Leveraging a global, federated, real-world data network to optimize investigator-initiated pediatric clinical trials: the TriNetX Pediatric Collaboratory Network.

Objective: Clinical research networks facilitate collaborative research, but data sharing remains a common barrier. Materials and Methods: The TriNetX platform provides real-time access to electronic health record (EHR)-derived, anonymized data from 173 healthcare organizations (HCOs) and tools for queries and analysis. In 2022, 4 pediatric HCOs worked with TriNetX leadership to found the Pediatric Collaboratory Network (PCN), facilitated via a multi-institutional data-use agreement (DUA). The DUA enables collaborative study design and execution, with institutional review board-approved transfer of complete datasets for further analyses on a per-protocol basis. Results and Discussion: Of the 41.2 million children with TriNetX records, the PCN represents nearly 10%. The PCN assisted several early-career investigators to bring study concepts from conception to an international scientific meeting presentation and journal submission. Conclusion: The PCN facilitates EHR vendor-agnostic multicenter pediatric research on the global TriNetX platform. Continued growth of the PCN will advance knowledge in pediatric health.

Mechanical Thromboprophylaxis and Hospital-Acquired Venous Thromboembolism Among Critically Ill Adolescents: A U.S. Pediatric Health Information Systems Registry Study, 2016-2023.

OBJECTIVES: To estimate the rate of mechanical thromboprophylaxis (mTP) prescription among critically ill adolescents using a multicenter administrative database and determine whether mTP prescription is inversely associated with hospital-acquired venous thromboembolism. DESIGN: Multicenter, observational, retrospective study of the Pediatric Health Information Systems (PHIS) Registry cohort, January 2016 to December 2023. SETTING: Thirty PICUs located within quaternary pediatric referral centers in the United States. PATIENTS: Critically ill children 12-17 years old, excluding encounters with a principal diagnosis at admission of venous thromboembolism. INTERVENTIONS: mTP prescription within the first 24 hours of hospitalization. MEASUREMENTS AND MAIN RESULTS: A total of 107,804 children met the study criteria, of which 21,124 (19.6%) were prescribed mTP. Hospital center prescribing rates ranged from 1.4% to 65.4% and decreased by 1.6% per year from 28.2% in 2016 to 17.1% in 2023. As compared with those without mTP, those with mTP more frequently had a concurrent central venous catheter (17.2% vs. 9.4%, p < 0.001), underwent invasive mechanical ventilation (37.4% vs. 24.8%, p < 0.001), were admitted for a primary surgical indication (30.9% vs. 12.7%, p < 0.001), and experienced a longer median duration of hospitalization (7 [interquartile range (IQR): 4-15] vs. 4 [IQR: 2-9] d, p < 0.001). Hospital-acquired venous thromboembolism occurred in 2.7% of the study sample and was more common among those with, as compared with without, prescription of mTP (4% vs. 2.4%, p < 0.001). In multivariable logistic regression models for hospital-acquired venous thromboembolism adjusting for salient prothrombotic risk factors, we failed to identify an association between mTP and greater odds of hospital-acquired venous thromboembolism (HA-VTE) among low-, moderate-, and high-risk tiers. However, we cannot exclude the possibility of 17-50% greater odds of HA-VTE in this population. CONCLUSIONS: In the multicenter PHIS cohort, 2016-2023, the prescribing patterns for mTP among critically ill adolescents showed a low rate of mTP prescription (19.6%) that varied widely across institutions, decreased annually over the study period by 1.6%/year, and was not independently associated with HA-VTE risk reduction.

Methods, precision, and analytical sensitivity of a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction.

INTRODUCTION: Fibrinolysis is a critical aspect of the hemostatic system, with assessment of fibrinolytic potential being critical to predict bleeding and clotting risk. We describe the method for a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction (the "modified mini-euglobulin clot lysis assay [ECLA]"), its analytic sensitivity to alterations in key fibrinolytic substrates/regulators, and its initial applications in acute and convalescent disease cohorts. METHODS: The modified mini-ECLA requires 50 µL of plasma, a maximal read time of 3 h (with most results available within 60 min), and is entirely performed in a 96-well microplate. Assay measurements were obtained in a variety of commercial control and deficient plasmas representing clinically relevant hypo- and hyperfibrinolytic states, and in three distinct adolescent cohorts with acute or convalescent illness: critically ill, following endotracheal intubation; acute COVID-19-related illness; and ambulatory, 3 months following a venous thromboembolic event. RESULTS: In 100% and 75% deficient plasmas, hypofibrinolysis for plasminogen-deficient, fibrinolysis for alpha-2-antiplasmin-deficient, and hyperfibrinolysis for plasminogen activator inhibitor-1-deficient plasmas were observed. CONCLUSION: The modified mini-ECLA Clot Lysis Time Ratio ("CLTR") demonstrated moderate-strength correlations with the Clot Formation and Lysis (CloFAL) assay, is analytically sensitive to altered fibrinolytic states in vitro, and correlates with clinical outcomes in preliminarily-studied patient populations.

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.

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.

What did we learn (and did not learn) from the pediatric direct oral anticoagulant trials, and how might we better design pediatric anticoagulant trials in the future?

A State of the Art lecture titled "What the direct oral anticoagulants (DOACs) trials did and didn't tell us" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. The use of DOACs in children is of particular interest as they exhibit several advantages over conventional anticoagulation agents most commonly used in pediatrics. To date, several DOAC pediatric investigational programs (PIPs) have been completed, and although they have provided some of the best quality of evidence in pediatric anticoagulation therapy, the data generated by these trials remain limited. Here, we review and summarize the currently available data provided by the DOAC PIPs, provide perspectives on what we have and have not learned from these trials, and how we might leverage this knowledge to optimize the design of future anticoagulant PIPs. Finally, we summarize relevant new data on this topic presented during the 2022 ISTH Congress.

Endoscopic Assessment and Serial Balloon Dilatation in a Toddler With Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome Following Bone Marrow Transplant: A Case Report.

We report a 3-year-old patient with suspected oropharyngeal graft-versus-host disease (GVHD) who developed progressive dysphagia to solids and liquids. The patient has a history of Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome with associated bone marrow failure requiring a nonmyeloablative matched sibling hematopoietic stem cell transplant. Esophagram revealed significant narrowing in the cricopharyngeal region. Subsequent esophagoscopy showed a proximal, high-grade pinhole esophageal stricture that was very difficult to visualize and cannulate. High-grade esophageal strictures are uncommon in very young children with GVHD. We believe the patient's underlying Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome in the setting of inflammatory changes seen in GVHD following hematopoietic stem cell transplant set the stage for a high-grade esophageal obstruction. The patient's symptoms improved with serial endoscopic balloon dilation.

Thrombosis in the Neonatal Intensive Care Unit.

Neonates, particularly critically ill and premature infants, have one of the highest risks of thromboembolic complications, particularly venous thromboembolism (VTE), in the pediatric population. Recent data suggest that the incidence of VTE has significantly increased in neonates over the last few decades. Critically ill and premature infants exhibit multiple risk factors that place them at a high risk for thromboembolic events including developmental hemostasis, propensity to infections, and frequent need for central venous access. The clinical presentation, diagnostic modalities, and treatment strategies for thromboembolic complications in neonates vary based on several factors, including the etiology of the thromboembolic event, the anatomic site affected, and the patient's underlying comorbidities. Although guidelines for management are available, they are mostly based on consensus recommendations and on extrapolation from adult data due to a lack of high-quality data in the neonatal population. Current guidelines recommend anticoagulation for specific scenarios. More studies are necessary to elucidate optimal management strategies for newborns with thromboembolic complications.

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.

Updated guidance for efficacy and safety outcomes for clinical trials in venous thromboembolism in children: communication from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis.

Despite the growing number of pediatric antithrombotic clinical trials, standardized safety and efficacy outcome definitions for pediatric venous thromboembolism (VTE) clinical trials have not been updated since 2011. Many recent trials have adapted the recommended definitions, leading to heterogeneity in outcomes and limiting our ability to compare studies. The International Society on Thrombosis and Haemostasis Scientific and Standardization Subcommittee (SSC) on Pediatric and Neonatal Thrombosis and Hemostasis organized a Task Force to update the efficacy and safety outcome definitions for pediatric VTE clinical trials. The outcome definitions used in the recent pediatric antithrombotic trials, definitions recommended for adult studies, and regulatory guidelines were summarized and reviewed by the Task Force as the basis for this updated guidance. Major updates to the efficacy outcomes include the removal of VTE-related mortality as a part of a composite primary outcome and explicit inclusion of all deep venous anatomic sites. Safety outcomes were updated to include a new bleeding severity category: patient important bleeding, no intervention, which encompasses bleeding for which a patient seeks care but there is no change in management. Menstrual bleeding can now be included in any bleeding category when the criteria are met. We hope that these updated outcome definitions will allow the investigators to focus on clinically relevant and patient-important outcomes and provide standardization to facilitate continued high-quality evidence for the use of antithrombotic therapies in children.

Recommendations for standardized definitions, clinical assessment, and future research in pediatric clinically unsuspected venous thromboembolism: Communication from the ISTH SSC subcommittee on pediatric and neonatal thrombosis and hemostasis.

Clinically unsuspected venous thromboembolism (VTE) in children is defined as a VTE diagnosed via imaging test performed for surveillance (i.e., with an intent to identify clinically silent VTEs) or incidentally found (most often via imaging performed for evaluation of regional pathology unrelated to VTE) in the absence of any VTE-associated signs or symptoms. Our understanding of the clinical significance of these events in children is limited by a paucity of data on the epidemiology and outcomes of this complication. There is an urgent need for further research in this area to inform optimal management. Recognizing this knowledge gap, this Task Force has previously published a systematic review of the literature in this topic. We now provide guidance recommendations for standardization of definitions and identify future research needs on clinically unsuspected VTE in children. These recommendations will serve to enhance the quantity and quality of evidence on the topic and facilitate the design and execution of cooperative observational studies, and interventional trials of risk-stratified management approaches aimed at preventing and optimizing long-term outcomes of clinically unsuspected VTE in children.

Venous thromboembolism in pediatric patients with sickle cell disease: A north American survey on experience and management approaches of pediatric hematologists.

BACKGROUND: There is a lack of pediatric-specific data to guide recommendations for prevention and management of venous thromboembolism (VTE) in sickle cell disease (SCD). Experience and expert opinion in this area have not been reported. OBJECTIVES: To characterize the management practices of pediatric hematologists in SCD-associated VTE. We hypothesized there is substantial variability in duration of therapy and prophylaxis preferences. METHODS: Electronic survey among pediatric hematologists members of three international subspecialty societies/consortia. RESULTS: Among 52 complete respondents (response rate, 42%), 47% of physicians reported treating 1-2 patients with SCD-associated VTE, while 20% treated 3-5 patients during the preceding 12 months. Most respondents (86%) estimated the risk of VTE recurrence at <5%. The vast majority (98%) of respondents prescribed anticoagulation for symptomatic VTE treatment. Duration of therapy varied by VTE type, 95% reported prescribing 6 weeks-3 months for provoked DVT, while 60% reported prescribing a similar duration for provoked PE with the remaining 40% reporting treating PE for longer duration. There was notable variation in the treatment practices for asymptomatic or unprovoked VTE. Lastly, half of physicians indicated to be "somewhat" (40%) and "not at all" (10%) confident making decisions regarding the duration and intensity of prophylactic anticoagulation. CONCLUSIONS: We identified significant variability in practice, a lower than expected perceived risk of recurrence, and uncertainty regarding VTE prophylaxis strategies in pediatric SCD. Cooperative multicenter studies are needed to generate evidence for future treatment guidelines development, and to identify opportunities for interventions aimed at managing and preventing VTE in pediatric SCD.

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.

Community-Onset Venous Thromboembolism in Children: Pediatric Emergency Medicine Perspectives.

Pediatric venous thromboembolism (VTE) is a condition increasingly encountered by emergency medicine physicians. Unfortunately, despite increased incidence, the diagnosis of pediatric VTE relies on a high index of suspicion from clinicians. Delays in diagnosis and initiation of treatment can lead to poor outcomes in children, including an increased risk of mortality from pulmonary embolism, increased risk of VTE recurrence, and the development of the post-thrombotic syndrome. The majority of pediatric VTE events are associated with the presence of at least one underlying prothrombotic risk. Timely recognition of these risk factors in the emergency department (ED) setting is paramount for a prompt diagnosis and treatment initiation. Compared with children with hospital-acquired VTE, children presenting to the ED with new onset VTE tend to be older (>11 years of age), have a lower incidence of co-morbidities, and present more frequently with a deep venous thrombosis of the lower extremity. Currently, there are no validated pediatric-specific VTE clinical pretest probability tools that reliably assist with the accurate and timely diagnosis of pediatric VTE. Compression ultrasound with Doppler is the most common imaging modality used for VTE diagnosis, and low molecular weight heparins are the most common anticoagulants initiated in children presenting with VTE in the ED. Special consideration should be given to patients who present to the ED already on anticoagulation therapy who may require acute management for clinically-significant bleeding or change in antithrombotic therapy approach for progression/recurrence of VTE.

Primary Immunodeficiency in Children With Autoimmune Cytopenias: Retrospective 154-Patient Cohort.

Background: Primary immunodeficiency is common among patients with autoimmune cytopenia. Objective: The purpose of this study is to retrospectively identify key clinical features and biomarkers of primary immunodeficiency (PID) in pediatric patients with autoimmune cytopenias (AIC) so as to facilitate early diagnosis and targeted therapy. Methods: Electronic medical records at a pediatric tertiary care center were reviewed. We selected 154 patients with both AIC and PID (n=17), or AIC alone (n=137) for inclusion in two cohorts. Immunoglobulin levels, vaccine titers, lymphocyte subsets (T, B and NK cells), autoantibodies, clinical characteristics, and response to treatment were recorded. Results: Clinical features associated with AIC-PID included splenomegaly, short stature, and recurrent or chronic infections. PID patients were more likely to have autoimmune hemolytic anemia (AIHA) or Evans syndrome than AIC-only patients. The AIC-PID group was also distinguished by low T cells (CD3 and CD8), low immunoglobulins (IgG and IgA), and higher prevalence of autoantibodies to red blood cells, platelets or neutrophils. AIC diagnosis preceded PID diagnosis by 3 years on average, except among those with partial DiGeorge syndrome. AIC-PID patients were more likely to fail first-line treatment. Conclusions: AIC patients, especially those with Evans syndrome or AIHA, should be evaluated for PID. Lymphocyte subsets and immune globulins serve as a rapid screen for underlying PID. Early detection of patients with comorbid PID and AIC may improve treatment outcomes. Prospective studies are needed to confirm the diagnostic clues identified and to guide targeted therapy.

Venous Thromboembolism among Critically Ill Children: A Narrative Review.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality among hospitalized patients, including children. In recent years, it has become clear that hospitalization and critical illness bestow an increased VTE risk in pediatrics and relate to mortality and life-limiting comorbidities. For critically ill children, reported rates of VTE vary by study sampling techniques, presence of inherited or acquired thrombophilia, acute and chronic immobility, underlying illness prompting hospitalization, and clinical factors related to illness severity such as central venous catheterization, length of stay, mechanical ventilation, and patient age. Accordingly, critically ill children with new signs of venous congestion, acute inflammation, or unexplained acute organ dysfunction should be routinely evaluated for VTE. This narrative review summarizes recent and historical literature regarding risk factors, prevention, presentation, treatment, and outcomes of VTE in critically ill children. In addition, we identify knowledge gaps and priorities for future collaborative research on this vital condition. Special attention is given to the clinical trial opportunities, challenges, and ongoing efforts in thromboprophylaxis in critically ill children, including those hospitalized for disease related to novel coronavirus (COVID-19) and multisystem inflammatory disease in children.

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.