Post-thrombotic Syndrome In Children Research Articles

French Canadian cross-cultural adaptation of CAPTSure©, an index for the Clinical Assessment of Post-Thrombotic Syndrome in children

PurposePost-thrombotic syndrome (PTS) is the most common complication of deep venous thrombosis (DVT). The index for the Clinical Assessment of Post-Thrombotic Syndrome in children (CAPTSure©) is a clinical tool for the diagnosis and severity rating of PTS in pediatric patients. The purpose of this study was to translate and adapt CAPTSure© for French-speaking patients.MethodsWe conducted a cross-sectional study to perform linguistic and cultural adaptation of CAPTSure©, using a rigorous translation process followed by cognitive debriefings in twenty French-speaking pediatric patients aged up to 18 years old with a history of upper or lower extremity DVT at least 6 months prior.ResultsForward and backward translations were used to produce a pre-final French version of CAPTSure©, followed by cognitive debriefings in twenty participants (median age: 11.5 years, 55% male, median CAPTSure© score: 26). The participants felt that the questionnaire was thorough, with an adequate length. Eight out of fourteen (57%) items in the LE questionnaire and 7/12 (58%) of the items in the UE questionnaire were modified following participants’ and a multidisciplinary expert committee’s input, leading to the final French version of CAPTSure©.ConclusionsCAPTSure© was successfully adapted for French-speaking pediatric patients. This will ease the diagnosis and severity rating of PTS in children in clinical practice and allow international research collaborations for additional non-English-speaking patients.

Post-thrombotic syndrome in children (review)

Post-thrombotic syndrome (PTS) is a long-term consequence of deep vein thrombosis. The development of PTS leads to the loss of venous access, cosmetic defects and poor quality of life due to restrictions in physical and/or daily activities. The review contains data on the prevalence, pathogenesis, prognostic factors and evaluation of PTS. Understanding the occurrence and prevention is very serious because if PTS develops after deep vein thrombosis, children can suffer from various physical and social consequences that may last for many years. The review contains data on the prevalence, pathogenesis, risk factors and diagnosis of PTS.

Direct Oral Anticoagulants: Overcoming the Challenges of Managing Venous Thromboembolism in Children

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism, is relatively common among adults, with estimated incidence rates ranging from approximately 10 to 1200 per 100 000 adults aged ≥30 years. 1 Raskob G.E. Angchaisuksiri P. Blanco A.N. Büller H. Gallus A. Hunt B.J. et al. Thrombosis: a major contributor to global disease burden. Semin Thromb Hemost. 2014; 40: 724-735 Crossref PubMed Scopus (73) Google Scholar VTE is less common in children than in adults, with estimated incidence rates ranging from 0.7 to 4.9 per 100 000 children. 2 Andrew M. David M. Adams M. Ali K. Anderson R. Barnard D. et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994; 83: 1251-1257 Crossref PubMed Google Scholar , 3 van Ommen C.H. Heijboer H. Büller H.R. Hirasing R.A. Heijmans H.S. Peters M. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr. 2001; 139: 676-681 Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar , 4 Stein P.D. Kayali F. Olson R.E. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr. 2004; 145: 563-565 Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar , 5 Tuckuviene R. Christensen A.L. Helgestad J. Johnsen S.P. Kristensen S.R. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr. 2011; 159: 663-669 Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar However, it can have serious consequences, such as death, recurrence of thrombosis, loss of vessel patency required for future intravascular cannulation or organ transplantation, chronic pulmonary hypertension, or post-thrombotic syndrome. 2 Andrew M. David M. Adams M. Ali K. Anderson R. Barnard D. et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994; 83: 1251-1257 Crossref PubMed Google Scholar ,6 Goldenberg N.A. Donadini M.P. Kahn S.R. Crowther M. Kenet G. Nowak-Göttl U. et al. Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica. 2010; 95: 1952-1959 Crossref PubMed Scopus (137) Google Scholar , 7 Greene L.A. Goldenberg N.A. Deep vein thrombosis: thrombolysis in the pediatric population. Semin Intervent Radiol. 2012; 29: 36-43 Crossref PubMed Scopus (18) Google Scholar , 8 Pelland-Marcotte M.C. Tucker C. Klaassen A. Avila M.L. Amid A. Amiri N. et al. Outcomes and risk factors of massive and submassive pulmonary embolism in children: a retrospective cohort study. Lancet Haematol. 2019; 6: e144-e153 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Despite its relative rarity, the incidence of pediatric VTE has increased in recent years. 5 Tuckuviene R. Christensen A.L. Helgestad J. Johnsen S.P. Kristensen S.R. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr. 2011; 159: 663-669 Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar ,9 Sandoval J.A. Sheehan M.P. Stonerock C.E. Shafique S. Rescorla F.J. Dalsing M.C. Incidence, risk factors, and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk. J Vasc Surg. 2008; 47: 837-843 Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar ,10 Carpenter S.L. Richardson T. Hall M. Increasing rate of pulmonary embolism diagnosed in hospitalized children in the United States from 2001 to 2014. Blood Adv. 2018; 2: 1403-1408 Crossref PubMed Scopus (38) Google Scholar This increase is considered related to a number of factors, including the increased use of central venous catheters (CVCs), improved survival rates for children with chronic or critical conditions, and more frequent VTE diagnoses through improved pediatrician awareness and imaging techniques. 11 Raffini L. Huang Y.S. Witmer C. Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics. 2009; 124: 1001-1008 Crossref PubMed Scopus (569) Google Scholar ,12 Malec L. Young G. Treatment of venous thromboembolism in pediatric patients. Front Pediatr. 2017; 5: 26 Crossref PubMed Scopus (18) Google Scholar First to the public, next to youThe Journal of PediatricsVol. 240PreviewThanks to direct-to-consumer marketing, snappy jingles, familiar spokespeople, and ubiquitous slogans, you are probably familiar with some direct oral anticoagulants (as well as any number of other classes of medications), such as rivaroxaban (Xarelto) and apixaban (Eliquis). You might not have focused on their use, however, since they were initially developed for use in adults. This volume of The Journal includes a Medical Progress report on direct anticoagulants (DOACs) for use in children with venous thromboembolism, including data from the latest trials and projected approval by the US Food and Drug Administration. Full-Text PDF

Characteristics of upper- and lower-extremity deep vein thrombosis and predictors of postthrombotic syndrome in children

AbstractOur understanding of postthrombotic syndrome (PTS) predictors in children is evolving. The present study aimed to investigate differences in patient- and deep vein thrombosis (DVT)–related characteristics between central venous catheter (CVC)–related and non–CVC-related thrombosis in children, as well as early PTS predictors. Children aged 0 to 18 years were prospectively recruited ≥6 months after imaging-proven upper- or lower-extremity DVT. PTS was measured using CAPTSure. Early predictors included age at DVT diagnosis, DVT symptoms, DVT burden, and days on therapeutic anticoagulation within 30 days post-DVT diagnosis. Analysis of predictors was stratified by CVC-related and non–CVC-related thrombosis. Generalized estimating equations were used for data analyses. In total, 313 DVT-affected extremities of 256 patients were assessed; 275 (88%) DVT cases were CVC related. Patients with non–CVC-related thrombosis were older (median age, 5.8 years; 25th-75th percentile, 4.9-6.4 years vs 3.5 months; 25th-75th percentile, 0.7-18.7 months; P < .001) and more likely to have thrombophilia (64% vs 22%; P < .001) and obesity (30% vs 13%; P = .01) than patients with CVC-related thrombosis. CAPTSure scores were 9.5 points higher (standard error, 3.0; P = .02) in the non–CVC-related thrombosis stratum. Age at the time of DVT predicted PTS in both strata; DVT burden and time from DVT diagnosis to PTS assessment predicted PTS in CVC-related thrombosis. In sum, PTS severity was higher in non–CVC-related vs CVC-related thrombosis. Increasing age at the time of DVT was associated with higher PTS severity. DVT burden and time from DVT diagnosis to PTS assessment were significant PTS predictors in CVC-related thrombosis, indicating that long-term follow-up of these children is important.

Outcomes and Risk Factors Associated with Thrombosis Recurrence and Post-Thrombotic Syndrome in Children and Adolescents with May-Thurner Syndrome

Introduction : May-Thurner syndrome (MTS) is a condition in which the right iliac artery compresses the left iliac vein, predisposing affected individuals to venous outflow obstruction and deep vein thrombosis (DVT). Despite the frequency of this anatomic variant, found in 20-25% of adults, not everyone with this variant will develop a DVT. Adults with MTS are treated with catheter-directed thrombolysis (CDT), anticoagulation, and often iliac vein stent placement. There is no standard of care established for pediatric MTS patients. The aims of this study are to 1) describe risk factors, clinical factors, and outcomes (complications of CDT, recurrence rate, post-thrombotic syndrome) in a pediatric MTS cohort and 2) determine what factors are associated with thrombus resolution, recurrence, and development of post-thrombotic syndrome (PTS).Methods : A retrospective cohort of children (0-21 years) diagnosed with MTS and DVT were identified between January 1, 2012 and July 15, 2017. MTS was confirmed by CT venogram, MR venogram, intravascular ultrasound, and/or conventional endovascular venography. Patient demographic, clinical, and thrombophilic risk factors, clinical outcomes (resolution, recurrence, PTS using modified Villalta scale), and bleeding complications were abstracted from review of the electronic medical record. Bleeding complications were defined by ISTH definitions for pediatric trials. Student's t test, Wilcoxon rank sum test, Chi square test and logistic regression analysis were used for statistical analysis (SAS v9.4, Cary, NC, USA).Results : The cohort was comprised of 23 subjects, 65% of them female (n=15), with a median age at presentation of 16.1 years (9.9-19.7 years). The median follow-up time was 505 days. The most frequent risk factor was thrombophilia (n=10), which included Factor V Leiden mutation (n=6), antithrombin deficiency (n=3), protein S deficiency (n=3), lupus anticoagulant (n=3), prothrombin gene mutation (n=1), protein C deficiency (n=1), or more than one thrombophilia (n=3). Other risk factors included hormone therapy (n=8), obesity (n=7), family history of DVT (n=6), immobility (n=5), central line (n=2), lupus (n=1), pregnancy (n=1), trauma (n=1), surgery (n=1), nephrotic syndrome (n=1), and retroperitoneal fibrosis (n=1). One subject had no risk factor, while 14 (61%) had multiple risk factors. Among the subjects, 78% underwent CDT (n=18) and 83% had stent placement (n=19). The remaining subjects will have future stent placement. Following CDT, there were no major bleeding complications (1 minor and 1 clinically relevant non-major bleeding complication). Other complications included pain (n=8), hemolysis (n=7), hemoglobinuria (n=2), hypofibrinogenemia requiring cryoprecipitate infusion (n=2), and transient increase in creatinine (n=1). Primary patency, defined as >90% patency of vessel diameter in the first week after CDT, was achieved in 91% (n=21). Thrombosis resolution was seen in 91% (n=21) of the cohort. Anticoagulant treatment prescribed included enoxaparin (65%), rivaroxaban (30%) and warfarin (26%). In univariate analyses, the only factor associated with thrombus resolution was primary patency (p=0.0012). DVT recurred in 13% (n=3), with a median time of 32 days off anticoagulation. The only factor associated with recurrence was antithrombin deficiency (p=0.048). Ten subjects (43%) had no evidence of PTS and 13 had mild PTS (57%). There were no significant factors associated with the development of PTS.Conclusions : To our knowledge, this is the largest retrospective cohort of pediatric subjects with MTS and DVT. Underlying thrombophilia was the most common risk factor found, suggesting that patients diagnosed with MTS warrant thrombophilia evaluation. Bleeding complications associated with CDT were minimal and non-bleeding complications were transient, demonstrating that CDT is safe in the pediatric population. Efficacy of CDT in this population is supported by the finding that primary patency is an important factor for thrombosis resolution. Lastly, thrombosis recurrence was not uncommon (13%) and was likely to occur soon after stopping anticoagulation. These findings demonstrate that multicenter studies are needed in children with MTS to evaluate the efficacy of CDT to achieve thrombus resolution, and that evaluation of thrombophilic risk factors should be considered. DisclosuresNo relevant conflicts of interest to declare.

Post-thrombotic syndrome in children: current state of affairs

Post-thrombotic syndrome (PTS) is one of the most significant complications that develops in patients after deep vein thrombosis. Patients with PTS have persistent and often worsening chronic venous insufficiency which can lead to permanent impairment of the affected organ, tissue or limb. Despite their importance, the issues of diagnosis and prevention of PTS in children are understudied in Russia. This paper is based on the analysis of recently published data and presents the current state of affairs regarding PTS in pediatrics.

The Edoxaban Hokusai VTE PEDIATRICS Study: An open‐label, multicenter, randomized study of edoxaban for pediatric venous thromboembolic disease

BackgroundLittle evidence is available for treatment of pediatric venous thromboembolism (VTE). Large randomized controlled trials are challenging in children. Current antithrombotic agents have many limitations, including nonoral administration and frequent monitoring. Edoxaban is an oral direct inhibitor of factor Xa without need of monitoring. In adults with VTE, edoxaban has shown to be effective and safe. ObjectivesThe Edoxaban Hokusai VTE PEDIATRICS Study is an open‐label, randomized clinical trial to evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of edoxaban and whether edoxaban is noninferior to standard of care in treatment of pediatric VTE. MethodsA goal of 274 patients will be recruited in 5 age categories. A multidose PK/PD assessment on day 5 in the first 12 patients of each age group is incorporated into this study. The primary composite efficacy outcome comprises symptomatic recurrent VTE, death due to VTE, and no change or extension of thrombotic burden. The principal safety end point is a combination of major and clinically relevant nonmajor bleeding. PK end points include apparent systemic clearance and volume of distribution of edoxaban. PD end points include prothrombin time, activated partial thromboplastin time, and anti‐factor Xa level for the edoxaban treatment arm. ResultsTo increase feasibility, the multidose PK/PD study is integrated in the phase 3 trial. In addition, thrombotic burden, which is a prognostic factor for post thrombotic syndrome in children, is one of the components of the primary composite efficacy outcome. ConclusionThis study will increase the level of evidence for treatment in pediatric VTE.

A Rise in Plasma Coagulability during the First 3 Months Following Provoked Venous Thromboembolism Is Associated with the Development of Post-Thrombotic Syndrome in Children and Young Adults: Analysis of the Kids-DOTT Multicenter Trial-Derived Biobank

Background:Knowledge of prognostic factors for the development of post-thrombotic syndrome (PTS) is limited, particularly in the pediatric population. Elevated plasma levels of D-dimer and FVIII, both markers of coagulation activation and inflammation, are associated with an increased risk of adverse thrombosis outcomes, including PTS, in children. Similarly, increased levels of inflammatory cytokines, such as interleukin-6 (IL-6), have been associated with venous endothelial dysfunction and fibrosis, suggesting a potential role in the development of PTS. Given the strong interplay between inflammation and coagulation, the aims of this study were to: (1)Investigate a hypothesized association between increased levels of plasma cytokines during the first 3 months post-diagnosis of deep venous thrombosis (DVT) with the development of PTS in patients &lt;21 years old; and (2) to investigate an association between increased plasma coagulability during the first 3 months post-DVT diagnosis with the development of PTS. Methods:We used banked plasma biospecimens and masked clinical data from an ongoing NHLBI-sponsored multinational multicenter trial of VTE treatment in patients &lt;21 years old (the Kids-DOTT trial, NCT00687882). All patients with an extremity DVT who underwent PTS assessment at 1 year were included in this analysis. The Clot Formation and Lysis (CloFAL) spectrophotometric assay was performed, as previously described, on banked plasma samples obtained at 6 weeks and 3 months post-VTE diagnosis. All samples were pre-treated with heparinase prior to assay. Assay measurements included maximal amplitude of the CloFAL waveform (MA), time to maximal amplitude (T1), and area under the curve at 60 minutes, indexed to that of the pooled normal plasma standard (AUC60). Levels of IL-6, IL-8, IL-12/IL-23p40, IL-17, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, interferon (IFN)-γ and C-reactive protein (CRP) were measured via V-Plex kit (Meso Scale Discovery, Rockville, MD). For each patient, the change in each laboratory parameter between the 3 months and 6 weeks post-VTE time points was calculated. The diagnosis of PTS was made at the one year follow-up assessment using the Manco-Johnson Instrument. Descriptive statistics were used to summarize data on patient and VTE characteristics as well as PTS outcome. Putative prognostic factors for PTS (age group, complete thrombus occlusion, CloFAL parameters, and inflammatory cytokines) were evaluated via univariate logistic regression, using odds ratios (OR) and 95% confidence intervals (CI). Variables with P-values &lt;0.1 in univariate analyses were pre-specified for inclusion in an adjusted (multivariate) regression analysis. The blind was maintained in the Kids-DOTT trial throughout data transfer and analysis. Results: A total of 80 patients were included in the present analysis. Median age was 12.7 years (range 0.04 - 20.8 years). Patient and VTE characteristics at baseline, as well as PTS outcomes, are summarized in Table 1. PTS developed in 34% of patients by the 1 year post-VTE follow up visit. Univariate logistic regression analysis identified change in CloFAL AUC60 (OR=1.46, 95%CI=1.02-2.09; P=0.036) and complete thrombus occlusion at 6 weeks post-VTE (OR=3.29, 95%CI=0.93-11.6; P=0.064) as putative prognostic factors for PTS (Table 2). After adjustment in multivariate regression, change in CloFAL AUC60 remained the only possibly-significant (P=0.06) independent prognostic factor for PTS. Specifically, for each 1 A.U. increase in CloFAL AUC from the 6 weeks to 3 months post-VTE diagnosis, the odds of PTS increased by more than 40% (OR=1.43, 95%CI=0.99-2.08; Table 3). Changes in none of the measured inflammatory cytokines were prognostic of PTS. Conclusions: PTS developed in 34% of patients &lt;21 years old enrolled in enrolled in an ongoing multicenter trial of provoked DVT treatment. A rise in plasma coagulability during the first 3 months post-DVT diagnosis, as measured by increase in AUC60 in the CloFAL assay is a candidate prognostic factor for PTS in patients &lt;21 years old with provoked DVT. Future work should seek to investigate the mechanisms of increased plasma coagulability following a course of anticoagulation therapy in young VTE patients, and to substantiate findings of its potential prognostic significance for the development of PTS. Disclosures Everett: ImmunArray: Consultancy, Patents &amp; Royalties. Goldenberg:NIH: Other: research support and salary support.

Characterization of Post-Thrombotic Syndrome in Children with Cardiac Disease

To assess the validity of existing clinical scales assessing the presence of physical and functional abnormalities for diagnosing post-thrombotic syndrome (PTS) in children, including specific evaluation of use in children with congenital heart disease (CHD). One hundred children aged >2 years (average age, 6 years), including 33 with CHD and previously proven extremity deep vein thrombosis (DVT), 37 with CHD and no previous DVT, and 30 healthy siblings, were blindly assessed for PTS using the modified Villalta Scale (MVS). All patients aged <6 years underwent neurodevelopmental testing and an age-appropriate quality of life assessment. The MVS identified mild PTS in 20 children and moderate PTS in 1 child (including 14 of 33 [42%] in the CHD/DVT group, 5 of 37 [14%] in the CHD/no DVT group, and 2 of 30 controls [7%]). The diagnosis of PTS was confirmed clinically in 14 patients, all of whom had previous thrombosis and 1 of whom was MVS-negative. MVS had an accuracy of 91% and performed reasonably well as a screening tool but poorly as a diagnostic tool. MVS reliability was acceptable. Children with PTS had similar quality of life as those without PTS but had higher rates of neurodevelopmental delays in gross motor skills (70% vs 24%; P = .02) and problem-solving indicators (60% vs 15%; P = .008). Using the MVS scale for PTS screening in children with CHD is feasible and reliable, and the scale has good correlation with a clinical diagnosis of PTS despite a high prevalence of false-positive findings. Further research is needed to determine the clinical relevance of PTS in this population.

Post-thrombotic syndrome in children

The post-thrombotic syndrome (PTS) is the most common long-term complication of pediatric deep venous thrombosis (DVT). It is a burdensome condition that can lead to severe disability and poor quality-of-life of affected children. Although its pathophysiology remains poorly understood, it is thought to be the result of chronic venous hypertension. Recent studies have shown that the inflammatory response associated with an acute DVT likely plays a key role in the development of PTS. The Manco-Johnson Instrument and the modified Villalta Scale are the most widely used instruments for the diagnosis of pediatric PTS. To date, few prognostic indicators for the development of PTS following pediatric-onset DVT have been identified and substantiated in published research, limiting our ability to identify those patients at high-risk for the development of this complication. There is also limited evidence on therapeutic strategies and long-term outcomes of pediatric PTS. Further research aimed at improving our understanding of the pathophysiology and prognostic indicators of PTS is needed to enhance the currently limited risk prediction models for pediatric PTS. Early identification of pediatric patients at risk for PTS is essential to investigate preventive and therapeutic interventions aimed at decreasing the risk and severity of this complication in children. This review aims to summarize the current available evidence on the pathophysiology, risk factors, diagnosis, and management of pediatric PTS.

Post thrombotic syndrome following deep vein thrombosis in paediatric patients.

Background Although well characterised in adults, less is known about post-thrombotic syndrome in children. In this review, current knowledge regarding paediatric post-thrombotic syndrome is summarised, with particular emphasis on pathophysiology, aetiology, diagnosis and management. Methods A Medline literature review was performed using search terms 'post thrombotic syndrome', 'post phlebitic syndrome', paediatric and children. Relevant articles were identified and included for summation analysis. Results The incident of paediatric venous thromboembolism is rising. Deep vein thrombosis can cause venous hypertension through a combination of venous reflux, venous obstruction and impairment of the calf muscle pump, leading to development of post-thrombotic syndrome. In children, this is more likely to occur if deep vein thrombosis diagnosis and treatment are delayed, if a higher number of vessels are involved, and if factors such as D-dimer are elevated at diagnosis and throughout treatment. Post-thrombotic syndrome occurs in about 26% of paediatric deep vein thrombosis, though the results of individual studies vary widely. A number of tools exist to diagnose paediatric post-thrombotic syndrome, including the modified Villalta scale and Manco-Johnson instrument. Once post-thrombotic syndrome develops, the mainstay of treatment remains supportive, with little evidence of benefit from pharmacological measures. Conclusion Surgical or interventional treatment is not advised except in exceptional cirumstances, due to variable prognosis of PTS in paediatric populations with rising incidence of paediatric venous thromboembolism, it follows that the prevalence of post-thrombotic syndrome in children may also increase. Evidence-based venous thromboembolism prevention strategies need to be implemented for prevention of deep vein thrombosis, but when it does occur, deep vein thrombosis requires prompt and effective treatment to prevent post-thrombotic syndrome. Optimum treatment strategies for post-thrombotic syndrome require further investigation.

Development of CAPTSureTM – a new index for the assessment of pediatric postthrombotic syndrome

Background Postthrombotic syndrome (PTS) is a complication of deep vein thrombosis defined by the presence of characteristic signs and symptoms. We developed a discriminative and evaluative index for the assessment of upper extremity (UE) and lower extremity (LE) pediatric PTS. Methods The items to be included in the index were voted for by 26 pediatric thrombosis experts invited to participate in a Delphi survey. Subsequent item weighting was based on item importance elicited by the use of multicriteria decision analysis (MCDA); 122 healthcare providers and patients/parents were invited to participate in item weighting. The implications of the overall scores were explored by comparison with PTS diagnosis (independently assessed by two clinical experts) and parental satisfaction/dissatisfaction with their child's current condition. Results Items voted for inclusion by at least 70% of the Delphi survey respondents (81% response rate) were pain, paresthesia, swelling, heaviness, endurance, collateral circulation and arm circumference difference for the UE, and pain, paresthesia, swelling, heaviness, tightness, tired limb, redness/purple or blotchy skin, endurance, ulcers and thigh/calf circumference difference for the LE. Items were then weighted by the use of MCDA (82% response rate). The index had excellent discrimination for patients with/without PTS. For every 10-point increase in index scores (with higher scores being indicative of worse PTS), the odds of parental dissatisfaction increased by 75% and 92% in the UE and LE, respectively. Conclusion We report the development of the CAPTSure™ (index for the Clinical Assessment of Postthrombotic Syndrome in children), which reflects collective judgement of the severity of pediatric PTS. We also provide information on the meaning of the scores.

Pediatric post-thrombotic syndrome in children: Toward the development of a new diagnostic and evaluative measurement tool

ObjectiveOur goal was to conduct the item generation and piloting phases of a new discriminative and evaluative tool for pediatric post-thrombotic syndrome. MethodsWe followed a formative model for the development of the tool, focusing on the signs/symptoms (items) that define post-thrombotic syndrome. For item generation, pediatric thrombosis experts and subjects diagnosed with extremity post-thrombotic syndrome during childhood nominated items. In the piloting phase, items were cross-sectionally measured in children with limb deep vein thrombosis to examine item performance. ResultTwenty-three experts and 16 subjects listed 34 items, which were then measured in 140 subjects with previous diagnosis of limb deep vein thrombosis (70 upper extremity and 70 lower extremity). The items with strongest correlation with post-thrombotic syndrome severity and largest area under the curve were pain (in older children), paresthesia, and swollen limb for the upper extremity group, and pain (in older children), tired limb, heaviness, tightness and paresthesia for the lower extremity group. ConclusionThe diagnostic properties of the items and their correlations with post-thrombotic syndrome severity varied according to the assessed venous territory. The information gathered in this study will help experts decide which item should be considered for inclusion in the new tool.

Acute Prognostic Factors for Post-Thrombotic Syndrome in Children with Limb DVT: A Bi-Institutional Cohort Study

BackgroundEarly identification of children with deep venous thrombosis (DVT) of the limb who are at heightened risk for post-thrombotic syndrome (PTS) is important in order to evaluate therapeutic interventions aimed at decreasing the risk and severity of PTS. ObjectiveWe sought to evaluate acute prognostic factors for PTS in children following DVT of the limbs. Materials and MethodsIn this bi-institutional mixed cohort study with prospective ascertainment of PTS using a validated pediatric instrument, we collected data on patient/thrombus characteristics, thrombophilia testing results, and outcomes in children (<21years at event) diagnosed with acute limb DVT at Rady Children's Hospital of San Diego and Children's Hospital Colorado. ResultsMedian age at presentation was 13years (range, 0–18years). Cumulative incidence (i.e. risk) of PTS was 23%, at a median follow-up duration of 33months (range, 13.2-65months). The presence of a lupus anticoagulant by dilute Russell Viper venom time (dRVVT) testing within two weeks of DVT diagnosis was associated with markedly increased odds of developing clinically-significant PTS (OR: 16.8, 95%CI 1.60-176.2; P=0.02). The presence of an infectious or inflammatory condition at DVT presentation was neither associated with PTS risk nor dRVVT positivity. CONCLUSION: An acutely positive dRVVT following diagnosis of limb DVT appears to be a significant prognostic factor for development of clinically significant PTS in children. Larger collaborative cohort studies are required to substantiate these findings, evaluate other prognostic factors, and determine whether the present association is modulated by persistent dRVVT positivity or beta-2-glycoprotein-I dependence.

Prognostic Factors for Post-Thrombotic Syndrome in Children with Limb DVT: A Bi-Institutional Cohort Study

AbstractAbstract 3401 Background:Early identification of children with deep venous thrombosis (DVT) of the limb, whoare at heightened risk for post-thrombotic syndrome (PTS), is important in order to evaluate therapeutic interventions aimed at decreasing the risk and severity of PTS. Objective:We sought to evaluate prognostic factors for PTS in children following DVT of the limbs. Methods:In this bi-institutional mixed cohort study with prospective ascertainment of PTS using a validated pediatric instrument, we collected data on patient/thrombus characteristics, thrombophilia testing results, and outcomes in children (<21 years at event) diagnosed with acute limb DVT at Rady Children’s Hospital of San Diego and Children’s Hospital Colorado. Results:Median age at presentation was 13 years (range, 0–18 years). Cumulative incidence (i.e., risk of PTS) was 23%, at a median follow-up duration of 33 months (range: 13.2–65 months). The presence of a lupus anticoagulant by dilute Russell Viper venom time (dRVVT) testing within two weeks of DVT diagnosis was associated with markedly increased odds of developing clinically-significant PTS (OR 16.8, 95%CI (1.60–176.2); P=0.02). The presence of an infectious or inflammatory condition at DVT presentation was neither associated with PTS risk nor dRVVT positivity. Conclusions:An acutely positive dRVVT following diagnosis of limb DVT appears to be a significant prognostic factor for development of clinically significant PTS in children. Larger collaborative cohort studies are required to substantiate these findings, evaluate other prognostic factors, and determine whether the present association is modulated by persistent dRVVT positivity or beta-2-glycoprotein-I dependence.Table 1Patient CharacteristicsVariableDVT events n=35Clinically Significant PTS n=8No Clinically Significant PTS n=27P valueAge (year)Median1315.5100.06Range0.2–180.6–170.2–18Gender (%)0.41Male22 (63)4 (50)18 (67)Female13 (37)4 (50)9 (33)BMI %Median73.168.7576.450.48Range0.1–99.80.1–9618.9–99.8Clinical Characteristics (%)Central Line Associatedà14 (40)2 (25)12 (44)0.43Infection/Inflammatory ConditionÆ14 (40)3 (38)11 (41)1.00Laboratory ParametersFV Leiden Heterozygote – (%)7 (20)2 (25)5 (19)1.00FV Leiden Homozygote – (%)1 (3)1 (13)0 (0)0.23FII G20210A heterozygote– no. tested (%)0/34 (0)0/8 (0)0/26 (0)1.00Moderate/Severe protein C, protein S, or AT deficiency – no. tested (%)3/30 (10)0/7 (0)3/23 (13)1.00FVIII Level (IU/dL)(n=19)(n =4)(n=15)Median (n =23)221A226.52080.55Range99.9–413.7215.9–295.599.9–413.7dRVVT – no. positive/tested (%)11/26 (42)6/7 (86)5/19 (26)0.02D-dimer > 500 ng/mL (%)20/26 (77)6/6 (100)14/20 (70)0.28Veno-Occlusion at Diagnosis (%)23 (66)8 (100)15 (56)0.03Veno-Occlusion 3 months after diagnosis (%)7 (20)2 (25)5 (19)0.65Recurrent VTE (%)7 (20)2 (25)5 (19)0.65Follow-Up (months)Median3340300.27Range13.2–6519–6013–65àCentral line at time of VTE or within the preceding 30 days.ÆInflammatory/Infectious Conditions include acute infection (sepsis n=2, influenza n=2, pneumonia n=2, viral encephalitis n=1, osteomyelitis n=1, necrotizing enterocolitis n=1, CNS tuberculosis n=1), inflammatory bowel disease n=1, hemolytic uremic syndrome n=2, diabetic ketoacidosis n=1, systemic lupus erythematosus n= 1, anti-NMDA receptor encephalitis n= 1, malignancy n=1 (Several subjects with > 1 disorder).Table 2Univariate Logistic Regression Analysis of Prognostic Factors for Clinically-Significant PTS* Following Diagnosis of VTEPrognostic FactorUnivariate Odds Ratio (95% CI)P valueAge1.15 (0.96–1.38)0.12BMI0.99 (0.96–1.02)0.38Gender0.50 (0.10–2.48)0.40Central Line0.42 (0.07–2.45)0.33Veno-Occlusion at Diagnosis4.15 (0.42–40.6)0.22Proximal DVT0.88 (0.08–9.79)0.91Inflammatory or Infectious condition0.87 (0.17–4.43)0.87FVIII1.00 (0.99–1.02)0.78dRVVT16.8 (1.60–176.2)0.02D-dimer > 500 ng/mL2.14 (0.2–22.5)0.53Inherited thrombophilia#1.72 (0.32–9.10)0.53*Score > 1 in both physical examination and functional limitation categories, according to the Manco-Johnson instrument, a standardized PTS assessment tool.#Presence of one or more of the following: factor V Leiden polymorphism, factor II G20210A polymorphism, or plasma protein C activity < 40%; plasmas free protein S antigen level <40%, or plasma antithrombin activity < 60% after 6 months of age. [Display omitted] Disclosures:Goldenberg:Eisai Inc: Research Funding; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees; CPC Clinical Research: Consultancy.

Clinical course of postthrombotic syndrome in children with history of venous thromboembolism

Postthrombotic syndrome (PTS) is a chronic morbidity of venous thromboembolism (VTE) in children. Information about the evolution of PTS is lacking in children. Present study was aimed to evaluate the time-course of extremity PTS in children who were serially followed in a hematology clinic. This retrospective cohort study included 69 consecutive children with documented VTEs that presented with symptoms of extremity VTE: 67 extremity VTEs with or without extension to vena cava, 2 inferior vena cava VTEs. Severity of PTS was assessed using modified Villalta scale. Median age of the cohort was 12.6 years (interquartile range 1.6-15 years) while median follow-up was 28.7 months (interquartile range 13.3-33.4 months. PTS prevalence was 46.8% [95% confidence interval (CI) 37.9-57.7%]. Lower extremity VTE was associated with development of PTS compared to upper extremity VTE regardless of catheter use (P = 0.002). The time-course of PTS fluctuated in 11 of 33 children (33%; 95% CI 20-47%) at a median interval of 12 months from diagnosis of VTE (range 4-14 months): three progressed from mild/moderate to severe, one improved from moderate to mild, seven fluctuated between mild and moderate. Recurrence and incomplete resolution of VTE were associated with variability in PTS severity (P < 0.05). In summary, this study suggested that almost 50% of study cohort developed PTS, and the time-course of PTS was not static in one third of children. Future research should focus on identifying the predictors contributing to the worsening of PTS and developing risk-stratified treatment interventions so as to improve the outcome of children with VTE.

Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors

Post-thrombotic syndrome is a manifestation of chronic venous insufficiency following deep venous thrombosis. This systematic review was conducted to critically evaluate pediatric evidence on frequency of occurrence, validity of outcome measures, and prognostic indicators of post-thrombotic syndrome. A comprehensive literature search of original reports revealed 19 eligible studies, totaling 977 patients with upper/lower extremity deep venous thrombosis. Calculated weighted mean frequency of post-thrombotic syndrome was 26% (95% confidence interval: 23-28%) overall, and differed significantly by prospective/non-prospective analysis and use/non-use of a standardized outcome measure. Standardized post-thrombotic syndrome outcome measures included an adaptation of the Villalta scale, the Clinical-Etiologic-Anatomic-Pathologic classification, and the Manco-Johnson instrument. Data on validity were reported only for the Manco-Johnson instrument. No publications on post-thrombotic syndrome-related quality of life outcomes were identified. Candidate prognostic factors for post-thrombotic syndrome in prospective studies included use/non-use of thrombolysis and plasma levels of factor VIII activity and D-dimer. Given that affected children must endure chronic sequelae for many decades, it is imperative that future collaborative pediatric prospective cohort studies and trials assess as key objectives and outcomes the incidence, severity, prognostic indicators, and health impact of post-thrombotic syndrome, using validated measures.

Post-thrombotic Syndrome in Children: A Single Center Experience

Development of post-thrombotic syndrome (PTS) is increasingly being recognized as a complication of deep venous thrombosis (DVT) in children. To determine the prevalence, clinical characteristics, and predictors of moderate to severe PTS in children. A retrospective chart review was performed on those children who were followed in the coagulation clinic for objectively confirmed DVTs from December 2004 to December 2006. The scoring system used by Kuhle et al was used to grade the severity of PTS as: mild, moderate, and severe. PTS developed in 20% (11/55; 95% confidence interval 9.4-30.1) of children, in which 8/11 were moderate and 3/11 were severe. Median interval between diagnosis of PTS and DVT was 90 days (range, 46 d to 3 y). The majority (72.7%) of patients in the non-PTS group received treatment intervention within 48 hours of diagnosis of DVT. Delay in treatment initiation (>48 h) and recurrence of DVT were associated with the development of PTS (P<0.05). Variables including occlusive thrombus, location and number of vessels involved with DVT, age at diagnosis, underlying thrombophilia, intensity of anticoagulation, and body mass index were not associated with the development of PTS. Other debilitating consequences of DVT requiring intervention included portal hypertension (n=2), chylothorax (n=1), and reflux sympathetic dystrophy (n=1). The small sample size and limited follow up restricted the statistical analysis. PTS is a significant problem in children with symptomatic DVTs. Early treatment intervention within the first 48 hours of diagnosis of DVT and prevention of thrombosis recurrence may prevent development of PTS. Although PTS refers to consequences of intravenous hypertension owing to extremity DVTs, sequlae of nonextremity DVTs require special consideration in pediatric PTS classification.

A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children

Important predictors of adverse outcomes of thrombosis in children, including postthrombotic syndrome (PTS), have recently been identified. Given this knowledge and the encouraging preliminary pediatric experience with systemic thrombolysis, we sought to retrospectively analyze our institutional experience with a thrombolytic regimen versus standard anticoagulation for acute, occlusive deep venous thrombosis (DVT) of the proximal lower extremities in children in whom plasma factor VIII activity and/or D-dimer concentration were elevated at diagnosis, from within a longitudinal pediatric cohort. Nine children who underwent the thrombolytic regimen and 13 who received standard anticoagulation alone were followed from time of diagnosis with serial clinical evaluation and standardized PTS outcome assessments conducted in uniform fashion. The thrombolytic regimen was associated with a markedly decreased odds of PTS at 18 to 24 months compared with standard anticoagulation alone, which persisted after adjustment for significant covariates of age and lag time to therapy (odds ratio [OR] = 0.018, 95% confidence interval [CI] = < 0.001-0.483; P = .02). Major bleeding developed in 1 child, clinically judged as not directly related to thrombolysis for DVT. These findings suggest that the use of a thrombolysis regimen may safely and substantially reduce the risk of PTS in children with occlusive lower-extremity acute DVT, providing the basis for a future clinical trial.

A cross-sectional study evaluating post-thrombotic syndrome in children

Background: Post-thrombotic syndrome (PTS) in adults, characterized by swelling, skin pigmentation, pain, and ulceration of the limb, is secondary to deep vein thrombosis (DVT). In contrast to the extensive documentation on PTS in adults, little is known about the risk of PTS in children. Objective: To determine the incidence, clinical characteristics, and predictors of PTS in children. Methods: A cross-sectional study in 153 nonselected children with objectively confirmed DVT. All children were assessed for PTS using a standardized score. As per the PTS score, severity was classified as: absent, mild, moderate, or severe. Results: Post-thrombotic syndrome was present in 96/153 children (63%), in which 80 (83%) were mild and 16 (17%) were moderate. Swelling was the most frequently recorded subjective symptom (43%) while increased limb circumference (71%) and presence of collateral circulation (53%) were the most frequently recorded objective symptoms. Risk factors for development of PTS were: lack of resolution of the DVT by radiographic assessment (OR 3.96, 95% CI 1.68–9.30), number of vessels involved in the initial DVT (OR 2.05, 95% CI 1.52–2.77), and length of follow-up (OR 1.22, 95% CI 1.08–1.39). Conclusions: These findings demonstrate that PTS is a clinically significant disease in children with previous DVT.