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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., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: The National Hemophilia Foundation (NHF) conducted extensive, inclusive community consultations to guide prioritization of research in coming decades in alignment with its mission to find cures and address and prevent complications enabling people and families with blood disorders to thrive., Research Design and Methods: With the American Thrombosis and Hemostasis Network, NHF recruited multidisciplinary expert working groups (WG) to distill the community-identified priorities into concrete research questions and score their feasibility, impact, and risk. WG6 was charged with identifying the infrastructure, workforce development, and funding and resources to facilitate the prioritized research. Community input on conclusions was gathered at the NHF State of the Science Research Summit., Results: WG6 detailed a minimal research capacity infrastructure threshold, and opportunities to enable its attainment, for bleeding disorders centers to participate in prospective, multicenter national registries. They identified challenges and opportunities to recruit, retain, and train the diverse multidisciplinary care and research workforce required into the future. Innovative collaborative approaches to trial design, resource networking, and funding to surmount obstacles facing research in rare disorders were elucidated., Conclusions: The innovations in infrastructure, workforce development, and resources and funding proposed herein may contribute to facilitating a National Research Blueprint for Inherited Bleeding Disorders.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2021 International Society on Thrombosis and Haemostasis.)

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., Competing Interests: Dr. Jaffray received grant funding for this study from the National Institutes of Health (NIH) from the National Center for Advancing Translational Science (grant number UL1TR001855), the Children’s Hospital Saban Research Mentored Career Development Award, and The Hemostasis and Thrombosis Research Society Mentored Research Award, supported by an independent educational grant from Takeda Pharmaceuticals U.S.A. Dr. Mahajerin received grant funding from to The Hemostasis and Thrombosis Research Society Mentored Research Award and CHOC Children’s Hospital and University of California Irvine Physician-Scientist Research Award program. Dr. Goldenberg receives salary and research support from NIH National Heart, Lung, and Blood Institute (NHLBI) via a U01 award. Drs. Jaffray, Branchford, and Goldenberg received support for article research from the NIH. Dr. Branchford received funding from Kedrion, Bioproducts Lab, Biomarin, Shire, Innovative Biopharma, Advio, Bayer, and Octapharma. Drs. Branchford and Goldenberg received support for article research from the NHLBI. Dr. Silvey received funding from Genetech and Bayer. Dr. Amankwah received funding from Bristol Myers Squibb and Pfizer. Dr. Goldenberg received funding from the NIH, the NHLBI, Daiici Sankyo, Anthos Therapeutics, and the Academic Research Organization CPC Clinical Research. The remaining authors have disclosed that they do not have any potential conflicts of interest. Funding sources did not have a role in study design, data analysis, writing, or submission of the manuscript. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Pediatric hospital-acquired venous thromboembolism (HA-VTE) rates have increased dramatically. To achieve generalizable knowledge in the derivation and validation of HA-VTE risk factors and risk prediction models and inform future risk-stratified prevention strategies, multi-institutional studies are needed., Objectives: This paper presents an investigator-initiated, multicenter pediatric case-cohort study designed to identify risk factors for HA-VTE to create a HA-VTE risk prediction model., Methods: A registry, which houses pertinent variables from HA-VTE subjects and non-HA-VTE controls, was created for the Children's Hospital-Acquired Thrombosis (CHAT) study. Specific variables from the registry associated with HA-VTE risk will be identified using multivariable regression to create a pediatric HA-VTE risk prediction model to be prospectively validated., Results: Seven large pediatric institutions have entered over 600 HA-VTE subjects aged 0-21years of age into the registry. Subjects showed a male predominance (57%), a median age of three years (IQR 0.3-13) and were most likely admitted to an intensive care unit (57%) at VTE diagnosis. Median time to HA-VTE was 10days after admission. The most prevalent risk factors include central venous catheters (80%), surgery (43%), systemic steroids (31%), congenital heart disease (27%), infection (14%) and cancer (13%)., Conclusions: CHAT, with its creation of a risk prediction model with prospective validation using the CHAT registry, is a novel study design and will be the first step in identifying safe and effective strategies to decrease HA-VTE in children by helping define the highest risk population for initial, or more aggressive, thromboprophylaxis efforts., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Venous thromboembolism is occurring with increasing frequency in children resulting in the more widespread use of anticoagulation in pediatrics. Antithrombotic drugs in children can be divided into the standard and alternative agents. This review discusses standard and alternative anticoagulants. Because standard anticoagulants have significant limitations, including variable pharmacokinetics, issues with therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects, it is expected that the use of alternative anticoagulants will increase over time. With their improved properties and recent prospective clinical trial data, the current and future use of these agents will likely slowly replace of the standard anticoagulants., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Thrombotic complications are increasing at a steady and significant rate in children resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the standard agents (heparin, low molecular weight heparin, and vitamin K antagonists) and alternative agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the standard and alternative anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. Clearly, the standard anticoagulants all have significant shortcomings including variable pharmacokinetics, issues with therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The alternative anticoagulants have properties which overcome these shortcomings and prospective clinical trial data are presented supporting the current and future use of these agents in place of the standard anticoagulants., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Thrombotic complications are increasing at a steady and significant rate in children, resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the older multitargeted agents (heparin, low-molecular-weight heparin, and warfarin) and the newer targeted agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the multitargeted and targeted anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. The various agents differ in their pharmacokinetics, requirements for therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The targeted anticoagulants have properties that may make them more attractive for use in specific clinical situations. Prospective clinical trial data are presented supporting the current and future use of these agents in children., (© 2015 by The American Society of Hematology. All rights reserved.)

Introduction: The thromboelastograph is a point-of-care, global hemostasis assay that measures the dynamics of clot formation, including physical properties, over time and is licensed for use in monitoring coagulation during complex surgical procedures. It has more recently been used as a research tool to investigate various bleeding and clotting disorders. Although attempts have been made to use thromboelastography to detect hypercoagulable states, thus far a consistent, reliable approach has not been discovered. The objective of this study was to develop a novel approach utilizing thromboelastography that is sensitive for detecting hypercoagulability., Materials and Methods: Healthy, adult volunteers provided blood samples that were subjected to pre-analytic modifications from standard thromboelastography methods with the goal of prolonging clot initiation and propagation times. The methods which resulted in the desired changes in a consistent and reliable manner utilized corn trypsin inhibitor, a contact pathway inhibitor, on unactivated blood samples. To demonstrate that these methods are sensitive to detecting hypercoagulability, increasing concentrations of recombinant human thrombin were added as a surrogate for hypercoagulability., Results: Our methods were able to consistently and statistically significantly change the baseline TEG parameters of R time, K time, and angle in the desired fashion. Additionally, these methods were able to detect increasing concentrations of thrombin., Conclusions: We describe a novel approach in which thromboelastography is highly sensitive to detecting increasing concentrations of thrombin in vitro. Further studies are underway to determine if these methods will be sensitive for detecting hypercoagulable states in vivo., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Pediatric physicians regularly face the problem of uncertain procedural anticoagulation in children, especially in neonates. We sought to evaluate the safety, plasma concentration (pharmacokinetics, PK), pharmacodynamics (PD), and dosing guidelines of bivalirudin when used as a procedural anticoagulant in pediatric percutaneous intravascular procedures., Methods and Results: Pediatric subjects undergoing percutaneous intravascular procedures for congenital heart disease were enrolled and received the current weight-based dose used in percutaneous coronary interventions (0.75 mg/kg bolus, 1.75 mg/kg/hr infusion). Blood samples for PK/PD analyses were drawn, and safety was evaluated by monitoring bleeding and thrombosis events. A total of 110 patients (11 neonates, 33 infants, 32 young children, and 34 older children) were enrolled; 106 patients received the protocol dose. The PK/PD response of bivalirudin was predictable and behaved in a manner similar to that in adults. Weight-normalized bivalirudin clearance rates were more rapid in neonates and decreased with increasing age. Bivalirudin concentrations were slightly lower in neonates, with a trend to an increase with age. Activating clotting time response was consistent with adult studies and prolonged in all age groups, and there was reasonable correlation between activating clotting time and bivalirudin plasma concentrations across all age groups. There were few major bleeding (2 of 110, 1.8%) or thrombotic events (9 of 110, 8.2%) reported., Conclusions: PK/PD response of bivalirudin in the pediatric population is predictable and behaves in a manner similar to that in adults. Using adult dosing, bivalirudin safely provided the expected anticoagulant effect in the pediatric population undergoing intravascular procedures for congenital heart disease., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Thromboembolism in children is typically treated with unfractionated heparin (UH) or low molecular weight heparin (LMWH). Both rely on antithrombin (AT) for their action. In addition, heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin use in children. Bivalirudin or other direct thrombin inhibitors may be a useful alternative to heparins in treating thrombosis in children., Procedure: We report a retrospective review to assess the efficacy and safety of bivalirudin in pediatric patients with thrombosis., Results: Sixteen children received bivalirudin for thrombosis or prevention of thrombosis at the Children's Hospital of Illinois from January 2005 to January 2007. Patients received a bolus dose of 0.25 mg/kg followed by a continuous infusion (0.16 +/- 0.07 mg kg(-1) hr(-1)) titrated to 1.5-2.5 times the baseline activated partial thromboplastin time (aPTT). Positive correlation between the bivalirudin average infusion rate and aPTT was observed in twelve patients. Ultrasonographic evidence of thrombus regression was noted at 72 hr in 10 of 10 patients. One patient experienced hematuria after catheterization of the urethra., Conclusion: Bivalirudin was effective and well-tolerated in these patients. Further studies should be conducted to better define safety and efficacy of bivalirudin in pediatric patients.

Thrombosis is an increasingly recognized complication occurring primarily in children with serious underlying conditions and most often associated with intravenous catheters. There are few clinical trials available to guide the decision-making in the diagnosis and treatment of thrombosis. Although there are published guidelines which suggest how to manage such patients, they are based on data from adult studies and uncontrolled pediatric studies and it is unclear how widely these guidelines are utilized in clinical practice. What is clear is that many additional studies are needed to provide the data required to make evidence-based decisions. Nevertheless, patients today are being diagnosed with thrombosis and must be treated. Diagnosis is based largely on various diagnostic-imaging methods. While Doppler ultrasonography is non-invasive and relatively inexpensive, its sensitivity for the upper venous system is poor. Venography/angiography, the most sensitive method to diagnose venous/arterial thrombosis is underutilized due to the need for peripheral venous access for venography and arterial catheterization for angiography as well as interventional radiology. Newer methods such as computed tomography and magnetic resonance imaging are useful for large vessel disease but are not validated in pediatrics. Treatment is based on the methods that are best at restoring circulation rapidly balanced by the risk for bleeding. Both thrombolysis and anticoagulation can be utilized with the circumstances of each individual patient dictating the choice. The field of pediatric thrombosis continues to advance with numerous new studies currently underway or being planned. In the near future, the results of these studies will allow for better management of pediatric patients with thrombosis.

IntroductionAcute lymphoblastic leukemia (ALL) therapy confers risk for venous thromboembolism (VTE) and associated acute and long-term morbidity. Obesity increases VTE risk in the general population but its impact on ALL therapy-associated VTE is unknown.MethodsIn a retrospective cohort of children treated for ALL between 2008 and 2016 (n = 294), we analyzed obesity at diagnosis (body mass index [BMI] ≥95%) and subsequent development of VTE. A subset participated in two concurrent prospective ALL trials studying body composition via dual-energy X-ray absorptiometry (DXA) (n = 35) and hypercoagulability via thromboelastography (TEG) (n = 46). Secondary analyses explored whether precise measurement of body fat and/or global hemostasis ex vivo by TEG could further delineate VTE risk in the obese.ResultsOverall, we found 27/294 (9.2%) patients developed symptomatic VTE during therapy, 19/27 (70%) occurred during Induction. Study-defined "serious" VTE developed in 4/294 (1.4%) of patients. Obesity but not overweight was strongly predictive of symptomatic VTE (obesity odds ratio = 3.8, 95% confidence interval 1.5-9.6, p = 0.008). In the DXA subset, only 2/35 patients developed symptomatic VTE. However, within those prospectively screened during Induction, 30% (14/46) developed VTE; eight (17%) of these were asymptomatic and found only via screening.ConclusionsIn this pediatric ALL cohort, obesity conferred more than a three-fold increased risk for symptomatic VTE. In a subgroup of patients who underwent active screening, up to a third were noted to have VTE (symptomatic and asymptomatic). TEG did not predict VTE. Additional studies are necessary to validate these findings and to further refine a risk-stratified approach to thrombo-prevention during ALL therapy.

Introduction: Emicizumab is a humanized bispecific monoclonal antibody licensed for patients with severe haemophilia A. Breakthrough bleeding still occurs in patients on emicizumab and can be managed with recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC). Thrombotic events were reported when patients on emicizumab received concomitant aPCC at relatively high doses. We studied the effect of infusing various doses of aPCC to patients on emicizumab. Material and methods: Nine patients with severe haemophilia A with inhibitors who are on emicizumab were recruited to participate. Patients were infused with varying doses of aPCC in vivo. Samples were tested with thrombin generation (TG) assay. Results: In the current in vivo arm of the study four out of nine patients reached the highest dose, 75 U/kg of aPCC and six out of nine patients were actually eligible for the highest dose. In the previous in vitro arm of the study seven out of eight patients reached the normal plasma with spiking aPCC at a very low concentration equivalent to 5 U/kg. Conclusion: The in vitro portion of the study demonstrated that clinically relevant concentrations of aPCC resulted in excessive TG, however, in vivo administration of aPCC to the same patients demonstrated that most of the patients had normal TG at the approved doses of aPCC. In the management of breakthrough bleeding clinicians should heed the boxed warning for concomitant use of emicizumab and aPCC, however, should also be aware that low doses of aPCC may not result in sufficient TG. [ABSTRACT FROM AUTHOR]

Deficiency of antithrombin ( AT), protein C ( PC) or protein S ( PS) constitutes a major risk factor for venous thromboembolism ( VTE). Individuals at high risk for recurrence who benefit from screening need to be identified. The primary study objective was to determine the individual recurrence risk among children with a first non-central-venous-catheter-associated VTE with respect to their thrombophilia status and to evaluate if the clinical presentation at first VTE onset differs between children with AT, PC or PS deficiency versus no thrombophilia. We calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia, age, sex and positive family VTE history in 161 consecutively enrolled paediatric VTE patients. The presence of a deficiency relative to no thrombophilia was evaluated as a potential predictor of recurrence. Predictors for recurrence were AT deficiency (hazard ratio/95% CI: 6·5/2·46-17·2) and female gender (2·6/1·1-6·35). The annual recurrence rates (95% CIs) were 5·4% (2·6-10) in AT-deficient children, 1·3% (0·3-3·8) in patients with PC deficiency, 0·7% (0·08-2·4) in the PS-deficient cohort and 0·9% (0·4-1·8) in patients with no thrombophilia. Positive family VTE history or combined thrombophilias did not predict recurrence. Given the overall annual incidence rate of recurrence of 1·5% we suggest screening for AT deficiency in children with VTE. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The recent proliferation of deep vein thrombosis in children has been attributed to the increased use of central venous catheters, specifically tunneled lines and peripherally inserted central catheters. A formal comparison of the incidence rate for deep vein thrombosis between tunneled lines and peripherally inserted central catheters has not been undertaken. Methods: Children <18years of age who were admitted to Children’s Hospital Los Angeles from July, 2005 to July, 2012 were eligible for inclusion. Data were extracted from the hospital discharge database which includes data on all procedures and up to 20 diagnoses per admission. Diagnoses and procedures were identified by International Classification of Disease, Ninth Revision coding. Patients were excluded if they received more than one central line. Data collected included type of central line, deep vein thrombosis event, and underlying medical illnesses classified according to chronic complex conditions. Results: Over the seven year study period there was an overall rate of 73 deep vein thromboses per 10,000 hospital discharges. Of the 6915 eligible subjects, 181 had a deep vein thrombosis for an overall incidence rate of 2.6%. There were 152 thrombi (2.6%) in subjects with peripherally inserted central catheters and 29 thrombi (3.1%) in subjects with tunneled lines [OR=.83 (0.55, 1.29), p=0.38]. Conclusion: Despite the relative ease and simplicity of use of peripherally inserted central catheters leading to a substantial rise in their use, this study demonstrates that such lines pose a substantial risk for venous thrombosis and no difference in incidence was detected between such lines and tunneled lines. [Copyright &y& Elsevier]

Background: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.Methods: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.Results: A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.Conclusions: Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .). [ABSTRACT FROM AUTHOR]