Adolescent acquired thrombotic thrombocytopenic purpura: An analysis of the Pediatric Health Information System database.

The outcomes and characteristics of acquired thrombotic thrombocytopenic purpura (TTP) in adolescents is poorly understood due to an absence of studies focused on this population. To better understand the life-threatening disorder in this age, we performed an analysis of adolescent patients (ages 10-21) with TTP in the Pediatric Health Information Systems database from 2009 to 2020. The primary outcomes evaluated were in-hospital mortality and rate of TTP relapse. Secondary outcomes included rates of hemorrhagic and thrombotic complications during hospitalizations for TTP. Patients were included if they had a thrombotic microangiopathy diagnostic code, ADAMTS13 lab obtained, and received therapeutic plasmapheresis. Patients that received treatment for other non-TTP microangiopathies were excluded. A total of 99 patients with 123 hospitalizations for TTP treatment were identified. In-patient mortality occurred in 6 % (n = 6) and TTP relapse in 20 % (n = 20) of the cohort. Median time from initial admission to relapse was 33 days (IQR 15, 92). A hemorrhagic complication was identified in 29 % (n = 36) and thrombotic complication in 15 % (n = 19) of the cohort. The presence of underlying comorbidities was not associated with TTP relapse and only a diagnosis of cancer was associated with increased mortality. The rate of mortality and relapse in adolescent TTP is lower than that seen in adult registries. Long term prospective studies are needed to understand the long-term consequences of adolescent onset acquired TTP.

Practical considerations and consensus opinion for children's hospital-based inpatient hemostasis and thrombosis (HAT) consultative services: Communication from the ISTH SSC Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis.

Caring for children and adolescents with disorders of hemostasis and thrombosis (HAT) has become more specialized and requires a unique skill set that many providers are not able to obtain in standard pediatric hematology/oncology/bone marrow transplant fellowship training programs. The influx of numerous therapeutic advances and increasing medical complexity has expanded the need for experienced HAT providers and subspecialty collaboration in the inpatient setting due to the nuances in the management of patients with HAT complications and concerns. While there are data highlighting the benefits of an inpatient hemostasis, thrombosis, and anticoagulation management service in adult hospitals, there are limited pediatric data supporting such programs. In this article, we summarize the current practices of various pediatric institutions in the inpatient management of HAT patients and provide a consensus opinion for the development of a pediatric inpatient HAT service at tertiary care referral centers.

A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response.

Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome) is a rare, X-linked disorder caused by pathogenic variants in membrane-bound transcription factor protease, site 2 (MBTPS2). Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research-based exome sequencing to harbor a novel, maternally inherited MBTPS2 missense variant (c.766 G>A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel MBTPS2 variant and cytopenias, bone marrow fibrosis, and chronic diarrhea.

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.

Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B.

Adeno-associated virus (AAV) vectors are a leading platform for gene-based therapies for both monogenic and complex acquired disorders. The success of AAV gene transfer highlights the need to answer outstanding clinical questions of safety, durability, and the nature of the human immune response to AAV vectors. Here, we present longitudinal follow-up data of subjects who participated in the first trial of a systemically delivered AAV vector. Adult males (n = 7) with severe hemophilia B received an AAV2 vector at doses ranging from 8 × 1010 to 2 × 1012 vg/kg to target hepatocyte-specific expression of coagulation factor IX; a subset (n = 4) was followed for 12-15 years post-vector administration. No major safety concerns were observed. There was no evidence of sustained hepatic toxicity or development of hepatocellular carcinoma as assessed by liver transaminase values, serum α-fetoprotein, and liver ultrasound. Subjects demonstrated persistent, increased AAV neutralizing antibodies (NAbs) to the infused AAV serotype 2 (AAV2) as well as all other AAV serotypes tested (AAV5 and AAV8) for the duration of follow-up. These data represent the longest available longitudinal follow-up data of subjects who received intravascular AAV and support the preliminary safety of intravascular AAV administration at the doses tested in adults. Data demonstrate, for the first time, the persistence of high-titer, multi-serotype cross-reactive AAV NAbs for up to 15 years post- AAV vector administration. Our observations are broadly applicable to the development of AAV-mediated gene therapy.

Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures.

INTRODUCTION: Emicizumab is a recombinant humanized bispecific antibody that bridges factor IXa and factor X to mimic the cofactor function of factor VIII. It is approved to prevent bleeding in patients with haemophilia A (HA). Outside of clinical trials, there is limited data on outcomes of patients treated with emicizumab, particularly in children without inhibitors. AIM: To report our experience treating patients with emicizumab, including (a) bleeding rates pre and postemicizumab, (b) peri-procedural management and outcomes and (c) serious drug-related adverse events. METHODS: Multicentre observational study in patients with HA who started emicizumab prior to 15 May 2019. Data collection continued until 15 October 2019 and included demographics, disease history, bleeding events, invasive procedures, thrombotic events and death. Annualized bleeding rates (ABR) prior to emicizumab were compared to postemicizumab. RESULTS: Ninety-three patients (including three females) met inclusion criteria, 19 with an active inhibitor. Median age was 8.6 years; patients <12 years without inhibitors (n = 49) accounted for the majority. ABR dropped from 4.4 (inhibitors) and 1.6 (non-inhibitors) to 0.4 (both groups) on emicizumab, P = .0012 and .0025, respectively. There were 28 minor (21 port removals) and two major procedures. Three patients received 1-2 doses of unplanned factor postoperatively to treat minor bleeding events. No patient discontinued therapy, and there were no thrombotic events or deaths. DISCUSSION: Our favourable clinical experience with emicizumab is similar to that reported in the clinical trials. Notably, this is the largest cohort of patients <12 years without inhibitors treated with emicizumab.

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics.

A survey of pediatric hematology/oncology specialists regarding management of central line associated venous thrombosis.

Central venous catheters (CVCs) account for the largest proportion of thrombotic events in pediatric patients. Questions remain regarding adequate treatment and prevention methods. We surveyed pediatric hematology/oncology specialists, using hypothetical cases to assess management strategies for acute CVC thrombosis and secondary prevention. Survey respondents varied in the use of the thrombophilia evaluation (33.3%, 41/123) and duration of treatment (6 weeks: 54.1%, 66/122). Secondary CVC prophylaxis was utilized by 36.6% (45/123) of respondents and by 24.4% (30/123) but only if there was a documented thrombophilia. This heterogeneity highlights the need for clinical studies to address these important clinical questions.

A Multicenter Cohort Study of Inferior Vena Cava Filter Use in Children.

BACKGROUND: To describe inferior vena cava (IVC) filter use in pediatric patients admitted to U.S. children's hospitals and to determine factors associated with prophylactic placement. PROCEDURE: This retrospective multicenter cohort study utilized data from the Pediatric Health Information Systems (PHIS) administrative database, with 44 participating children's hospitals. Subjects included for analysis were less than 21 years of age, admitted to a PHIS hospital between January 1, 2004 and December 31, 2012 and had a procedure code for IVC filter placement. ICD-9-CM discharge codes were used to identify subjects with a venous thromboembolism (VTE). Pharmaceutical billing codes were used to identify anticoagulation use. RESULTS: During this 9-year-study period, 276 subjects met the inclusion criteria. The median age of subjects was 15 years (range 1 month-20 years). Subjects had an ICD-9-CM code for VTE 76% of the time and were started on anticoagulation after IVC filter placement 77% of the time. The mean number of IVC filters placed per year was 6 per 100,000 admissions (SD-1.4), which was constant throughout the study period (P = 0.12). The median number of filters placed by center was 4.5 (range 0-32). In multivariate analysis, subjects undergoing orthopedic surgery were more likely to have prophylactic placement of an IVC filter (OR 4.5; 95%CI 1.8-11). CONCLUSIONS: IVC filter placement in pediatric patients remains a rare event and is most common in adolescents. Unlike in adults, pediatric IVC filter placement does not appear to be increasing over time and is predominantly used in the setting of a venous thrombotic event.

Comparison of 3 Postthrombotic Syndrome Assessment Scales Demonstrates Significant Variability in Children and Adolescents With Deep Vein Thrombosis.

Postthrombotic syndrome (PTS) is an important outcome in children with deep vein thrombosis (DVT). There are several instruments to measure PTS, and no accepted "gold standard." The objective of this cross-sectional prospective study was to compare the prevalence of PTS in patients above 8 years old with a history of DVT using 3 scales: the Villalta scale, a pediatric modification of the Villalta scale, and the Manco-Johnson instrument. Forty-four subjects (22 females) were enrolled; mean age 16.6 years (SD 3.6 y). The majority had a lower extremity DVT. The average duration from DVT to PTS assessment was 2.6 years. The proportion of subjects with PTS using the adult Villalta scale was 11%, which was significantly less than the 66% of patients identified using both pediatric scales (P<0.0001). The majority of patients with PTS as determined by the pediatric scales had mild PTS. There was significant discordance between the prevalence of PTS using the Villalta scale compared with the 2 pediatric scales. This is especially relevant when considering which instrument to use in adolescent patients. This study demonstrates that PTS, as defined by these scales, is not a well-defined or standardized outcome, particularly when comparing adult and pediatric instruments.

Extensive thrombotic complications after inferior vena cava filter placement in 2 adolescents with spinal cord injury: a cautionary tale and review.

We report extensive thrombotic complications of inferior vena cava (IVC) filters that were placed for primary prophylaxis in 2 pediatric trauma patients with spinal cord injuries. Although thrombosis is a known common complication in adults with IVC filters, we were unable to find any reports in the literature of this complication in children. These cases highlight a significant problem with the use of prophylactic IVC filters that are not subsequently retrieved, particularly in young trauma patients with decades to live. The overall reported complications of IVC filters in the pediatric literature are also reviewed.

Safety of prophylactic anticoagulation at a pediatric hospital.

The importance of preventing venous thromboembolism (VTE) in hospitalized adults is well recognized. We recently developed and published our institutional guidelines for the prevention of VTE in high-risk hospitalized patients in a pediatric hospital. The objective of this prospective observational study was to evaluate the safety of anticoagulation after these guidelines were instituted. The primary outcome was major bleeding and secondary outcomes included minor bleeding and VTE. Eighty-nine patients were enrolled, with a mean age of 16.6 years. The most common risk factors for VTE were impaired mobility, lower extremity orthopedic surgery, and obesity. The majority of patients (63%) had 3 or more risk factors. There were 2 major bleeding events, and minor bleeding occurred in 5 patients, all in patients who had undergone major orthopedic surgery. Therefore the risk of major bleeding in orthopedic surgery patients was 4% (2/51), and 0% (0/38) in the remaining patients. No patient developed a non-catheter-related VTE, which was the primary intent of our guidelines. Although there remains much work to be done to optimize VTE strategies in pediatric patients, this study provides information regarding the risks of VTE prophylaxis using a pragmatic approach in hospitalized patients with multiple risk factors for VTE. More studies are needed to better define the risk:benefit ratio in this population.

Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.

BACKGROUND: Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. METHODS: We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years. FINDINGS: AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. INTERPRETATION: The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. FUNDING: Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007.

OBJECTIVES: The goals were to determine whether there has been an increase in the rate of venous thromboembolism (VTE) in pediatric tertiary care hospitals and to evaluate the use of anticoagulants in the treatment of hospitalized pediatric patients with VTE. METHODS: A retrospective cohort study of patients <18 years of age who were discharged from 35 to 40 children's hospitals (depending on the year) across the United States in 2001-2007 was performed. By using the Pediatric Health Information System administrative database, cases were assessed for discharge diagnosis codes for VTE; the use of anticoagulants was assessed by using patient-specific pharmacy files. RESULTS: During the 7-year study period, in which 11 337 hospitalized patients were diagnosed with VTE, the annual rate of VTE increased by 70%, from 34 to 58 cases per 10,000 hospital admissions (P < .001). This increase was observed in neonates, infants, children, and adolescents. The majority (63%) of children with VTE had > or =1 coexisting chronic complex medical condition. Pediatric malignancy was the medical comorbid condition associated most strongly with recurrent VTE (P < .001). The proportion of children with VTE who were treated with enoxaparin increased from 29% to 49% during this time period (P < .001); the use of warfarin decreased slightly from 11.4% to 9.6% (P= .02). Increasing age was associated with increased likelihood of patients with VTE being treated with either enoxaparin or warfarin. CONCLUSION: This multicenter study demonstrates a dramatic increase in the diagnosis of VTE at children's hospitals from 2001 to 2007.

Varied opinions on thrombolysis for venous thromboembolism in infants and children: findings from a survey of pediatric hematology-oncology specialists.

BACKGROUND: Recent guidelines discourage routine use of thrombolytic agents for treatment of venous thromboembolism (VTE) in pediatric patients, but actual practice patterns are unknown. PROCEDURE: An electronic survey was emailed to all active and trainee members of the American Society of Pediatric Hematology/Oncology in April 2008. Respondents were asked a series of multiple-choice questions based on hypothetical case scenarios describing pediatric VTE, pertinent to the implementation of thrombolytic therapy and other professional demographic information. RESULTS: Two hundred eighty-five evaluable responses were obtained (22% response rate) which varied greatly with respect to all spheres of questioning. Tissue plasminogen activator (tPA) was the thrombolytic agent chosen by most respondents, but no clear consensus emerged as to appropriate indications (although preference for thrombolytic therapy increased with severity of the posed clinical scenario), mode of tPA delivery (systemic vs. catheter-directed), dose (high-dose vs. low-dose regimen) or a suitable maximum duration of therapy (range: 1-168 hr; varied according to specific dosing regimen chosen). Expertise in pediatric thrombosis, years out from fellowship training and volume of experience with cases of pediatric thrombosis were not largely associated with respondent choices; however, institutional experience with pharmacologic thrombolysis exhibited the most notable association of the professional demographic factors analyzed. CONCLUSIONS: The survey results support that clinical practice pertaining to use of thrombolytic agents in pediatric VTE varies widely but also provide useful benchmarks to aid clinical decision-making and future clinical trial design. Such varied practices stem from the lack of strong evidence supporting one therapeutic approach versus another.

The clinical management of hemophilia and head trauma: a survey of current clinical practice among pediatric hematology/oncology physicians.

BACKGROUND: Determining the appropriate evaluation for a pediatric patient with hemophilia and head trauma is a diagnostic challenge with no neuroimaging guidelines and limited clinical evidence to direct care. PROCEDURE: A questionnaire, with two case scenarios, was emailed to members of the American Society of Pediatric Hematology/Oncology. The case scenarios involved asymptomatic toddlers with severe hemophilia who had either fallen from a height (case 1) or from standing (case 2). Respondents were asked to select from six management options. The case scenarios were then altered to include: a large palpable hematoma, prophylactic factor infusion 24 hr prior, the trauma occurred 48 hr prior, wearing a soft helmet, or emesis. RESULTS: The completed response rate was 23% (252/1,077). Computed tomography (CT) was selected by 68.9% (#1) and 56.4% (#2) of respondents. In both case scenarios the presence of a palpable bruise resulted in a statistically significant increase in CT usage to 83.7% and 82.8% (P < 0.001). The use of prophylaxis did not result in a statistically significant decrease in CT usage. Duration of factor replacement was variable ranging from 1 to 4 days. CONCLUSION: Physician self reported management of pediatric patients with hemophilia and head trauma is diverse. The use of CT imaging for mild head trauma in patients without signs or symptoms of intracranial hemorrhage was very common. The use of prophylaxis did not reduce the use of head CT imaging. This variation in clinical practice demonstrates the lack of evidence regarding the management of head trauma in patients with hemophilia.