BACKGROUND:Contemporary data show an increasing incidence of venous thromboembolism in children, yet there are few evidence-based treatment guidelines on direct oral anticoagulant use for venous thromboembolism in this population. We aimed to investigate the safety and efficacy of apixaban in paediatric patients with venous thromboembolism. METHODS:This prospective, open-label, multicentre, randomised, controlled descriptive study was conducted in 120 sites in 14 countries and included a 12-week main treatment phase followed by an optional 6-12-week extension in the apixaban treatment group for patients who required additional anticoagulation for their index event, were adherent to apixaban administration, and had completed all study visits and activities. Patients were eligible if they were younger than 18 years with an index venous thromboembolism event confirmed by the investigator via imaging and were currently tolerating enteric medications. Exclusion criteria included more than 14 days of standard-of-care anticoagulant treatment before random assignment, active bleeding or a high risk of bleeding, and baseline abnormal liver function or inadequate kidney function. Patients were randomly assigned 2:1 to oral apixaban or standard-of-care (unfractionated heparin, low-molecular-weight heparin, or vitamin K antagonists) per local practice via a central randomisation and drug assignment system (stratified by age). The study used a fixed-dose-by-bodyweight-tier oral apixaban regimen (with nasogastric or gastric feeding, if required). Neonates initiated 0·1 mg oral apixaban twice daily for days 1-7, with the dose remaining at 0·1 mg twice daily thereafter unless otherwise indicated by the results of pharmacokinetics analysis on day 1. For children aged 28 days or older, doses ranged from 0·6 mg twice daily for the first 7 days and 0·3 mg thereafter (4 kg to <5 kg tier) and 10 mg twice daily for the first 7 days and 5 mg twice daily thereafter (highest weight tier, ≥35 kg). The primary efficacy endpoint was a composite of incidence of recurrent venous thromboembolism and venous thromboembolism-related mortality during the main phase (analysed in all randomly assigned patients). The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding during the main phase (analysed in all randomly assigned and treated patients). Efficacy and safety endpoints were adjudicated by an independent committee whose members were masked to treatment assignment. Adverse events were monitored using a combination of solicited and unsolicited event collection. The study is registered with ClinicalTrials.gov (NCT02464969) and is complete. FINDINGS:Between Nov 22, 2015, and April 30, 2024, 229 patients were randomly assigned: 155 to apixaban and 74 to standard of care. Median age was 14·2 years (IQR 6·1-16·5), with 137 (60%) patients age 12 years to younger than 18 years, 44 (19%) age 2 years to younger than 12 years, 32 (14%) age 28 days to younger than 2 years, and 16 (7%) age 27 days or younger. 128 (56%) patients were female, 101 (44%) were male, and 175 (76%) were White. Median treatment duration during the main phase was 83 days (IQR 78-90) in the apixaban group and 83 days (77-86) in the standard-of-care group. The primary efficacy endpoint occurred in four (2·6% [95% CI 0·8-6·7]) of 155 patients assigned to apixaban and two (2·7% [0·2-9·9]) of 74 assigned to standard of care; all events were recurrent venous thromboembolism. The primary safety endpoint occurred in two (1·3% [0·1-5·0]) of 152 apixaban-treated patients and one (1·4% [0·0-8·1]) of 73 standard-of-care-treated patients; all events were clinically relevant non-major bleeding, with no major bleeding events. Rates of any-grade adverse events were numerically similar in the apixaban (131 [86%] of 152 patients) and standard-of-care (61 [84%] of 73]) groups. The most common events were headache (25 [16%] in the apixaban group vs 11 [15%] in the standard-of-care group), epistaxis (24 [16%] vs 14 [19%]), and vomiting (20 [13%] vs four [5%]). There were three treatment-related serious adverse events with apixaban (two [1%] participants with haematochezia and one [1%] with cerebral venous sinus thrombosis) and none with standard of care. There were no treatment-related deaths during the study. INTERPRETATION:In this descriptive study, the safety and efficacy profile of a fixed-dose-by-bodyweight-tier apixaban regimen was similar to that of standard of care for the treatment of venous thromboembolism and prevention of venous thromboembolism recurrence in children younger than 18 years, providing a potential additional treatment option in this patient population. FUNDING:Pfizer and Bristol Myers Squibb.

OBJECTIVE:While an improved understanding of the epidemiology and outcomes of hormonal contraceptive use in persons with sickle cell disease is needed to better inform evidence-based guidelines, patterns of contraception use remain understudied. Our objective was to examine patterns of contraception use among patients with sickle cell disease and employer-sponsored insurance. STUDY DESIGN:Our analyses utilized the Merative™ MarketScan® Commercial Database (2012-2019). The study included females 12-44 years meeting the study definition of sickle cell disease (presence of three ICD-9 or ICD-10 codes consistent with sickle cell disease). We utilized pharmacy and procedure claims to capture hormonal contraception use. RESULTS:We identified 5957 unique females of reproductive age (12-44 years) with sickle cell disease, 1653 (28%) of whom utilized hormonal contraception. When examining the first identified contraception prescription, 43.9% were prescribed estrogen-containing agents and 56.1% were prescribed progestin-only. The most frequently prescribed contraceptive was combined contraceptive pills (n = 645, 39%), followed by depot medroxyprogesterone acetate (n = 413, 25%). Intrauterine devices and subcutaneous implants were prescribed to 15.7% and 6.4% of individuals, respectively. CONCLUSIONS:Our work identified hormonal contraception use in less than one-third of reproductive-age females with sickle cell disease using employer-sponsored insurance. Over 40% of new users of hormonal contraception received prescriptions for estrogen-containing agents, demonstrating a need for education regarding the 2024 U.S. MEC recommendations, which contradict estrogen for patients with sickle cell disease. Future directions should also include understanding patient characteristics and health outcomes among combined hormonal contraceptive users with sickle cell disease to better inform eligibility criteria. IMPLICATIONS:Estrogen-containing agents make up a substantial percentage of contraception prescriptions in women with sickle cell disease and employer-sponsored insurance. High-quality data regarding the safety of hormonal contraception in the setting of sickle cell disease are needed to inform evidence-based guidelines and medical eligibility criteria.

Von Willebrand Disease (VWD) is the most common inherited bleeding disorder and is often diagnosed in the setting of heavy menstrual bleeding (HMB). Because estrogen upregulates von Willebrand factor synthesis, pregnancy and the management of menses may influence VWD testing and diagnosis. Throughout the lifespan, the management of women’s reproductive health is frequently impacted by VWD. We seek to describe the interplay between VWD and women’s reproductive health at three distinct phases in life: menarche and menstruation, maternal health and fertility, and menopause and aging. Planning for care requires screening for VWD in the setting of reproductive bleeding counseling patients about expectations, and monitoring for iron deficiency across all three phases. Hemostatic plans should be tailored to both factor levels and patient preference. Emphasis is placed on areas lacking vital data.

BACKGROUND:Though tonsillectomies are commonly performed in children, the rate of post-tonsillectomy hemorrhage in those with von Willebrand disease (VWD) is unknown. OBJECTIVES:To determine the rate of post-tonsillectomy hemorrhage in children with VWD. METHODS:We performed a retrospective analysis of individuals 0-18 years with VWD who underwent tonsillectomy and received a hemostatic agent on the day of procedure between October 2015 and September 2023 via the Pediatric Health Information Systems (PHIS) database. The primary outcome was the rate of hemorrhage within 14 days of tonsillectomy. Secondary outcomes included the rate of postoperative emergency department (ED) visits and subsequent surgical procedures for hemorrhage. Data on demographics, setting (inpatient vs. outpatient), and tonsillectomy indication were collected. RESULTS:A total of 753 individuals with VWD underwent tonsillectomy. Postoperative bleeding occurred in 17.5% (n = 132). A total of 4.5% (n = 34) presented to the ED with hemorrhage following tonsillectomy, with repeat surgery in 5.0% (n = 38). Individuals whose perioperative hemostatic regimen included only an antifibrinolytic had an increased bleeding rate (24.2%; n = 31) compared to desmopressin (14.5%; n = 8) or VWF replacement alone (2.4%; n = 1; p = 0.004). Older age was associated with bleeding (p = 0.006), as those 6-18 years had a bleeding rate of 22% compared to 4.3%-12.8% in the younger age groups. CONCLUSIONS:Our study represents a nine-fold increased rate of post-tonsillectomy hemorrhage in children with VWD compared to the general pediatric population. This suggests the need for aggressive preventive management with normalizing of VWF levels around the time of tonsillectomy and close clinical supervision to prevent hemorrhagic complications.

ABSTRACT:Pediatric patients with acute lymphoblastic leukemia and lymphoma (ALL/LL) and obesity are at increased risk for venous thromboembolism (VTE). The PREVAPIX-ALL trial was an open-label, randomized, controlled trial assessing the safety and efficacy of apixaban for VTE prevention in pediatric patients with ALL/LL. An a priori subgroup analysis of patients with obesity in the PREVAPIX-ALL trial was planned because of increased VTE risk in this group. Patients with obesity, aged ≥2 to <18 years, central venous catheter, and chemotherapy containing asparaginase were randomized to apixaban (prophylactic dose) vs standard of care (SOC; no anticoagulation) during induction chemotherapy. The primary efficacy end point was a composite of nonfatal symptomatic and asymptomatic VTE and VTE-related death. The primary and secondary safety outcomes were major bleeding and a composite of major and clinically relevant nonmajor (CRNM) bleeding, respectively. A total of 82 PREVAPIX-ALL participants presented with obesity, of whom 42 were randomized to apixaban. For the primary efficacy end point, a significant decrease in VTE events was present in the apixaban arm (1/42 [2.4%]) as compared with the SOC arm (10/40 [25%]; relative risk [RR], 0.09; 95% confidence interval [CI], 0.01-0.97; P = .007). There was a statistically significant treatment obesity interaction, P = .03. No statistically significant difference was observed for the primary efficacy end point among the nonobese group (RR, 0.85; 95% CI, 0.53-1.37; P = .50). No statistically significant difference in major or CRNM bleeding was observed. Apixaban prophylaxis in patients with obesity and ALL/LL resulted in a statistically significant VTE risk reduction with no increase bleeding. This trial was registered at www.clinicaltrials.gov as #NCT02369653.

BACKGROUND/OBJECTIVES:Approximately half of male cancer survivors experience infertility following cancer treatment, which can lead to psychosocial distress. The aim of this study was to identify support needs and reflections on the decision-making process related to sperm banking among adolescent male cancer survivors and their caregivers at 1 year post-diagnosis. METHODS:As part of a randomized controlled trial testing a family-centered sperm banking decision-making intervention, males diagnosed with cancer (12-25 years old) and their caregivers completed semi-structured interviews 1 year post-diagnosis. Thematic analysis was conducted by three independent coders (κ = 0.80) and focused on two interview questions: (1) Is there anything you wish you would have known or done before making the [sperm banking] decision? and (2) What information or support do you think is needed regarding your/your son's future fertility goals? RESULTS:Qualitative interviews with adolescents (n = 20) and caregivers (n = 18) revealed three primary themes: (1) satisfaction with information received at diagnosis, but retrospective desire for more decision-making time; (2) current desire for additional fertility-related support; (3) potential need for future fertility-related support. CONCLUSION:Despite satisfaction with the oncofertility consultation at diagnosis, clinical teams should prioritize fertility education moving forward and allow additional time for sperm banking decision-making (when possible) at diagnosis. Counseling gaps can lead to uncertainty, unplanned pregnancies, and adverse mental health outcomes. Thus, it is important to revisit issues surrounding fertility and family planning after treatment, particularly among adolescents transitioning to adulthood.

BACKGROUND/OBJECTIVES:The Family-centered Adolescent Sperm banking values clarification Tool (FAST) was developed to facilitate sperm banking communication and decision-making pre-cancer treatment. The FAST was tested in a pilot parallel randomized controlled trial (Fertility Preservation Discussions And Decisions: "FP-DAD"-NCT04268004), aiming to (i) assess feasibility/acceptability of FP-DAD; and (ii) examine efficacy regarding banking attempts (yes/no) and decision quality. Differences in decision quality by banking attempt were explored. DESIGN/METHODS:Males (12-25 years, new cancer diagnosis) and caregivers were randomized to standard of care (fertility consult) or FP-DAD (fertility consult + FAST + interventionist-led discussion). One month later, FP-DAD participants completed acceptability surveys. Both arms completed the Brief Subjective Decision Quality measure. Descriptive statistics, chi-square, and independent samples t-tests/mixed-models examined relationships between variables. RESULTS:Acceptability ratings of FP-DAD were high (88%-100%). Recruitment and participation challenges limited the final sample size (21 adolescents and 32 caregivers). Banking attempts (67% in standard of care vs. 82% in FP-DAD) did not differ by arm. While decision quality was not significantly different between groups, effect sizes were medium-large for four of six items for adolescents (d = 0.6 to -0.90) and two of six for caregivers (d = 0.36 to -0.78). Decision quality was significantly higher across several domains among those who banked. CONCLUSIONS:FP-DAD had high acceptability, though feasibility challenges (e.g., time contraints) limited full family participation. Findings showed limited efficacy, but effect sizes suggest this may be due to sample size. Relationships between banking attempts and decision quality emphasize banking benefits. Findings will inform adaptations to the FAST for clinical implementation.

Whereas the symptoms that make up chronic abnormal uterine bleeding (AUB) in the reproductive years have been well described and the subject of extensive clinical investigation, acute heavy menstrual bleeding has received relatively little attention. Acute heavy menstrual bleeding has been defined by the International Federation of Gynecology and Obstetrics as an episode of heavy bleeding in the reproductive years, unrelated to pregnancy, that, in the opinion of the clinician, is of sufficient quantity to require immediate intervention. These women often present with a background of chronic heavy menstrual bleeding, often with iron deficiency, which makes them particularly vulnerable to the consequences of an acute episode. Only a few studies have evaluated acute heavy menstrual bleeding; relatively little guidance is available for clinicians worldwide. Management of acute heavy menstrual bleeding requires the expertise of several medical specialties, including primary care, pediatrics, gynecology, hematology, and emergency medicine. This article is the result of a virtual multidisciplinary panel meeting designed to raise awareness of the problem of acute heavy menstrual bleeding, including its pathogenesis, clinical manifestations, and management, and to examine the evidence gaps and barriers that continue to impair basic and clinical research in the development of effective interventions. Although there are challenges to performing clinically relevant and well-designed research, it is necessary from both policy and clinical perspectives. Such investigation must be coupled with initiatives designed to inform clinicians in a fashion that provides effective guidance in the management of this vexing clinical problem.

STUDY OBJECTIVE:To test patient engagement and satisfaction with mobile app menstrual monitoring in young adolescents. We hypothesized that at least two-thirds of study participants would demonstrate sustained engagement with menstrual tracking over 6 months. METHODS:The study cohort included menstruating adolescents 10-14 years of age with regular access to a smartphone or tablet. Our study design allowed for a completely remote participant experience, and participants were primarily recruited through electronic platforms. Participants used our HIPAA-compliant Teen-Period (T-Dot) mobile app to track menstrual bleeding and related symptoms over a 6-month timeframe. RESULTS:A total of 156 participants were included in the data analysis (median age 13 years, IQR 12-14). One hundred participants (64.1%) met the primary outcome of engagement with T-Dot, meaning they entered data for ≥3 menses. Usability of T-Dot was positively rated by study participants, with the majority agreeing or strongly agreeing that T-Dot was easy to use (n = 108, 74.5%) and helped to track menses effectively (n = 104, 77.2%). Usability scores did not decrease from Week 6 to Month 6, nor did the frequency of T-Dot use. Participant engagement did not differ significantly by age, race, body weight, or presence of heavy menstrual bleeding. CONCLUSION:In this preliminary study of a teen-focused HIPAA-compliant menstrual tracking app, we achieved our enrollment goals and successfully implemented a decentralized prospective cohort study. Our findings demonstrate that menstrual tracking research is possible even in early adolescents.

Introduction: Central venous catheters (CVCs) are increasingly placed in children for administration of medications, fluids, parenteral nutrition as well as frequent blood collection. CVC type or insertion technique, underlying medical conditions and type of infused medications can impact CVC function and longevity. CVC malfunction is known to be associated with deep vein thrombosis (DVT). Our previous study of children with CVCs (Jaffray, et al, Blood 2020), found those with a CVC malfunction were six times more likely to develop a DVT. The aim of this subanalysis was to evaluate risk factors for CVC malfunction and subsequently the development of a DVT in children with peripherally inserted central catheters (PICCs) and tunneled lines (TLs) within our Clot Incidence Rates in Central Lines (CIRCLE) study. Methods: This is a subanalysis of the multicenter, prospective CIRCLE study conducted from October 2013 to June 208. Randomly selected children aged 6 months to <18 years of age with newly placed PICCs or TLs were enrolled and monitored until CVC removal or end of the study period. A CVC malfunction was defined as any CVC that required tissue plasminogen activator (t-PA) or had malfunction reported as ‘blockage’ or ‘mechanical’. CVC related risk factors for DVT included type, size, material, length, number of lumens of CVC and insertion technique including number of insertion attempts, placement via ultrasound guidance and whether CVC was placed by an interventional radiology (IR) technique. Patient related factors included age, medical history, vein accessed, location of CVC tip, having a catheter associated blood stream infection (CLABSI), receiving total parental nutrition or anticoagulation (other than routine heparin flushes). DVT was confirmed on radiologic examination of those subjects with symptoms of CVC-associated DVT. To examine associations between risk factors and CVC malfunction, we performed survival analysis by fitting univariate and multivariate Weibull regression models. From these models, we obtained hazard ratios (HR) and their respective 95% confidence intervals (CI). Results: A total of 1951 CVCs were included in this analysis. There were 380 (19.5%) CVCs with at least one malfunction. Median [interquartile range (IQR)] time from CVC insertion to the first malfunction was 20 [7.75-57] days. The majority of CVCs with malfunction had one episode (n= 219, 57.6%), followed by two malfunctions (n= 75, 19.7%) and 22.7%(n=86) had three or more malfunctions. There was a significantly higher rate of malfunction in PICCs as compared to TLs (HR=2.14, 95% CI:1.71-2.68, p value<0.0001). On multivariable analysis, risk factors associated with an increased risk of malfunction included previous CVC (HR=1.5, 95% CI:1.2-1.9, p=0.002), CVC size < 4 French (HR=3.23, 95% CI:2.51-4.17, p<0.0001), having two or more catheter lumens (HR=2.9, 95% CI:2.3-3.6, p<0.0001) and more than two insertion attempts (HR=2.2, 95% CI:1.4-3.5, p=0.0005). CVCs placed by IR (HR=0.4, 95% CI:0.3-0.5, p<0.0001) and the presence of a CLABSI (HR=0.6, 95% CI:0.4-0.9, p=0.009) were associated with significantly lower risk of CVC malfunction. DVT was diagnosed in 22 (5.8%) CVCs with a malfunction and the median (IQR) time to diagnosis of DVT after CVC malfunction was 6 (1-18.5) days. The HR of DVT development for those requiring one t-PA dose versus those receiving no t-PA was 0.87 (95% CI:0.16-4.57, p= 0.87), compared to a HR of 1.23 (95% CI:0.21-7.23, p= 0.81) for two doses, 1.15 for three doses (95% CI:0.15-8.68, p=0.89) and 3.37 for four or more doses (95% CI:0.66-17.27, p=0.11) of t-PA. Conclusion: Our previous study identified that CVCs with malfunction were more likely to develop a DVT. PICCs had nearly a 9-fold increased risk of DVT as compared to TLs. In this sub-analysis, nearly one fifth of CVCs placed in children had a malfunction. Malfunction risk factors included a previous CVC, smaller lumen size, multi-lumen CVCs, multiple insertion attempts and CVCs not being inserted by IR technique. Interestingly, the presence of a CLABSI was associated with lower rates of CVC malfunction which could be attributed to frequent CVC access that maintains patency or use of medication locks for CLABSI. Although not statistically significant, likely due to small numbers, CVC-associated DVT seems to increase with multiple doses of t-PA which should raise suspicion to screen for DVT if a CVC requires repeated t-PA instillation.

BackgroundPrimary dysmenorrhea, menstrual pain occurring in the absence of pelvic pathology, typically starts in the first 3 years post-menarche as ovulatory cycles are established. Prior studies have generally been observational, cross-sectional, or retrospective leading to recall bias, and few have assessed the impact of dysmenorrhea in the early post-menarcheal years. The aim of this study was to prospectively characterize dysmenorrhea and global quality of life (QoL) during menses in early adolescents over 6-months.MethodsA prospective, observational IRB approved study utilizing a multi-platform mobile application that allowed real-time assessment of menses was conducted. English speaking, post-menarcheal, biological female adolescents, aged 10-14 years, who had regular access to a smart device were enrolled from outpatient primary and specialty clinics. Participants could document the following during each menses: 1) pattern and flow of menses using the Pictorial Blood Loss Assessment Chart, 2) intensity, location, and duration of dysmenorrhea, and 3) QoL in 6 domains (family, friends, health, extracurriculars, school, job). Impact on job was minimal given age group assessed and thus was excluded. Descriptive analyses included medians (interquartile ranges) for continuous variables and counts (percentages) for categorical variables.Results126 participants were included in analyses with a median age of 13.0 years, 79 (63%) were white, 56 (45%) overweight/obese, and gynecological age was < 3 years in 112 (89%). Among all participants, 506 menstrual cycles were documented with a median number of four cycles per participant. Median duration of menses and dysmenorrhea were 5.0 and 2.0 days, respectively. Dysmenorrhea was present in 375 (74%) of 506 cycles. Median pain intensity per cycle was 4 out of 10. In 275 (54%) of cycles, pain was reported in abdomen, 244 (48%) pelvis, 138 (27%) back, and 58 (11%) thighs. QoL was impacted in 232 (46%) cycles in any domain. Top three QoL domains impacted were health 142 (28%), extracurriculars 112 (22%), and school 90 (18%). Most prevalent concerns in these domains included: tiredness, headache, nausea, anxiety, poor concentration, leaking, and inability to use restroom. Family and friend domains were impacted in 82 (16%) and 50 (9.9%) cycles, respectively, with top concerns being over-reacting, fighting, or missing a family/friend event.ConclusionsProspective analysis of menses was feasible in early adolescents utilizing a mobile application. Among early post-menarcheal biological females, dysmenorrhea was present in most menstrual cycles, and some impact on QoL occurred in almost half of cycles.

Introduction: Children requiring pediatric intensive care unit (PICU) management are at increased risk for venous thromboembolism (VTE) as well as bleeding complications due to critical illness. There is limited understanding regarding the subset of patients who may benefit from thromboprophylaxis during their PICU stay. The purpose of this study was to determine the risk factors for VTE in critically ill children and to develop and validate a risk assessment model (RAM) tailored for this patient population. Methods: Data from the Pediatric Health Information System (PHIS) was used for this study. Data for children (1 month - 21 years of age) directly admitted or transferred to the PICU within 5 days of admission were collected from PHIS from 2015-2023. Patients were excluded if they had a billing code for a neonatal ICU admission or missing sex information. Subsequent encounters for the same patient were also excluded. Data were collected regarding demographics, duration of hospitalization, reason for admission, acute organ dysfunction and underlying complex chronic condition (CCC). VTE was defined as presence of deep vein thrombosis (DVT), pulmonary embolism (PE) or both. For those with a VTE, data were collected regarding the type and location of VTE. Training (70%) and validation (30%) datasets were randomly generated using the 2015-2020 data. RAM testing was then performed on three consecutive annual datasets (2021, 2022, and 2023). For RAM derivation, 35 variables were initially chosen based on their relevance as VTE risk factors and data availability from PHIS. Predictors were screened using generalized logistic regression models. Predictors with p <0.05 were included in the final multivariable model. Least Absolute Shrinkage and Selection Operator (LASSO) was used to generate the final regression model. Discrimination was measured using receiver operating characteristic (ROC) curves and calibration plots were used to assess model accuracy. Results: We identified a total of 98,589 unique PICU managed patients. 56% of the study population were male and 44% were non-Hispanic White race. Of these, 5,060 (5.13%) experienced a VTE. Deep vein thrombosis was the most common VTE (n=3960, 78%) followed by pulmonary embolism (n=523, 10%). Median age at the time of hospitalization was 7.2 years (IQR: 1.0-14.8 years) for those with VTE compared to 3.6 years (IQR: 0.7-11.6 years) for those without a VTE (p <0.0001). Length of PICU stay was longer for those with a VTE (median of 11 days [IQR: 5-25] vs. 5 days [IQR: 3-8], p<0.01). Patients with VTE had 2.7 times higher odds of mortality in comparison to those without a VTE (p<0.001). Among the variables that were included in the final regression model: central venous line (CVL) (OR 6.52; 95% CI: 6.03-7.04); acute renal dysfunction (OR 3.95; 95% CI: 3.71-4.21); acute hemostatic derangement (OR 3.76; 95% CI: 3.47-4.08); sepsis (OR 3.26; 95% CI: 3.05-3.49); solid or hematopoietic cell transplantation (OR 3.09; 95% CI: 2.75-3.46); acute cardiac dysfunction (OR 2.80; 95% CI: 2.63-2.98); mechanical ventilation (OR 2.34; 95% CI: 2.20-2.50); recent surgery (OR 2.05; 95% CI: 1.93-2.18); chronic cardiac (OR 1.88; 95% CI: 1.78-1.99), GI (OR 1.56; 95% CI: 1.47-1.66), hematologic/immune (OR 2.20; 95% CI: 2.02-2.38), metabolic (OR 2.58; 95% CI: 2.41-2.74), and renal conditions (OR 2.20; 95% CI: 2.04-2.38); trauma (OR 1.51; 95% CI: 1.39-1.64) and age (OR 1.05; 95% CI: 1.04-1.05) were identified as independent risk factors for VTE. The ROC area under the curve (AUC) for the validation model was 0.78. Upon testing in the 3 independent annual cohorts, the RAM performed well with ROC AUCs of 0.80 (2021), 0.80 (2022), and 0.78 (2023). Conclusions: Using an administrative database, we successfully derived and validated a RAM specifically for PICU associated VTE. Among the several known risk factors, CVL was the most important predictor of VTE risk. While prospective validation is needed, this new RAM may improve VTE risk stratification and guide thromboprophylaxis use in children managed in the PICU.

Background: Although the risk of pregnancy-related morbidity and mortality in people with sickle cell disease (SCD) is well established, limitations in data sources and heterogeneity in outcome reporting hinder the ability to make meaningful comparisons between historical and contemporary populations. This study used a national administrative claims database to compare pregnancy outcomes in people with SCD between 2006-2011 and 2012-2018. Materials and Methods: Pregnant females aged 16-44 years with SCD were identified from the Centers for Medicare and Medicaid Service Analytic eXtract, along with a control cohort of pregnant people. People were followed from first identified pregnancy until one year postpartum. Outcomes of interest were identified with ICD-9 or 10 codes. Results: We included 6,388 people with SCD and 17,278 controls in analyses. Preeclampsia/eclampsia, hypertension, thrombosis, poor fetal growth, preterm delivery, and postpartum hemorrhage were all more common in people with SCD compared with controls. Maternal death occurred in 0.5% of people with SCD versus <0.1% in those without SCD (p < 0.001). When comparing infant deliveries in 2006-2011 to those occurring in 2012-2018, all pregnancy-related complications except preterm delivery, including maternal death, occurred at similar or higher frequencies in more recent years. Conclusions: Between 2006 and 2018, maternal death occurred in approximately 1 out of every 200 publicly insured people with SCD in the year following infant delivery. Our work confirms, on a national-level, that pregnancy-related outcomes in people with SCD in the United States have not improved with time, and that some complications have in fact increased in frequency.

ABSTRACT:Serial prophylactic exchange blood transfusion (SPEBT) is increasingly used in sickle cell disease (SCD) pregnancy, despite a lack of robust evidence. The Transfusion Antenatally in Pregnant Women with Sickle Cell Disease (TAPS2) study assessed the feasibility and acceptability of conducting a definitive randomized controlled trial of SPEBT (intervention) vs standard care (control) in this population. Women aged ≥18 years with SCD, between 6+0 and 18+6 weeks of singleton gestation, were randomized 1:1 every 6 -10 weeks throughout pregnancy in 7 hospitals in England. The main outcomes were recruitment rate (primary outcome), acceptability, and retention. Secondary outcomes were safety and maternal/infant outcomes. In total, 194 women were screened over 42 months (extended because of the pandemic), 88 were eligible, and 35 (39.8%) consented to participate; 18 participants were randomized to intervention, and 17 to control. Follow-up data were collected on all participants. Twelve patients in the intervention group received at least 1 SPEBT, of these, 11 received ≥3. The remaining patient was withdrawn from SPEBT because of transfusion reaction. Sixteen control participants required at least 1 transfusion. There were no statistically significant differences in maternal, infant, and postnatal outcomes. A trend toward a lower incidence of vaso-occlusive crisis, preterm delivery, and improved birthweight was observed in the intervention. The study achieved satisfactory recruitment and retention, confirming its acceptability to participants. TAPS2 demonstrates that it is feasible to perform a definitive international trial of SPEBT in SCD pregnancy. These trials were registered at www.ClinicalTrials.gov as #NCT03975894 and International Standard Randomized Controlled Trial Number (www.isrctn.com; #ISRCTN52684446).

Background: In children, the incidence of VTE was initially reported to be very low at 0.07-0.14 per 10,000 children; however, contemporary data revealed a higher incidence for hospitalized children: ≥ 106 per 10,000 admissions (Andrew M et al. Blood 1994;83:1251-7, van Ommen CH et al. J Pediatr 2001;139:676-81, O'Brien SH et al. Pediatrics 2022;149:e2021054649). Pediatric evidence-based VTE treatment guidelines recommend unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or vitamin K antagonists (VKAs) as standard of care (SOC), acknowledging the gap surrounding the use of direct oral anticoagulants, such as apixaban, in children (Monagle P et al. Chest 2012;141[suppl 2]:e737S-e801S, Monagle P et al. Blood Adv 2018;2:3292-3316). The safety and efficacy profile of apixaban in adults with VTE has been established (Agnelli G et al. N Engl J Med 2013;368:699-708 and 2013;369:799-808). This study assessed the efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of apixaban in pediatric patients (pts) requiring anticoagulation for the treatment of VTE. Methods: In this 12-week, open-label, active-controlled descriptive study (NCT02464969), pediatric pts (aged < 18 years) with image-confirmed VTE were randomized 2:1 to receive apixaban dosed according to a fixed-dose, body weight tiered (mg/kg) regimen by age group (birth to 27 days, 28 days to < 2 years, 2 to < 12 years, 12 to < 18 years), or SOC prescribed per local practice (VKA, LMWH, and UFH). The primary efficacy endpoint was image-confirmed and adjudicated recurrent VTE defined as contiguous progression or non-contiguous new thrombus (new), including deep vein thrombosis (DVT), pulmonary embolism (PE), other thrombosis, paradoxical embolism, and VTE-related mortality. The primary safety endpoint was adjudicated major bleeding and clinically-relevant non-major bleeding (CRNMB). Secondary endpoints included new or recurrent symptomatic/asymptomatic DVT, PE, VTE other than DVT or PE, stroke, index event status, minor bleeding events, and apixaban PK/PD (plasma concentration and anti-Factor Xa activity [AXA] of apixaban). Pts who discontinued anticoagulation completed end-of-treatment and safety visits. The study was not powered and used descriptive statistics. Results: Overall, 229 pts were randomized (full analysis set: apixaban n = 155, SOC n = 74). In total, 26 pts (11.4%) discontinued treatment (apixaban n = 17, SOC n = 9) and 4 (1.7%) were not treated (apixaban n = 3, SOC n = 1). The majority of pts were female (55.9%) and White (76.4%); median (range) age was 14.2 (0.04-18.0) years. Baseline demographics were comparable between treatment arms. Primary efficacy endpoint: in the apixaban group, 4 (2.6%, 95% CI 0.8-6.7) pts had ≥ 1 symptomatic or asymptomatic recurrent VTE event compared with 2 (2.7%, 95% CI 0.2-9.9) pts in the SOC group; no pts had VTE-related death. Primary safety endpoint: no pts in either treatment group had major bleeding events. In the apixaban group, 2 (1.3%, 95% CI 0.1-5.0) pts had CRNMB compared with 1 (1.4%, 95% CI 0.0-8.1) in the SOC group. The overall safety profile of apixaban was similar to SOC based on the incidence of treatment-emergent adverse events (AEs) and serious AEs. No clinically meaningful treatment differences in hematology and clinical chemistry laboratory parameters were observed. Day 14 pre-dose and corresponding post-dose median apixaban concentrations were similar across age groups at the administered doses. AXA was linearly correlated to apixaban concentrations across all age groups and body-weight tiers. Conclusions: In this active-controlled descriptive study in children from birth to < 18 years of age with acute VTE, treatment with apixaban resulted in a low risk of VTE recurrence and comparable risk of major and CRNMB events compared to SOC therapy. No new safety signals were observed in apixaban-treated pts. The safety profile was generally consistent with that reported in adult VTE studies. PK/PD findings demonstrated linear correlation and were consistent across age and body-weight tiers. Study support: This study was sponsored by Pfizer and Bristol Myers Squibb. Acknowledgments: We thank the Study B0661037 investigators and patients for their participation. Editorial and medical writing support were provided by Caudex, a division of IPG Health Medical Communications, New York, NY, USA, and were funded by Pfizer and Bristol Myers Squibb.

Introduction Heavy menstrual bleeding (HMB) is common in menstruating adolescents. Accurately identifying HMB can be clinically challenging due to difficulties in measuring blood loss. The Pictorial Bleeding Assessment Chart (PBAC) assesses menstrual blood loss via sanitary product saturation but does not capture the full patient experience. Given the significant emotional, physical, and social impacts of HMB, assessing its effect on health-related quality of life (HRQoL) is essential for comprehensive evaluation and management. The Adolescent Menstrual Bleeding Questionnaire (aMBQ), adapted from the MBQ and validated by Pike et al. (2021) with 75 participants in Nova Scotia, Canada, assesses QoL related to menstrual bleeding in adolescents ≤18. This study aims to measure the utility of the aMBQ in a larger, more culturally diverse adolescent population. Methods Participants were recruited from primary care clinics at Nationwide Children's Hospital (Columbus, OH)- which serves a diverse and predominantly underserved population. Those with a prior diagnosis of a bleeding disorder or chronic illness associated with iron deficiency were excluded. HMB was defined as PBAC score ≥100. The aMBQ is a 21-item instrument with scores ranging from 0-77; higher scores indicate worse HRQoL. Statistical analyses were conducted using Wilcoxon rank sum test, Fisher's exact test, two-sample t-tests, and two-way ANOVA test, with significance set at p<0.05. The aMBQ's ability to distinguish between participants with and without HMB was evaluated using sensitivity, specificity, and the area under the curve (AUC) and corresponding 95% CI from receiver operating characteristic (ROC) analysis. Results A total of 320 participants completed the aMBQ and PBAC. Median PBAC score was 94 (IQR 50 -186), and median aMBQ score was 17 (IQR 11-25). 65% of participants identified as Black, 18% White, 17% other races, and 8% as Hispanic. Mean age was 14.8 years (SD 2.1). 46.9% of participants (n=150) had HMB (PBAC ≥100). Median aMBQ score for those with HMB was higher than those without HMB (24, IQR 17-30 vs. 13, IQR 9-17; p < .001), indicating decreased HRQoL, consistent with the original study. Median age of adolescents with HMB was also significantly higher (15 vs 14 yrs, p=0.002), as was the median time since menarche (4 vs 2 yrs, p < .001). No significant difference in race/ethnicity was observed between the groups. Age at menarche did not significantly differ between those with and without HMB, consistent with the original study. Mean (±SD) aMBQ score for participants with HMB was significantly higher in the original study (29.8, ± 8.5) compared to this study (24.2, ± 9.3; p=0.0105). For those without HMB, the mean aMBQ score in the original study was 19.6 (± 7.6) versus 14.3 (± 7.6) in this study (p=0.0026). The aMBQ had an AUC of 0.81 (95% CI: 0.76-0.86) for HMB (PBAC ≥100). An optimal aMBQ cutoff score of 16.5 showed 79% sensitivity and 71% specificity, compared to the original study's cutoff of ≥30, which had 70% sensitivity and 84% specificity. Personal communication with Pike et al. suggests that a cutoff of 16 in the original study yields similar sensitivity (78%) and specificity (68%). In a sub-analysis with PBAC ≥150 denoting HMB, the mean aMBQ score for those with HMB was 26.3 (± 9.4) vs 15.4 (± 7.8) for those without (p < .001), with an AUC of 0.82 (95% CI: 0.77-0.87) and a cutoff score of 17.5, 69% sensitivity, and 82% specificity. Conclusion This study evaluated the aMBQ in a culturally diverse adolescent cohort, supporting its discriminatory power and utility in assessing HRQoL in menstruating adolescents. The substantial impact of HMB on adolescents' HRQoL, as demonstrated by higher aMBQ scores, highlights the importance of including quality of life measures in HMB evaluation. Higher reported HRQoL compared to the original study may be due to cultural differences in perception and reporting, or a higher prevalence of chronic conditions. Menstrual issues may seem less significant amidst other life challenges and adolescents in underserved populations may have developed coping mechanisms to manage HMB. Future research should further examine the aMBQ across various demographic groups and cultures to enhance its applicability. Reference Pike M, et al. Quality of life in adolescents with heavy menstrual bleeding: Validation of the Adolescent Menstrual Bleeding Questionnaire. Res Pract Thromb Haemost. 2021 Nov 8;5(7):e12615.

Methods 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 25 mg twice daily of apixaban as a 25 mg tablet, 05 mg tablets, or 04 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 05 mg tablets or the 04 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.Findings 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] 069, 95% CI 045-105; p=0080). Two major bleeding events occurred in each group (RR 10, 95% CI 014-701; p=10). 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 367, 95% CI 104-1297, p=0030). 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).Interpretation 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.

Background and Significance: Exercise intolerance and dyspnea on exertion (DOE) are frequent after pulmonary embolism (PE) despite anticoagulation and may impact quality of life. There is little research that fully explains why this occurs, nor are there specific treatments or guidelines for PE complications in children or young adults. The FUVID Program (NCT04583878) will examine the impact of 3 mechanisms underlying exercise intolerance and DOE: cardiac (right ventricular maladaptation and its coupling with the pulmonary circulation) dysfunction, pulmonary limitations secondary to persistent vascular obstruction, and skeletal muscle metabolic abnormalities on exercise intolerance and DOE after PE. Study Design and Methods: This prospective, multi-center, observational study is enrolling previously healthy patients ages 8-21 years with acute, first-episode PE with or without DVT. A positive control group with no PE but with physical activity restrictions mimicking a deconditioning effect as patients with PE (cohort 1) and control group with no prescribed physical activity restrictions and otherwise considered healthy (cohort 2) will be enrolled. Patients will be enrolled within 8 weeks of diagnosis of PE from 13 enrollment and 25 recruitment sites across the US. Due to the complexity of the cutting-edge metabolic and functional tools only available at UTSW (namely, MR spectroscopy at 7 Telsa to study in-vivo muscle metabolic function and perfusion and exercise cardiac MRI), research assessments will occur centrally at 3- and 12-months post-diagnosis. Exercise capacity will be defined as peak oxygen uptake (VO2), expressed as a percent predicted based on ideal body weight during cardiopulmonary exercise testing. The primary comparison will be between participants with and without exercise intolerance. Key secondary subgroup analyses will include: sex (male/female), PE category (low risk/non-low-risk), and thrombolysis (yes/no). Results/Discussion: We have enrolled 67 PE participants (planned=80) from participating enrollment sites and 30 case-controls (planned=30). We propose that 1) the right ventricle will be unable to overcome afterload placed on it during exercise, preventing optimal coupling with pulmonary circulation, 2) arterial desaturation during maximal cycling exercise combined with dysfunctional breathing of deconditioning will provoke greater DOE and intolerance, and 3) depletion and recovery of muscle phosphocreatine in-vivo will predict exercise intolerance. Our results will provide critically informative data to phenotype pediatric post-PE syndrome accurately and allow investigation of cardiac, vascular, and musculoskeletal mechanisms associated with post-PE syndrome assessed during exercise.