition, depending on the patient's condition (avoiding the vein with history of thrombosis or vasculitis) and the operator's experience, different approaches were selected including the approach of internal jugular vein, subclavian vein, and femoral vein. All catheter insertion approaches were conducted by experienced physicians conforming to the standard operating procedure of the product instructions which was universal for all patients throughout the hospital. No adverse reaction of the insertion process in our study was reported during the perioperative period.

Study endpoints
The study's clinical endpoints were the presence of intraductal thrombosis during the observation period, CRT detected using the Doppler ultrasound, computed tomography, or venography, and infections caused by CRT, further DVT, and PE. Figure 1 illustrates the clinical pathway for CRT detection.

Data analysis
The data were analyzed using the IBM ® SPSS ® software, version 20.0 (IBM Corporation, Armonk, NY, USA). The risk factors associated with CRT were determined using univariate and logistic regression analyses, and the odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from the data describing the patients' baseline characteristics, and catheter-and catheter care-related factors. The group of patients that did not have CRT represented the reference group. The chi-squared and Fisher's exact tests were used to calculate the p values for the aforementioned factors. The t-test was used to determine the significance of the catheterization duration. The associations between CRT and the presence of malignancy, history of thrombophilia, and the use of anticoagulants were analyzed using the univariate analysis only, because the data that all departments submitted were the sum.

From 19
March 2019 until 30 March 2019, a total of 1,532 patients who underwent catheterization were included in the survey. Of the patients shown in Table 1, 51.1% were male, 48.9% were female, aged smaller than 5 years were not reported, 13.3% were aged 5-15 years,   Table 1, there were no significant differences between the groups in relation to sex (p = 0.31) or age (p = 0.63). The univariate analysis of the patients' physical factors showed that the risk of CRT was lower in the patients without malignancy than that in the patients with malignancy (OR = 0.39 (95% CI = 0.18-0.82)), and the chi-squared test showed that the presence of a malignancy was significantly associated with CRT (p = 0.01). The patients without a catheterization history had a lower risk of CRT compared with that in the patients with a catheterization history (OR = 0.42 (95% CI = 0.18-0.95)), and the chi-squared test showed that the result was statistically significant (p = 0.04). The risk of CRT was lower among the patients who did not have a history of thrombophilia (OR = 0.41 (95% CI = 0.17-0.98)). Compared with the patients who had undergone surgery during the week before catheterization, those who had not undergone surgery had a significantly reduced risk of CRT (p < 0.01; OR = 0.15 (95% CI = 0.06-0.37)). The patients who used anticoagulant therapy had a significantly lower risk of CRT (OR = 0.15 (95% CI = 0.02-1.12); p = 0.03).
The analysis about catheter-and catheter care-related factors was shown in Table 2. The risk of CRT did not differ in relation to the catheter brand (p = 0.17), the catheter lumen number (p = 0.50), or the catheter insertion approach (p = 0.63). A longer catheterization duration significantly increased the risk of CRT (p = 0.036), and although prefilled saline delivery devices seemed to reduce the risk of CRT compared with the use of syringes (OR = 0.51 (95% CI = 0.22-1.21)), the difference was not significant based on the chi-squared test. In addition, Table 3 presents data describing the types of and numbers of patients with malignancy within the study population, the patients' histories of thrombophilia, and their use of anticoagulants.

Discussion
Our result had shown that the presence of malignancy, catheterization history, history of thrombophilia, surgery during the week before catheterization, the catheterization duration, and anticoagulant therapy were significant risk factors associated with CRT (all p < 0.05). Meanwhile, there were no significant associations between the catheter brand, the number of lumens, the insertion approach, or the catheter care-related factors and CRT (all p > 0.05).
A previous study showed that among catheterized patients, the CRT rate can be as high as 66%. 18 CRT can cause post-thrombotic syndrome, further DVT, PE, catheter occlusion, and catheter infections. [19][20][21] Up to 10% of patients with symptomatic CRT may have a PE. 22 Another study from 112 patients with CRT showed that post-thrombotic syndrome was difficult to relieve without removal of the CVCs and anticoagulation. 23 Although this study's findings did not indicate the presence of further venous thromboembolism, events associated with post-thrombotic syndrome were detected, and we must consider the factors that may trigger CRT to prevent more dangerous complications caused by CRT. Thrombosis occurred more frequently in patients with malignancy 24 which was consistent with our result that the presence of a malignancy increased the risk of CRT. A review of the relationship between malignancy and thrombosis at the molecular level suggested that malignancy cells can show the abnormal expression of tissue factor (TF), release malignancy cell-derived TF particles, and express cancer coagulation factors and cell surface proteases that directly promote coagulation. In addition, cancer cells can release cytokines, factor X-activating cysteine protease, mucinous glycoproteins, or circulating TF-bearing microparticles that affect platelets, white blood cells, and endothelial cells, thereby promoting thrombosis indirectly. 25 Meanwhile, malignancy may differentially express the genes including RAS family, phosphatase and tensin homolog (PTEN), and tumor protein p53 (TP53) that influence the genesis of thrombosis. 26,27 Malignancy is associated with a high risk of CRT, especially among patients with advanced or active malignancy, 24 and this demands clinical attention. The 2019 version of the National Comprehensive Cancer Network (NCCN) guidelines on cancer-related venous thromboembolic diseases recommended that prophylactic anticoagulation therapy should administered to patients who have been diagnosed with cancer or were clinically suspected of cancer. 28 Many studies' findings have demonstrated the efficacy and safety of rivaroxaban administered to cancer patients to prevent thrombosis. [29][30][31][32][33] Our clinical practice indicated that rivaroxaban may be the first choice for anticoagulation in cancer patients with CVCs; these findings will be verified in further trials.
This study's data demonstrated that a history of thrombophilia was associated with a greater risk of CRT. Previous study's findings have shown that a history of venous thromboembolism was the most important external risk factor for predicting CRT (OR = 2.0 (95% CI = 1.1-3.9)). 12 Besides, as loads of evidence shown, the platelet count and inflammatory factors such as interleukin (IL)-3, IL-6, and thrombopoietin (TPO) in inflammatory bowel disease (IBD) were significantly higher, which was considered to be related to the intestinal inflammatory response. 34,35 Previous study have shown that during infectious disease such as pneumonia and cutaneous infection, platelets interact with neutrophils by multiple interactions leading to endothelial damage, platelet activation and aggregation, and increases in pro-coagulant proteins such as TF, F VII/F VIIa, and thrombin driving thrombi generation. 36,37 Meanwhile, multiple cytokines such as IL-1, IL-6, and tumor necrosis factor α (TNFα) released by activated leucocytes and also promote thrombi formation. 37 For the history of catheterization and surgery during the week before catheterization, Virchow's triad may help us to comprehend which described changes in the flow and composition of blood, endothelial damage, and inflammation as components that may cause thrombosis. [38][39][40] Surgery during the week before catheterization was associated with a high risk of thrombosis 41 ; hence, reasonable catheter maintenance should be achieved during the perioperative period. The 2019 version of the NCCN guidelines also recommended that prophylactic anticoagulation therapy should be administered to hospitalized and surgical patients 28 ; this was a recommendation that we follow in our hospital to prevent CRT. However, a fixed-dose schedule for the anticoagulation of CRT in surgical patients with CVCs is yet to be agreed, and the anticoagulation of CRT requires further investigation. Regarding our investigation of catheter-related factors, neither the brand nor the number of lumens of catheter influenced the risk of CRT. One study's findings showed that a greater number of lumens were associated with an increased risk of CRT. 42 The findings from a randomized controlled trial have shown that among the three approaches of CVCs implantation, a subclavian vein placement decreased the risk of CRT compared with femoral vein (hazard ratio = 3.4 (95% CI = 1.2-9.3)), jugular, and subclavian vein placements that had similar levels of risk while other studies' findings have also shown that femoral and subclavian vein catheterization did not differ regarding the overall rate of mechanical complications (17.3% vs. 18.8%; p = 0.74). 43,44 However, our analysis showed that there were no statistical differences among the three different approaches of catheter implantation in relation to the risk of CRT, which was not in accordance. Regarding the catheterization duration, we have found that a longer catheter exposure time is associated with an increased risk of CRT, which is a finding that is supported by other studies' data. 43,44 Catheter movement can damage vessels, and as the catheterization duration increases, the greater the possibility that smooth muscle cells and endothelial cells will become embedded in the fibrin on the surface or in the cavity of the catheter, thereby increasing the risks of blood infection and CRT. In terms of the catheter carerelated factors, using prefilled saline delivery devices did not differ from syringes regarding the CRT risk. A metaanalysis showed that there was no statistical difference between heparin saline and 0.9% normal saline used for catheter maintenance. 45 However, no studies have explored the differences between prefilled saline delivery devices and syringes in relation to the risk of CRT. Compared with syringes, prefilled saline delivery devices can reduce the occurrence of infections and accurately control the volume of liquid administered, and they are extremely safe. 46 Prefilled saline delivery devices may reduce the frequency of catheter infections, thereby helping to prevent CRT; however, the data do not support this notion. At present, most hospitals use syringes to draw normal saline and heparin saline to seal the tube.
Catheter care-related factors should be explored further.
Meanwhile, our study also has some limitations. First, only univariate logistic regression and chi-squared analyses were conducted because the data submitted were the sum and the confounding factor analysis was not undertaken. Second, patient inserted the catheter for transfusion of medications, blood products, antibiotics or parenteral nutrition for perioperative period, shock or other conditions depending on the attending physician. But the exact transfusion volume or time of different kinds of liquid for each patient was not recorded which may affect CRT, and further investigation was necessary to be conducted. In addition, 95% CI of some results was relatively wide and included 1 while the p < 0.05 on the ground that the number of samples may be not be adequate, so further studies involving larger scale are needed. For the reason that adverse events, including catheter failure, catheter infections, catheter-related DVT, and PE did not occur during this investigation, and a longer followup duration is needed to determine the evolution of CRT.

Conclusion
Our findings showed that the presence of malignancy, history of thrombophilia, history of catheterization, and surgery during the week before catheterization were associated with increased risks of CRT. Prophylactic anticoagulation, which we highly recommend, is an effective and safe for the prevention and treatment of CRT in hospitalized and surgical patients with CVCs.

Availability of Data and Materials
The data are shown in this article.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.