The present findings provide prospective evidence that PMT/PPMT with/without adjunctive CDTI can be used safely in children, targeting a subgroup of adolescents with DVT known to be at high a priori risk for PTS. Peri-procedural symptomatic pulmonary embolism occurred in only one patient and major bleeding was absent among 16 consecutively enrolled cases in the cohort study. Despite acute locally recurrent DVT in 40%, 83% of these were successfully re-lysed. While late recurrent DVT occurred in 27% overall, all were in the setting of severe hypercoagulable states. Although signs and/or symptoms of PTS were still observed in some patients even when PMT/PPMT was performed within 10 days of symptom onset, the rate of functionally significant PTS occurred in only 13% of these high-risk patients. These findings identify PMT/PPMT with adjunctive CDTI as worthy of further prospective study as an effective and potentially safer (vis-à-vis systemic bleeding risk) alternative to systemic thrombolysis in children with occlusive proximal limb DVT who have adverse prognostic biomarkers at acute presentation.
Several additional observations in this study are important, including use of retrievable IVC filters and endovascular stents. Outcomes for the use of retrievable IVC filters in children have rarely been reported previously. The present finding of non-retrievability in two of six cases (33%) in which retrievable IVC filters were placed is consistent with a similar observation in one of six cases in the single prospective pediatric series of IVC filter use published to date [16
]. In our series, non-retrievability was associated with accumulation of organized thrombus at the site where the filter legs apposed the IVC wall. In one case, there was a prolonged interval to filter retrieval (three months from time of placement). In the other, retrieval was within a conventional timeframe (six weeks from placement), but the patient’s course was complicated by prolonged, severe coagulation activation as multimodal immunosuppressive and antithrombotic therapies were being escalated for the treatment of thrombotic storm in APS. These cases highlight the importance of careful consideration of risks and benefits of retrievable IVC filters in children, and the need for collaborative studies to provide more extensive data on this issue in the context of a rare disease.
Our preliminary finding of a low risk of recurrent VTE following iliac vein stenting for May-Thurner anomaly in children without sever underlyinig thrombophilia is supported by the two prior series (both retrospective) in this area [17
]. None of the patients ≤ 21 years of age in these reports suffered recurrent VTE, at median follow-up durations of 11 and 18 months. Like our study, these prior series involved PMT/PPMT with/without CDTI prior to stent placement. Our prospective series involved six cases of May-Thurner anomaly. Among the five adolescents with May-Thurner anomaly in whom PMT/PPMT was performed within six weeks of symptom onset, with a median follow-up duration of 10 months, locally recurrent DVT developed in two subjects, both with severe underlying thrombophilia. In another case, recurrent VTE consisted of a distant event (subclavian DVT at the site of peripherally-inserted central catheter) unrelated to May-Thurner anomaly. Taken together, these experiences suggest that, in a disorder for which risk of recurrent VTE historically appears to be high, interventional thrombolysis with iliac vein stent placement may provide an effective means of secondary VTE prevention. However, our sample size with May-Thurner anomaly is small; as with the case of retrievable IVC filters, larger efforts are needed to adequately investigate this issue.
A recent systematic review of the literature revealed a weighted mean frequency of PTS in children of nearly 25%, albeit with considerable variability across eligible studies [3
]. Pediatric findings with the use of a standardized PTS scoring system (adapted from Villalta scale) were first published in 2003 in a retrospective analysis by the Childhood Thrombophilia Program at the Hospital for Sick Children [19
]; this study reported a prevalence of PTS of 63%. Prospective evidence using a pediatric PTS outcome measure, the Manco-Johnson instrument (for which validation data were subsequently published [2
]), has indicated a cumulative incidence of PTS (as defined by physical or functional findings) of 33% at 1–2 years among unselected children [11
]. In addition, a cumulative incidence of 77% was observed at approximately 2 years using the Manco-Johnson instrument in a small cohort of children with completely-occlusive lower limb DVT treated with standard anticoagulation in whom plasma levels of factor VIII and D-dimer were acutely elevated [2
]. In this latter group, the frequency of PTS characterized by both physical and functional findings was 31%. The present finding of a cumulative incidence of physically and functionally significant PTS of only 13% at 1–2 years in a cohort of children sharing these adverse prognostic clinical and laboratory features indicates that PPMT deserves further evaluation as a potential means for PTS risk-reduction in this high-risk stratum of pediatric DVT.
The pathophysiology of PTS is thought to ultimately involve venous hypertension [20
], which, in turn, is believed to derive from venous valvular reflux and/or persistent thrombotic veno-occlusion following DVT. The fact that PTS developed in several children in the present cohort in whom patency was both achieved acutely following PPMT and maintained long-term suggests that these patients may have irreversible valvular damage in the affected limb at the time of presentation or ongoing vascular inflammation following successful lysis. While plethysmography and other techniques of assessing venous valvular function were not performed in this cohort study, it should be recognized that PTS has been shown to correlate poorly with the presence of reflux by conventional methods [21
]. As an alternative pathophysiological explanation to reflux secondary to mechanical valve damage, it is possible that valvular fibrosis and damage due to inflammation (whether systemic or localized to the vasculature) may be sufficient to cause insufficiency in these cases. Indeed, some evidence to date in adult DVT identifies elevated levels of interleukin-6 and D-dimer as prognostic of PTS [22
]; the latter was a key inclusion criterion for cases in this cohort, based upon prior knowledge of prognostic factors for adverse outcomes of thrombosis in children [11
Findings from a recent meta-analysis of randomized controlled trials (RCTs) of additional thrombolysis (systemic infusion or CDTI) versus standard anticoagulation alone revealed that, although mortality and the risk of recurrent VTE are not reduced by thrombolysis, the acute rate of complete patency is significantly increased (RR=4.14, 95% CI=1.22–14.01), and the risk of PTS is decreased (RR=0.66, 95% CI=0.47–0.94) [24
]. However, a slight but statistically significant increase in acute major bleeding risk was ascribed to thrombolysis by systemic infusion/CDTI [RR=1.73, 95% CI=1.04–2.88]. Furthermore, the findings for PTS were based on only two RCTs in which this outcome was reported [25
]. Recently (and not included in the aforementioned Cochrane review), early outcomes from the CaVenT trial indicate a significant risk reduction in chronic venous obstruction among adult patients with acute proximal DVT treated by additional CDTI when compared to those who received standard anticoagulation alone [27
]. Evaluation for the primary endpoint of this trial, the rate of PTS at two years, is ongoing.
A potential advantage of the PMT/PPMT approach is the reduction in total dose of thrombolytic agent administered relative to thrombolysis by systemic infusion or CDTI, with a consequent theoretical benefit of decreased bleeding risk. Furthermore, PMT/PPMT offers the advantage of minimizing systemic
lytic exposure in particular, thereby presumably decreasing systemic bleeding risks involving critical sites such as the central nervous system. No RCTs of PMT/PPMT have been published, and prospective data on this lytic intervention for DVT are limited to two adult studies focused upon CDTI, in which PMT/PPMT was reported in a few cases each [28
]. By comparison, nine retrospective studies have been reported, totaling approximately 200 adult DVT patients treated by PMT/PPMT with/without adjunctive CDTI [30
]. However, published experience with a regimen of PMT/PPMT followed by adjunctive CDTI is limited to three retrospective studies in adults, in which the number of patients receiving this regimen ranged between eight and 20 [30
With regard to safety of PMT/PPMT with/without CDTI, only six cases of acute major bleeding and zero cases of acute symptomatic PE were reported among the nine retrospective studies, out of 172 and 107 patients, respectively, in whom this outcome was assessed. These low rates of peri-procedural hemorrhage and PE are consistent with our prospective findings in the present cohort. As for potential efficacy of PMT/PPMT, acute patency rates were high across the nine retrospective studies. However, long-term patency was only reported by Lin and colleagues [31
], who determined a rate of 65%. No cases of acute recurrent DVT were reported among a cumulative total of 62 subjects in the retrospective studies wherein this outcome was assessed. Our findings of a higher rate of early local recurrent VTE in this prospective cohort could be explained by one or more of the following possibilities: (1) the risk of acute re-occlusion may be higher in children than adults; (2) observation biases may have led to under-reporting in the retrospective studies; (3) children in the present study were generally more prothrombotic than the adults reported in prior series. Given the latter possibility, and the low bleeding risks observed here, the present authors currently advocate for more aggressive peri-procedural anticoagulation than employed in these subjects. With regard to PTS, the findings reported here are the first among prospective or retrospective studies of PMT/PPMT in children or adults. Future analyses of PMT/PPMT must build upon this work, emphasizing PTS as a key outcome, and using validated measures.
Principal strengths of the present work include: the prospective inception cohort design; comprehensive clinical and laboratory evaluation for predisposing conditions (including venous stenoses and thrombophilia states); standardization of peri-procedural and extended anti-coagulant regimens; and PTS outcomes measurement, using a standardized instrument for which data on validity have been published in children. The principal limitations of the present observational study are its non-randomized design and its relatively small size. As in other non-randomized studies, selection biases may exist (e.g., clinical determination of PMT vs. PPMT and use/non-use of CDTI). Additionally, in spite of the fact that this is the largest pediatric series on PMT/PPMT, and similar in size to previous adult studies of PMT/PPMT in which adjunctive CDTI was frequently employed, it must be emphasized that our outcome estimates (e.g.: acute locally recurrent DVT, PE, and major hemorrhage; late recurrent VTE; PTS) may be imprecise given the size of our study population. In particular, PTS may develop over time, and may be underestimated here; yet, in prior work by the authors, for all children found to be affected at 2 years, PTS had been evident at 1 year post-event [2
]. Given the study limitations of sample size, the tendencies observed for putative prognostic indicators of long-term patency and PTS must also be considered speculative. Therefore, larger prospective studies are required in order to confirm the safety of PMT/PPMT with adjunctive CDTI, evaluate its efficacy for PTS risk reduction, and define additional prognostic factors in this young patient population.