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.

Initial von Willebrand factor antigen values in adolescent females predict future values.

INTRODUCTION: Diagnosing von Willebrand Disease (VWD) in adolescent females is challenging as menstruation and physiologic stress elevate von Willebrand factor (VWF) laboratory values. AIM: To develop a VWF prediction model for adolescent females based on initial VWF results. METHODS: We identified female patients aged 9 to 21 years with any VWF laboratory test over a 5-year period (2017-2021) at any Texas Children's Hospital facility. Patient demographics, VWF testing, haemoglobin concentration, serum ferritin and site of clinical testing were collected (initial and subsequent laboratory evaluations). A Bayesian linear regression model was developed. Prediction intervals were analysed to identify thresholds for patients in whom repeat testing was unlikely to identify low VWF levels (< 50%), consistent with VWD. RESULTS: A total of 6125 adolescent females underwent VWF testing; 1204 (19.7%) had repeat testing. Based on the prediction model, initial VWF antigen values of 80%, 90% and ≥100% carried a 92.6%, 96.6% and ≥98.0% probability of having repeat normal repeat VWF values, respectively. Subjects assessed in outpatient adolescent medicine or gynaecology clinics were more likely to have low VWF values compared to those assessed in the acute care setting (p < .001). Median presenting haemoglobin and serum ferritin were 12.4 g/dL and 13 ng/mL, respectively and were similar in those with normal versus low VWF antigen values. CONCLUSION: Repeat testing in adolescent females whose initial VWF antigen values are ≥90% is unlikely to identify additional patients with VWD. Iron deficiency screening should be performed in all adolescent females.

Pulmonary embolism in pediatric and adolescent patients with COVID-19 infection during the SARS-CoV-2 delta wave.

Coronavirus disease 2019 (COVID-19) infection in children has been associated with thrombosis, though few cases of COVID-associated pulmonary embolism (PE) have been described. We performed a retrospective review of the nine cases of COVID-19-associated PE during the B.1617.2 variant surge at Texas Children's Hospital. The patient cohort largely contained unvaccinated obese adolescents. All patients were critically ill with two requiring catheter-directed thrombolysis in addition to anticoagulation. Eight of the nine patients had COVID pneumonia along with PE. This report stresses the importance of maintaining a high index of suspicion for PE in pediatric COVID-19 infection and vaccinating obese adolescent patients.

COVID-19 vaccine (mRNA BNT162b2) and COVID-19 infection-induced thrombotic thrombocytopenic purpura in adolescents.

The mRNA COVID-19 vaccine and COVID-19 infection caused by the SARS-CoV-2 virus may be immunologic triggers for the development of thrombotic thrombocytopenic purpura (TTP). There is not yet literature that discusses TTP induced by COVID-19 vaccination or infection in pediatric or adolescent patients. We describe three adolescents presenting with TTP (both de novo and relapsed disease) following administration of the Pfizer COVID-19 vaccine or after COVID-19 infection. Our observations demonstrate that the Pfizer-BioNTech mRNA vaccine and COVID-19 infection can act as triggers for the development/relapse of both congenital and acquired TTP.

Patient Characteristics and Treatment Outcomes of Symptomatic Catheter-Related Arterial Thrombosis in Infants: A Retrospective Cohort Study.

OBJECTIVE: To describe the clinical characteristics, outcomes, and adverse events of treatment for symptomatic infant catheter-related arterial thrombosis. STUDY DESIGN: Single-center retrospective medical record review of 99 infants (age <365 days) with catheter-related arterial thrombosis, either following indwelling arterial catheter placement or cardiac catheterization, who were treated with anticoagulation over an 8-year span at a pediatric tertiary care center. Outcomes measured include thrombosis progression, bleeding events, and thrombus resolution following the treatment period. RESULTS: Thromboses were secondary to indwelling arterial catheter placement in 51 (51.5%) and cardiac catheterization in 48 (48.5%). The median age at diagnosis of catheter-related arterial thrombosis was 52 days. All patients received therapeutic anticoagulation with either unfractionated heparin or low molecular weight heparin for a maximum of 28 days. Progression of catheter-related arterial thrombosis occurred in 8 (8.1%) patients. One (1%) major and 3 (3%) minor bleeding events occurred within the cohort. Complete thrombus resolution was observed in 60 (60.6%), partial resolution in 33 (33.3%), and no resolution in 6 (6.1%) following the treatment period. Factors associated with complete thrombus resolution included time from intervention to catheter-related arterial thrombosis diagnosis (median of 1 day vs 5 days in those who experienced thrombus resolution vs those who did not, P = .035), and iliac and/or femoral artery involvement (P = .015). CONCLUSIONS: Our treatment approach to infant catheter-related arterial thrombosis is safe and effective. Limitations of the study are its retrospective nature with a limited number of patients from a single institution. Additional prospective studies are needed to determine the optimal treatment approach to catheter-related arterial thrombosis in infants.

Emicizumab in pediatric hemophilia: Bleeding and surgical outcomes from a single-center retrospective study.

Real-world data describing emicizumab prophylaxis in pediatric hemophilia A is limited with current literature providing a heterogenous approach to procedural management. We performed a retrospective review on the 28 patients who have been treated with emicizumab prophylaxis at Texas Children's Hospital from 2018 to 2021. After starting emicizumab, the mean annualized bleeding rate reduced from 3.61 to 0.44. Seven surgical procedures were performed in the cohort, and all treated with pre- and postoperative factor replacement resulting in one minor bleeding event. We demonstrate a successful experience with emicizumab prophylaxis and safe perioperative approach with a focus on minimizing postoperative bleeding.

Diagnosis, Clinical Characteristics, and Treatment Modalities of Adolescent May-Thurner Syndrome-associated Deep Venous Thrombosis.

May-Thurner syndrome (MTS) predisposes individuals to develop lower extremity deep venous thrombosis (DVT) because of compression of the left common iliac vein. Diagnosis of the anatomic obstruction is critical for effective therapy, as treatment by interventional radiology is often required in addition to anticoagulation to prevent thrombus progression and recurrence. The authors performed a retrospective review of adolescent patients who presented with MTS-associated DVT at a pediatric tertiary care center from 2009 to 2018 to assess for delays in MTS diagnosis after the presentation. Fourteen patients (median age 16.5 y, range, 13.8 to 17.9 y) were included, no DVTs were provoked by a central venous catheter. The median time from DVT to MTS diagnosis was 0.65 months (range, 0 to 21.5 mo). The initial imaging modalities used for DVT diagnosis were not able to diagnosis MTS. All patients were treated with anticoagulation and 13 underwent interventional therapy. Four patients had thrombus progression or recurrence, whereas 6 had complete thrombus resolution on follow-up imaging. Three patients who had a delayed MTS diagnosis had clinical worsening despite therapeutic anticoagulation requiring rehospitalization. Adolescent patients with "unprovoked" left lower extremity DVT should undergo appropriate imaging to diagnose MTS to allow for adequate medical and interventional therapy.

Clinical characteristics and outcomes of combined thrombolysis and anticoagulation for pediatric and young adult lower extremity and inferior vena cava thrombosis.

Effective treatment for acute, extensive, symptomatic lower extremity (LE) thrombosis involves thrombolysis in addition to anticoagulation. There is limited available data on the outcomes and safety of thrombolysis to help guide its use in pediatrics and young adults. A retrospective study of children and young adults (<21 years of age) that received catheter directed thrombolysis (CDT) for LE and inferior vena cava (IVC) thrombosis was performed over a 5-year span at a pediatric tertiary care center. A total of 29 patients were identified for inclusion in the study, 76% (n = 22) received overnight CDT while 24% (n = 7) received tissue plasminogen activator as a bolus dose during a single interventional procedure. The median age of the cohort was 15.8 years (range 0-19.1). All patients were treated with a course of therapeutic anticoagulation. The thromboses represented were extensive, with 93% (n = 27) being occlusive and affecting multiple venous segments. Thrombus resolution occurred in 35% (n = 10) of patients. Rivaroxaban use (p < 0.01) during the course of anticoagulation and estrogen-containing hormonal therapy (p = 0.01) use prior to diagnosis were associated with thrombus resolution, while Hispanic ethnicity (p = 0.06) had a trend toward thrombus persistence. There were one major and 3 minor bleeding events that occurred as complications of thrombolysis and no treatment related deaths. This study provides baseline information that can be used to help guide clinicians treating similar patients and suggests the need to develop an improved, uniform treatment approach for superior resolution rates.

Protocol for Reducing Time to Antibiotics in Pediatric Patients Presenting to an Emergency Department With Fever and Neutropenia: Efficacy and Barriers.

OBJECTIVES: Patients with febrile neutropenia are at high risk of morbidity and mortality from infectious causes. Decreasing time to antibiotic (TTA) administration is associated with improved patient outcomes. We sought to reduce TTA for children presenting to the emergency department with fever and neutropenia. METHODS: In a prospective cohort study with historical comparison, TTA administration was evaluated in patients with neutropenia presenting to the Children's of Alabama Emergency Department. A protocol was established to reduce delays in antibiotic administration and increase the percentage of patients who receive treatment within 60 minutes of presentation. One hundred pre-protocol patient visits between August 2010 and December 2011 were evaluated and 153 post-protocol visits were evaluated between August 2012 and September 2013. We reviewed individual cases to determine barriers to rapid antibiotic administration. RESULTS: Antibiotics were administered in 96.9 ± 57.8 minutes in the pre-protocol patient group, and only 35% of patients received antibiotics within 60 minutes of presentation and 70% received antibiotics within 120 minutes. After implementation of the protocol, TTA for neutropenic patients was decreased to 64.3 ± 28.4 minutes (P < 0.0001) with 51.4% receiving antibiotics within 60 minutes and 93.2% within 120 minutes. CONCLUSIONS: Implementing a standard approach to patients at risk for neutropenia decreased TTA. There are numerous challenges in providing timely antibiotics to children with febrile neutropenia. Identified delays included venous access (time to effect of topical anesthetics, and difficulty obtaining access), physicians waiting on laboratory results, and antibiotic availability.

Nutritional Strategies for Managing Iron Deficiency in Adolescents: Approaches to a Challenging but Common Problem.

Iron deficiency (ID) is a common and challenging problem in adolescence. In order to prevent, recognize, and treat ID in this age range, it is critical to understand the recommended daily intake of iron in relation to an adolescent's activity, dietary habits, and basal iron losses. Adolescents following vegetarian or vegan diets exclusively rely on plant-based, nonheme iron, which has decreased bioavailability compared with heme iron and requires increased total iron intake. Individuals with disordered eating habits, excessive menstrual blood loss, and certain chronic health conditions (including inflammatory bowel disease and heart failure) are at high risk of ID and the development of symptomatic iron deficiency anemia (IDA). Adolescent athletes and those with sleep and movement disorders may also be more sensitive to changes in iron status. Iron deficiency is typically treated with oral iron supplementation. To maximize iron absorption, oral iron should be administered no more than once daily, ideally in the morning, while avoiding foods and drinks that inhibit iron absorption. Oral iron therapy should be provided for ≥3 mo in the setting of ID to reach a ferritin of 20 ng/mL before discontinuation. Intravenous iron is being increasingly used in this population and has demonstrated efficacy and safety in adolescents. It should be considered in those with persistent ID despite a course of oral iron, severe and/or symptomatic IDA, and chronic inflammatory conditions characterized by decreased gastrointestinal iron absorption.

Traumatic intracranial hemorrhage in pediatrics: Implications of factor XIII deficiency and consumptive coagulopathy in abusive head trauma evaluation.

For infants that present with intracranial hemorrhage in the setting of suspected abusive head trauma (AHT), the standard recommendation is to perform an evaluation for a bleeding disorder. Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder associated with intracranial hemorrhages in infancy, though testing for FXIII is not commonly included in the initial hemostatic evaluation. The current pediatric literature recognizes that trauma, especially traumatic brain injury, may induce coagulopathy in children, though FXIII is often overlooked as having a role in pediatric trauma-induced coagulopathy. We report an infant that presented with suspected AHT in whom laboratory workup revealed a decreased FXIII level, which was later determined to be caused by consumption in the setting of trauma induced coagulopathy, rather than a congenital disorder. Within the Child Abuse Pediatrics Research Network (CAPNET) database, 85 out of 569 (15 %) children had FXIII testing, 3 of those tested (3.5 %) had absent FXIII activity on qualitative testing, and 2 (2.4 %) children had activity levels below 30 % on quantitative testing. In this article we review the literature on the pathophysiology and treatment of low FXIII in the setting of trauma. This case and literature review demonstrate that FXIII consumption should be considered in the setting of pediatric AHT.

Intravenous iron therapy in pediatrics: who should get it and when is the right time?

Iron-deficiency anemia occurs most commonly in young children due to a low-iron diet and adolescent girls due to menstrual blood loss. However, children with gastrointestinal conditions such as intestinal failure, inflammatory bowel disease, celiac disease, and/or other chronic conditions, including chronic kidney disease and heart failure, also commonly have iron deficiency. Many patients with classic iron-deficiency anemia will improve with oral iron therapy. However, in children who have an incomplete response to oral iron, intravenous iron therapy is increasingly being used. Benefits of intravenous iron therapy include a rapid repletion of iron stores in addition to resolution of anemia, less gastrointestinal side effects, and relief for patients and families struggling with long-term iron supplementation. Indications for first-line therapy with intravenous iron in children with chronic conditions have also increased. Four intravenous iron formulations have approved indications in pediatrics, and many are increasingly used off-label in children as well. Here we discuss the indications and appropriate timing of intravenous iron therapy in children with a wide range of underlying etiologies.

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.

Human endothelial cells and fibroblasts express and produce the coagulation proteins necessary for thrombin generation.

In a previous study, we reported that human endothelial cells (ECs) express and produce their own coagulation factors (F) that can activate cell surface FX without the additions of external proteins or phospholipids. We now describe experiments that detail the expression and production in ECs and fibroblasts of the clotting proteins necessary for formation of active prothrombinase (FV-FX) complexes to produce thrombin on EC and fibroblast surfaces. EC and fibroblast thrombin generation was identified by measuring: thrombin activity; thrombin-antithrombin complexes; and the prothrombin fragment 1.2 (PF1.2), which is produced by the prothrombinase cleavage of prothrombin (FII) to thrombin. In ECs, the prothrombinase complex uses surface-attached FV and γ-carboxyl-glutamate residues of FX and FII to attach to EC surfaces. FV is also on fibroblast surfaces; however, lower fibroblast expression of the gene for γ-glutamyl carboxylase (GGCX) results in production of vitamin K-dependent coagulation proteins (FII and FX) with reduced surface binding. This is evident by the minimal surface binding of PF1.2, following FII activation, of fibroblasts compared to ECs. We conclude that human ECs and fibroblasts both generate thrombin without exogenous addition of coagulation proteins or phospholipids. The two cell types assemble distinct forms of prothrombinase to generate thrombin.

Production and control of coagulation proteins for factor X activation in human endothelial cells and fibroblasts.

Human endothelial cells (ECs) synthesize, store, and secrete von Willebrand factor multimeric strings and coagulation factor (F) VIII. It is not currently known if ECs produce other coagulation factors for active participation in coagulation. We found that 3 different types of human ECs in primary culture produce clotting factors necessary for FX activation via the intrinsic (FVIII-FIX) and extrinsic (tissue factor [TF]-FVII) coagulation pathways, as well as prothrombin. Human dermal fibroblasts were used as comparator cells. TF, FVII, FIX, FX, and prothrombin were detected in ECs, and TF, FVII, FIX, and FX were detected in fibroblasts. In addition, FVII, FIX, FX, and prothrombin were detected by fluorescent microscopy in EC cytoplasm (associated with endoplasmic reticulum and Golgi proteins). FX activation occurred on human umbilical vein EC surfaces without the addition of external coagulation proteins, proteolytic enzymes, or phospholipids. Tumour necrosis factor, which suppresses the generation of activated protein C and increases TF, augmented FX activation. Fibroblasts also produced TF, but (in contrast to ECs) were incapable of activating FX without the exogenous addition of FX and had a marked increase in FX activation following the addition of both FX and FVII. We conclude that human ECs produce their own coagulation factors that can activate cell surface FX without the addition of exogenous proteins or phospholipids.

First case of neutropenia and thrombocytopenia in the setting of cerebral cavernous malformation 3.

Cerebral cavernous malformation 3 (CCM3) is a vascular malformation disorder causing brain slow-flow vascular parenchymal lesions. These lesions are the result of variants in the Programmed Cell Death Protein 10 (PDCD10) gene, located on 3q26.1. We report an 8-month-old patient who was presented with seizures and intracranial abscesses and was found to have a variant of PDCD10 on whole exome sequencing, representing, to our knowledge, the youngest case of CCM3 described in the literature. Her clinical course was complicated by the development of neutropenia, requiring granulocyte colony-stimulating factor, and thrombocytopenia, requiring intermittent platelet transfusions, with later development of B acute lymphoblastic leukemia 2 years after initial presentation. This case represents the first description in the literature of hematologic complications in the setting of CCM3. We hypothesize that these hematological manifestations are the result of alterations in the actin and microtubule cytoskeleton, affecting the process of hematopoiesis in a similar fashion to the documented effect of the PDCD10 variant on neuronal migration.