Venous Thromboembolism In Children Research Articles

Venous thromboembolism in children (VTE):Management of a case after the advent of a direct-acting oral anticoagulants (DOAC), obtainable under the health service

Venous thromboembolism in children (VTE):Management of a case after the advent of a direct-acting oral anticoagulants (DOAC), obtainable under the health service

Assessment of the CLOT (children's likelihood of thrombosis) real-time risk prediction model of hospital-associated venous thromboembolism in children with congenital heart disease

BackgroundChildren with congenital heart disease (CHD) are at high risk for hospital-associated venous thromboembolism (HA-VTE). The children's likelihood of thrombosis (CLOT) trial validated a real-time predictive model for HA-VTE using data extracted from the EHR for pediatric inpatients. We tested the hypothesis that addition of CHD specific data would improve model prediction in the CHD population. MethodsModel performance in CHD patients from 2010 to 2022, was assessed using 3 iterations of the CLOT model: 1) the original CLOT model, 2) the original model refit using only data from the CHD cohort, and 3) the model updated with the addition of cardiopulmonary bypass time, STAT Mortality Category, height, and weight as covariates. The discrimination of the three models was quantified and compared using AUROC. ResultsOur CHD cohort included 1457 patient encounters (median 2.0 IQR [0.5-5.2] years-old). HA-VTE was present in 5% of our CHD cohort versus 1% in the general pediatric population. Several features from the original model were associated with thrombosis in the CHD cohort including younger age, thrombosis history, infectious disease consultation, and EHR coding of a central venous line. Lower height and weight were associated with thrombosis. HA-VTE rate was 12% (18/149) amongst those with STAT Category 4-5 operation versus 4% (49/1256) with STAT Category 1-3 operation (P < .001). Longer cardiopulmonary bypass time (124 [92-205] vs. 94 [65–136] minutes, P < .001) was associated with thrombosis. The AUROC for the original (0.80 95% CI [0.75-0.85]), refit (0.85 [0.81-0.89]), and updated (0.86 [0.81-0.90]) models demonstrated excellent discriminatory ability within the CHD cohort. ConclusionThe automated approach with EHR data extraction makes the applicability of such models appealing for ease of clinical use. The addition of cardiac specific features improved model discrimination; however, this benefit was marginal compared to refitting the original model to the CHD cohort. This suggests strong predictive generalized models, such as CLOT, can be optimized for cohort subsets without additional data extraction, thus reducing cost of model development and deployment.

Venous Thromboembolism in Children: The Rivaroxaban Experience.

The incidence of venous thromboembolism (VTE) in the pediatric population has increased more than 10-fold in the last 20 years, as a consequence of the advancement of resuscitation and surgical techniques and the global increase in life expectancy of children suffering from chronic pathologies. Monitoring anticoagulant therapy to achieve outcomes within the target range in childhood VTE, parenteral administration of medications, and frequent blood tests in children are often cumbersome. Availability of safe and effective oral agents with pediatric data to support use would be of clear benefit. A physiologically based pharmacokinetic model was developed to estimate the appropriate dosing schedule for rivaroxaban in children. This incorporated growth/maturation and variability in anthropometrics (e.g., body height, weight, and body mass index), anatomy (e.g., organ weight), physiology (e.g., blood flow rates), metabolism and excretion. Rivaroxaban use in pediatric population underwent a complete investigational program, consisting mainly of one phase I pharmacokinetics/pharmacodynamics trial, three phase II trials, one phase III trial. The phase III trial enrolled 500 patients from birth to <18 years and documented the efficacy and safety of rivaroxaban regimens at dose equivalent to the adult 20 mg dose for the prevention of fatal or symptomatic nonfatal recurrent VTE and major bleeding versus heparin or vitamin K antagonists. Results were similar to those in rivaroxaban studies in adults. The efficacy and safety of rivaroxaban in children reported in the EINSTEIN JUNIOR trial provide further support to previous trials in adults (EINSTEIN Program), which demonstrate a favorable profile for the use of rivaroxaban for the management of VTE in challenging patient populations. Other clinical evidence contributing to the use of rivaroxaban among different risk groups in pediatric VTE population confirms the consistency with principal trial. Our review aims to describe the rationale for using rivaroxaban oral suspension in clinical practice and to summarize its multiple indications in each vascular bed (e.g., cerebral venous thrombosis, symptomatic or asymptomatic central venous catheter-associated thrombosis), etiology, and patients setting.

Improving Anticoagulation Care for Pediatric Oncology Patients: A Quality Improvement Initiative.

Cancer is associated with increased venous thromboembolism in children. Risk factors for venous thromboembolism in this cohort include using central venous catheters, mass effect from underlying malignancy, chemotherapy, and surgery. Anticoagulation management in this cohort is challenging, given recurrent episodes of thrombocytopenia, the need for invasive procedures, and coagulopathy. A quality improvement (QI) initiative was developed to improve hematology consultation services and provide documentation of an individualized anticoagulation care plan for this high-risk cohort. Through the use of QI methods, interviews of stakeholders, expert consensus, and review of baseline data, a multidisciplinary team was organized, and key drivers relevant to improving access to hematology consultations and documentation of individualized anticoagulation care plans were identified. We used a Plan-Do-Study-Act model to improve hematology consultations and documentation of anticoagulation care plan (process measure). Outcome measures were bleeding and thrombosis recurrence/progression. Seventeen patients with oncologic and venous thromboembolism diagnoses were included as baseline data. Slightly over half of these patients [53% (n = 9)] had a hematology consultation, and 7 (43.8%) had documentation of an anticoagulation care plan. After implementing QI methods, all 34 patients (100%) received hematology consultations and documentation of an anticoagulation care plan, and this measure was sustained for 1 year. Bleeding and thrombosis rates were similar in the baseline and post-QI cohorts. QI interventions proved effective in sustaining access to hematology consultations and providing anticoagulation care plans for patients with concomitant improved anticoagulation plan documentation for patients.

Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial

Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population. PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete. Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause). PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding. Bristol Myers Squibb-Pfizer Alliance.

Prognostic Value of Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging for Predicting Venous Thromboembolism in Children With Lymphoma

Positron emission tomography (PET)/computed tomography (CT) imaging can detect changes in arterial inflammation, but has not been used to evaluate chemotherapy-induced venous inflammation or assess risk for venous thromboembolism (VTE) in pediatric oncology. Therefore, the purpose of this study was to evaluate the prognostic value of fluorine-18-fluorodeoxyglucose PET/CT imaging of venous inflammation for predicting VTE occurrence in the 12 months after lymphoma diagnosis in pediatric, adolescent, and young adult patients. Pediatric, adolescent, and young adult patients with lymphoma diagnoses (n=71) who underwent whole-body PET/CT imaging at initial staging of disease and first therapeutic follow-up were retrospectively evaluated for serial changes in lower extremity venous uptake of fluorine-18-fluorodeoxyglucose. PET/CT images were used to segment and quantify serial changes in fluorine-18-fluorodeoxyglucose uptake for veins of interest (ie, popliteal and femoral). Incidence of VTE was assessed for 12 months after lymphoma diagnosis. PET/CT detected a significantly higher inflammatory response in the femoral (P=0.012) and popliteal (P=0.013) veins of patients who experienced a VTE event compared with those who remained VTE free in the 12 months after diagnosis. The area under the curve values for receiver operator characteristics analyses were 0.76 (femoral vein) and 0.77 (popliteal vein) based on incidence of VTE occurrence. Univariate analyses demonstrated that PET/CT-derived changes in femoral (P=0.008) and popliteal (P=0.002) vein inflammation were significantly associated with VTE-free survival at 12 months after diagnosis. Fluorine-18-fluorodeoxyglucose PET/CT imaging detects treatment-induced venous toxicity that may provide insight into risk of VTE events in pediatric and adolescent and young adult patients with lymphoma.

Biomarkers in pediatric venous thromboembolism: a systematic review of the literature

BackgroundAccurate prediction of the individual risk of venous thromboembolism (VTE) remains suboptimal in children, and biomarkers are currently not used to stratify the risk of VTE in children. ObjectivesThis study aimed to assess which biological or radiological biomarkers may predict VTE or VTE complications in children. Patients/MethodsA literature search was performed for peer-reviewed publications (1990-2022). We included studies addressing the use of biomarkers for patients aged 29 days to 18 years to predict VTE or its complications, including but not limited to TE-related death, VTE recurrence, or postthrombotic syndrome. Given the heterogeneity of the study designs, populations, and outcomes, no quantitative data synthesis was performed. ResultsForty studies were included, totaling 10,987 participants (median age: 4.7 years). Reports were often lacking critical methodological data, including blood collection method (68% of studies) and timepoints, laboratory testing technique (41%), or primary outcome definition (20%). Forty-six individual biomarkers were assessed for VTE prediction (32 studies, 9525 participants), including d-dimers, fibrinogen, platelet count, white blood cell count, and factor VIII. Albumin, C-reactive protein, d-dimers, factor VIII, and thrombin-antithrombin levels showed promising results for VTE prediction. In 9 studies (1606 participants), no biomarker was consistently predictive of postthrombotic syndrome, VTE persistence, or VTE recurrence in children. ConclusionsSeveral candidate biomarkers were promising in the prediction of VTE in children. Still, discrepancies between different studies and the high risk of bias from the current literature prevent their widespread use in the clinical setting. Further prospective research in various pediatric subpopulations is required.

Venous thromboembolism in children with acute lymphoblastic leukemia in China: a report from the Chinese Children's Cancer Group-ALL-2015.

Venous thromboembolism (VTE) is a complication in children with acute lymphoblastic leukemia (ALL). The Chinese Children's Cancer Group-ALL-2015 protocol was carried out in China, and epidemiology, clinical characteristics, and risk factors associated with VTE were analyzed. We collected data on VTE in a multi-institutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019. First, VTE occurred in 159 (2.08%) patients, including 90 (56.6%) during induction therapy and 108 (67.92%) in the upper extremities. T-ALL had a 1.74-fold increased risk of VTE (95% CI 1.08-2.8, P = 0.022). Septicemia, as an adverse event of ALL treatment, can significantly promote the occurrence of VTE (P < 0.001). Catheter-related thrombosis (CRT) accounted for 75.47% (n = 120); and, symptomatic VTE, 58.49% (n = 93), which was more common in patients aged 12-18 years (P = 0.023), non-CRT patients (P < 0.001), or patients with cerebral thrombosis (P < 0.001). Of the patients with VTE treated with anticoagulation therapy (n = 147), 4.08% (n = 6) had bleeding. The VTE recurrence rate was 5.03% (n = 8). Patients with VTE treated by non-ultrasound-guided venous cannulation (P = 0.02), with residual thrombus (P = 0.006), or with short anticoagulation period (P = 0.026) had high recurrence rates. Thus, preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.

The Incidence of Thromboembolic Events During Hospitalizations Following Surgical Resection of Lower Extremity Sarcomas in Children: Utilizing the Pediatric Health Information System Database.

Venous thromboembolism (VTE) is a frequent occurrence during treatment for adults with sarcoma. The incidence and underlying risk factors of postsurgical VTE in children and adolescents undergoing resection of sarcoma are unknown. Using International Classification of Disease revision-9 diagnostic and procedure codes, the Pediatric Health Information System database was queried for patients aged 18 years and younger, discharged from 2004 to 2015 with a diagnosis of lower extremity malignant neoplasm who had a tumor resection or amputation performed during the encounter. Malignant neoplasms of the pelvic bones and soft tissues were categorized as "pelvis tumors", whereas malignant neoplasms of bone and soft tissues of the lower limbs were categorized as "lower limb tumors". Hospitalizations were evaluated for the occurrence of VTE. Demographic characteristics (age at admission, sex, race, and race/ethnicity) and incidence of VTE were reported. There were 2400 patients identified. Of these, 19 experienced VTE (0.79%) during their surgical hospitalization encounter. By anatomic group, the rate of VTE was 1.4% (CI: 0.5%-3.2%) for tumors in the pelvis and 0.6% (CI: 0.3%-1.0%) in lower limb tumors. Categorizing by age, the incidence of VTE was 1.2% in patients aged zero to 5, 0.3% in patients 6 to 13, and 1.2% in patients 14 to 18 years old. (Table 1). The extremely low rate of VTE occurrence precluded further analysis of risk factors. In this analysis, postsurgical VTE during hospitalization after pelvic and lower extremity sarcoma resection was an uncommon event in children and adolescents. There seemed to be an increased incidence of postsurgical VTE in pelvic tumors when compared with lower limb tumors, however, the rarity of all events precluded formal statistical analysis. A more robust data set would be required to determine if there are subsets of children and adolescents with sarcoma at higher risk of VTE that could benefit from thromboprophylaxis in the postoperative setting. Level II.

High rate of recurrent venous thromboembolism in children and adolescents with unprovoked venous thromboembolism

BackgroundUnprovoked venous thromboembolism (VTE) is rare in pediatrics. Current recommendations for anticoagulation duration after unprovoked VTE differ for pediatric and adult populations. ObjectivesThis single-center, retrospective cohort study aimed to determine the incidence rate of recurrent VTE in children and adolescents with unprovoked VTE, evaluate the potential risk factors for recurrence, and describe the anticoagulation regimens and bleeding in this population. MethodsChildren with an index, unprovoked VTE at the age of 1 to <21 years between 2003 and 2021 were included. The time to recurrent VTE and anticoagulation duration were summarized using Kaplan-Meier estimators. Clinical covariates were assessed for association with recurrence using stratified Kaplan-Meier curves and univariate Cox proportional hazards regression. ResultsEighty-five children met the inclusion criteria, and there were 26 recurrent events in 250 person-years of follow-up (incidence rate = 104 [95% CI, 71-153] per 1000 person-years). An age of ≥12 years at index VTE (hazard ratio [HR], 7.56; 95% CI, 1.60-35.83) and inherited thrombophilia (HR, 2.28; 95% CI, 1.05-4.95) were significantly associated with recurrent VTE. Female sex had a nonstatistically significant decreased hazard of recurrence (HR, 0.56; 95% CI, 0.25-1.27). Duration of anticoagulation was variable, with a median duration of 274 days (IQR, 101-2357) for outpatient therapeutic anticoagulation. Twelve of the 26 (46%) recurrent events occurred while anticoagulation was prescribed. ConclusionThe incidence rate of recurrent VTE in pediatric patients with a prior unprovoked VTE is high, particularly for adolescents and those with inherited thrombophilia. Therefore, future research should focus on the efficacy of prolonged anticoagulation for this population.

1095: VENOUS THROMBOEMBOLISM IN HOSPITALIZED CHILDREN WITH NEPHROTIC SYNDROME

Introduction: Urinary loss of anticoagulant proteins, altered fibrinolysis, and intravascular fluid depletion as well as abnormalities in platelet aggregation and increased synthesis of prothrombotic factors in children with nephrotic syndrome (NS) are responsible for increased risk of venous thromboembolism (VTE). This study aimed to delineate national epidemiological data on hospitalized pediatric patients with NS and VTE. Methods: We performed a cross-sectional analysis utilizing the Kids’ Inpatient Database for the years 2016 and 2019. Children from birth to 20 years of age with a discharge diagnosis of NS were included. Predictors included demographic data and comorbidities. Outcomes included VTE, mortality, length of stay and resource use. Chi-square test, student t-test and multiple logistic regression were used for inferential statistical comparisons. Results: There were 10,934 discharges with NS out of a total of 12,157,889 (8.9 per 10,000 discharges) during the study period. A diagnosis of VTE was present in 193 discharges (1.8%) in the NS cohort. Among children with NS, there was no difference in gender, race/ethnicity or median household income between those with and without VTE. Acute pulmonary embolism occurred in 0.7% of all NS discharges and accounted for 42% of VTE among children with NS and VTE. Multiple logistic regression, adjusted for hypercoagulable conditions, revealed that the risk of VTE in children with NS was significantly more than in the general population (aOR 3.7; 95% CI: 3.2-4.4). Among children with NS, the presence of VTE was associated with an increased mortality rate (OR 5.9; 95%CI: 2.0-16.8) and longer mean LOS (16.8 days; 95% CI: 12.8-20.8 vs. 5.2 days; 95% CI: 5.0-5.4). Additionally, among children with NS, those with VTE were more likely to need hemodialysis/peritoneal dialysis (OR 3.5; 95% CI: 2.1-5.6), renal biopsy (OR 1.8; 95% CI: 1.1-2.7), mechanical ventilation (OR 6.2; 95% CI: 3.6-10.4), and were more likely to have AKI (OR 2.6; 95% CI: 1.8- 3.9), CKD (OR 1.7; 95% CI: 1.0-2.7), ESRD (OR 2.3; 95% CI: 1.5-4.1), and hypercoagulable conditions exclusive of NS (OR 14.0; 95% CI: 9.2-21.2). Conclusions: Children with NS are at higher risk for VTE. VTE is associated with increased morbidity, mortality and resource utilization in children with NS.

Thrombosis in Chronic Kidney Disease in Children.

Venous thromboembolism (VTE) in children is a rare condition. An increased incidence has been observed in the last few years due to several factors, such as increased survival in chronic conditions, especially chronic kidney disease (CKD), use of catheters, and increased sensitivity of diagnostic tools. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE in children is associated with a two to six times higher mortality risk and a 5-10% prevalence of post-thrombotic syndrome. Overall, 5% of VTE episodes in children are associated with chronic kidney disease. The etiology of VTE in chronic kidney disease covers a wide range of pathologies. Various types of thrombotic complications may occur during long-term use of a chronic dialysis catheter. VTE occurs in 3% of children with nephrotic syndrome (NS). The risks for VTE and arterial thromboembolism (ATE) were particularly high in the first 6 months after the onset of NS. Other causes of VTE are graft rejection due to thrombosis of vascular anastomoses after kidney transplantation (3%) and autoimmune diseases (lupus nephritis, antiphospholipid syndrome). In this state-of-the-art overview, we have reviewed the physiologic and pathologic mechanisms underlying pediatric thrombosis and updated current diagnostic and treatment options, emphasizing personal experience as well.

Anticoagulation Use for Secondary Prophylaxis Against Recurrent Venous Thromboembolism in Hospitalized Children: A Report from the Children's Hospital-Acquired Thrombosis (CHAT) Consortium

Introduction: Most venous thromboembolism (VTE) in children are provoked and have an overall low risk for recurrence, especially if the original provoking factor is mitigated. Nonetheless, certain factors heighten VTE recurrence risk, including hospitalization. In fact, the rate of VTE in hospitalized children has increased more than 200% since 20011. This staggering discovery emphasizes the dire need for more effective tactics aimed at VTE prevention. Historically, pediatric providers have been hesitant to initiate pharmacologic (i.e. anticoagulant) measures in children for a number of reasons. In our recent survey of practice patterns of secondary prevention against recurrent VTE in pediatrics, we found low use (<25%) of pharmacologic prophylaxis in high-risk children2. Additionally, most respondents did not feel comfortable initiating secondary pharmacologic prophylaxis in younger children2. In the wake of the COVID-19 pandemic, numerous trials have been conducted to evaluate anticoagulation for VTE prevention in affected individuals. The recently published COVID-19 Anticoagulation in Children- Thromboprophylaxis trial showed safety of low-dose enoxaparin in children hospitalized with COVID-19 or multisystem inflammatory syndrome in children (MIS-C)3. Furthermore, trials of direct oral anticoagulants have also shown safety and efficacy in secondary VTE prevention in children4. Importantly, these studies have consistently demonstrated low rates of bleeding. Methods: The CHAT Registry is an IRB-approved registry that captures clinical data on hospital-acquired VTE in children <21 years of age and non-VTE controls. Subjects were enrolled from 2012-2021 across 8 participating pediatric hospitals. Using this REDCap database, we performed a retrospective study of enrolled subjects to explore trends for secondary anticoagulation prophylaxis use in hospitalized children. Subjects (cases and controls) were included if they had a history of VTE. Descriptive statistics were used to analyze demographics/characteristics and VTE prophylaxis measures. Results: Fifty-two subjects (%) out of 2219 total CHAT subjects (1273 cases, 946 controls) reviewed had a prior history of VTE. Characteristics of these subjects are presented in Table 1. The mean age was 9.6 years with a slight male predominance (54%). Regarding VTE prophylaxis (Figure 1), 18 (35%) received VTE prophylaxis (mechanical and/or pharmacologic) during hospitalization. Of these, 11 subjects (61%) were prescribed pharmacologic prophylaxis either alone (8) or in combination with mechanical prophylaxis (3). The remaining seven (39%) received only mechanical prophylaxis. Four subjects were already on anticoagulation at the time of admission. Forty-four (85%) subjects experienced a hospital-acquired VTE recurrence. Only 16 (36%) of these had received some method of VTE prophylaxis. Of those who did not receive pharmacologic prophylaxis, only 3 had a documented contraindication. The most commonly documented contraindications to pharmacologic prophylaxis pertained to risk of bleeding, and included uncorrected coagulopathy, ongoing/uncontrolled hemorrhage and thrombocytopenia. The median time between admission and VTE event was 9 days. Conclusion: There is a high rate of recurrent VTE in hospitalized children with a history of prior VTE. These results underscore the significance of implementing consistent pharmacologic prophylaxis in high-risk children where appropriate. As the landscape is actively changing in terms of available anticoagulant formulations available for children, providers may feel more confident in initiating secondary pharmacologic prophylaxis particularly as new data confirm the safety. Nevertheless, ongoing definitive studies are required to better understand which particular factors yield the highest rates of VTE and hence warrant pharmacologic prophylaxis above standard mechanical measures. We want to acknowledge the CHAT Consortium sites who contributed to the CHAT Registry. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Longitudinal Trajectory and Predictors of Health-Related Quality of Life after First-Episode, Acute Onset Venous Thromboembolism in Children

Background/objectives: We prospectively measured change in the quality of life (QOL) in children during the 2 years after first-episode, acute venous thromboembolism (VTE) and evaluated predictors of QOL, including the impact of post-thrombotic sequelae on QOL. Patients/methods: Consecutive patients with acute VTE were recruited from 2016 to 2022 for the TOP (Thrombosis Outcomes in Pediatrics) study (ClinicalTrials.GOV ID: NCT03068923). A pre-planned QOL analysis was conducted at study visits at diagnosis and 3, 6, 12, 18, and 24 months. Patients with cancer, recurrent VTE, sickle cell disease, and those not anticoagulated were excluded. At each visit, a standardized assessment for post-thrombotic sequelae (recurrence, post-thrombotic syndrome (PTS), post-pulmonary embolism (PE) syndrome, portal HTN, and post-CSVT recovery) was performed, and participants self-completed QOL questionnaires using the Peds QoL. Mean within-patient change scores (baseline to 2 years) were assessed using paired t-tests (Hο: Δ = 0), where positive change scores indicate improvement in QOL. Change in QOL over time was assessed in the entire cohort and was compared between patients with and without adverse post-thrombotic sequelae. Predictors of QOL were evaluated, and the influence of post-thrombotic sequelae on QOL at two years was assessed using multivariable regression analyses. Results: Among the 120 children prospectively recruited, the median age was 13 years (range 0-18). 56% were males (n=66) and 28% were Hispanics. The most common VTE site was lower extremity DVT (41%), and 80 % had a provoked event. 15% had comorbidities. The cumulative incidence of adverse post-VTE outcomes at 2 years was 26% (10 children within the entire cohort developed recurrence identified objectively, 5 of 67 with extremity thrombosis had clinically significant PTS as assessed with the Manco-Johnson Instrument instruments, 9 of 36 with PE had post-PE exercise intolerance on cardiopulmonary exercise testing, 2 of 9 with portal vein thrombosis developed portal HTN and 4 of 23 with CSVT had impaired neurocognitive recovery measured by the pediatric stroke recurrence and recovery questionnaire). QOL scores below the population mean were documented at diagnosis (32%), 3 (37%), 6 (20%),12 (23%), 18 (19%) and 24 (13%) months. On average, QOL scores improved during follow-up, with most improvement occurring in the first six months following post-diagnosis. However, patients who developed adverse post-thrombotic sequelae had lower scores at all visits and significantly less improvement in QOL over time. Multivariable regression analyses showed that female sex (p=0.01), non-extremity thrombosis (p=0.008), presence of post-thrombotic sequelae (p=<0.001) and long-term anticoagulation (p=<0.001) independently predicted 2-year post-diagnosis impaired QOL. Conclusions: We evaluated QOL during the 2 years following an episode of acute We found that, on average, QOL scores tended to improve during follow-up and that most of the improvement in QOL occurred in the first 6 months after VTE. However, patients who developed post-thrombotic sequelae had poorer QOL, less overall improvement in QOL, and slower improvement in QOL. Our findings are of direct importance to patients. On average, patients with VTE who do not develop post-thrombotic sequelae can expect that at 2 years, their QOL will improve to a level like that of the general population. Further, our study provides prognostic information on patient-reported outcomes after VTE and emphasizes the need for effective prevention and treatment of the post-thrombotic sequelae. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venous Thromboembolism in Children, Adolescents and Young Adults: Findings from the Riete Registry

Background: Venous thromboembolism (VTE) is rare in patients younger than 21 years of age. The differences in clinical features between pediatric, adolescent, and young adult VTE patients have not been well defined. Aims: To compare clinical characteristics at baseline, risk factors, management and outcomes between pediatric, adolescent and young adult patients with VTE. Methods: Data from the prospective international RIETE registry were used. Patients younger than 21 years of age with all types of objectively confirmed VTE were stratified into three sub-cohorts: children up to 12 years old, adolescents 12 - 18 years, and young adults 18 - 21 years. Adolescents and young adults were also compared with patients older than 21 years. Results: Of the 97,827 RIETE patients enrolled until March 2022, 31 were children, 219 adolescents and 830 young adults (median [IQR] age 4 [0-10], 16 [15-17], 20 [19-21] years, respectively). Most younger patients were males (P < 0.001), with increasing proportion of females once hormone use became a risk factor (after the age of 12, P < 0.001). Children presented with less pulmonary emboli and more cerebral sinus vein thrombosis and catheter related thrombosis (P < 0.01). Most pediatric patients were treated with LMWH (Table 1). Rates of VTE recurrence, major bleeding and all-cause mortality were comparably low among adolescents and young adults. None of these occurred in children younger than 12 years. None of the patients in any of the pediatric sub-cohort died from VTE recurrence (Table 2). Conclusions: Although often grouped together, children, adolescents and young adults have distinctive VTE features. While VTE presentation may be similar among adolescents and young adults as compared to older patients, the outcomes of patients younger than 21 years are more favorable. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia

AbstractIn the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel–weighted rate difference, −0.135; 95% confidence interval, −0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

Safety and Efficacy of Direct Oral Anticoagulants for Treatment of Venous Thromboembolism in Pediatric Oncology Patients.

Children with cancer have an increased risk for developing a venous thromboembolism (VTE) during their treatment course. Direct oral anticoagulants (DOACs) represent a relatively new class of oral medications to treat VTE; however, data are limited to support use in this patient group. Given the safety and efficacy data from numerous perspective adult studies, providers now consider off-label use in select children. We performed a single-center, retrospective review of children 0 to 20 years of age from 2012 to 2020 with malignancy and confirmed VTE, with the objective to evaluate the hypothesis that the safety and the efficacy of DOACs are noninferior to enoxaparin in this population. The primary composite efficacy outcome comprises symptomatic recurrent VTE, death due to VTE, and thrombus progression. The principal safety outcome is a combination of major and clinically relevant nonmajor bleeding. The safety and efficacy outcomes collected revealed that DOAC use was equivalent when compared with the enoxaparin group for treatment of VTE. One patient in the DOAC group had clinically relevant, nonmajor bleeding compared with 2 patients in the enoxaparin group. No treatment failures were observed. This single-center study suggests that DOACs are both safe and efficacious for the treatment of VTE in children with cancer. It also highlights the need for larger studies to address this clinical question.

Treatment and Prevention of Venous Thromboembolism in Children: Current State and Future Directions

Treatment and Prevention of Venous Thromboembolism in Children: Current State and Future Directions

Risk of venous thromboembolism in children and adolescents with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUNDA two- to three-fold increased risk of venous thrombotic events (VTE) has been demonstrated in patients with inflammatory bowel disease (IBD) compared to the general population, but less is known about the risk of VTE in child- and pediatric-onset IBD. In recent years, several studies have reported the rising incidence rate of VTE in juvenile patients with IBD, and the related risk factors have been explored.AIMTo evaluate the risk of VTE in children and adolescents with IBD.METHODSArticles published up to April 2021 were retrieved from PubMed, Embase, Cochrane Library, Web of Science, SinoMed, CNKI, and WANFANG. Data from observational studies and clinical work were extracted. The outcome was the occurrence of VTE according to the type of IBD. The available odds ratio (OR) and the corresponding 95% confidence interval (CI) were extracted to compare the outcomes. Effect size (P), odds ratio (OR), and 95%CI were used to assess the association between VTE risk and IBD disease. Subgroup analyses stratified by subtypes of VTE and IBD were performed. RESULTSTwelve studies (7450272 IBD patients) were included in the meta-analysis. Child and adolescent IBD patients showed increased VTE risk (P = 0.02, 95%CI: 0.01-0.03). Subgroup analyses stratified by IBD (ulcerative colitis (UC): P = 0.05, 95%CI: 0.03-0.06; Crohn’s disease (CD): P = 0.02, 95%CI: 0.00-0.04) and VTE subtypes (portal vein thrombosis: P = 0.04, 95%CI: 0.02-0.06; deep vein thrombosis: P = 0.03, 95%CI: 0.01-0.05; central venous catheter-related thrombosis: P = 0.23, 95%CI: 0.00-0.46; thromboembolic events: P = 0.02, 95%CI: 0.01-0.03) revealed a significant correlation between VTE risk and IBD. Patients with IBD were more susceptible to VTE risk than those without IBD (OR = 2.99, 95%CI: 1.45-6.18). The funnel plot was asymmetric, suggesting the presence of significant publication bias. Pediatric and adolescent IBD patients have an increased VTE risk. UC and CD patients exhibited a high risk of VTE. The risk of VTE subtypes was increased in IBD patients.CONCLUSIONThe current meta-analysis showed that the incidence and risk of VTE are significantly increased in pediatric and adolescent IBD patients. Thus, IBD might be a risk factor for VTE in children and young adults. High-quality prospective cohort studies are necessary to confirm these findings.

Challenges in Management of VTE in Children With Cancer: Risk Factors and Treatment Options.

Venous thromboembolism (VTE) occurs in 2.1 to up to 50% of children with cancer and contributes to long term morbidity as well as early mortality in this population. Pediatric patients with malignancy are predisposed to VTE due to the prothrombotic nature of cancer and its associated coagulopathies as well as chemotherapeutic agents, use of central venous catheters, surgery, radiotherapy, and concomitant thrombophilia. Management of thrombosis in this population is challenging due to concomitant thrombocytopenia, associated bleeding risks, concurrent co-morbidities, and toxicities of therapy. The aim of this paper is to highlight clinically relevant issues and management dilemmas using clinical vignettes. We review the clinical significance of asymptomatic and symptomatic thrombosis, examine the various options for asparaginase-associated thrombosis, address the role and controversies of direct oral anticoagulants, and describe our approach to managing anticoagulation therapy in the context of chemotherapy-induced thrombocytopenia.