Hereditary factor X deficiency in America survey: impact on quality of life and burden of disease in patients and caregivers.

Hereditary factor X deficiency (HFXD) is a rare bleeding disorder causing delayed haemostasis and potentially life-threatening bleeds. Patient/caregiver burden and diagnosis path have not been well characterized. THE AIM OF THIS STUDY WAS TO: describe the diagnosis path, disease burden, and HFXD impact on quality of life (QoL) in patients and caregivers.This was a prospective, cross-sectional, web-based survey of patients with HFXD and caregivers addressing the patient/caregiver experience, QoL, humanistic and unmet needs.Thirty patients and 38 caregivers completed the survey with mean ages 24.7 and 44.6 years, respectively. Mean age at diagnosis was 4.1 years. The diagnostic process was somewhat/very difficult for 23% of patients and 26% of caregivers. Approximately half (53%) received single factor replacement (SFR) as prophylaxis or on-demand. Most patients (71%) reported regular prophylaxis treatment. Over one-fourth (27%) reported treatment with fresh frozen plasma. Bleeding episodes were less common in patients using SFR versus non-SFR: three bleeds or fewer were reported by 92% SFR and 75% non-SFR patients. HFXD patients reported low well being in work/school/social activities with mean HFXD-adapted Hemophilia Well being Index. Patient symptoms negatively impacted caregiver burden with a mean HFXD-adapted Hemophilia Caregiver Index (±SD) of 15.9 (4.6), but also unexpectedly had a positive impact on self-worth and inner strength.To our knowledge, this is the first study to assess patient and caregiver burden of HFXD and impact on QoL. Improvements in symptom recognition, prompt diagnosis, and adherence to expert recommendations for treatment could improve QoL and decrease burden on HFXD patients and caregivers.

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

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

Corrigendum to ' Recurrent venous thromboembolism in hospitalized children with a history of prior venous thromboembolism: a report from the Children's Hospital-Acquired Thrombosis Consortium' [Research and Practice in Thrombosis and Haemostasis Volume 7, Issue 5, July 2023, 102139].

[This corrects the article DOI: 10.1016/j.rpth.2023.102139.].

Evaluation of venous thromboembolism risk factors reveals subtype heterogenicity in children with central venous catheters: a multicenter study from the Children's Hospital Acquired Thrombosis consortium.

BACKGROUND: Acutely ill and medically complex children frequently rely on central venous catheters (CVCs) to provide life-sustaining treatment. Unfortunately, catheter-related thrombosis (CRT) is a serious and common complication. Little is known why some with a CVC develop CRT and others develop venous thromboembolism unrelated to the CVC (non-CRT). OBJECTIVES: The aim of this study was to identify factors associated with CRT in children with hospital-acquired venous thromboembolism (HA-VTE). METHODS: This case-case study included participants in the Children's Hospital Acquired Thrombosis Registry with HA-VTE and CVC aged 0 to 21 years from 8 US children's hospitals. Participants were excluded if they developed HA-VTE prior to CVC insertion or if the CVC insertion date was unknown. Logistic regression models were used to assess associations between clinical factors and CRT status. RESULTS: There were 1144 participants with HA-VTE who had a CVC. CRT developed in 833 participants, and 311 developed non-CRT. Multivariable analysis showed increased odds of CRT (compared with non-CRT) in participants with peripherally inserted central catheters (odds ratio [OR], 3.80; 95% CI, 2.04-7.10; p < .001), CVCs inserted in the femoral vein (OR, 4.45; 95% CI, 1.70-11.65; p = .002), multiple CVCs (OR, 1.42; 95% CI, 1.18-1.71; p < .001), and CVC malfunction (OR, 3.30; 95% CI, 1.80-6.03; p < .001). CONCLUSION: The findings of this study provide new insights on risk factor differences between CRT and non-CRT. Prevention efforts should be directed at modifying the type of CVC, insertion location, and/or number of CVCs placed, if possible, to decrease the incidence of CRT.

Safety and Efficacy of Direct Oral Anticoagulants for Treatment of Venous Thromboembolism in Pediatric Oncology Patients.

BACKGROUND/OBJECTIVES: Children with cancer have an increased risk for developing a venous thromboembolism (VTE) during their treatment course. Direct oral anticoagulants (DOACs) represent a relatively new class of oral medications to treat VTE; however, data are limited to support use in this patient group. Given the safety and efficacy data from numerous perspective adult studies, providers now consider off-label use in select children. METHODS: We performed a single-center, retrospective review of children 0 to 20 years of age from 2012 to 2020 with malignancy and confirmed VTE, with the objective to evaluate the hypothesis that the safety and the efficacy of DOACs are noninferior to enoxaparin in this population. The primary composite efficacy outcome comprises symptomatic recurrent VTE, death due to VTE, and thrombus progression. The principal safety outcome is a combination of major and clinically relevant nonmajor bleeding. RESULTS: The safety and efficacy outcomes collected revealed that DOAC use was equivalent when compared with the enoxaparin group for treatment of VTE. One patient in the DOAC group had clinically relevant, nonmajor bleeding compared with 2 patients in the enoxaparin group. No treatment failures were observed. CONCLUSIONS: This single-center study suggests that DOACs are both safe and efficacious for the treatment of VTE in children with cancer. It also highlights the need for larger studies to address this clinical question.

Risk factors for hospital acquired venous thromboembolism in congenital heart disease patients: A report from the children's hospital acquired thrombosis (CHAT) consortium.

INTRODUCTION: The incidence of pediatric hospital-acquired venous thromboembolism (HA-VTE) has increased over time. Congenital heart disease (CHD) as a co-morbidity has been demonstrated to significantly increase HA-VTE risk among hospitalized children. OBJECTIVE: To identify specific risks factors for the development of HA-VTE in hospitalized children with CHD. MATERIALS AND METHODS: This retrospective case-control study included hospitalized participants aged 0-21 years within the Children's Hospital Acquired Thrombosis (CHAT) Consortium Registry with a co-morbidity of CHD. Participants with HA-VTE and non-VTE controls with a past medical history of CHD were selected from the CHAT Registry and data regarding multiple clinical variables were extracted. These variables were then analyzed to assess their association with HA-VTE development. RESULTS: Three hundred and thirty-three participants with a co-morbidity of CHD were identified, comprising 275 HA-VTE cases and 58 controls. Median age for HA-VTE cases was 0.4 (IQR = 0-2.6) years compared to 3.4 (IQR = 0.7-6.5) for controls. Male participants were predominant in both groups (57.5 % HA-VTE cases vs 51.7 % controls). Multivariable analysis identified prior recent hospitalization (OR = 4.12, 95%CI = 1.66-10.24), intensive care unit (ICU) admission (OR = 3.29, 95 % CI = 1.15-9.40), and CVC placement (OR = 9.14, 95 % CI = 3.38-24.72) as significant risk factors for HA-VTE in subjects with CHD. CONCLUSIONS: ICU admission, CVC placement, and prior hospitalization were identified as statistically significant predictors associated with HA-VTE development in hospitalized children with history of CHD. Prospective studies are needed to validate these results and help develop strategies to mitigate HA-VTE development in these patients.

Risk of venous thromboembolism in pediatric hospitalized patients undergoing noncardiac surgery: A report from the Children's Hospital-Acquired Thrombosis consortium.

Background: Surgery is a known risk factor for hospital-acquired venous thromboembolism (HA-VTE) in children. Objectives: To assess whether the odds of HA-VTE differs across six anatomic sites of noncardiac surgery and to identify risk factors for HA-VTE in these children. Methods: This was a multicenter, case-control study. Anatomic sites of surgery and risk factors for HA-VTE were collected on hospitalized pediatric patients who had undergone a single noncardiac surgery and developed HA-VTE (cases), and those who did not develop HA-VTE (controls), via the Children's Hospital-Acquired Thrombosis (CHAT) Registry. Logistic regression estimated the odds ratio (OR) and 95% confidence intervals (CIs) between six anatomic sites of surgery and 16 putative HA-VTE risk factors. Variables with a p value of 0.10 or less in unadjusted analyses were included in adjusted models for further evaluation. The final model used backward selection, with a significance level of 0.05. Results: From January 2012 to March 2020, 163 cases (median age, 5.7 years; interquartile range [IQR], 0.3-14.2) and 208 controls (median age of 7.5 years; IQR, 3.7-12.9) met our criteria. There was no statistically significant increased odds of VTE among the types of noncardiac surgery. In the final adjusted model, central venous catheter (CVC; OR, 14.69; 95% CI, 7.06-30.55), intensive care unit (ICU) stay (OR, 5.31; 95% CI, 2.53-11.16), and hospitalization in the month preceding surgery (OR, 2.75; 95% CI, 1.24-6.13) were each independently significant risk factors for HA-VTE. Conclusion: In children undergoing noncardiac surgery, placement of CVCs, admission/transfer to the ICU, or hospitalization in the month prior to surgery were positively associated with HA-VTE.

Apolipoprotein A-I, elevated in trauma patients, inhibits platelet activation and decreases clot strength.

Apolipoprotein A-I (ApoA-I) is elevated in the plasma of a subgroup of trauma patients with systemic hyperfibrinolysis. We hypothesize that apoA-I inhibits platelet activation and clot formation. The effects of apoA-I on human platelet activation and clot formation were assessed by whole blood thrombelastography (TEG), platelet aggregometry, P-selectin surface expression, microfluidic adhesion, and Akt phosphorylation. Mouse models of carotid artery thrombosis and pulmonary embolism were used to assess the effects of apoA-I in vivo. The ApoA-1 receptor was investigated with transgenic mice knockouts (KO) for the scavenger receptor class B member 1 (SR-BI). Compared to controls, exogenous human apoA-I inhibited arachidonic acid and collagen-mediated human and mouse platelet aggregation, decreased P-selectin surface expression and Akt activation, resulting in diminished clot strength and increased clot lysis by TEG. ApoA-I also decreased platelet aggregate size formed on a collagen surface under flow. In vivo, apoA-I delayed vessel occlusion in an arterial thrombosis model and conferred a survival advantage in a pulmonary embolism model. SR-BI KO mice significantly reduced apoA-I inhibition of platelet aggregation versus wild-type platelets. Exogenous human apoA-I inhibits platelet activation, decreases clot strength and stability, and protects mice from arterial and venous thrombosis via the SR-BI receptor.

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.

Current practices in pediatric hospital-acquired thromboembolism: Survey of the Children's Hospital Acquired Thrombosis (CHAT) Consortium.

Background: A rise in hospital-acquired venous thromboembolism (HA-VTE) in children has led to increased awareness regarding VTE prophylaxis and risk assessment. Despite no consensus exists regarding these practices in pediatrics. Objective: To describe common practices in VTE prophylaxis, VTE risk assessment models, and anticoagulation dosing strategies in pediatric hospitals that are members of the Children's Hospital Acquired Thrombosis (CHAT) Consortium. Methods: An electronic survey of 44 questions evaluating practices surrounding pediatric HA-VTE risk assessment and prevention was distributed between August 9, 2021, and August 30, 2021, to the primary investigators from the 32 institutions within the CHAT Consortium. Results: The survey response rate was 100% (n = 32). In total, 85% (n = 27) of the institutions assess HA-VTE, but only 63% (n = 20) have formal hospital guidelines. Within the institutions with formal guidelines, 100% (n = 20) include acute systemic inflammation or infection and presence of a central venous catheter (CVC) as risk factors for VTE. Pharmacologic prophylaxis is prescribed at 87% (28) of institutions, with enoxaparin being the most frequent (96%, n = 27). Variability in responses persisted regarding risk factors, risk assessment, thromboprophylaxis, dosing of prophylactic anticoagulation or anticoagulant drug monitoring. A majority of providers were comfortable providing thromboprophylaxis across all age groups. In addition, the global coronavirus disease 2019 increased the providers' use of prophylactic anticoagulation 78% (n = 25). Conclusion: Practices among institutions are variable in regard to use of HA-VTE prophylaxis, risk assessment, or guideline implementation, highlighting the need for further research and a validated risk assessment model through groups like the CHAT Consortium.

Symptomatic pulmonary embolus after catheter removal in children with catheter related thrombosis: A report from the CHAT Consortium.

BACKGROUND: Appropriate timing of central venous catheter (CVC) removal, in relation to start of anticoagulation, in children after the diagnosis of a CVC-related thrombosis (CRT) is not well established. OBJECTIVES: This retrospective cohort study evaluated the incidence of symptomatic pulmonary embolism (PE) after CVC removal using data from the multi-institutional Children's Hospital-Acquired Thrombosis (CHAT) Consortium Registry. PATIENTS/METHODS: The CHAT Registry consists of data from children aged 0-21 years with a hospital-acquired venous thromboembolism. Eligible subjects were those with CRT diagnosed <3 days after CVC removal. Subjects were excluded if the CRT was due to a failed CVC insertion. Subjects were divided into three groups: those with CVC removal without anticoagulation, those with CVC removal <48 h after starting anticoagulation, and those with CVC removal ≥48 h after starting anticoagulation. RESULTS: A total of 687 CRT events from 663 subjects were included. A majority of CRT events were in subjects with peripherally inserted central catheters (62.3%, n = 428). For the 611 CRT events in which the CVC was removed, there was only one case of symptomatic PE (0.16%), which occurred <48 h after initiation of anticoagulation. CONCLUSIONS: While current guidelines suggest anticoagulation before CVC removal in the setting of a CRT to prevent embolization, CVC removal is not associated with symptomatic PE regardless of duration of anticoagulation before CVC removal.

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

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

Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report.

BACKGROUND: Emicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products. OBJECTIVE: To better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project. PATIENTS/METHODS: A retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55-79.8 years, on emicizumab a median 213 days; range, 51-1229 days) with hemophilia A (35.3% with past or current inhibitor). RESULTS: Adverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every-week or every-2-week dosing, but some had alternative dosing frequency. CONCLUSIONS: Real-world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.

International pediatric thrombosis network to advance pediatric thrombosis research: Communication from the ISTH SSC subcommittee on pediatric and neonatal thrombosis and hemostasis.

Pediatric thromboembolism is a rare and heterogenous disease. As a result, there is a paucity of knowledge with regard to natural history, management, and outcomes of most types of pediatric venous and arterial thromboembolism. International research collaboration is needed to fill these knowledge gaps. Not only randomized controlled trials, but also representative observational studies are required to answer all research questions. Therefore, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis initiated the International Pediatric Thrombosis Network (IPTN). The aims of the IPTN include (1) development of the Throm-PED registry to facilitate international prospective observational studies, and (2) establishment of a network of pediatric thrombosis centers experienced in effectively conducting clinical trials and observational studies. The IPTN needs dedicated clinicians all over the world and several funding sources to obtain high-quality research data to reach its ultimate goal of improving care in children with thrombosis. The aim of this communication is to call for active participation in the IPTN to all physicians taking care of children with thrombosis worldwide.

Improvements in Communication and Coordination of Care in a Hemophilia Treatment Center.

INTRODUCTION: In response to the increasing complexity of care for patients with bleeding disorders, we established new clinical teams for our hemophilia treatment center (HTC). AIMS: We undertook a quality improvement project to improve the coordination and communication with our patients by establishing primary assignments of clinical staff to individual patients (primary teams). METHODS: A quality improvement project group was formed that established the goals and assignment of primary teams. Patients were surveyed for their knowledge of their primary teams as well as their ability to schedule and contact their primary providers. As a measure of the effects on clinical staff, a balancing survey was also conducted among providers impacted by the clinical assignment of teams. RESULTS: Our results demonstrate improvements across both coordination and communication as reported by patients. Additionally, the assignment of primary teams was met with high satisfaction and improvement in coordination and communication as reported by the clinical staff members of the HTC. CONCLUSIONS: Initiation of a quality improvement project and the creation of a primary team system were feasible at a large HTC and resulted in improvements in both patient-reported and staff-reported outcomes of coordination and communication of care.

Optimizing language for effective communication of gene therapy concepts with hemophilia patients: a qualitative study.

BACKGROUND: For communities of people living with hemophilia and other genetic conditions, gene therapy could represent a paradigm shift in treatment strategies. As investigational therapeutic modalities such as gene therapy become more widely used and discussed, there is a critical need for all stakeholders to communicate using a lexicon that is intelligible, accurate, consistent, and representative of novel treatments. In doing so, expectations can be more carefully managed and potential risks, benefits, and limitations better understood. In recognition of this need, a first-ever study of gene therapy lexicon was conducted using established methods of market research and linguistic analysis. METHODS: Ninety-four participants representing hematologists, nurses, caregivers, and people with hemophilia A, in six countries (US, UK, Spain, Germany, France, Italy) took part in a series of in-depth interviews, face-to-face focus groups, an advisory board meeting, and online group interviews to develop, refine, and test verbal, written, and pictorial language concepts through a three-phase iterative process. Sessions were conducted in local languages using detailed discussion guides. Feedback from participants was captured using real-time instant-response dial testing to measure moment-by-moment emotional responses to language stimuli. Semiquantitative analysis of the responses informed selection of preferred language concepts for final testing, and qualitative discussion explored preference rationale. Participants also completed polling and forced rank and choice written exercises. RESULTS: Study feedback showed that the hemophilia community has preferences around consistent lexicon to describe hemophilia and its management. Expert linguistic analysis of feedback from the three phases enabled agreement of a consensus lexicon of vocabulary and an optimized summary narrative for talking about gene therapy amongst people affected by hemophilia A. Preferences were largely consistent across audiences and countries, although some country-specific recommendations were made. A representative summary phrase was agreed: "Gene therapy is being studied in clinical trials with the aim to allow the body to produce factor VIII protein on its own". CONCLUSIONS: The use of preferred language across different stakeholders increases understanding and comfort during discussions of novel and complex therapeutic modalities such as gene therapy. Consistent use of community-informed lexicon minimizes miscommunication and facilitates informed decision-making regarding potential future treatment opportunities.

Temporal and anatomic relationship between superficial and deep vein thromboses in hospitalized children.

BACKGROUND: Recent publications have increasingly demonstrated a link between superficial-vein thrombosis (SVT) and deep-vein thrombosis (DVT) in the adult population and have led to changes in SVT treatment considerations. A similar relationship between SVT and DVT in pediatric populations, however, is not currently well established. OBJECTIVES: We sought to evaluate the temporal and anatomic relationship between SVT and DVT among pediatric inpatients in order to determine to what degree SVT is associated with DVT. METHODS: We first retrospectively reviewed our institution's local prospective hospital-acquired VTE (HA-VTE) registry to identify all children (age 0-21 years, inclusive) admitted to Children's Hospital Colorado for more than 48 h between January 2012 and September 2017 who developed a DVT while hospitalized. We then reviewed each patient's electronic health record for evidence of SVT to identify SVT + DVT cases. Afterwards, we utilized a list of ICD codes to identify all patients during this time frame who developed an SVT and removed patients whom we previously identified as SVT + DVT cases to obtain the number of patients with isolated SVT. RESULTS: Of 59,910 patients admitted during the study period, 438 (0.7%) developed a thrombosis while hospitalized - 197 (0.3%) with isolated SVT, 161 (0.3%) with isolated DVT, and 80 (0.1%) with both SVT + DVT. These 80 SVT + DVT patients represent 33% of the 241 total DVT patients and 29% of the 277 total SVT patients. Of the 12 SVT + DVT patients in whom the SVT was diagnosed before the DVT, the subsequent DVT occurred within a mean of 6.4 (range 1-22) days and at the same anatomic site in 6 (50%). The age breakdown for this cohort was: 0 (0%) 0-1 months, 2 (17%) 1 month-2 years, 3 (25%) 2-12 years, 3 (25%) 12-16 years, and 4 (33%) 16-21 years. CONCLUSIONS: Our results indicate a temporal and anatomic relationship between SVT and DVT in hospitalized children, particularly those with central venous catheters.

Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel.

Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.