CRAT is an under-described yet growing problem [11]. Several studies report a broad range of prevalence rates of CRAT in adults [12] between 2 and 12.8% [6] and even up to 29% in a prospective postmortem study [7]. The difference in the published incidence rates could be explained by the asymptomatic nature of many CRAT cases [6]. The available statistics from the pediatric literature are scarce. In their retrospective review of 156 children with cancer, Korones et al. reported an incidence rate of 8.8% of CRAT in their cohort diagnosed on routine echocardiograms [13]. We identified CRAT only in 6 (0.79%) patients in our cohort of 764 children. We are not able to explain the discrepancy between our and Korones et al.’s results, but it could be related to the site catheter-tip location whereby we showed that the risk of CRAT development is increased in patients in whom the catheter tips were located within the right atrium at the time of the catheter insertion; most of the CRAT cases reported in Korones et al.’s paper had their catheter-tips placed within the right atrium.
Three (50%) patients in the CRAT group were diagnosed incidentally on routine echocardiograms, and three had symptoms that prompted the echocardiogram including two patients with anterior chest swelling and one patient with catheter malfunction. This is in agreement with many previous published studies that concluded that many of the CRAT cases are asymptomatic [6]. In this study, we observed a statistically significant preponderance of female gender in the CRAT group as compared to the control group: 44 (36.7%) versus 5 (83.3%) with a p value of 0.022 (Table 1). In the previously published literature, there appears to be no statistical difference in the propensity of developing CRAT between the male and female genders [13, 14].
It has been suggested in the literature that children with ALL are more prone to catheter-related thrombosis when compared to children with other types of malignancies [13]; this is due to hemostatic alterations in patients with ALL that are apparent prior to therapy with a cumulative effect that leads to a hypercoagulable state in the patients [15]. In addition to hemostatic changes, ALL patients are at an increased risk of thrombotic events due to the chemotherapeutic agents’ effect on hemostatic proteins and endothelium [16]. Similarly, in our study, 5 out of 6 patients who developed CRAT had active ALL.
Male et al. concluded that the risk of catheter-related atrial thrombosis is increased in patients with left-sided catheters (p=0.048) and when catheters are inserted in the subclavian vein (p=0.025) [17]. On the other hand, Chick et al. showed no statistically significant difference in the risk of CRAT development in relation to the site and laterality of catheter insertion (p=0.23 and p=0.52, respectively) [18]. In our study, most of the patients who developed CRAT had a catheter placed in the right external jugular vein 5 (83.3%); however, this is probably related to our local preference of line placement, whereby we place most of our catheters through the right external jugular vein.
Korones et al. demonstrated a significantly higher prevalence of CRAT in patients in whom the catheter tips were placed within the right atrium as compared to the superior vena cava (20 versus 2%, p=0.004) [13]. Other authors showed up to a 46.2% increase in the incidence of CRAT when the tip was placed in the right atrium [19]. The thrombogenic phenomenon is initiated by the right atrial wall endothelial damage that is seen because of the mobile catheter tip that is free-floating in the beating right atrium [8, 20]. None of our patients who developed CRAT had their catheter tips positioned in the distal superior vena cava, and three patients (50%) had their catheter-tips in the right atrium and three (50%) at the superior vena cava-right atrial junction. However, in the control group, 120 (100%) had their catheter-tips placed at the superior vena cava-right atrial junction at the time of placement; this difference statistically significant (p value=0.000). This relatively higher tendency of CRAT development in patients in whom the catheter tips are placed in the right atrium could be explained by the fact that in these situations, the catheters might change position from the initial insertion placement because of physical activity, thus promoting thrombus formation [8]. On the other hand, in patients in whom the catheters are placed within the distal SCV, the catheters tend to stay in place, hence the lower chances of developing CRAT [8].
Multiple risk factors have been identified for the development of catheter-related thrombotic complications [21]. Various chemotherapeutic agents have been recognized in the literature as independent thrombogenic risk factors in cancer patients particularly 5-fluoro-uracil, cisplatin, and L-asparaginase [22]. L-asparaginase, a widely used chemotherapeutic agent, has a well-established risk of thrombosis. L-asparaginase increases the risk of thrombosis by decreasing the formation of proteins implicated in coagulation and fibrinolysis such as plasminogen, anti-thrombin III, and the anticoagulant proteins C and S [23]. Steroids are also given with chemotherapeutic agents for the treatment of malignancies, which further increases the risk of thrombosis. Steroids can lead to an increase in Von Willebrand factor, clotting factor VIII, prothrombin, and antithrombin III [24]. In our study, we have identified five out of six patients with CRAT who received both L-asparaginase and steroids at the time when the right atrial clot was diagnosed.
Catheter-related bloodstream infection has been identified in the literature as a risk factor for catheter-related atrial thrombosis [25]. The infectious process can initiate the thrombosis cascade or the thrombus itself can be a medium for infection [26]. The inflammatory process associated with systemic infections has also been implicated in the development of thrombi. While 47 (39.2%) of patients in the control group developed systemic infection while the catheter was in place, all the patients who developed CRAT had either positive blood cultures, urine cultures, or both in the presence of the central venous catheter. This, however, did not reach the level of statistical significance (p value=0.180).
CRAT may develop any time after the catheter placement; some authors have reported CRAT within a week after insertion [19, 21], while others have reported CRAT that was diagnosed around a year after the catheter was removed [13]. In our series, the mean timing for the diagnosis of the atrial clot was 5.00 ± 3.24 months after insertion.
Recommendations for screening patients with IVADs for CRAT are equivocal. Some authors have recommended echocardiograms in patients with catheter dysfunction [27]; others have recommended screening in high-risk patients such as in patients with the catheter tips situated in the right atrium and patients on pharmaceutical agents with known thrombogenic potentials such as L-asparaginase [28], while others went further and recommended routine screening echocardiographs in all patients with long-term central venous catheters.
Guidelines for thrombosis prophylaxis in children with long-term IVADs are not clear in the literature, with most evidence being not in favor of prophylaxis. A systematic review of more than 3000 children concluded that thromboprophylaxis in the pediatric population does not reduce the incidence of catheter-related thrombotic complications [29]. In our practice, we do not provide prophylactic anti-thrombotic agents to patients with IVADs and none of the identified patients with CRAT received any prophylaxis against thrombosis prior to the diagnosis of the complication.
The literature lacks high-quality evidence for the best treatment option for CRAT, especially when it comes to the pediatric population as most of the treatment protocols are derived from adult literature [30, 31]. The treatment approach depends mainly on the size of the clot and the medical status of the patient [6]. Clot size exceeding 2 cm, anti-coagulation contraindications, and hemodynamic instability favor surgical excision of the thrombus [6, 27]. Thrombolysis of the clot is not without risks, pulmonary embolism from the disintegration of the clot has been reported in the literature [27], systemic embolisms due to a patent foramen ovale can also occur [32]. Systemic anticoagulation and subsequent catheter removal are generally recommended as the first-line therapy in uncomplicated cases of catheter-related atrial thrombosis [6]. One study reported effective treatment of 20 adult hemodialysis patients with anticoagulation and catheter removal and positioning the new catheter-tip at a different location from the clot [9].
Some authors advocate for catheter removal regardless of the circumstances; Stavroulopoulos et al. concluded in their meta-analysis of 71 CRAT cases in hemodialysis patients that catheters of confirmed CRAT patients should be removed because of the high morbidity and mortality rates that accompany catheter preservation [6]. The worse outcomes correlated with retaining the catheter in place are potentially due to the mechanical damage caused by the catheter-tip on the atrial walls, especially when the tip is positioned in the right atrium instead of the distal superior vena cava, in addition to the possible bacterial colonization of the catheter. On the other hand, successful treatment of CRAT with anticoagulation without having to remove the catheter in stable and asymptomatic patients has been frequently reported in the literature [21]. Chick et al. reported successful preservation of 92% of the catheters in incidentally diagnosed CRAT [18]. All our CRAT patients received low molecular weight heparin (subcutaneous enoxaparin sodium) starting at a dose of 1mg/kg/dose twice daily with doses adjustment based on monitoring of anti-Xa levels and for a minimum of 3 months if the catheter remained in situ. The catheters were removed in the three symptomatic patients and preserved in the three asymptomatic patients.
Due to its retrospective nature, this study falls into inherent limitation gaps including missing data in the medical records and possibly inaccurate information due to the loss of some patients to follow-up.
