The eTHINK Study: Cognitive and Behavioral Outcomes in Children with Hemophilia.

OBJECTIVE: To assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care. STUDY DESIGN: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK) is a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1-21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible. Participants underwent neurologic examinations and age-appropriate neuropsychological assessments, including standardized tests/ratings scales of early development, cognition, emotional/behavioral adjustment, and adaptive skills. RESULTS: Five hundred and fifty-one males with hemophilia A (n = 433) or B (n = 101) were enrolled. Performance on cognitive tests was largely comparable with that of age-matched US population norms, although participants in certain age groups (4-5 and 10-21 years) performed worse on measures of attention and processing speed. Furthermore, adolescents and young adults and those with comorbid attention-deficit/hyperactivity disorder (ADHD; n = 64) reported more adaptive and executive function problems in daily life. Incidence of ADHD in adolescents (21%) was higher than expected in the general population. CONCLUSIONS: In general, males with hemophilia demonstrated age-appropriate intellectual, behavioral, and adaptive development. However, specific patient/age groups showed poorer attention performance and concerns for executive and adaptive development. This study established a normative data set for monitoring neurodevelopment in individuals with hemophilia and highlight the importance of screening and intervention for challenges with cognitive and adaptive skills in this population. CLINICAL TRIAL REGISTRATION: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK); NCT03660774; https://clinicaltrials.gov/ct2/show/NCT03660774.

Real-world experience of direct oral anticoagulant use in a single pediatric center.

BACKGROUND: Pediatric venous thromboembolism has increased by 130%-200%, specifically in hospitalized children, and direct oral anticoagulants (DOACs) offer several therapeutic advantages. METHODS: This study aims to evaluate the real-world epidemiological and outcome data from a retrospective review of pediatric patients treated with DOACs from January 1, 2013 to December 31, 2022. In this single-center, IRB-approved study, 65 patients were identified and analyzed using SPSS statistical software, and a descriptive statistical analysis was conducted. RESULTS: Of the 65 patients, 37% were on apixaban, 61.5% were on rivaroxaban, and 1.5% were on dabigatran. Per the 2023 ISTH outcome definitions, one (2%) patient had a major bleeding episode, six (9%) had clinically relevant non-major bleeding, three (5%) patients had patient-important heavy menstrual bleeding (HMB), and one (1.5%) patient had minor bleeding. Seven (19%) of 37 postmenarchal patients had evidence of HMB. Six (9.2%) patients had recurrent venous thromboembolism while on a DOAC (one was on apixaban, and five were on rivaroxaban) and were transitioned to other forms of anticoagulation. CONCLUSION: Thus, bleeding rates after DOAC therapy are comparable to previous DOAC trials, as well as other anticoagulants in pediatrics. HMB is an important outcome measure and should continue to be investigated. This study reports a higher rate of recurrent thrombosis (9.2%) compared to other trials. However, this observation may be attributed to patients who had ongoing risk factors, as well as a longer duration of study follow-up. Additional multicentered outcome studies evaluating DOAC use in children are needed to determine long-term recurrence and HMB risks.

Considerations for instituting pediatric pulmonary embolism response teams: A tool kit.

The incidence of pediatric pulmonary embolism (PE) has increased by 200 % in the last decade, but at a single center, it is still infrequent. Given the unique epidemiologic features of pediatric PE, diagnosis is often delayed, and the management is empiric, based on individual physician experience or preference. Thus, there is a strong need for center-specific uniform management of pediatric PE patients. In adults, the development of pulmonary embolism response teams (PERTs) or PE critical care pathways has shortened the time to diagnosis and the initiation of definitive management. Evidence to support an improvement in PE outcomes after the development of PERTs does not exist in children. Nonetheless, we have summarized the practical practice guidelines that physicians and institutions can adopt to establish their institutional PERTs or critical pathways. We also provide strategies for resource-challenged institutions for partnering with centers with expertise in the management of pediatric PE.

Unusual Presentation of Thrombotic Thrombocytopenic Purpura in a Newly Diagnosed Pediatric Patient With Systemic Lupus Erythematosus in the Setting of MIS-C.

The understanding of coronavirus disease 2019 (COVID-19) immune dysregulation is evolving. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with alternations in both innate and adaptive immunity, probably caused by a complex interplay of genetics and environmental exposure with various triggers. A rare hematological complication of SLE as well as recently reported in an adult with COVID-19 is thrombotic thrombocytopenic purpura. We report a pediatric case with features suggestive of the multisystem inflammatory syndrome in children with coronary artery ectasia, thrombotic thrombocytopenic purpura, and new-onset SLE.

Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial.

IMPORTANCE: All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL. OBJECTIVE: To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively. DESIGN, SETTING, AND PARTICIPANTS: The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/µL) and high-risk APL (white blood cell count ≥10 000/µL) cohorts. INTERVENTIONS: All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered. MAIN OUTCOMES AND MEASURES: Event-free survival (EFS) at 2 years after diagnosis. RESULTS: Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL). CONCLUSIONS AND RELEVANCE: In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02339740.

Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17-21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on-line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID-19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress.

Concomitant use of combined hormonal contraceptives and antifibrinolytic agents for the management of heavy menstrual bleeding: A practice pattern survey.

INTRODUCTION: Concomitant antifibrinolytic agents and combined hormonal contraceptives (CHC) have been anecdotally used to manage refractory heavy menstrual bleeding (HMB). Yet, there remains uncertainty among clinicians regarding the safety of this therapeutic option as concomitant CHC is listed as a contraindication to tranexamic acid use in the United States. AIM: To describe current treatment practices and physician-reported safety and effectiveness of concomitant antifibrinolytics and CHCs. METHODS: We surveyed clinician members of the Hemostasis and Thrombosis Research Society and the Foundation of Women and Girls with Blood Disorders using a web-based survey. We also shared the survey link on Twitter. RESULTS: Of the 224 respondents who completed the survey, 214 treated women of reproductive age with HMB. Of the 214 respondents, 138 (64%) had treated at least 1 woman with concomitant antifibrinolytic agents and CHCs in the past 12 months. Over half of these respondents (n = 77, 57%) reported that at least 50% of women had resolution of refractory HMB. One respondent reported an arterial or venous thrombotic event that occurred in 1 woman. CONCLUSION: We found that the use of concomitant CHCs and antifibrinolytic agent for refractory HMB is prevalent, appears to be efficacious and is relatively safe. Further research is warranted.

Management of anticoagulation associated reproductive tract bleeding in adolescent and young adult females - Results of a multinational survey.

INTRODUCTION: Reproductive tract bleeding (RTB) is an important outcome in menstruating females on anticoagulant therapy (AC). The diagnosis and management of AC-RTB in adolescent and young adult (AYA) females is unknown. AIMS: The aim of this study was to survey the contemporary patterns of diagnosis and management of AC-RTB in AYA females. METHODS: SurveyMonkey® questions were sent to members of 1) Pediatric and Neonatal Thrombosis Hemostasis Subcommittee and Women's Health Subcommittee of the International Society on Thrombosis and Haemostasis and 2) Hemostasis and Thrombosis Research Society. Results are reported using descriptive statistics. RESULTS: Response rate was 33% (251 out of 753). AC-RTB was infrequently reported. Menstrual history was not routinely reviewed prior to initiation of AC. Respondents indicated a differential risk of AC-RTB, most frequently with Rivaroxaban. Respondents continued hormonal therapy (HT) if an AYA female was on it at the start of AC. When AC-RTB occurred, management strategies were variable with initiation of HT or antifibrinolytic therapy being the most frequent. The timing of AC-RTB after the thrombotic event influenced the respondents' choice of therapy. Differences were seen in the management strategies between US and non-US participants, with more US respondents initiating HT while more non-US respondents modifying the AC regimen. Respondents uniformly reported complications with AC-RTB and with its treatment. CONCLUSION: This survey highlights the need to review menstrual history at the start of and during AC and for future research into choosing the optimal AC in AYA females. The results can inform the design of future studies.

Current challenges for men and women with mild-to-moderate haemophilia.

Current treatments in the field of haemophilia are changing the phenotype of many patients with severe haemophilia to that of mild haemophilia. Despite this improvement, those with mild-to-moderate haemophilia A and haemophilia B continue to experience unmet needs. Whereas some patients with mild-to-moderate haemophilia experience similar complications to those of patients with severe haemophilia, they possess several unique attributes. These include a challenging diagnosis and variability in bleeding symptoms and treatment needs. In addition, haemophilia is an under-recognized condition in women even though many women with mild-to-moderate haemophilia experience the same symptoms and complications as men with haemophilia. These women also have their own unique challenges with this disease. This supplement highlights many of the unmet needs in men and women with mild-to-moderate haemophilia. The conclusions of each of these papers reinforce the need for additional research and resources for this patient population.

ETV6 germline mutations cause HDAC3/NCOR2 mislocalization and upregulation of interferon response genes.

ETV6 is an ETS family transcription factor that plays a key role in hematopoiesis and megakaryocyte development. Our group and others have identified germline mutations in ETV6 resulting in autosomal dominant thrombocytopenia and predisposition to malignancy; however, molecular mechanisms defining the role of ETV6 in megakaryocyte development have not been well established. Using a combination of molecular, biochemical, and sequencing approaches in patient-derived PBMCs, we demonstrate abnormal cytoplasmic localization of ETV6 and the HDAC3/NCOR2 repressor complex that led to overexpression of HDAC3-regulated interferon response genes. This transcriptional dysregulation was also reflected in patient-derived platelet transcripts and drove aberrant proplatelet formation in megakaryocytes. Our results suggest that aberrant transcription may predispose patients with ETV6 mutations to bone marrow inflammation, dysplasia, and megakaryocyte dysfunction.

Bivalirudin during thrombolysis with catheter-directed tPA in a heparin-refractory patient: A case report.

Venous thromboembolism has increasing significance in hospitalized pediatric patients. Patients who have life-threatening or limb-threatening thrombotic events require thrombolysis in addition to anticoagulation. In patients who show signs of heparin resistance or heparin-induced thrombocytopenia, it is imperative to identify alternative therapeutic options. We present a child in whom bivalirudin was used for systemic anticoagulation during catheter-directed thrombolysis along with tissue plasminogen activator (Alteplase® ) for the treatment of a near-occlusive organ-threatening thrombus. We also review the currently available literature on the use of combination therapy of an intravenous direct thrombin inhibitor with alteplase.

Neuropsychological function in children with hemophilia: A review of the Hemophilia Growth and Development Study and introduction of the current eTHINK study.

Almost all of what is known about neurologic and cognitive development in hemophilia derives from the Hemophilia Growth and Development Study, conducted during an era when treatment regimens and comorbidities differed significantly from the current environment. Results suggested hemophilia and human immunodeficiency virus had independent effects, and hemophilia negatively impacts academic achievement, attention, and behavior. The introduction of prophylaxis treatment in hemophilia has created the need for re-evaluation of the effects of hemophilia on neurodevelopment and cognition. We outline the Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (NCT03660774) study, which aims to meet this need.

Thrombotic events with recombinant activated factor VII (rFVIIa) in approved indications are rare and associated with older age, cardiovascular disease, and concomitant use of activated prothrombin complex concentrates (aPCC).

PURPOSE: Recombinant activated factor VII (rFVIIa; NovoSeven® RT; Novo Nordisk A/S, Bagsvaerd, Denmark) is approved in the United States for the treatment of bleeding and perioperative management in congenital hemophilia with inhibitors (CHwI), acquired hemophilia (AH), congenital factor VII (FVII) deficiency, and Glanzmann's thrombasthenia (GT) with refractoriness to platelets. The aim of the current analysis was to review clinical trials and registries pre- and post-licensure for each indication to establish the estimated rate of thrombosis and then to establish the association of all reported thrombotic events (TEs) with certain risk factors listed for many years in the prescribing information (PI). PATIENTS AND METHODS: A retrospective safety assessment of both clinical trials and registries used to support licensure and postmarketing surveillance was performed. The rate of thrombosis was calculated in the 4 indicated disorders and an assessment of TE risk factors was conducted through a review of all narratives within those indications in the safety database. RESULTS: In clinical trials and registries used to support licensure and in postmarketing surveillance, the overall rate of thrombosis was 0.17% of 12,288 bleeding and surgical episodes. The specific risk by indication was 0.11% for CHwI, 0.82% for FVII deficiency, 0.19% for GT, and 1.77% for AH. The most common associated risk factor-"elderly" (29%), defined in the PI as age ≥65 years-was particularly prevalent in patients with AH. TE was also frequently reported with concomitant cardiac or vascular disease (18%) and use of activated prothrombin complex concentrates (18%). CONCLUSION: Data show that the rate of TEs within the 4 licensed indications is low, as was originally described in the US PI from 1999 to 2009. It has remained stable over time during postapproval surveillance in multiple US and global registries with active surveillance for safety information across the 4 approved indications.

Recombinant Von Willebrand factor concentrate in 2A Von Willebrand disease: comparison to plasma-derived Von Willebrand factor concentrate therapy.

: Type 2A sub-type of Von Willebrand disease (VWD) is characterized by the loss of high molecular weight multimers. Several plasma-derived Von Willebrand factor concentrates (PD-VWFC) are available for treatment and recently a recombinant VWF concentrate (rVWFC) has been approved for use in VWD for adults in the United States. We describe a patient with Type 2A VWD who had persistent refractory epistaxis despite treatment with PD-VWFC. We describe differences in VWF multimeric composition and Factor VIII (FVIII) levels after plasma-derived and rVWF concentrates. Despite similar VWF levels, VWF multimeric composition after PD-VWFC remained abnormal while it corrected with rVWFC. Post-PD-VWFC, high levels of FVIII were seen, which were not observed after rVWFC. Recombinant VWFC may offer some advantages over PD-VWFC. This finding needs to be confirmed in larger studies.

Risk Markers for Significant Bleeding and Thrombosis in Pediatric Acute Promyelocytic Leukemia; Report From the Children's Oncology Group Study AAML0631.

Acute promyelocytic leukemia (APL) is characterized by a heightened risk of coagulopathy with significant morbidity and mortality. Here we report our evaluation of presenting white blood cell (WBC) and the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scoring system as markers for early death and nonlethal coagulopathy in pediatric APL. We evaluated 79 pediatric patients treated on a Children's Oncology Group phase III clinical trial. There were 4 early deaths and 13 nonlethal, clinically significant (grade III to IV) coagulopathy events during induction. Elevated presenting WBC was significantly associated with early death but not with both lethal and nonlethal coagulopathy events. An ISTH DIC score of ≥5 (the original ISTH criteria for overt DIC) was not associated with either early deaths or coagulopathy events. An ISTH DIC score threshold of 6, however, was significantly associated with early death (12% score ≥6 vs. 0% score <6) and with both lethal and nonlethal coagulopathy events (35% score ≥6 vs. 11% score <6). In pediatric APL patients, the presenting WBC is a marker for risk of early death. Although the ISTH score using a cutoff of ≥6 showed improved correlation with adverse coagulation events during induction, the sensitivity was only 70.6% (95% confidence interval, 44.0%-89.7%) and the specificity was 64.5% (95% confidence interval, 51.3%-76.3%). Thus, there is a strong need to identify other biomarkers that can predict APL-associated coagulopathy.