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.

Physical activity for children with deep vein thrombosis and pulmonary embolism on anticoagulation: a scoping review.

Context: There are no clear pediatric guidelines on the return to physical activity following deep vein thrombosis (DVT) or pulmonary embolism (PE), particularly while being treated with anticoagulation. Objective: This scoping review aimed to examine the current literature on physical activity beyond simple ambulation for patients with DVT/PE being treated with anticoagulation. Data Sources: An electronic search for articles in MEDLINE, Epub Ahead of Print, In-Process, and Other Non-Indexed Citations, Daily (1946 to April 4, 2022), and Embase+Embase Classic (1946 to 2022, week 13) was conducted. Study Selection: (1) Patients of any age with DVT/PE, treated with anticoagulation; (2) studies of any design providing information on physical activity (ie, sport, exercise) while on anticoagulation; and (3) studies in English. Data Extraction: Data from eligible studies obtained included the study design, population, disease characteristics, and information on physical activity participation. Results: A total of 26 eligible studies were included. Only 2 studies were specific to children. Studies recommend a gradual return to participation in noncontact or low-risk activities after the first 3-4 weeks of anticoagulation, with close monitoring of symptoms. Participation in contact sports and activities is typically delayed until after anticoagulants are discontinued. However, personalized anticoagulation with intermittent dosing schedules has been proposed for athletes after the first 3 months of anticoagulation treatment. Conclusions: Physical activity participation guidelines for children with DVT/PE being treated with anticoagulation are needed, and the evidence currently available is limited. Largely based on evidence from adult patients, we present evidence-informed options to facilitate clinician recommendations for returning to activity.

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.

Impact of deep vein thrombosis on adolescent athletes: Navigating an invisible disability.

Background: Injury in adolescent athletes that threatens their sport participation can result in a sense of identity loss during critical years for identity development, creating the potential for significant mental health challenges. The specific effect of deep vein thrombosis (DVT) in this vulnerable population has not been characterized. Purpose: To describe the impact of DVT diagnosis, treatment, and long-term complications on the mental well-being of athletes who sustained a DVT during adolescence and to identify strategies to improve the quality of care for these patients. Methods: Using a qualitative study design, athletes with a history of DVT during adolescence and their parents were recruited to participate in semistructured interviews. Interviews were transcribed and analyzed using thematic analysis. Participants were recruited until reaching thematic saturation. Results: In total, 19 participants (12 athletes, 7 parents) were recruited. Athletes were mainly males (67%), median age at time of DVT was 15 years (range, 12-18 years), and median age at study participation was 19 years (range, 16-34 years). Thematic analysis revealed four main themes: Theme 1: DVT posed a threat to sport participation; Theme 2: at a personal level, there were significant mental health challenges; Theme 3: at a societal level, DVT is an invisible disability; and Theme 4: physical, psychological, and transition support are important to improve the care of these patients. Conclusion: Deep vein thrombosis threatens an athlete's participation in sport, resulting in a significant and complex impact on their mental well-being. Heightened awareness and a multidisciplinary approach are needed to help young athletes navigate the consequences of DVT.

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.

Post-thrombotic syndrome in children: Measurement properties of CAPTSure, a new diagnostic tool.

BACKGROUND: CAPTsure (Clinical Assessment of PTS) is a new tool for diagnosis and severity rating of pediatric postthrombotic syndrome (PTS). Our objective was to test the reliability, measurement error, and minimal detectable change of CAPTSure. METHODS: Children aged newborn to 18 years who sustained upper extremity or lower extremity deep vein thrombosis (DVT) were enrolled ≥ 6 months after DVT diagnosis. Patients were assessed by 2 raters to determine the reliability of the clinician assessment component (CC) of CAPTSure. Patients/proxies completed CAPTSure at baseline and approximately 2 weeks later to assess test-retest reliability of the symptoms component (SC). RESULTS: Of 148 patients enrolled in the study; 30 had sustained either bilateral or both upper and lower extremity DVT. Hence, 178 extremities were assessed for PTS signs (86 upper extremity, 92 lower extremity). Intraclass correlation coefficient (ICC) for the CC was 0.89 (95% confidence interval [CI], 0.84-0.93) for upper extremity and 0.88 (95% CI, 0.83-0.92) for lower extremity. Nonclinicians performed 59% of measurements. Ninety-eight patients completed the SC at baseline and follow-up, for a total of 60 upper extremity and 61 lower extremity assessments. ICC for the SC was 0.89 (95% CI, 0.84-0.93) for upper extremity and 0.92 (0.87-0.95) for lower extremity. ICC for CAPTSure was 0.92 (95% CI, 0.87-0.95) for upper extremity and 0.93 (95% CI, 0.88-0.95) for lower extremity assessment. Measurement error ranged between 1.7 and 4.3 of 100 points. A change of approximately 11 of 100 points in CAPTSure score would be required to be confident that there was a change in PTS severity. CONCLUSION: CAPTSure has excellent reliability and a small measurement error, even when applied by nonhematologists.

Assessment of limb edema in pediatric post-thrombotic syndrome.

BACKGROUND: Pediatric tools for diagnosis of post-thrombotic syndrome (PTS) include the assessment of limb edema as a symptom (patient/proxy-reported) and as a sign. However, it is unclear whether these two approaches refer to the same clinical aspect of PTS. This could result in overestimation of disease severity. We sought to evaluate the correlation among different techniques to assess limb edema as a sign and as a symptom in children who sustained upper extremity (UE) or lower extremity (LE) deep vein thrombosis (DVT) and were, therefore, at risk of PTS. METHODS: Limb edema was cross-sectionally measured as a symptom (ie, patient- or proxy-reported) and as a sign (ie, clinician-assessed limb circumference difference, limb volume ratio, bioimpedance spectroscopy ratio (BIS), and durometry ratio) in 140 children at risk of PTS (n = 70 UE-DVT, n = 70 LE-DVT). Item-item correlations were estimated using Pearson or Spearman correlation coefficients, as appropriate, and separately for the UE and LE groups. RESULTS: In the UE-DVT group, proxy-reported swelling correlated weakly to moderately with circumference difference and with volume ratio, but not with BIS ratio. In the LE-DVT group, proxy-reported swelling correlated moderately with thigh circumference difference and volume ratio, and patient-reported swelling correlated moderately with BIS ratio. CONCLUSION: Our findings suggest that patient/proxy-reported and clinician-assessed limb edema measure slightly different aspects of PTS, justifying their inclusion in pediatric PTS tools. In addition, proxy-reported swelling was in closer agreement with clinician-assessed total limb size (ie, observed edema), and patient-reported swelling in the LE seemed to reflect limb fluid content (ie, perceived edema).

Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury.

Voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF) after traumatic brain injury (TBI) when it occurs during a delayed time window. In contrast, acute post-TBI exercise does not increase BDNF. It is well known that increases in glucocorticoids suppress levels of BDNF. Moreover, recent work from our laboratory showed that there is a heightened stress response after fluid percussion injury (FPI). In order to determine if a heightened stress response is also observed with acute exercise, at post-injury days 0-4 and 7-11, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) release were measured in rats running voluntarily or exposed to two daily 20-min periods of forced running wheel exercise. Forced, but not voluntary exercise, continuously elevated CORT. ACTH levels were initially elevated with forced exercise, but decreased by post-injury day 7 in the control, but not the FPI animals. As previously reported, voluntary exercise did not increase BDNF in the FPI group as it did in the control animals. Forced exercise did not increase levels of BDNF in any group. It did, however, decrease hippocampal glucocorticoid receptors in the control group. The results suggest that exercise regimens with strong stress responses may not be beneficial during the early post-injury period.

Vta1p and Vps46p regulate the membrane association and ATPase activity of Vps4p at the yeast multivesicular body.

Previous two-hybrid analysis of the 17 soluble class E Vps yeast proteins revealed that Vps46p/Did2p interacts with Vta1p and the AAA (ATPase associated with a variety of cellular activities) ATPase Vps4p. Here we report that the binding of Vps46p to Vps4p and Vta1p is direct and not mediated by additional proteins, and the binding of Vps46p to Vps4p is ATP independent. Vps46p regulates the membrane association of Vps4p and is required for the interaction of Vta1p with Vps32p/Snf7p of the ESCRT-III complex. Vta1p is a potent activator of Vps4p, stimulating the ATPase activity by 6- to 8-fold. These results reveal functional roles for the Vps46p and Vta1p proteins in regulating the ESCRT complex assembly/disassembly cycle in protein sorting at the yeast late endosome.