Clinical care of pediatric patients with or at risk of postthrombotic syndrome: guidance from the ISTH SSC Subcommittee on pediatric and neonatal thrombosis and hemostasis
Laura Avila 1), 2), 3); Marisol Betensky 4), 5); Clay Cohen 6); Sanjay Ahuja 7); Neil Goldenberg 4), 5), 8); Ayesha Zia 9).
1) Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
2) Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
3) Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
4) Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
5) Thrombosis Program and Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital, St Petersburg, Florida, USA
6) Department of Pediatrics, Section of Hematology-Oncology, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas, USA
7) Division of Pediatric Hematology/Oncology, University Hospitals Cleveland Medical Center, Rainbow Babies & Children’s Hospital, Cleveland, Ohio, USA
8) Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
9) Departments of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Children’s Health, Dallas, Texas, USA
ABSTRACT
Introduction
The incidence of pediatric venous thromboembolism (VTE) is rising [1–4]. Although VTE is perceived as an acute event, chronic complications such as a lack of thrombus resolution, recurrence, postthrombotic syndrome (PTS), and postpulmonary embolism syndrome are now better recognized [5,6]. PTS, a form of chronic venous insufficiency, develops in one-third of children after extremity deep venous thrombosis (DVT) [5,7–10]. PTS is clinically significant because of its impact on functioning and health-related quality of life (HR-QoL) [11].
There is scarce evidence to guide the management of pediatric PTS, resulting in heterogeneous clinical management. Additionally, the presentation of pediatric PTS is variable over time, leading to underrecognition and variation in care. This led the Post-Thrombotic Sequelae Working Group (WG) of the Scientific and Standardization Subcommittee on Pediatric and Neonatal Thrombosis and Haemostasis within the International Society on Thrombosis and Haemostasis to launch a project to provide guidance on key areas related to the care of pediatric PTS. This document summarizes the available evidence on PTS risk factors, PTS evaluation tools, prevention, and the treatment of pediatric PTS to guide clinicians regarding PTS prevention and treatment for children with or at risk of PTS following limb DVT.
Methods
The WG developed the document, anchored on an updated systematic review of pediatric PTS [12]. To guide the systematic review, the WG prioritized 10 relevant Population, Intervention, Comparison, Outcome, and Timing (PICOT) questions (Supplementary Tables S1–S10). The WG selected outcomes of interest for each question a priori. Two WG members were assigned to each question, and a third WG member acted as a mediator for areas of disagreement. A systematic search of publications included in MEDLINE (from 1960 to May 10, 2023), EMBASE (from 1960 to May 11, 2023), and the Cochrane Library (issue 5 of May 12, 2023) was performed. The search strategy was designed in consultation with one librarian experienced in systematic reviews of medical literature. MeSH and search strategy terms used were as follows: “Postthrombotic Syndrome” post-thromb∗ OR postthromb∗ OR PTS AND all child OR young adults. Relevant references from the papers identified were also reviewed. Case reports, case series, review articles, and conference abstracts were excluded. Following the search, duplicates were removed. Titles and abstracts were screened for assessment against review inclusion criteria for each PICOT question. The full text of selected citations was assessed in detail against the inclusion criteria. Any disagreements that arose between the reviewers were resolved through discussion. Based on the systematic review, the WG summarized the evidence for each of the 10 questions. Lastly, based on the existing data, research priorities were drafted by the WG members.
Summary Of Evidence
Screening and diagnosis of pediatric PTS
Risk factors for pediatric PTS
Question: What clinical and laboratory biomarkers are associated with PTS in pediatric patients with limb DVT?
Evidence Summary
Six studies were included in this question: 2 systematic reviews, a meta-analysis, 2 prospective cohorts, a cross-sectional, and a case-control study not already included in the systematic review or meta-analysis (Table 1) [8,12–16]. These studies included 1708 patients with extremity DVT, of whom 42% (n = 709) were diagnosed with PTS. The most frequently investigated prognostic clinical factors in these studies included patient-related factors (ie, age at diagnosis, sex, and comorbidities) and thrombus-related factors (ie, degree of thrombus burden, thrombus resolution, and thrombus recurrence). In the systematic review and meta-analysis of 12 studies investigating at least 1 prognostic factor for PTS (n = 1076; PTS = 434), central venous catheter (CVC)-associated DVT (pooled odds ratio [OR],1.8; 95% CI, 1.08-2.98), complete veno-occlusion (pooled OR,1.89; 95% CI, 1.04-3.46), and residual thrombosis (largely at the end of therapy, pooled OR, 2.07; 95% CI, 1.4-3.07) were found to be significantly associated with developing PTS [12]. Even though CVC-associated DVT was predictive for PTS in this meta-analysis, the 3 largest cohorts of patients with CVC and non-CVC DVT have shown that non-CVC-associated DVT confers an approximately 3-fold higher risk for PTS [7,8,17]. Similarly, the cross-sectional study of children with an extremity DVT (n = 150; PTS = 96) identified no change or extension of thrombosis (OR, 3.96; 95% CI, 1.68, 9.30; P = .0016) and >1 vessel involvement (OR, 2.05; 95% CI, 1.52, 2.77; P < .0001) as prognostic factors for PTS development [14]. Ipsilateral DVT recurrence was significantly associated with PTS (OR, 3.36; 95% CI, 1.28, 8.82) in a systematic review and individual patient data meta-analysis of pediatric patients with May-Thurner Syndrome (n = 103; PTS = 63) [13]. Longer time from the diagnosis of an extremity DVT to PTS assessment was associated with an increased risk for PTS development in a prospective cohort that included children with CVC-associated DVT (coefficient estimate, 0.9; 95% CI, 0.4, 1.3; P < .0001), while the cross-sectional study found that with every year of follow-up, the likelihood of having a higher PTS score increased by factor 1.22 (OR, 1.22; 95% CI, 1.08, 1.39; P = .0019) [8,14]. In addition, older age at the time of DVT diagnosis was associated with the development of PTS in both patients with CVC-related and non-CVC-related thrombosis (coefficient estimate [95% CI], 0.6 [0.1, 1.2]; P = .02 and 1.7 [1.0, 2.4]; P < .001, respectively) [8]. Lastly, an analysis of plasma biospecimens collected 6 weeks and 3 months after acute thrombosis in 79 children aged 0 to 21 years (only 7.5% of the patients were ≥19 years old) found that fibrinolytic activity and serum amyloid A could be potential predictors of PTS development in children [16].