The role of coagulation factors VIII, IX and XI in the prediction and mediation of recurrent thrombotic events in children with non-central venous catheter deep vein thrombosis.

BACKGROUND: The role of elevated coagulation factors VIII (FVIII), FIX, FXI for the prediction of recurrent thrombotic events in children after an index non-central venous catheter (non-CVC) related deep vein thrombosis (DVT) remains unclear. OBJECTIVE: This study investigates the predictive role of FVIII, FIX, and FXI for recurrent thrombosis in children with index non-CVC DVTs, and the mediation effect of FVIII on chronic inflammation and recurrent thrombosis. METHODS: Children aged 0-18 years diagnosed with an index non-CVC related DVT (1993-2020) were included in this single-center retrospective cohort study. Plasma levels of FVIII, FIX, FXI were measured cross-sectionally ≥30 days after the acute DVT. The association between the continuous variables FVIII, FIX, FXI and thrombosis recurrence was investigated using uni- and multivariable logistic regression, adjusting for age, sex, and chronic inflammation. Mediation analysis assessed the role of FVIII as a mediator between chronic inflammation and recurrent thrombosis. Ethics approval was obtained. RESULTS: A total of 139 children with an index non-CVC related DVT were included. Thirty-eight (27 %) had a recurrent thrombosis at a median of 237 days (P25-P75 65-657 days) after the index DVT. In uni- and multivariable-analysis, FVIII, FIX or FXI did not predict thrombosis recurrence; However, chronic inflammation was an independent predictor. There was no evidence that FVIII mediated the effect of chronic inflammation on thrombosis recurrence. CONCLUSION: We found no evidence that elevated FVIII, FIX or FXI predicted thrombosis recurrence, or evidence of a mediating role of FVIII. Underlying chronic inflammation predicted venous recurrent thrombotic events in this cohort.

Long-term outcomes of pulmonary embolism in children and adolescents.

ABSTRACT: Knowledge regarding the long-term consequences of pulmonary embolism (PE) in children is limited. This cohort study describes the long-term outcomes of PE in children who were followed-up at a single-center institution using a local protocol that included clinical evaluation, chest imaging, echocardiography, pulmonary function tests, and cardiopulmonary exercise tests at follow-up, starting 3 to 6 months after acute PE. Children objectively diagnosed with PE at age 0 to 18 years, who had ≥6 months of follow-up were included. Study outcomes consisted of PE resolution, PE recurrence, death, and functional outcomes (dyspnea, impaired pulmonary or cardiac function, impaired aerobic capacity, and post-PE syndrome). The frequency of outcomes was compared between patients with/without underlying conditions. In total, 150 patients were included; median age at PE was 16 years (25th-75th percentile, 14-17 years); 61% had underlying conditions. PE did not resolve in 29%, recurrence happened in 9%, and death in 5%. One-third of patients had at least 1 documented abnormal functional finding at follow-up (ventilatory impairments, 31%; impaired aerobic capacity, 31%; dyspnea, 26%; and abnormal diffusing capacity of the lungs to carbon monoxide, 22%). Most abnormalities were transient. When alternative explanations for the impairments were considered, the frequency of post-PE syndrome was lower, ranging between 0.7% and 8.5%. Patients with underlying conditions had significantly higher recurrence, more pulmonary function and ventilatory impairments, and poorer exercise capacity. Exercise intolerance was, in turn, most frequently because of deconditioning than to respiratory or cardiac limitation, highlighting the importance of physical activity promotion in children with PE.

Functional impact of pediatric postthrombotic syndrome.

BACKGROUND: Postthrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT) in children. OBJECTIVES: We aimed to assess the impact of pediatric PTS on functioning as assessed by movement ability, mobility, functional disability, and physical activity levels in children after diagnosis of limb DVT. METHODS: Patients aged 8-21 years in follow-up care after objectively documented limb DVT were prospectively recruited in this cross-sectional study. Measures of functioning (outcomes) included self-reported questionnaires that assessed: 1) movement ability, measured with the Movement Ability Measure-Computer Adaptive Test version; 2) mobility, evaluated with the Computer Adaptive Test version of the Patient-Reported Outcomes Measurement Information System Pediatric Physical Functioning, Mobility domain; 3) functional disability, evaluated with the Functional Disability Inventory; and 4) physical activity levels, evaluated with the Godin Leisure-Time Exercise Questionnaire. The main predictor was PTS severity, which was assessed using the index for the Clinical Assessment of PTS in children. The association between PTS and outcomes was analyzed using linear models. RESULTS: Eighty-seven patients (median age, 16 years; 25th-75th percentile, 15-18 years; 56% boys) were enrolled. Adjusted for age, sex, and underlying condition, increasing PTS severity was associated with lower current movement ability, a wider gap between current vs preferred movement ability, lower mobility, and slightly higher functional disability scores. There was a nonsignificant effect of PTS severity on moderate-strenuous physical activity. CONCLUSION: In children, increased PTS severity is associated with lower movement ability and impaired mobility. Reducing the gap between the patients' current vs preferred movement ability is a relevant aspect of PTS management in children.

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

Our 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.

Compression garments for the management of pediatric post-thrombotic syndrome: A prospective longitudinal study.

BACKGROUND: Graduated compression garments (CG) are a standard form of management of post-thrombotic syndrome (PTS) in adults, but data in children are lacking. OBJECTIVES: We aimed to study the attitudes toward CG and change in PTS severity score in children who were prescribed CG for PTS management. METHODS: Children with PTS were enrolled in this longitudinal prospective study at the time of CG prescription. PTS severity was measured at baseline and follow-up using CAPTSure© ; attitude toward CG was registered at follow-up. RESULTS: Forty-five patients were enrolled (median age 13 years, 25th-75th percentile 8-15 years; 53% male patients); 71% were prescribed socks and 29% sleeves; pressure was 15-20 mmHg in 84% of CG. Median baseline PTS CAPTSure© score was 31 points (25th-75th percentile 21-45 points). At follow-up, 49% of patients found CG helpful, 27% found CG not helpful, and 16% did not buy or wear the CG. Eight percent of enrolled patients did not return for study follow-up. Ninety-five percent of the children who found CG helpful wore them for ≥3 days/week. Hours of CG wear at the time of follow-up were associated with lower PTS scores at follow-up in a non-linear manner (e.g., wearing 12 vs. 0 h/day was associated with a 16-point reduction in PTS scores at follow-up, 95% CI -29 to -2 points). CONCLUSION: Nearly half the patients who were prescribed CG found them helpful. We observed non-linear improvement in PTS severity with the use of low-pressure CG for 8-12 h/day and ≥3 days/week, providing guidance in their prescription.

Diagnostic value of D-dimers for limb deep vein thrombosis in children: A prospective study.

The present study sought to evaluate the discriminative and predictive ability of D-dimer for pediatric limb DVT. Children aged 28 days-18 years requiring imaging to rule out limb DVT, as per the treating clinical team, were enrolled in the study. The outcome was ultrasound proven DVT. The D-dimer levels were obtained around the time of imaging. Receiver operating characteristic (ROC) curves and logistic regression models were used for data analyses. In total, 296 patients were enrolled between 2017-2020; 204 patients were diagnosed with DVT (DVT[+]). Median D-dimer levels were 2.3 µg/ml FEU (25th-75th percentile 0.9-3.9) among DVT(+) and 1.9 µg/ml FEU (25th-75th percentile 0.8-4.0) among DVT(-) patients (p = 0.60). The area under the ROC curve (AUC) was 0.52 (95% confidence interval [CI] 0.45-0.59). The odds ratio for D-dimer levels was 1.00 (95% CI 0.99-1.01), holding confounders constant. In a sub-group exploratory analysis including 23 patients with no underlying conditions or co-morbidities, the AUC curve was 0.90 (95% CI 0.76-1.00). In conclusion, in this prospective cohort study of consecutive children with suspected limb DVT, D-dimer levels had poor discriminative and predictive ability for DVT. However, D-dimer levels showed better discriminative and predictive ability for DVT in an exploratory sample of patients with no underlying conditions or co-morbidities at the time of diagnosis.

Pediatric May-Thurner Syndrome-Systematic review and individual patient data meta-analysis.

BACKGROUND: The outcomes of deep vein thrombosis (DVT) in children with May-Thurner Syndrome (MTS) remain unclear. OBJECTIVES: This systematic review and patient-level meta-analysis aims to describe the outcomes of children with MTS presenting with DVT. METHODS: A systematic review of the published literature was performed. Data related to patients <18 years diagnosed with MTS and DVT was extracted. Risk of bias was assessed using the Murad criteria. Outcomes included vessel patency post-treatment, DVT recurrence, and post-thrombotic syndrome (PTS). Predictive and explanatory models were developed for these outcomes. RESULTS: In total, 109 cases were identified (age range 4-17 years; 77 females) in 28 studies; 75% of patients had ≥1 additional risk factor for DVT. PTS was seen in 61% of patients, DVT recurrence in 38%, and complete vessel patency post-treatment in 65%. The models developed to predict and explain PTS performed poorly overall. Recurrent thrombosis (adjusted for age and patency) predicted PTS (odds ratio [OR] 3.36, 95% confidence interval [CI] 1.28-8.82). DVT management strategies (adjusted for age and DVT characteristics) predicted vessel patency (OR 2.10, 95% CI 1.43-3.08). Lack of complete vessel patency (adjusted for age and thrombophilia) predicted recurrent DVT (OR 2.70, 95% CI 1.09-6.67). Sensitivity analyses showed the same direction of effects for all outcomes. CONCLUSIONS: PTS and DVT recurrence occur frequently in pediatric MTS. PTS prediction is complex and it was not possible to identify early predictors to guide clinical practice. Use of imaging-guided therapy and thrombus burden predicted venous patency, and lack of patency predicted DVT recurrence.

Heparin-Induced Thrombocytopenia in a Pediatric Population: Implications for Clinical Probability Scores and Testing.

OBJECTIVES: To determine the applicability of the 4Ts score and the Heparin-Induced Thrombocytopenia (HIT) Expert Probability (HEP) score in children with suspected HIT and to estimate the number of children potentially at risk of HIT. STUDY DESIGN: We retrospectively estimated 4Ts and HEP scores in a cohort of 50 children referred for laboratory screening with enzyme immunoassay. In addition, minor modifications were introduced to the 4Ts score (modified 4Ts score) to adapt it for use in the pediatric setting. All patients with positive enzyme immunoassays were tested with serotonin release assay. We also extracted the number of patients started on heparins in a similar period of time. RESULTS: The median age at the time of testing was 4 years (25th-75th percentile, 8.7 months to 13.5 years); 78% of patients had low and 22% had intermediate risk pretest probability scores using the original 4Ts score; 86% had low risk and 14% had intermediate risk scores using the modified 4Ts score; 54% of children had a HEP score of ≥2. Six patients (12%) had a positive (≥0.40 optical density units) enzyme immunoassay, but none had a positive serotonin release assay. Based on anticoagulation dose, there were 1-2 new daily potentially high-risk exposures to heparinoids at our institution. CONCLUSIONS: The modified 4Ts and original 4Ts scores may be more adequate than the HEP score to determine HIT pretest probability in children. Despite the number of patients potentially at risk, HIT is rare in pediatrics.

Low molecular weight heparin for prevention of central venous catheter-related thrombosis in children.

BACKGROUND: The prevalence of children diagnosed with thrombotic events has been increasing in the last decades. The most common thrombosis risk factor in neonates, infants and children is the placement of a central venous catheter (CVC). It is unknown if anticoagulation prophylaxis with low molecular weight heparin (LMWH) decreases CVC-related thrombosis in children. This is an update of the Cochrane Review published in 2014. OBJECTIVES: To determine the effect of LMWH prophylaxis on the incidence of CVC-related thrombosis and major and minor bleeding complications in children. Further objectives were to determine the effect of LMWH on occlusion of CVCs, number of days of CVC patency, episodes of catheter-related bloodstream infection (CRBSI), other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis) and mortality during therapy. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 7 May 2019. We undertook reference checking of identified trials to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised trials comparing LMWH to no prophylaxis (placebo or no treatment), or low-dose unfractionated heparin (UFH) either as continuous infusion or flushes (low-dose UFH aims to ensure the patency of the central line but has no systemic anticoagulation activity), given to prevent CVC-related thrombotic events in children. We selected studies conducted in children aged 0 to 18 years. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible studies, which were assessed for study methodology including bias, and extracted unadjusted data where available. In the data analysis step, all outcomes were analysed as binary or dichotomous outcomes. The effects of interventions were summarised with risk ratios (RR) and their respective 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: One additional study was included for this update bringing the total to two included studies (with 1135 participants). Both studies were open-label RCTs comparing LMWH with low-dose UFH to prevent CVC-related thrombosis in children. We identified no studies comparing LMWH with placebo or no treatment. Meta-analysis found insufficient evidence of an effect of LMWH prophylaxis in reducing the incidence of CVC-related thrombosis in children with CVC, compared to low-dose UFH (RR 0.68, 95% CI 0.27 to 1.75; 2 studies; 787 participants; low-certainty evidence). One study (158 participants) reported symptomatic and asymptomatic CVC-related thrombosis separately and detected no evidence of a difference between LMWH and low-dose UFH (RR 1.03, 95% CI 0.21 to 4.93; low-certainty evidence; RR 1.17, 95% CI 0.45 to 3.08; low-certainty evidence; for symptomatic and asymptomatic participants respectively). There was insufficient evidence to determine whether LMWH impacts the risk of major bleeding (RR 0.27, 95% CI 0.05 to 1.67; 2 studies; 813 participants; low-certainty evidence); or minor bleeding. One study reported minor bleeding in 53.3% of participants in the LMWH arm and in 44.7% of participants in the low-dose UFH arm (RR 1.20, 95% CI 0.91 to 1.58; 1 study; 158 participants; very low-certainty evidence), and the other study reported no minor bleeding in either group (RR: not estimable). Mortality during the study period was reported in one study, where two deaths occurred during the study period. Both were unrelated to thrombotic events and occurred in the low-dose UFH arm. The second study did not report mortality during therapy per arm but showed similar 5-year overall survival (low-certainty evidence). No additional adverse effects were reported. Other pre-specified outcomes (including CVC occlusion, patency and CRBSI) were not reported. AUTHORS' CONCLUSIONS: Pooling data from two RCTs did not provide evidence to support the use of prophylactic LWMH for preventing CVC-related thrombosis in children (low-certainty evidence). Evidence was also insufficient to confirm or exclude a difference in the incidence of major and minor bleeding complications in the LMWH prophylaxis group compared to low-dose UFH (low and very low certainty respectively). No evidence of a clear difference in overall mortality was seen. Studies did not report on the outcomes catheter occlusion, days of catheter patency, episodes of CRBSI and other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis). The certainty of the evidence was downgraded due to risk of bias of the included studies, imprecision and inconsistency, preventing conclusions in regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombosis in children.

Outcomes and risk factors of massive and submassive pulmonary embolism in children: a retrospective cohort study.

BACKGROUND: Little is known about severe pulmonary embolism in children. We aimed to report pulmonary embolism outcomes, identify risk factors for unfavourable outcomes, and evaluate the discriminative ability of two clinical-severity indices in children. METHODS: In this retrospective cohort study, we included consecutive patients aged 18 years or younger with acute pulmonary embolism, objectively diagnosed radiologically or pathologically, between Jan 1, 2000, and Dec 31, 2016, from two Canadian paediatric hospitals (The Hospital for Sick Children, Toronto, ON, and the Children's Hospital of Eastern Ontario, Ottawa, ON). Exclusion criteria were sudden death without radiological or pathological pulmonary embolism confirmation and non-thromboembolic pulmonary embolism. The primary outcome was a composite of unfavourable outcomes of pulmonary embolism-related death and pulmonary embolism recurrence or progression. Potential predictors of the composite unfavourable outcome (ie, age at pulmonary embolism diagnosis, sex, underlying cardiac disease, severity of the pulmonary embolism, presence of a central venous catheter, associated venous thromboembolism, family history of thrombosis, treatment modalities, thrombophilia, obesity, and recent surgery) were explored with logistic regression. We calculated pulmonary embolism severity index (PESI) and simplified PESI (sPESI) using age-adjusted parameters; we estimated the ability of PESI and sPESI to predict mortality using receiver-operating characteristic (ROC) curve analysis. FINDINGS: Of the 170 patients included, 37 (22%) had massive, 12 (7%) submassive, and 121 (71%) non-massive pulmonary embolism. Patients with massive or submassive pulmonary embolism were younger (median age 12·5 years [IQR 0·6-15·1] vs 14·4 years [9·3-16·1], p<0·0001), more likely to have a cardiac condition (16 [33%] vs 17 [14%] patients, p=0·009), and had more central venous catheters (29 [59%] vs 48 [40%] patients, p=0·027) than patients with non-massive pulmonary embolism. Aggressive treatment modalities were more commonly used in massive or submassive pulmonary embolism (22 [45%] vs 7 [6%] patients, p<0·0001). Of the predictors tested, only pulmonary embolism severity was associated with the composite unfavourable outcome in the multivariable analysis (odds ratio 3·53, 95% CI 1·69-7·36; p=0·011). The area under the ROC curve for PESI to predict 30-day mortality was 0·76 (95% CI 0·64-0·87). Sensitivity of sPESI was 100% and specificity was 30%. INTERPRETATION: Massive or submassive pulmonary embolism led to higher rates of unfavourable outcomes than non-massive pulmonary embolism in children. Further adaptations of PESI and sPESI are required to improve their clinical usefulness in paediatric patients. FUNDING: Trainee Start-Up Fund (The Hospital for Sick Children).

Can thrombophilia predict recurrent catheter-related deep vein thrombosis in children?

The role of thrombophilia testing in predicting catheter-related deep vein thrombosis (DVT) after an incident (ie, first) catheter-related DVT in children remains unclear. The present study investigated the association between thrombophilia and recurrent catheter-related DVT. Children with thrombophilia testing, performed according to the clinician's judgment and the family's preference, and a history of objectively confirmed catheter-related DVT were included in the study. Recurrent catheter-related DVT after placement of a new catheter was the main outcome. Thrombophilia was classified as minor, major, or none. Analysis was conducted using mixed effect logistic regression. A total of 245 patients had 1,365 catheters inserted; 941 of these catheters were placed after the incident catheter-related DVT. Anticoagulants as treatment or prophylaxis were administered in 78.1% of inserted catheters for at least 50% of the time they were in place. Minor thrombophilia was found in 12.7% of patients, whereas major thrombophilia was seen in 8.2% of children. The incidence rate of recurrent events was 0.23/100 catheter-days (95% confidence interval, 0.19-0.28 catheter-days); 34.3% (95% confidence interval, 28.6%-40.0%) of patients requiring a new catheter after their incident thrombotic event had at least 1 recurrent event. The incidence proportion of bleeding complications was 4.6/100 patients receiving anticoagulation. Young age of the patient at the time of catheter insertion and lack of administration of treatment or prophylactic doses of anticoagulant were predictive of recurrent events. In contrast, thrombophilia was not predictive of recurrent catheter-related DVT during subsequent catheter insertions among tested patients. Our findings suggest that thrombophilia testing to predict recurrence in these patients may be unnecessary.