Predictors of Post-Thrombotic Syndrome (PTS) in Pediatric Thrombosis: A Systematic Review and Meta-Analysis of the Literature
Authors: Engel Elissa , Albisetti Manuela , Brandao Leonardo R. , Amankwah Ernest , Nguyen Anthony , Goldenberg Neil A , Betensky Marisol 
Published: October 2019

Abstract
BACKGROUND: Post-thrombotic syndrome (PTS) is the most common long-term complication in pediatric deep venous thrombosis (DVT), affecting approximately 25% of children with an extremity DVT. PTS leads to a high physical, psychological and financial burden in affected patients. Although several risk factors have been associated with the development of pediatric PTS, few of them have been validated in the pediatric literature. A better understanding of the prognostic factors leading to PTS is a vital step for early identification of those children at greatest risk in order to develop risk-stratified interventions aimed at preventing this complication.
AIM: To perform a systematic review and meta-analysis of available published evidence from the pediatric literature on prognostic factors for pediatric PTS.
METHODS: A systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2017 was performed. MeSH terms and search strategy employed were as follows: "postthrombotic syndrome" OR "postphlebitic syndrome" AND "all child 0-18 years" AND "young adult 19-24 years". A study was eligible for inclusion if it evaluated the development of PTS in pediatric patients (<21 years of age) with a confirmed extremity DVT and reported on at least one prognostic factor for the development of PTS. Single case reports, narrative reviews, and commentaries were excluded. Studies assessing the efficacy/safety of thrombolysis, and studies including patients >21 years of age with outcomes not reported by age group, were also excluded. Two reviewers independently screened all studies and extracted the data of interest. Data were analyzed using STATA v.15 statistical software. Meta-analyses were conducted for risk factors reported in at least three studies. Summary odds ratios (ORs) and 95% confidence intervals (CI) were calculated from the effect estimates from the individual studies using a random effects model. Statistical heterogeneity was quantified by I2 statistic.
RESULTS: A total of 12 studies met the final inclusion criteria (Figure 1), nine cohort studies, two cross-sectional studies, and one case-control study. These studies reported a total of 1,160 patients with venous thromboembolism (VTE), of whom 938 (81%) were assessed for PTS (Table 1). Median age across studies ranged from 0.02 - 15.5 years. VTE was considered provoked in nearly 80% of patients. The most common reported risk factor for VTE was the presence of a central venous catheter (CVC, 54%) followed by congenital heart disease (26%). PTS was diagnosed in 46% (n=434) of patients with an extremity DVT. The median time from DVT diagnosis to PTS diagnosis ranged from 12 to 33 months across studies. Among studies reporting this information, mild PTS was most frequently diagnosed, followed by moderate and severe PTS (35%, 5% and 0.6% of patients respectively). Most common prognostic factors associated with PTS in individual studies included patient characteristics: age and gender; and DVT characteristics: recurrent DVT, symptomatic DVT, DVT degree of occlusion, and time between DVT diagnosis and PTS assessment. Three studies investigated the association of elevated factor VIII and d-dimer levels with PTS. Elevated levels of these biomarkers were found to be associated with development of adverse VTE outcomes in one study but this finding was not confirmed in the other studies. Meta-analysis of reported prognostic factors identified the presence of a CVC and occlusive DVT as significant risk factors for the development of pediatric PTS (OR= 1.8, 95%CI=1.08-2.98, and OR=1.89, 95%CI=1.04-3.46 respectively; Figure 2).
CONCLUSION: Among 12 studies evaluating prognostic factors for PTS in children and meeting criteria for this meta-analysis, CVC-related DVT and complete occlusion were associated with pediatric PTS. Overall, high-quality evidence on pediatric PTS is lacking. Collaborative prospective cohort studies and trials that use validated pediatric PTS measures and standardized prognostic factor definitions are needed to better understand the risk factors associated with PTS.

Disclosures
No relevant conflicts of interest to declare.