Genomic analysis of venous thrombosis in children with acute lymphoblastic leukemia from diverse ancestries.

Venous thrombosis is a common adverse effect of modern therapy for acute lymphoblastic leukemia (ALL). Prior studies to identify risks of thrombosis in pediatric ALL have been limited by genetic screens of pre-identified genetic variants or genome- wide association studies (GWAS) in ancestrally uniform populations. To address this, we performed a retrospective cohort evaluation of thrombosis risk in 1,005 children treated for newly diagnosed ALL. Genetic risk factors were comprehensively evaluated from genome-wide single nucleotide polymorphism (SNP) arrays and were evaluated using Cox regression adjusting for identified clinical risk factors and genetic ancestry. The cumulative incidence of thrombosis was 7.8%. In multivariate analysis, older age, T-lineage ALL, and non-O blood group were associated with increased thrombosis while non-low-risk treatment and higher presenting white blood cell count trended toward increased thrombosis. No SNP reached genome-wide significance. The SNP most strongly associated with thrombosis was rs2874964 near RFXAP (G risk allele; P=4x10-7; hazard ratio [HR] =2.8). In patients of non-European ancestry, rs55689276 near the α globin cluster (P=1.28x10-6; HR=27) was most strongly associated with thrombosis. Among GWAS catalogue SNP reported to be associated with thrombosis, rs2519093 (T risk allele, P=4.8x10-4; HR=2.1), an intronic variant in ABO, was most strongly associated with risk in this cohort. Classic thrombophilia risks were not associated with thrombosis. Our study confirms known clinical risk features associated with thrombosis risk in children with ALL. In this ancestrally diverse cohort, genetic risks linked to thrombosis risk aggregated in erythrocyte-related SNP, suggesting the critical role of this tissue in thrombosis risk.

Promoting penicillin allergy de-labeling for children attending a hematology clinic.

BACKGROUND: Up to 10% of children are reported to be allergic to penicillin, but many allergy labels are unverified and may require formal testing. Inaccurate drug allergy labels are associated with a range of adverse clinical outcomes. Patients with hematological disorders may experience frequent and severe infections; those who have been incorrectly labeled penicillin allergic may benefit from allergy de-labeling (ADL) efforts to facilitate access to beta-lactam antibiotics. We developed a multidisciplinary, pharmacist-driven process that enabled non-allergist trained providers to assess and de-label penicillin allergies in a pediatric hematology center. METHODS: Volunteers, including physicians, advanced practice providers, nurses, and pharmacists, were trained in skin testing and oral challenge procedures. Patients were identified by review of electronic medical records for penicillin or penicillin-derivative allergy. Patient and family interviews were conducted in cases where a true penicillin allergy was deemed uncertain based on chart review. If allergy could not be de-labeled by chart review or interview alone, patients were offered skin and/or oral challenge testing. RESULTS: Fifty-nine patients were initially labeled as penicillin allergic. Allergy labels of 11 (19%) were removed by chart review only, and 15 (25%) after conducting interviews. A total of two (3%) patients were ineligible due to contraindications, and five (9%) declined participation. Twenty-six patients (44%) underwent allergy testing (50% skin testing, 50% oral challenge) of which 23 (88%) were negative. CONCLUSIONS: ADL was possible in most patients previously identified as penicillin allergic. Testing was well tolerated with no serious adverse effects.

Empirically derived profiles of neurocognitive functioning in youth and young adults with sickle cell disease.

OBJECTIVE: Sickle cell disease (SCD) is an inherited blood disorder associated with neurocognitive deficits. In contrast to variable-centered approaches, no known research has utilized person-centered strategies to identify multidimensional patterns of neurocognitive functioning of an individual with SCD. The purpose of the present study was to create empirically derived profiles and identify predictors of neurocognitive functioning subgroups among youth and young adults with SCD. METHODS: Individuals with SCD (N = 393, mean age 14.05 years, age range 8-24, 50.4% female/49.6% male) completed neurocognitive assessments. Latent profile analysis derived subgroups/classes of neurocognitive functioning and determined relations with demographic and medical variables. RESULTS: Three latent classes emerged: average functioning (n = 102, 27%), low average functioning (n = 225, 60%), and exceptionally low functioning (n = 46, 12%). Older age was associated with membership in the low average and exceptionally low functioning groups (relative to the average group). Being prescribed hydroxyurea was associated with membership in the average functioning group (relative to the low average group) and absence of hydroxyurea use was associated with membership in the exceptionally low group (relative to the low average group). Lower social vulnerability was associated with membership in the average functioning group compared to the low average and exceptionally low groups. CONCLUSIONS: Clinicians can help reduce disparities in cognitive development for individuals with SCD by promoting early treatment with hydroxyurea and implementing methods to reduce social vulnerabilities that can interfere with access to evidence-based care.

Clinical characteristics and outcomes of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis managed with different cytoreductive methods.

BACKGROUND: Hyperleukocytosis in patients with acute myeloid leukemia (AML) has been associated with worse outcomes. For cytoreduction, leukapheresis has been used but its clinical utility is unknown, and low-dose cytarabine (LD-cytarabine) is used as an alternative method. METHODS: Children with newly diagnosed AML treated between 1997 and 2017 in institutional protocols were studied. Hyperleukocytosis was defined as a leukocyte count of ≥100 × 109 /L at diagnosis. Clinical characteristics, early complications, survival data, and effects of cytoreductive methods were reviewed. Among 324 children with newly diagnosed AML, 49 (15.1%) presented with hyperleukocytosis. Initial management of hyperleukocytosis included leukapheresis or exchange transfusion (n = 16, considered as one group), LD-cytarabine (n = 18), hydroxyurea (n = 1), and no leukoreduction (n = 14). RESULTS: Compared with patients who received leukapheresis, the percentage decrease in leukocyte counts following intervention was greater among those who received LD-cytarabine (48% vs. 75%; p = .02), with longer median time from diagnosis to initiation of protocol therapy (28.1 vs. 95.2 hours; p < .001). The incidence of infection was higher in patients (38%) who had leukapheresis than those who receive LD-cytarabine (0%) or leukoreduction with protocol therapy (14%) (p = .008). No differences were noted in the outcomes among the intervention groups. Although patients with hyperleukocytosis had higher incidences of pulmonary and metabolic complications than did those without, no early deaths occurred, and the complete remission, event-free survival, overall survival rates, and outcomes of both groups were similar. CONCLUSION: LD-cytarabine treatment appears to be a safe and effective means of cytoreduction for children with AML and hyperleukocytosis.

Incorporating G6PD genotyping to identify patients with G6PD deficiency.

Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is a common X-linked enzyme disorder associated with hemolytic anemia after exposure to fava beans or certain medications. Activity testing is the gold standard for detecting G6PD deficiency; however, this test is affected by various hematologic parameters. Clinical G6PD genotyping is now included in pharmacogenetic arrays and clinical sequencing efforts and may be reconciled with activity results. Patients (n = 1391) enrolled on an institutional pharmacogenetic testing protocol underwent clinical G6PD genotyping for 164 G6PD variants. An algorithm accounting for known interferences with the activity assay is proposed. We developed clinical decision support alerts to inform prescribers when high-risk medications were prescribed, warning of gene-drug interactions and recommending therapy alteration. Of 1391 patients with genotype results, 1334 (95.9%) patients were predicted to have normal G6PD activity, 30 (2.1%) were predicted to have variable G6PD activity and 27 (2%) were predicted to have deficient G6PD activity. Of the 417 patients with a normal genotype and an activity result, 415 (99.5%) had a concordant normal G6PD phenotype. Of the 21 patients with a deficient genotype and an activity result, 18 (85.7%) had a concordant deficient activity result. Genotyping reassigned phenotype in five patients with discordant genotype and activity results: three switched from normal to deficient, and two switched from deficient to normal. G6PD activity and genotyping are two independent testing methods that can be used in conjunction to assign a more informed G6PD phenotype than either method alone.

Associated comorbidities, healthcare utilization & mortality in hospitalized patients with haemophilia in the United States: Contemporary nationally representative estimates.

INTRODUCTION: Current in-hospital burden and healthcare utilization patterns for persons with haemophilia (PWH) A and B, including both children (ages < 18 years) and adults (ages ≥ 18 years), in the United States (US) are lacking. AIM: To evaluate healthcare utilization, the prevalence of comorbidities, and mortality in hospitalized paediatric and adult PWH using a contemporary nationally representative cohort. METHODS: Hospitalizations of PWH either as the primary reason for admission (principal diagnosis) or one of all listed diagnoses were identified using ICD-10 codes from the 2017 Nationwide Inpatient Sample (NIS), the largest publicly available all-payer inpatient discharge database in the US. Sampling weights were applied to generate nationally representative estimates. RESULTS: The contemporary cohort included 10,555 hospitalizations (paediatrics, 18.3%; adults, 81.7%) among PWH as one-of-all listed diagnoses (n = 1465 as principal diagnosis). Median age (interquartile range) was 46 (24-66) years overall; adults, 54 (35-70) years and paediatric, 4 (1-11). The most common comorbidities in adults were hypertension (33.4%), hyperlipidaemia (23.6%), and diabetes (21.1%). In children, hemarthrosis (11.4%), contusions (9.6%), and central line infections (9.3%) were the most common. The overall mortality rate was 2.3%. Median hospital charges per haemophilia admission were $52,616 ($24,303-$135,814) compared to $26,841 ($12,969-$54,568) for all-cause admissions in NIS. CONCLUSION: Bleeding and catheter-related infections are the significant reasons for paediatric haemophilia admissions. Adult haemophilia admissions tend to be associated with age-related comorbidities. Costs for haemophilia-related hospitalizations are higher than the national average for all-cause hospitalizations.

Current and future treatment approaches for Barth syndrome.

Barth Syndrome is an X-linked disorder of mitochondrial cardiolipin metabolism caused by pathogenic variants in TAFAZZIN with pleiotropic effects including cardiomyopathy, neutropenia, growth delay, and skeletal myopathy. Management requires a multidisciplinary approach to the organ-specific manifestations including specialists from cardiology, hematology, nutrition, physical therapy, genetics, and metabolism. Currently, treatment is centered on management of specific clinical features, and is not targeted toward remediating the underlying biochemical defect. However, two clinical trials have been recently undertaken which target the mitochondrial pathology of this disease: a study to examine the effects of elamipretide, a cardiolipin targeted agent, and a study to examine the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist. Treatments to directly target the defective TAFAZZIN pathway are under development, including enzyme and gene therapies.

How we approach thrombosis risk in children with COVID-19 infection and MIS-C.

Thrombosis within the microvasculature and medium to large vessels is a serious and common complication among critically ill individuals with coronavirus disease 2019 (COVID-19). While children are markedly less likely to develop severe disease than adults, they remain at risk for thrombosis during acute infection and with the post-acute inflammatory illness termed multisystem inflammatory syndrome in children. Significant knowledge deficits in understanding COVID-19-associated coagulopathy and thrombotic risk pose clinical challenges for pediatric providers who must incorporate expert opinion and personal experience to manage individual patients. We discuss clinical scenarios to provide framework for characterizing thrombosis risk and thromboprophylaxis in children with COVID-19.

Diagnostic utility of telomere length testing in a hospital-based setting.

Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1, in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

Kaposiform lymphangiomatosis treated with multimodal therapy improves coagulopathy and reduces blood angiopoietin-2 levels.

Kaposiform lymphangiomatosis (KLA) is a rare, life-threatening congenital lymphatic malformation. Diagnosis is often delayed due to complex indistinct symptoms. Blood angiopoietin-2 (ANG2) levels are elevated in KLA and may be useful as a biomarker to monitor disease status. We report a 7-year-old male child with easy bruising, inguinal swelling, and consumptive coagulopathy, diagnosed with KLA. A multimodal treatment regimen of prednisone, sirolimus, vincristine, and adjunctive zoledronate was used. Plasma ANG2 levels were highly elevated at diagnosis but decreased during treatment. The patient showed significant clinical improvement over a 38-month period and normalization of ANG2 levels correlated with resolution of the coagulopathy.

Factors associated with red blood cell, platelet, and plasma transfusions among inpatient hospitalizations: a nationally representative study in the United States.

BACKGROUND: Demographic and hospital-level factors associated with red blood cell (RBC), plasma, and platelet transfusions in hospitalized patients across the U.S. are not well characterized. METHODS: We conducted a retrospective analysis of the National Inpatient Sample (2014). The unit of analysis was a hospitalization; sampling weights were applied to generate nationally-representative estimates. The primary outcome was having ≥ 1 RBC transfusion procedure; plasma and platelet transfusions were similarly assessed as secondary outcomes. For each component, factors associated with transfusion were measured using adjusted prevalence ratios (adjPR) and 95% confidence intervals (95% CI) estimated by multivariable Poisson regression. RESULTS: The prevalence of RBC, plasma, and platelet transfusion was 5.8%, 0.9%, and 0.7%, respectively. RBC transfusions were associated with older age (≥ 65 vs. < 18 years; adjPR = 1.80; 95% CI = 1.66-1.96), female sex (adjPR = 1.13; 95% CI = 1.12-1.14), minority race/ethnic status, and hospitalizations in rural hospitals compared to urban teaching hospitals. Prevalence of RBC transfusion was lower among hospitalizations in the Midwest compared to the Northeast (adjPR = 0.73; 95% CI = 0.67-0.80). All components were more likely to be transfused in patients with a primary hematologic diagnosis, patients with a higher number of total diagnoses, patients who experienced a higher number of other procedures, and patients who eventually died in the hospital. In contrast to RBC transfusions, prevalence of platelet transfusion was greater in urban teaching hospitals (vs. rural; adjPR = 1.71; 95% CI = 1.49-1.98) and lower in blacks (vs. whites; adjPR = 0.80; 95% CI = 0.76-0.85). CONCLUSIONS: Nationally, there is heterogeneity in factors associated with transfusion between each blood component, including by hospital type and location. This variability presents patient blood management programs with potential opportunities to reduce transfusions.

Platelet transfusion practices in immune thrombocytopenia related hospitalizations.

BACKGROUND: The role of platelet transfusions in management of Immune Thrombocytopenia (ITP) remains controversial. Current guidelines recommend that platelet transfusions in ITP be reserved for catastrophic hemorrhage or invasive surgical procedures. This study assesses the nationwide platelet transfusion practices in hospitalized children and adults with ITP. STUDY DESIGN AND METHODS: We studied hospitalizations with ITP as the primary admitting diagnosis from 2010-2014 in National Inpatient Sample (NIS), the largest all-payer inpatient database. Univariate and multivariable logistic regression analyses were used to determine factors predicting platelet transfusions. Sampling weights were applied to generate nationally representative estimates. Propensity score matching was used to perform sensitivity analyses. RESULTS: From 2010 to 2014, there were 78,376 admissions with ITP as the primary admission diagnosis (mean ± SD age: 45 ± 27 years; females 56%, children [age < 18 years] 22%) and 282,285 with ITP as one of all the admission diagnoses. Overall, 27% admissions with ITP as primary (children 4%) and 15% admissions with ITP as one of all the diagnoses documented at least one platelet transfusion. On multivariable adjustment the following factors were associated with worsening disease severity and a higher odds of platelet transfusion, adult age (adjOR = 9.03, 95% CI = 7.40-11.02), male gender (adjOR = 1.21, 95% CI = 1.11-1.31), bleeding occurrence (intracranial/gastrointestinal/genitourinary/epistaxis) (adjOR = 1.78, 95% CI = 1.61-1.96), admission to rural non-teaching hospital (adjOR = 1.85, 95% CI = 1.52-2.22), and small bed-size hospital (adjOR = 1.23, 95% CI = 1.05-1.45). Of admissions reporting platelet transfusions, only 26% reported a bleeding complication, and 11% had a major operating-room surgery/procedure. Overall, 65% of transfused patients had neither bleeding nor a major operative procedure during the hospitalization. Admissions with platelet transfusions had a significantly longer mean length of hospitalization 2.2 days (95% CI = 1.96-2.41, p < 0.001), and accrued higher mean total hospital charges; $31,150 USD (95% CI = 27,644-34,656, p < 0.001). However, platelet transfusions were not associated with in-hospital mortality (adjOR = 1.02, 95% CI = 0.73-1.45, p = 0.892). CONCLUSION: Platelets are administered to a small fraction of the hospitalized ITP patients. In a majority of these cases however, platelet usage does not appear to be concordant with the current guidelines or associated with improvement in clinical outcomes.

Correlates of successful transition in young adults with sickle cell disease.

The transition period from pediatric care to adult care for patients with sickle cell disease (SCD) is associated with increased mortality and morbidity. Identification of risk factors for unsuccessful transition may aid in developing strategies to improve the transition process and health outcomes in this population. We examined factors associated with unsuccessful transition from pediatric to adult care for patients with SCD at the Johns Hopkins Hospital. We found that public insurance and increased hospitalization rates were associated with poor transition to adult care. The findings provide possible areas of intervention.

Diagnosis of congenital and acquired focal lesions in the neck, abdomen, and pelvis with contrast-enhanced ultrasound: a pictorial essay.

Contrast-enhanced ultrasound (CEUS) is a versatile imaging modality that improves the diagnostic potential of conventional ultrasound. It allows for portable imaging at the bedside. In this paper, we illustrate how CEUS can be used in evaluating several focal lesions in the pediatric population, including liver hemangioma, telangiectasias, splenic hamartomas, and bladder lesions. We describe the ultrasound findings and contrast enhancement patterns associated with these lesions. Findings are correlated with MRI, CT, and/or pathology when available. This paper demonstrates the value of CEUS in improving characterization of many focal lesions in the pediatric population. CONCLUSION: CEUS is a valuable bedside technique for use in the pediatric population to evaluate focal lesions in various organs, and will allow for safe, more efficient diagnostic imaging. What is Known: • CEUS offers many advantages over CT and MRI and is underutilized in the United States. • It is only FDA approved for vesicoureteral reflux and liver in the pediatric population. However, off label uses are well described. What is New: • This pictorial essay describes ultrasound findings and contrast enhancement patterns associated with liver hemangioma, liver telangiectasia, splenic hamartoma, hemorrhagic ovarian cyst, urachal remnant, spinning top urethras, and kaposiform hemangioendothelioma. • We demonstrate the utility of CEUS in expanding the diagnostic potential of conventional ultrasound.

Risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation.

BACKGROUND: Paediatric hospital-associated venous thromboembolism is a leading quality and safety concern at children's hospitals. OBJECTIVE: The aim of this study was to determine risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or therapeutic cardiac catheterisation. METHODS: We conducted a retrospective, case-control study of children admitted to the cardiovascular intensive care unit at Johns Hopkins All Children's Hospital (St. Petersburg, Florida, United States of America) from 2006 to 2013. Hospital-associated venous thromboembolism cases were identified based on ICD-9 discharge codes and validated using radiological record review. We randomly selected two contemporaneous cardiovascular intensive care unit controls without hospital-associated venous thromboembolism for each hospital-associated venous thromboembolism case, and limited the study population to patients who had undergone cardiothoracic surgery or therapeutic cardiac catheterisation. Odds ratios and 95% confidence intervals for associations between putative risk factors and hospital-associated venous thromboembolism were determined using univariate and multivariate logistic regression. RESULTS: Among 2718 admissions to the cardiovascular intensive care unit during the study period, 65 met the criteria for hospital-associated venous thromboembolism (occurrence rate, 2%). Restriction to cases and controls having undergone the procedures of interest yielded a final study population of 57 hospital-associated venous thromboembolism cases and 76 controls. In a multiple logistic regression model, major infection (odds ratio=5.77, 95% confidence interval=1.06-31.4), age ⩽1 year (odds ratio=6.75, 95% confidence interval=1.13-160), and central venous catheterisation (odds ratio=7.36, 95% confidence interval=1.13-47.8) were found to be statistically significant independent risk factors for hospital-associated venous thromboembolism in these children. Patients with all three factors had a markedly increased post-test probability of having hospital-associated venous thromboembolism. CONCLUSION: Major infection, infancy, and central venous catheterisation are independent risk factors for hospital-associated venous thromboembolism in critically ill children following cardiothoracic surgery or cardiac catheter-based intervention, which, in combination, define a high-risk group for hospital-associated venous thromboembolism.

Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities.

Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, and anticoagulant use in this population has become common, despite the absence of US Food and Drug Administration (FDA) approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials (RCTs) in adults, smaller dose-finding and observational studies in children, and expert opinion. The recently FDA-approved direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, provide potential advantages over oral vitamin K antagonists and subcutaneous low-molecular-weight heparins (LMWHs). However, key questions arise regarding their potential off-label clinical application in pediatric thromboembolic disease. In this Perspective, we provide background on the use of LMWHs such as enoxaparin as the mainstay of treatment of pediatric provoked VTE; identify key questions and challenges with regard to DOAC trials and future DOAC therapy in pediatric VTE; and discuss applicable lessons learned from the recent pilot/feasibility phase of a large multicenter RCT of anticoagulant duration in pediatric VTE. The challenges and lessons learned present opportunities to improve evidence for anticoagulant therapies in pediatric VTE through future clinical trials.

Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality.

While platelets are primary mediators of hemostasis, there is emerging evidence to show that they may also mediate pathologic thrombogenesis. Little data are available on risks and benefits associated with platelet transfusions in thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT) and immune thrombocytopenic purpura (ITP). This study utilized the Nationwide Inpatient Sample to evaluate the current in-hospital platelet transfusion practices and their association with arterial/venous thrombosis, acute myocardial infarction (AMI), stroke, and in-hospital mortality over 5 years (2007-2011). Age and gender-adjusted odds ratios (adjOR) associated with platelet transfusions were calculated. There were 10 624 hospitalizations with TTP; 6332 with HIT and 79 980 with ITP. Platelet transfusions were reported in 10.1% TTP, 7.1% HIT, and 25.8% ITP admissions. Platelet transfusions in TTP were associated with higher odds of arterial thrombosis (adjOR = 5.8, 95%CI = 1.3-26.6), AMI (adjOR = 2.0, 95%CI = 1.2-3.3) and mortality (adjOR = 2.0,95%CI = 1.3-3.0), but not venous thrombosis. Platelet transfusions in HIT were associated with higher odds of arterial thrombosis (adjOR = 3.4, 95%CI = 1.2-9.5) and mortality (adjOR = 5.2, 95%CI = 2.6-10.5) but not venous thrombosis. Except for AMI, all relationships remained significant after adjusting for clinical severity and acuity. No associations were significant for ITP. Platelet transfusions are associated with higher odds of arterial thrombosis and mortality among TTP and HIT patients.