Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ11. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.

Assessment of rare bleeding disorders in adolescents with heavy menstrual bleeding.

INTRODUCTION: There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available. AIM: We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB. METHODS: We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified. RESULTS: In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described. CONCLUSION: Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype-phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB.

Epidemiology of clinically unsuspected venous thromboembolism in children with cancer: A population-based study from Maritimes, Canada.

Inconsistencies in the definition of clinically unsuspected venous thromboembolism (VTE) in pediatric patients recently led to the recommendation of standardizing this terminology. Clinically unsuspected VTE (cuVTE) is defined as the presence of VTE on diagnostic imaging performed for indications unrelated to VTE in a patient without symptoms or clinical history of VTE. The prevalence of cuVTE in pediatric cancer patients is unclear. Therefore, the main objective of our study was to determine the prevalence of cuVTE in pediatric cancer patients. All patients 0-18 years old, treated at the IWK in Halifax, Nova Scotia, from August 2005 through December 2019 with a known cancer diagnosis and at least one imaging study were eligible (n = 743). All radiology reports available for these patients were reviewed (n = 18,120). The VTE event was labeled a priori as cuVTE event for radiology reports that included descriptive texts indicating a diagnosis of thrombosis including thrombus, central venous catheter-related, thrombosed aneurysm, tumor thrombosis, non-occlusive thrombus, intraluminal filling defect, or small fragment clot for patients without documentation of clinical history and or signs of VTE. A total of 18,120 radiology reports were included in the review. The prevalence of cuVTE was 5.5% (41/743). Echocardiography and computed tomography had the highest rate of cuVTE detection, and the most common terminologies used to diagnose cuVTE were thrombus and non-occlusive thrombus. The diagnosis of cuVTE was not associated with age, sex, and type of cancer. Future efforts should focus on streamlining radiology reports to characterize thrombi. The clinical significance of these cuVTE findings and their application to management, post-thrombotic syndrome, and survival compared to cases with symptomatic VTE and patients without VTE should be further studied.

Hospital-Acquired Venous Thromboembolism and Invasive Mechanical Ventilation: A Report From the Children's Hospital Acquired Thrombosis Consortium.

OBJECTIVES: To determine if the duration of invasive mechanical ventilation (IMV) was associated with hospital-acquired venous thromboembolism (HA-VTE) among critically ill children. DESIGN: A multicenter, matched case-control study as a secondary analysis of Children's Hospital Acquired Thrombosis (CHAT) Consortium registry. SETTING: PICUs within U.S. CHAT Consortium participating centers. PATIENTS: Children younger than 21 years old admitted to a PICU receiving IMV for greater than or equal to 1 day duration from January 2012 to March 2022 were included for study. Cases with HA-VTE were matched 1:2 to controls without HA-VTE by patient age groups: younger than 1, 1-12, and older than 12 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was IMV duration in days. Descriptive data included demographics, anthropometrics, HA-VTE characteristics (i.e., type, location, and timing), central venous catheterization data, thromboprophylaxis practices, and Braden Q mobility scores. Descriptive, comparative, and associative (multivariate conditional logistic regression for HA-VTE) statistics were employed. A total of 152 cases were matched to 304 controls. Cases with HA-VTE were diagnosed at a median of 7 days (interquartile range [IQR], 3-16 d) after IMV. The HA-VTE were limb deep venous thromboses in 130 of 152 (85.5%) and frequently central venous catheterization-related (111/152, 73%). Cases with HA-VTE experienced a longer length of stay (median, 34 d [IQR, 18-62 d] vs. 11.5 d [IQR, 6-21 d]; p < 0.001) and IMV duration (median, 7 d [IQR, 4-15 d] vs. 4 d [IQR, 1-7 d]; p < 0.001) as compared with controls. In a multivariate logistic model, greater IMV duration (adjusted odds ratio, 1.09; 95% CI, 1.01-1.17; p = 0.023) was independently associated with HA-VTE. CONCLUSIONS: Among critically ill children undergoing IMV, HA-VTE was associated with greater IMV duration. If prospectively validated, IMV duration should be included as part of prothrombotic risk stratification and future pediatric thromboprophylaxis trials.

Tenecteplase in Acute Stroke: What About the Children?

Tenecteplase is replacing alteplase as the fibrinolytic agent of choice for the acute management of ischemic stroke in many adult stroke centers due to practical and pharmacokinetic advantages in the setting of similar outcomes. Although thrombolytic use is increasing for acute childhood stroke, there is very limited experience with tenecteplase in children for any indication, and importantly, there are no data on safety, dosing, or efficacy of tenecteplase for childhood stroke. Changes in fibrinolytic capacity over childhood, pediatric pharmacological considerations such as age-specific differences in drug clearance and volume of distribution, and practical aspects of drug delivery such as availability in children's hospitals may impact decisions about transitioning from alteplase to tenecteplase for acute pediatric stroke treatment. Pediatric and adult neurologists should prepare institution-specific guidelines and organize prospective data collection.

Anticoagulation with Intravenous Direct Thrombin Inhibitors in Pediatric Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature.

Although intravenous (IV) direct thrombin inhibitors (DTI) have gained interest in pediatric extracorporeal membrane oxygenation (ECMO), dosing and safety information is limited. The objective of this systematic review was to characterize DTI types, dosing, monitoring, and outcomes (bleeding and thromboembolic) in pediatric ECMO patients managed with IV DTIs. We conducted searches of MEDLINE (Ovid) and Embase (Elsevier) from inception through December 2022. Case reports, retrospective studies, and prospective studies providing per-patients or summary data for patient(s) <18 years of age receiving IV DTI for ECMO anticoagulation were included. Study selection and data extraction were conducted independently by two reviewers. A total of 28 studies: 14 case reports, 13 retrospective studies, and 1 prospective study were included, totaling 329 patients. Bivalirudin was utilized in 318 (96.7%), argatroban in 9 (2.7%), and lepirudin in 2 (0.6%) patients. Infusion dosing included: bivalirudin 0.14 ± 0.37 mg/kg/h, argatroban 0.69 ± 0.73 µg/kg/min, lepirudin 0.14 ± 0.02 mg/kg/h. Laboratory monitoring tests utilized were the activated clotting time, activated partial thromboplastin time (aPTT), diluted thrombin time, and thromboelastography measures. The aPTT was utilized in most patients (95%). Thromboembolism, bleeding, or death were observed in 17%, 17%, and 23% of bivalirudin, argatroban, and lepirudin patients, respectively. Bivalirudin appears to be the most frequently used DTI in pediatric ECMO. Dosing and laboratory monitoring varied, and bleeding and thromboembolic events were reported in 17% of patients. Prospective studies are warranted to establish dosing, monitoring, safety, and efficacy of bivalirudin and other IV DTI in pediatric ECMO.

Dosing, Monitoring, Blood Product Utilization, and Thromboembolic Complications of Four-Factor Prothrombin Complex Concentrate as Part of an Institutional Protocol in Pediatric Cardiac Surgery: A Retrospective Cohort Study.

Pediatric cardiac surgery patients are predisposed to blood loss. Blood product administration can lead to complications. Prothrombin complex concentrates (PCCs) offer potential advantages of factor composition, small volume, decreased immunogenicity/infectious risks, and accessibility. The objective of this study was to describe dosing, monitoring, blood product utilization, and thromboembolic complications of administering four-factor PCC (4F-PCC) in pediatric cardiac surgery. We performed a retrospective review of patients aged <18 years undergoing cardiac surgery from June 2020 to May 2022 (inclusive) who received 4F-PCC. Outcomes of interest included 4F-PCC dosing (units/kg) and number of doses administered, chest tube output, blood product administration, donor exposure, length of stay, and thromboembolic events. Eighty-six patients met eligibility criteria. The median (range) age and weight were 0.37 (0.01-16.3) years and 5.3 (1.6-98) kg, respectively. Median (range) total 4F-PCC dose per patient was 25 (9.2-50) units/kg, with 6 patients (7%) receiving a total of two doses. Median (range) 24-hour postoperative packed red blood cells, platelet, plasma, and cryoprecipitate administration volumes were 0 (0-2.57) mL/kg/24 h, 0 (0-1.09), 0 (0-2.64), and 0 (0-0.28 mL/kg/24 h), respectively. Median (range) length of stay and 24-hour postoperative chest tube output were 10 (6-26) days and 1.1 (0.1-4.2) mL/kg/h, respectively. Two (2%) patients experienced a thromboembolic event within 30 days of 4F-PCC administration. These retrospective findings suggest no worsening of hemostatic parameters, a mild median improvement in fibrinogen, low blood product utilization, and low thromboembolism rates following 4F-PCC use in pediatric cardiac surgery.

Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19-related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a postinfectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and evaluate associated risk factors. We classified patients into 1 of 3 groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (COVID-19, n = 426; MIS-C, n = 138; and asymptomatic SARS-CoV-2, n = 289) in 814 patients, there were 20 patients with thrombotic events (TEs; including 1 stroke). Patients with MIS-C had the highest incidence (9 [6.5%] of 138) vs COVID-19 (9 [2.1%] of 426) or asymptomatic SARS-CoV-2 (2 [0.7%] of 289). In patients with COVID-19 or MIS-C, a majority of TEs (89%) occurred in patients age ≥12 years. Patients age ≥12 years with MIS-C had the highest rate of thrombosis at 19% (9 of 48). Notably, 71% of TEs that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13 of 564), but it was 28% (5 of 18) in patients with TEs. Our findings may help inform pediatric thromboprophylaxis strategies.

What can the plasma proteome tell us about platelets and (vice versa)?

Multi-omics approaches are being used increasingly to study physiological and pathophysiologic processes. Proteomics specifically focuses on the study of proteins as functional elements and key contributors to, and markers of the phenotype, as well as targets for diagnostic and therapeutic approaches. Depending on the condition, the plasma proteome can mirror the platelet proteome, and hence play an important role in elucidating both physiologic and pathologic processes. In fact, both plasma and platelet protein signatures have been shown to be important in the setting of thrombosis-prone disease states such as atherosclerosis and cancer. Plasma and platelet proteomes are increasingly being studied as a part of a single entity, as is the case with patient-centric sample collection approaches such as capillary blood. Future studies should cut across the plasma and platelet proteome silos, taking advantage of the vast knowledge available when they are considered as part of the same studies, rather than studied as distinct entities.

Platelets are key cellular elements of blood with plasma constituting the liquid component. Both platelets and proteins found in plasma rapidly work in unity to prevent/limit blood loss in response to blood vessel damage. Proteomics is the analysis of the entire protein complement of a cell, tissue, or organism under a specific, defined set of conditions. Of note, research to date has shown that platelet and plasma proteomes share many common proteins. In some disease scenarios, plasma proteomes can be used to identify platelet function or dysfunction, while in other scenarios, platelet-specific proteins are needed for physiological assessment. Thus, it may be beneficial to simultaneously study the plasma and platelet proteomes, thereby exploiting the considerable wealth of information provided under such circumstances.

Effects of Cumulative Head Impact Exposure in Adolescent Male Contact and Collision Sport Student Athletes.

OBJECTIVE: This prospective cohort study aimed to investigate the association between head impact exposure (HIE) and neuropsychological sequelae in high school football and ice hockey players over 1 year. SETTING: Community sample. PARTICIPANTS: A cohort of 52 adolescent American football and ice hockey players were enrolled in the study, with a final study sample of 35 included in analyses. DESIGN: The study followed a prospective cohort design, with participants undergoing neuropsychological screening and accelerometer-based measurement of HIE over 1 season. MAIN MEASURES: Changes in cognition, emotions, behavior, and reported symptoms were assessed using standardized neuropsychological tests and self-reported questionnaires. RESULTS: Cumulative HIE was not consistently associated with changes in cognition, emotions, behavior, or reported symptoms. However, it was linked to an isolated measure of processing speed, showing inconsistent results based on the type of HIE. History of previous concussion was associated with worsened verbal memory recognition (ImPACT Verbal Memory) but not on a more robust measure of verbal memory (California Verbal Learning Test [CVLT]). Reported attention-deficit/hyperactivity disorder history predicted improved neurocognitive change scores. No associations were found between reported history of anxiety/depression or headaches/migraines and neuropsychological change scores. CONCLUSION: Overall, our findings do not support the hypothesis that greater HIE is associated with an increase in neuropsychological sequelae over time in adolescent football and ice hockey players. The results align with the existing literature, indicating that HIE over 1 season of youth sports is not consistently associated with significant neuropsychological changes. However, the study is limited by a small sample size, attrition over time, and the absence of performance validity testing for neurocognitive measures. Future studies with larger and more diverse samples, longer follow-up, and integration of advanced imaging and biomarkers are needed to comprehensively understand the relationship between HIE and neurobehavioral outcomes. Findings can inform guidelines for safe youth participation in contact sports while promoting the associated health and psychosocial benefits.

Ketorolac in neonates and infants following congenital heart surgery: a retrospective review.

INTRODUCTION: Pain management is essential in the immediate post-surgical period. We sought to describe the ketorolac dose regimen in neonates and infants following cardiac surgery. Secondary outcomes included renal dysfunction, bleeding, and pain management. METHODS: We performed a single-centre retrospective cohort study of neonates and infants (aged < 12 months) who received ketorolac following cardiac surgery, from November 2020 through November 2021 (inclusive). Ketorolac was administered at 0.5 mg/kg every 6 hours. Safety was defined by absence of a clinically significant decline in renal function (i.e., increase in serum creatinine [SCr] by ≥ 0.3 mg/dL from baseline within 48 hours and/or urine output ≤ 0.5 mL/kg/hour for 6 hours) and absence of clinically significant bleeding defined as major by International Society on Thrombosis and Hemostasis paediatric criteria or Severe/Fatal Bleeding Events by Nellis et al. Efficacy measures included pain scores and opioid utilisation. RESULTS: Fifty-five patients met eligibility criteria. The median (range) dose and duration of ketorolac administration was 0.5 mg/kg/dose for 48 (6-90) hours. Among all patients, there was not a statistically significant difference observed in median SCr within 48 hours of baseline (p > .9). There were no major or severe bleeding events. The median (range) opioid requirements (morphine intravenous equivalents per kg per day) at 48 hours post-ketorolac initiation was 0.1 (0-0.8) mg/kg/day. CONCLUSIONS: If validated prospectively, these findings suggest that a ketorolac regimen 0.5 mg/kg/dose every 6 hours in neonates and infants post-cardiac surgery may be safe with regard to renal function and bleeding risk, and effective regarding opioid-sparing capacity.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 OF EVIDENCE: Level II.

Venous Thromboembolism among Noncritically Ill Hospitalized Children: Key Considerations for the Pediatric Hospital Medicine Specialist.

Venous thromboembolism (VTE) is a leading cause of morbidity and preventable harm among noncritically ill hospitalized children. Several clinical factors relevant to the noncritically ill hospitalized child significantly increase the risk of VTE including the presence of central venous catheters, systemic inflammation, and prolonged immobilization. Although risk mitigation strategies have been described, the diagnosis, treatment, and prevention of VTE require standardization of institutional practices combined with multidisciplinary collaboration among pediatric hospitalists, hematologists, and other care providers. In this narrative review, we summarize the epidemiology of VTE, risk models identifying high-risk conditions associated with VTE, and prevention and treatment strategies. We further describe successful quality improvement efforts implementing institutional VTE risk stratification and thromboprophylaxis procedures. Finally, we highlight unique challenges facing pediatric hospital medicine specialists in the era of the COVID-19 pandemic, including caring for adults admitted to pediatric hospital units, and describe future research opportunities for VTE in the noncritically ill hospitalized child.

Venous Thromboembolism in Premature Neonates.

While the incidence of venous thromboembolism (VTE) is lower among children than adults, the newborn period is one of two bimodal peaks (along with adolescence) in VTE incidence in the pediatric population. Most VTE cases in neonates occur among critically ill neonates being managed in the neonatal intensive care unit, and most of these children are born premature. For this reason, the presentation, diagnosis, management, and outcomes of VTE among children born premature deserve special emphasis by pediatric hematologists, neonatologists, pharmacists, and other pediatric health care providers, as well as by the scientific community, and are described in this review.

Defining the Healthy Infant Metabolome: Liquid Chromatography Tandem-Mass Spectrometry Analysis of Dried Blood Spot Extracts from the Prospective Research on Early Determinants of Illness and Children's Health Trajectories Birth Cohort Study.

Newborn screening using dried plasma spots offers preanalytical advantages over conventional cards for plasma-associated targets of interest. Herein we present dried plasma spot-based methods for measuring metabolites using a 250+ compound liquid chromatography tandem mass spectrometry library. Quality assurance reduced this library to 134, and from these, 30 compounds determined the normal newborn reference ranges.

Endothelial HMGB1 Is a Critical Regulator of LDL Transcytosis via an SREBP2-SR-BI Axis.

OBJECTIVE: LDL (low-density lipoprotein) transcytosis across the endothelium is performed by the SR-BI (scavenger receptor class B type 1) receptor and contributes to atherosclerosis. HMGB1 (high mobility group box 1) is a structural protein in the nucleus that is released by cells during inflammation; extracellular HMGB1 has been implicated in advanced disease. Whether intracellular HMGB1 regulates LDL transcytosis through its nuclear functions is unknown. Approach and Results: HMGB1 was depleted by siRNA in human coronary artery endothelial cells, and transcytosis of LDL was measured by total internal reflection fluorescence microscopy. Knockdown of HMGB1 attenuated LDL transcytosis without affecting albumin transcytosis. Loss of HMGB1 resulted in reduction in SR-BI levels and depletion of SREBP2 (sterol regulatory element-binding protein 2)-a transcription factor upstream of SR-BI. The effect of HMGB1 depletion on LDL transcytosis required SR-BI and SREBP2. Overexpression of HMGB1 caused an increase in LDL transcytosis that was unaffected by inhibition of extracellular HMGB1 or depletion of RAGE (receptor for advanced glycation endproducts)-a cell surface receptor for HMGB1. The effect of HMGB1 overexpression on LDL transcytosis was prevented by knockdown of SREBP2. Loss of HMGB1 caused a reduction in the half-life of SREBP2; incubation with LDL caused a significant increase in nuclear localization of HMGB1 that was dependent on SR-BI. Animals lacking endothelial HMGB1 exhibited less acute accumulation of LDL in the aorta 30 minutes after injection and when fed a high-fat diet developed fewer fatty streaks and less atherosclerosis. CONCLUSIONS: Endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, enhancing SR-BI expression. Translocation of HMGB1 to the nucleus in response to LDL requires SR-BI.

A phase 2 pharmacodynamic dose-finding, safety, and efficacy study of dalteparin for pediatric venous thromboembolism treatment in children with and without cancer.

Data from registrational trials of pediatric venous thromboembolism (VTE) treatment are sparse, especially among cancer patients. We conducted a prospective, multicenter, open-label trial (NCT00952380) on dose-finding, safety, and efficacy (measured by 90-day risks of clinically relevant bleeding [CRB] and symptomatic recurrent VTE [srVTE]) of twice-daily subcutaneous dalteparin for acute VTE treatment in patients ≤18 years old. Among 38 patients (cancer, n = 26; noncancer, n = 12), median dalteparin dose requirements per kilogram varied with age but not cancer status. Risks of CRB and srVTE were <4% in cancer and noncancer subgroups. Dalteparin is an important FDA-approved treatment for pediatric VTE, particularly with cancer.

A New Risk Assessment Model for Hospital-Acquired Venous Thromboembolism in Critically Ill Children: A Report From the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVES: To create a risk model for hospital-acquired venous thromboembolism in critically ill children upon admission to an ICU. DESIGN: Case-control study. SETTING: ICUs from eight children's hospitals throughout the United States. SUBJECTS: Critically ill children with hospital-acquired venous thromboembolism (cases) 0-21 years old and similar children without hospital-acquired venous thromboembolism (controls) from January 2012 to December 2016. Children with a recent cardiac surgery, asymptomatic venous thromboembolism, or a venous thromboembolism diagnosed before ICU admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The multi-institutional Children's Hospital-Acquired Thrombosis registry was used to identify cases and controls. Multivariable logistic regression was used to determine the association between hospital-acquired venous thromboembolism and putative risk factors present at or within 24 hours of ICU admission to develop the final model. A total of 548 hospital-acquired venous thromboembolism cases (median age, 0.8 yr; interquartile range, 0.1-10.2) and 187 controls (median age, 2.4 yr; interquartile range, 0.2-8.3) were analyzed. In the multivariable model, recent central venous catheter placement (odds ratio, 4.4; 95% CI, 2.7-7.1), immobility (odds ratio 3.6, 95% CI, 2.1-6.2), congenital heart disease (odds ratio 2.9, 95% CI, 1.7-4.7), length of hospital stay prior to ICU admission greater than or equal to 3 days (odds ratio, 2.5; 95% CI, 1.1-5.6), and history of autoimmune/inflammatory condition or current infection (odds ratio, 2.1; 95% CI, 1.2-3.4) were each independently associated with hospital-acquired venous thromboembolism. The risk model had an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.73-0.84). CONCLUSIONS: Using the multicenter Children's Hospital-Acquired Thrombosis registry, we identified five independent risk factors for hospital-acquired venous thromboembolism in critically ill children, deriving a new hospital-acquired venous thromboembolism risk assessment model. A prospective validation study is underway to define a high-risk group for risk-stratified interventional trials investigating the efficacy and safety of prophylactic anticoagulation in critically ill children.

A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD.

OBJECTIVES: To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0-18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria. RESULTS: We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common. CONCLUSION: There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.