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Robert F Sidonio Jr,1 Ayesha Zia,2 Dana Fallaize3 1Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA; 2Division of Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3Department of Life Sciences, Charles River Associates, Boston, MA, USACorrespondence: Robert F Sidonio JrAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, 1760 Haygood Drive, HSRB W340, Atlanta, GA 30322, USATel +1 404 785 1637Email robert.sidonio@choa.orgIntroduction: Von Willebrand disease (VWD) is a common inherited bleeding disorder, but awareness among health care professionals is low. We estimated the number of cases of undiagnosed VWD or other mucocutaneous bleeding disorders among commercially insured patients in the United States with a recent history of bleeding events.Methods: Patients with a VWD diagnosis who were users of or candidates for von Willebrand factor replacement were identified from the IMS PharMetrics Plus Database (2006–2015). We constructed a unary patient-finding model based on 12 prediagnosis variables that best defined this population, and applied this to undiagnosed patients with recent bleeding events from the same database. Cases of symptomatic undiagnosed VWD or other mucocutaneous bleeding disorders in the commercially insured population were estimated from the “best fit” (positive predictive value [PPV] 83%) and “good fit” (PPV 75%) patients thus identified.Results: Overall, 507,668 undiagnosed patients with recent bleeding events were identified (86% female, 14% male). Application of the VWD model identified 3318 best-fit and 37,163 good-fit patients; 91% of best-fit patients were females aged Discussion: Computer modeling suggests there may be a significant number of patients with symptomatic, undiagnosed VWD or other mucocutaneous bleeding disorder in the commercially insured population. Enhanced awareness of VWD symptoms and their impact, and of screening and testing procedures, may improve the diagnosis of VWD and reduce disease burden.Keywords: medical insurance claims, delayed diagnosis, von Willebrand disease

Background: The Kids-DOTT multinational randomized clinical trial (RCT) revealed non-inferiority of a six-week versus three-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old, in regard to net clinical benefit at one year., Objective: To evaluate non-inferiority at two years., Patients/methods: Patients whose repeat imaging six weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation versus receive a total three-month course and followed for two years for the occurrence of symptomatic recurrent (SR-) VTE (efficacy outcome) and clinically-relevant bleeding (CRB, safety outcome). Outcomes were centrally adjudicated and net clinical benefit was compared between treatment arms via a pre-specified bivariate non-inferiority boundary, using 95% confidence intervals (CIs) in absolute risk differences (ARDs) between treatment arms., Results: Kaplan-Meier estimates of two-year cumulative incidences in the six-week and three-months arms of the intention-to-treat (ITT) population (n=417) were 1.7% (95% CI: 0%, 3.7%) and 2.9% (95% CI: 0.3%, 5.4%) for SR-VTE and 1.1% (95% CI: 0%, 2.5%) and 3.2% (95% CI: 0.6%, 5.7%) for CRB. Bivariate analysis of the ARDs in the ITT population demonstrated that a six-week anticoagulation duration was non-inferior to a three-month course., Conclusions: These findings support durability of the Kids-DOTT RCT findings of net clinical benefit at two years., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting about 0.6% to 1.3% of the population, and is characterized primarily by mucocutaneous bleeding secondary to defective platelet adhesion and aggregation. Current therapeutic options for those with severe disease are limited and require frequent intravenous infusions., Areas Covered: This review discusses the current and recently completed clinical trials involving pathways to FVIII augmentation for the treatment of VWD. Clinical trials registered on clinicaltrials.gov and published data via PubMed searches through June 2024 were included., Expert Opinion: Available treatment options to those with VWD are limited in part due to limited clinical trials, the complexity of VWD types, and the pharmacokinetics of current treatment options. The development of therapeutic options that reduce treatment burden is necessary to improve quality of life and reduce bleeding complications and in recent years there has been an increased interest from industry to apply novel therapeutics for VWD. The FVIII mimetic, emicizumab, has demonstrated early success in patients with severe VWD and is a promising treatment option for those who require prophylaxis. Furthermore, products like efanesoctocog alfa (Altuviiio®) and BT200 have achieved enhanced VWF/FVIII half-life extension could expand the current treatment landscape while concurrently minimizing treatment burden.

Background: The activity of von Willebrand factor (VWF) in facilitating platelet adhesion and aggregation correlates with its multimer size. Traditional ristocetin-dependent functional assays lack sensitivity to multimer sizes. Recently, nanobodies targeting the autoinhibitory module and activating VWF were identified., Objectives: To develop an assay that can differentiate the platelet-binding activity of VWF multimers., Methods: A novel enzyme-linked immunosorbent assay (nanobody-triggered glycoprotein Ib binding assay [VWF:GPIbNab]) utilizing a VWF-activating nanobody was developed. Recombinant VWF, plasma-derived VWF (pdVWF), and selected gel-filtrated fractions of pdVWF were evaluated for VWF antigen and activity levels. A linear regression model was developed to estimate the specific activity of VWF multimers., Results: Of the 3 activating nanobodies tested, 6C11 with the lowest activation effect exhibited the highest sensitivity for high-molecular-weight multimers (HMWMs) of VWF. VWF:GPIbNab utilizing 6C11 (VWF:GPIbNab 6C11 ) produced significantly higher activity/antigen ratios for recombinant VWF (>2.0) and HMWM-enriched pdVWF fractions (>2.0) than for pdVWF (∼1.0) or fractions enriched with shorter multimers (<1.0). The differences were much larger than those produced by VWF:GPIbNab utilizing other nanobodies, VWF:GPIbM, VWF:GPIbR, or VWF:CB assays. Linear regression analysis of 5 pdVWF fractions of various multimer sizes produced an estimated specific activity of 2.7 for HMWMs. The analysis attributed >90% of the VWF activity measured by VWF:GPIbNab 6C11 to that of HMWMs, which is significantly higher than all other activity assays tested., Conclusion: The VWF:GPIbNab 6C11 assay exhibits higher sensitivity to HMWMs than ristocetin-based and collagen-binding assays. Future studies examining the application of this assay in clinical settings and any associated therapeutic benefit of doing so are warranted., Competing Interests: Declaration of competing interests R.L. and Q.L. are coinventors on a pending patent describing applications of nanobodies to measure the von Willebrand factor activity. The other coauthors declare no conflicts of interest., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Von Willebrand disease (VWD) is underdiagnosed, often delaying treatment. VWD claims coding is limited and includes no severity qualifiers; improved identification methods for VWD are needed. The aim of this study is to identify and characterize undiagnosed symptomatic persons with VWD in the US from medical insurance claims using predictive machine learning (ML) models., Research Design and Methods: Diagnosed and potentially undiagnosed VWD cohorts were defined using Komodo longitudinal US claims data (January 2015-March 2020). ML models were built using key characteristics predictive of VWD diagnosis from the diagnosed cohort. Two ML models predicted VWD diagnosis with the highest accuracy in females (random forest; 84%) and males (gradient boosting machine; 85%). Undiagnosed persons suspected to have VWD were identified using an 80% cutoff probability; profiles of key characteristics were constructed., Results: The trained ML models were applied to the undiagnosed cohort (28,463 females; 20,439 males) with suspected VWD. Fifty-two percent of undiagnosed females had heavy menstrual bleeding, a key pre-diagnosis symptom. Undiagnosed males tended to have more frequent medical procedures, hospitalizations, and emergency room visits compared with undiagnosed females., Conclusions: ML algorithms successfully identified potentially undiagnosed symptomatic people with VWD, although many may remain undiagnosed and undertreated. External validation of the algorithms is recommended.

Heavy menstrual bleeding (HMB) is often the presenting symptom for females with inherited bleeding disorders (IBD). Multidisciplinary clinics leverage the expertise of hematologists and women's health specialists. This study characterizes the complexity of HMB management for adolescents with IBDs from a large multidisciplinary clinic. Adolescents often required multiple different menstrual suppression treatments, with only about 20% achieving acceptable suppression with their first treatment. Adolescents switched therapy most often for uncontrolled bleeding, followed by adverse effects, and patient preference. Given the difficulty in achieving adequate menstrual suppression, multidisciplinary clinics offer necessary expertise in accomplishing bleeding control with minimal adverse effects., (© 2024 Wiley Periodicals LLC.)

People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq ® ) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null F8 mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa., Competing Interests: AK has received speakers fees from CSL-Behring, Novo Nordisk, and Takeda and support for attending scientific meetings from Roche and Takeda. RFS has acted as a consultant and/or received research funding from the following companies: Bayer, Biomarin, Bioverativ, Genentech, Grifols, Hema Biologics, Kedrion, Novo Nordisk, Octapharma, Pfizer, Shire, and UniQure. GY has received consulting fees from ApcinteX, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, and Takeda and has received funds for research support from Genentech/Roche, Grifols, and Takeda. MEM has acted as a paid consultant/advisor/speaker for Bayer, Biomarin, CSL-Behring, Grifols, Kedrion, LFB, Octapharma, Novo Nordisk, Pfizer, Roche, Sanofi, Swedish Orphan Biovitrum, Takeda, Spark Therapeutics, and UniQure. MTÁ-R has received honoraria for speaking and consulting and funds for research from Amgen, Bayer, CSL-Behring, Grifols, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Swedish Orphan Biovitrum, and Takeda. NB has no conflicts of interest to declare. MJ is a full-time employee of Pharmazeutika Produktionsges m.b.H., Vienna, Austria. SK is an employee of Octapharma AG, Lachen, Switzerland., (© The Author(s), 2024.)

Abstract: Activation of von Willebrand factor (VWF) is a tightly controlled process governed primarily by local elements around its A1 domain. Recent studies suggest that the O-glycosylated sequences flanking the A1 domain constitute a discontinuous and force-sensitive autoinhibitory module (AIM), although its extent and conformation remains controversial. Here, we used a targeted screening strategy to identify 2 groups of nanobodies. One group, represented by clone 6D12, is conformation insensitive and binds the N-terminal AIM (NAIM) sequence that is distal from A1; 6D12 activates human VWF and induces aggregation of platelet-rich plasma at submicromolar concentrations. The other group, represented by clones Nd4 and Nd6, is conformation sensitive and targets the C-terminal AIM (CAIM). Nd4 and Nd6 inhibit ristocetin-induced platelet aggregation and reduce VWF-mediated platelet adhesion under flow. A crystal structure of Nd6 in complex with AIM-A1 shows a novel conformation of both CAIM and NAIM that are primed to interact, providing a model of steric hindrance stabilized by the AIM as the mechanism for regulating GPIbα binding to VWF. Hydrogen-deuterium exchange mass spectrometry analysis shows that binding of 6D12 induces the exposure of the GPIbα-binding site in the A1 domain, but binding of inhibitory nanobodies reduces it. Overall, these results suggest that the distal portion of NAIM is involved in specific interactions with CAIM, and binding of nanobodies to the AIM could either disrupt its conformation to activate VWF or stabilize its conformation to upkeep VWF autoinhibition. These reported nanobodies could facilitate future studies of VWF functions and related pathologies., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Despite rapid technological advancement in factor and nonfactor products in the prevention and treatment of bleeding in haemophilia patients, it is imperative that we acknowledge gaps in our understanding of how hemostasis is achieved. The authors will briefly review three unresolved issues in persons with haemophilia (PwH) focusing on the forgotten function that red blood cells play in hemostasis, the critical role of extravascular (outside circulation) FIX in hemostasis in the context of unmodified and extended half-life FIX products and finally on the role that skeletal muscle myosin plays in prothrombinase assembly and subsequent thrombin generation that could mitigate breakthrough muscle hematomas., (© 2024 John Wiley & Sons Ltd.)

Abstract: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: In patients with mild type 1 von Willebrand disease (VWD), treatment guidelines suggest individualization of surgical management. However, these conditional recommendations are based on very low-certainty evidence due to limited data on surgical outcomes in this population., Objectives: To characterize procedural bleeding prophylaxis strategies and outcomes in children with mild type 1 VWD., Methods: This is a retrospective cohort study that included patients aged between 0 and 21 years with mild type 1 VWD (defined as von Willebrand factor antigen and/or an activity of 30-50 IU/dL) who underwent a procedure from July 1, 2017, to July 1, 2022. Demographic, surgical, medication, and bleeding data were collected by manual chart review., Results: A total of 161 procedures were performed in 108 patients. The population was primarily female (75%), White (77.8%), and non-Hispanic (79.6%). Median age was 15.8 years (IQR, 8.2-17.6). Fifty-nine surgeries were classified as major, 66 as minor, and 36 as dental. For most procedures, patients received only antifibrinolytics for bleeding prophylaxis ( n  = 128, 79.5%); desmopressin was used in 17 (10.6%) procedures, and von Willebrand factor concentrate was used in 12 (7.5%) procedures. Bleeding complications occurred in 8 (5.0%) procedures: these included 1 major, 4 clinically relevant nonmajor, and 3 minor bleeding events. No patient required blood transfusion or an additional procedure to achieve hemostasis. Most bleeding complications were seen following intrauterine device (IUD) placement (5/8). Nearly 30% of patients who underwent IUD placement reported bleeding., Conclusion: Pediatric patients with mild type 1 VWD can safely undergo procedures using a tailored approach. Bleeding complications were uncommon, with the majority following IUD placement., (© 2024 The Authors.)

Background: Sickle cell disease (SCD) is associated with hypercoagulability, but adults with SCD also have an increased incidence of bleeding including heavy menstrual bleeding (HMB). HMB is common among adolescent females, but the impact of HMB in pediatric SCD is unclear. The objectives of this study were to examine menstrual health status, knowledge, and quality of life (QOL)., Methods: We performed a single-institutional multi-clinic cross-sectional study comprised of a five-part survey in pediatric participants with SCD. The survey included the validated Menstrual Bleeding Questionnaire (MBQ) and Self-administered Bleeding Assessment Tool (Self-BAT)., Results: Forty-eight participants with a median age of 16 years (range: 12-21 years) completed the study. The mean age at onset of menarche was 13 ± 1.3 years. On the MBQ, 29% reported heavy/very heavy menstrual flow, 61% reported moderate or severe dysmenorrhea, and 96% had menses lasting less than 1 week. The Self-BAT revealed that 42% of participants reported a history of HMB. Participants with severe dysmenorrhea or HMB had higher MBQ scores, corresponding to worse QOL. Despite this, less than 20% of participants had attempted any hormonal therapy for menstrual regulation. The odds of hormonal therapy utilization were comparable among participants on hydroxyurea versus not on hydroxyurea (odds ratio 1.58, 95% confidence interval [CI]: 0.33-7.56)., Conclusions: The prevalence of HMB and dysmenorrhea is high among adolescents and young women with SCD. Strategies that incorporate menstrual health assessment into routine medical care in this population would help address this important area of pediatric health., (© 2023 Wiley Periodicals LLC.)

Introduction: Recent guidelines for von Willebrand Disease (VWD) highlighted the challenges in diagnosis and management. Identifying the number of persons with VWD (PwVWD) internationally will help target support to aid diagnosis of PwVWD., Aim: To examine international registration rates of PwVWD, the influence of income status, geographical region and the age and sex profile. Cumulatively, these data will be used to inform future strategy from the World Federation of Haemophilia (WFH) to address unmet clinical and research needs., Methods: Data from the 2018/2019 WFH Annual Global Survey (AGS) were analysed, providing a global perspective on VWD registration., Results: Registration rates are lowest in South Asia (0.6/million population) and highest in Europe/Central Asia (50.9/million population, 0.005%), but below the expected prevalence rate (0.1%). National economic status impacted VWD registration rates, reflecting variation in access to optimal healthcare infrastructure. Females represented the majority of PwVWD globally, however, in low-income countries (LIC) males predominated. Age profile varied, with markedly higher rates of paediatric registrations in North America, Middle East and North Africa and South Asia. Rates of type 3 VWD registrations were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings., Conclusion: Significant variation in registration rates of PwVWD exist internationally and is influenced by income status and the presence of HTC networks. Improved understanding of registration rates will enable targeting of advocacy to improve awareness, diagnosis and support for PwVWD internationally., Key Points: Registration rates of People with Von Willebrand Disease (PwVWD) vary internationally and are influenced by national income status Although females represent the majority of PwVWD globally, in low income countries (LIC) males predominated, possibly related to stigma surrounding gynaecological bleeding. Rates of type 3 VWD registration were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Aim: To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA)., Methods: This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time., Results: Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0-5.0) for patients receiving prophylaxis and 3.2 (1.6-6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as 'excellent' or 'good' after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development., Conclusion: This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA., Trial Registration: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).

The United States Supreme Court's ruling to overturn Roe v. Wade has potential grave implications, impacting access to reproductive healthcare for women across the country. Similarly, women and adolescent girls with bleeding disorders need access to high-quality reproductive health care because there is a significant risk of bleeding complications in these patients. Treatment decisions need to be made by patients and treating physicians and not as a consequence of political ideology. Women including those with bleeding disorders should be given the autonomy to make their own reproductive health decisions., Competing Interests: Declaration of competing interests D.C.S.: None. R.S.: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Sobi: Consultancy; Catalyst: Consultancy; Biomarin: Consultancy; Novo Nordisk: Consultancy; Genentech: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; Bayer: Consultancy; Pfizer: Consultancy; Grifols: Consultancy, Research Funding; Kedrion: Consultancy; HEMA Biologics: Consultancy. S.A.: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; ClotChip: Patents & Royalties; TraumaChek: Patents & Royalties; State of Ohio Rare Disease Advisory Council: Membership on an entity's Board of Directors or advisory committees., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objective: We assessed sociodemographic and clinical characteristics associated with depression and anxiety in individuals with Von Willebrand disease (VWD) aged ≥12 years., Methods: The study collected data on patients' sociodemographic, joint problems and health-related quality of life (HRQoL) using EQ-5D-3L, 8-item patient health questionnaire for depression and 7-item Generalized Anxiety Disorder Questionnaire from participants in seven geographically diverse US haemophilia treatment centres., Results: Analyses included 77 participants. The rates of depression and anxiety were 63.6% and 58.3%, respectively. Persons with low VWF displayed higher rates of depression (86.7%) or anxiety (69.2%) compared to those with VWD (58.1%, p = .04 for depression, and 55.9%, p = .38 for anxiety). Logistic regression analyses demonstrated that having joint problems (odds ratio [OR] = 6.3, confidence interval [CI] = 2.0-20.1) was the most important variable associated with depression, followed by being single, divorced, widowed, or separated in adult participants or parents of participants age < 18 years (OR = 7.0, CI = 1.7-29.0. The most important variable associated with anxiety was being single or lacking a partner (OR = 10.8, CI = 2.5-47.5), followed by age 12-17 years old (OR = 6.7, CI = 1.6-26.9), or having worse health compared to 3-months ago (OR = 12.3, CI = 1.3-116.2). Mean covariates adjusted EQ visual analogue scale score was significantly lower among persons with depression (68.77 ± 3.15 vs. 77.58 ± 4.24, p = .03) than those without depression., Conclusions: Our study revealed concerning levels of depression and anxiety in this VWD sample. Lack of social support was determined an important factor associated with depression and anxiety in this sample. Mental health screening is critical in VWD clinical evaluation and care., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research., Research Design and Methods: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk., Results: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging., Conclusions: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community.

Thrombin plays an essential role in achieving and maintaining effective hemostasis and stable clot formation. In people with hemophilia, deficiency of procoagulant factor (F)VIII or FIX results in insufficient thrombin generation, leading to reduced clot stability and various bleeding manifestations. A correlation has been found between the bleeding phenotype of people with hemophilia and the extent of thrombin generation, with individuals with increased thrombin generation being protected from bleeding and those with lower thrombin generation having increased bleeding tendency. The amount, location, and timing of thrombin generation have been found to affect the formation and stability of the resulting clot. The goal of all therapies for hemophilia is to enhance the generation of thrombin with the aim of restoring effective hemostasis and preventing or controlling bleeding; current treatment approaches rely on either replacing or mimicking the missing procoagulant (ie, FVIII or FIX) or rebalancing hemostasis through lowering natural anticoagulants, such as antithrombin. Global coagulation assays, such as the thrombin generation assay, may help guide the overall management of hemostasis by measuring and monitoring the hemostatic potential of patients and, thus, assessing the efficacy of treatment in people with hemophilia. Nevertheless, standardization of the thrombin generation assay is needed before it can be adopted in routine clinical practice., (© 2023 The Authors.)

Most people with von Willebrand disease (VWD) have a partial quantitative deficiency of plasma von Willebrand factor (VWF) or type 1 VWD. In contrast to type 2 and type 3 VWD, laboratory assays will not always establish the diagnosis in type 1 VWD. This is because plasma VWF levels in type 1 VWD, especially those with levels closer to 50 IU/dL, overlap with the general population. Assessment is further complicated by increased plasma VWF levels in response to physiologic stressors or aging. Diagnosis of those with type 1 VWD with plasma VWF levels 30 to 50 IU/dL (previously referred to as "low VWF") requires expert assessment of bleeding phenotype as well as an understanding of the limitations of both bleeding assessment tools (BATs) and laboratory testing. Using the available evidence and highlighting research gaps, we discuss common dilemmas facing providers relating to assessment of adolescents, transition from pediatrics to adult care, and older individuals with type 1 VWD., (Copyright © 2022 by The American Society of Hematology.)

Introduction: Persons with haemophilia(PWH) have been shown to have low bone mineral density likely the result of prolonged immobility, recurrent hemarthrosis, decreased weight bearing, lower physical activity level and obesity. Bone health has been poorly characterized in haemophilia carriers (HC) and persons with von Willebrand disease (PWvWD)., Aim: To estimate the prevalence of osteoporosis, osteoarthritis and bone fractures in HC and PWvWD and identify risk factors for poor bone health., Methods: This is a retrospective study using a population level, commercial database - Explorys (IBM Watson Health, Cleveland, USA). We compared prevalence rates of osteoporosis, osteoarthritis and fractures among cases (HC or PWvWD) and controls (general population without an underlying bleeding disorder) from 1999 to 2020. Prevalence of common risk factors for poor bone health were compared among cases and controls., Results: Among 72,917,850 active persons in the database, we identified 940 women with the diagnosis of HC and 19,580 PWvWD. Among HC and PWvWD, prevalence of osteoporosis, osteoarthritis and fractures were significantly higher in cases, when compared to controls. In HC, the prevalence of vitamin D deficiency, obesity, hypothyroidism, smoking, diabetes mellitus, hypocalcaemia, corticosteroid use, malignancy, renal failure and Nonsteroidal anti-inflammatory drugs (NSAID) use were significantly higher among the cases. In PWvWD, the prevalence of risk factors was significantly higher in cases when compared to controls., Conclusion: The prevalence of osteoporosis, osteoarthritis and fractures is significantly higher among HC and PWvWD. This data highlights the importance of screening patients for risk factors for poor bone health and provide education to prevent these complications., (© 2022 John Wiley & Sons Ltd.)

BACKGROUND: A mainstay of treatment in patients with hemophilia with inhibitors (PWIs) is the use of a recombinant factor VIIa (rFVIIa) bypassing agent. A new rFVIIa product may allow reduced rFVIIa utilization for on-demand treatment of bleeding episodes (BEs). OBJECTIVE: A decision analytic health economic model was developed to compare the utilization and consequent need for bleed-related clinical encounters of 2 rFVIIa products, with the International Nomenclature Name of eptacog alfa (EA) and eptacog beta (EB). METHODS: This study uses recent, peer-reviewed, and published data from clinical trials with similar endpoints for 1 million insured male lives in the United States. rFVIIa product utilization was modeled in hemophilia (A and B) PWI for on-demand treatment of BEs with rFVIIa treatment. Estimated annual BE rates were modeled to include prophylaxis and on-demand management. The clinical encounter avoidance estimates are based on refractory bleeding through 24 hours. RESULTS: In a cohort of 1 million insured, 5-6 patients with hemophilia A or B with inhibitors annually receive on-demand treatment for a total of 59 mild/moderate BEs. The model suggests that EB requires less unit utilization per BE (13,125 μg and 17,850 μg for the 75μg/kg and 225μg/kg dose regimens, respectively) than EA 90 μg/kg dosing (20,178μg), with wholesale acquisition costs expanding the difference. Further, both EB initial dose regimens would permit decreased total nonmedication health plan spending for the acute treatment of BEs by reducing the need for clinical encounters arising from BEs that fail to respond within 24 hours. CONCLUSIONS: With reduced infusion requirements, the model consistently shows that EB could generate lower insured-cohort drug utilization, as well as reduce costly clinical encounters by keeping mild and moderate BEs amenable to home bypassing agent management. DISCLOSURES: The article was funded by HEMA Biologic, LLC. The authors approved all content and results in this article without being subject to sponsor censorship. Mr Jensen, Mr Cyr, and Ms Hathway are employees of PRECISIONheor, which provides consulting services to the pharmaceutical industry, including HEMA Biologics, LLC. Dr Batt is an advisor to PRECISIONheor. Dr Alexander is a former employee of HEMA Biologics, LLC, and provides consulting services to the pharmaceutical industry.

Introduction: Women and girls affected by haemophilia, including haemophilia carriers (WGH) are at risk of bleeding symptoms that may go unrecognized, including heavy menstrual bleeding (HMB) and musculoskeletal bleeding. Terminology continues to evolve., Aim: To describe the current recommendations for nomenclature surrounding WGH, and the current understanding of HMB, iron deficiency, and musculoskeletal complaints in these patients., Methods: Literature was reviewed and summarized., Results: With regards to nomenclature, women with factor levels less than 50% should be classified as having haemophilia, while carriers with normal levels should be characterized accordingly to symptomatology. HMB and resultant iron deficiency are common among WGH, have a multitude of downstream effects, and maybe overlooked due to stigma around menstruation. Musculoskeletal bleeding and resultant joint changes are increasingly recognized in this population but do not necessarily correlate with factor levels., Conclusion: Although progress has been made in the care of WGH, much work remains to further improve their care., (Haemophilia© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Haemophilia B is a rare X-linked genetic deficiency of coagulation factor IX (FIX) that, if untreated, can cause recurrent and disabling bleeding, potentially leading to severe arthropathy and/or life-threatening haemorrhage. Recent decades have brought significant improvements in haemophilia B management, including the advent of recombinant FIX and extended half-life FIX. This therapeutic landscape continues to evolve with several non-factor replacement therapies and gene therapies under investigation. Given the rarity of haemophilia B, the evidence base and clinical experience on which to establish clinical guidelines are relatively sparse and are further challenged by features that are distinct from haemophilia A, precluding extrapolation of existing haemophilia A guidelines. Due to the paucity of formal haemophilia B-specific clinical guidance, an international Author Group was convened to develop a clinical practice framework. The group comprised 15 haematology specialists from Europe, Australia, Japan, Latin America and North America, covering adult and paediatric haematology, laboratory medicine and biomedical science. A hybrid approach combining a systematic review of haemophilia B literature with discussion of clinical experience utilized a modified Delphi format to develop a comprehensive set of clinical recommendations. This approach resulted in 29 recommendations for the clinical management of haemophilia B across five topics, including product treatment choice, therapeutic agent laboratory monitoring, pharmacokinetics considerations, inhibitor management and preparing for gene therapy. It is anticipated that this clinical practice framework will complement existing guidelines in the management of people with haemophilia B in routine clinical practice and could be adapted and applied across different regions and countries., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Daniel P Hart has received personal or institutional honoraria from Bayer, Biotest, BioMarin, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, Spark, Takeda and UniQure; and personal or institutional consulting fees from Bayer, Biotest, BioMarin, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, Spark, Takeda, UniQure. Davide Matino has received honoraria from Novo Nordisk, Octapharma, Pfizer, Sanofi and Sobi; received grant support from Bayer, Octapharma and Pfizer (to McMaster University); and has participated on Advisory Boards for Novonordisk, Pfizer and Sobi. Jan Astermark has received honoraria from Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda and Sobi; received grant support from Bayer, CSL Behring, Shire/Takeda and Sobi/Biogen; and has participated on Data Safety Monitoring Boards or Advisory Boards for Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, Sobi and Uniqure. Gerard Dolan has received honoraria from CSL Behring, Novo Nordisk, Pfizer and Sobi; personal consulting fees from CSL Behring, Novo Nordisk, Pfizer and Sobi; support for attending meetings or travel from CSL Behring, Novo Nordisk, Pfizer and Sobi; and has participated on Data Safety Monitoring Boards or Advisory Boards for CSL Behring, Novo Nordisk, Pfizer and Sobi. Roseline d’Oiron has received honoraria from Baxalta/Shire/Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche and Sobi; support for attending meetings and/or travel from Baxalta/Shire/Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche and Sobi; and has participated on Data Safety Monitoring Boards or Advisory Boards for Baxalta/Shire/Takeda, Biomarin, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Spark Therapeutics, Sobi and UniQure. Cédric Hermans has received honoraria from Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Takeda and Uniqure; consulting fees from Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Takeda and Uniqure; and has participated on a Data Safety Monitoring Board or Advisory Board for CSL Behring. Victor Jiménez-Yuste has received honoraria from CSL Behring, Novo Nordisk, Pfizer and Sobi; and consulting fees from CSL Behring, Novo Nordisk, Pfizer and Sobi. Adriana Linares has declared no conflict of interest. Tadashi Matsushita has received honoraria from Bayer, Chugai, CSL Behring, JB, KMB, Novo Nordisk, Pfizer, Sanofi and Takeda; consulting fees from Bayer; grant and research support from Chugai, JB and KMB; a leadership or fiduciary role from Aichi Pt Union; and has participated on Data Safety Monitoring Boards or Advisory Boards for Bayer, Chugai, Novo Nordisk, Sanofi and Takeda. Simon McRae has received honoraria from Pfizer; and a leadership or fiduciary role from the Australian Bleeding Disorders Registry. Margareth C. Ozelo has received personal honoraria from Bayer, BioMarin, Novo Nordisk, Roche and Takeda; consulting fees from Pfizer; grant and research support from BioMarin, Novo Nordisk, Pfizer, Roche, Sanofi and Takeda; support for attending meetings and/or travel from Novo Nordisk, Roche and Takeda; a leadership or fiduciary role from Novo Nordisk; other financial or non-financial interests from Grifols; and has participated on Data Safety Monitoring Boards or Advisory Boards for Bayer, BioMarin, Novo Nordisk, Roche, Sanofi and Takeda. Sean Platton has received personal honoraria from Pfizer; and has participated on a Data Safety Monitoring Board or Advisory Board for Novo Nordisk. Darrel Stafford has received honoraria from Sobi; and royalties and patents from VKOR. Robert F. Sidonio has received honoraria from BioMarin and Sanofi; consulting fees from Bayer, BioMarin, Genentech, Hema Biologics, Kedtion, Novo Nordisk, Octapharma, Takeda; research grants from Genentech, Octapharma and Takeda; and has participated on a Data Safety Monitoring Board or Advisory Board for Uniqure. Andreas Tiede has received personal or institutional honoraria from Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi and Takeda; and research grant/support from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi and Takeda., (© The Author(s), 2022.)

von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown., Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age., Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021., Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism., Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve)., Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively)., Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk., Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.

Introduction: Oral health is an important component of care at haemophilia treatment centres (HTCs). Correlations between oral health and inflammation suggest that proper oral health may improve joint health., Aim: To evaluate the dental habits, needs, and oral health status of paediatric patients with bleeding disorders, and identify predicters of poor oral health., Methods: From May 2016 to October 2017, consecutive paediatric HTC patients completed a 14-question survey and were examined by dental professionals. Descriptive analyses, chi-square tests and logistic regression models identified characteristics associated with four main dental outcomes., Results: Evaluations from 226 consecutive patients (age 1-20 years) were included. Diagnoses included haemophilia A and B (64%), von Willebrand disease (25%) and other bleeding disorders (13%). Nearly half of patients reported not brushing their teeth twice a day (44%). One-quarter of patients did not currently have a dentist (27%), and 15% reported specific challenges with access to dental care. Oral screening demonstrated significant pathology: 89% of patients had plaque accumulation, 37% had gingivitis and 8% had lesions suggestive of dental caries. Multivariate analysis revealed that having a primary caregiver with active decay was associated with significantly higher rates of suspicious lesions (OR 4.34, CI 1.41-13.35) and gingival erythema (OR 3.44, CI 1.63-7.25) and lower rates of twice daily teeth brushing (OR .17, CI .08-.37)., Conclusion: Children with bleeding disorders commonly have significant dental pathology and report obstacles to dental care, posing the potential risk for morbidity. Primary caregiver dental health is strongly associated with dental pathology in children., (© 2021 John Wiley & Sons Ltd.)

Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder. The bleeding phenotype is variable, and some individuals have persistent symptoms post-diagnosis., Aim: To characterize bleeding patterns in patients with VWD before and after diagnosis., Methods: De-identified claims data for commercially insured patients in the IQVIA PharMetrics® Plus US database (Jan-2006 to Jun-2015) were extracted. Eligible patients had ≥2 claims for VWD (ICD-9 code 286.4), and continuous health-plan enrolment for ≥2 years before and after diagnosis. Bleeding event, treatment and treating-physician type were analysed for 18 months before and 7-24 months after diagnosis, according to pre-diagnosis bleeding phenotype (claims from one vs multiple bleed sites) and post-diagnosis bleeding status (resolved [no post-diagnosis bleed claims] vs continued [≥1 claim])., Results: Data for 3756 eligible patients (72.6% female; 71.0% aged ≥18 years at diagnosis) were analysed. Overall, 642 (17.1%) and 805 (21.4%) patients had single- and multiple-site bleed claims pre-diagnosis, respectively, and 1263 (33.6%) patients (38.5% of women, 20.8% of men) continued to bleed post-diagnosis. Multiple-site bleeding was associated with pre-diagnosis heavy menstrual bleeding (HMB), oral contraceptive (OC) use and nasal cauterization. Continued bleeding post-diagnosis was associated with pre-diagnosis gastrointestinal bleeding, HMB and epistaxis; pre-diagnosis use of OCs, aminocaproic acid and nasal cauterization; and younger age at diagnosis. Few patients consulted a haematologist for bleed management., Conclusion: Many patients with VWD have persistent bleeding from multiple sites and continue to bleed post-diagnosis. Our findings suggest a need to optimize management to reduce the symptomatic burden of VWD following diagnosis., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

The biology of factor IX deficiency leading to hemophilia B has important distinctions from factor VIII deficiency that leads to hemophilia A. In this article, the authors explore the unique biology of factor IX in hemostasis, including the importance of FIX distribution to the extravascular space and the implications on dosing of factor concentrates. The authors review basic treatment principles of hemophilia B, including extended half-life products, and highlight areas of ongoing therapeutic innovation for hemophilia B prophylaxis., Competing Interests: Disclosure L. Malec has received research support from Sanofi Genzyme. She has received consultancy fees from Bayer, CSL, Sanofi Genzyme, Spark, Takeda, Sobi. R. Sidonio has received research support from Takeda/Shire, Octapharma, Genentech, and Grifols. He has received consultancy fees from Bayer, Sanofi Genzyme, Takeda, Sobi, Spark, Biomarin, Novo Nordisk, Pfizer, and Emergent Solutions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Females may have haemophilia with the same factor VIII (FVIII) or factor IX (FIX) levels as affected males. Characterization of females with haemophilia would be useful for health care planning to meet their unique needs. Federally-funded haemophilia treatment centres (HTCs) in the United States contribute data on all individuals with bleeding disorders receiving care to the Population Profile (HTC PP) component of the Community Counts Public Health Surveillance of Bleeding Disorders project., Aims: To estimate the number of females with haemophilia receiving care at HTCs in the United States and compare their characteristics with those of males with haemophilia., Methods: HTC PP data collected on people receiving care at an HTC from January 2012 through September 2020 with haemophilia A and B were evaluated by sex for demographic and clinical characteristics., Results: A factor level < 40% was reported for 23,196 males (97.8%) and 1667 females (47.6%) attending HTCs; 51 (.48%) severe, 79 (1.4%) moderate, and 1537 (17.9%) mild haemophilia patients were female. Females were older, more often White, and less often non-Hispanic than males. Females were less likely to have history of HIV or HCV infection, even among those with severe disease, but twice as likely to have infection status unknown. Females with mild haemophilia were more often uninsured than males., Conclusions: Females with severe or moderate haemophilia are uncommon, even in specialized care centres; however, almost one in five patients with mild haemophilia was female, indicating needs for specialized care based on factor level and history for affected females., (© 2021 John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: Inhibitor development is the most serious treatment-related complication of replacement coagulation factor VIII (FVIII) therapy for patients with haemophilia A. Immune tolerance induction (ITI), which involves intensive and prolonged treatment with plasma-derived or recombinant FVIII, is the only clinically proven strategy for eradication of inhibitors. The bispecific antibody emicizumab is approved for use in patients with and without inhibitors to prevent bleeding but does not eliminate inhibitors. MOTIVATE (www.motivate-study.com) aims to capture different approaches to the treatment and management of patients with haemophilia A and inhibitors, document current ITI approaches from real-world clinical experience, and evaluate the efficacy and safety of ITI, emicizumab prophylaxis and ITI with emicizumab prophylaxis., Methods: The investigator-initiated MOTIVATE study [ClinicalTrials.gov identifier: NCT04023019; EudraCT 2019-003427-38] will investigate in real-life clinical practice the management of patients with haemophilia A of any severity who have developed inhibitors to FVIII. All treatment is at the investigator's discretion. The following treatment approaches will be evaluated: Group 1 - ITI with Nuwiq ® , octanate ® or wilate ® and aPCC/rFVIIa if needed to treat bleeding episodes (BEs) or during surgery or for prophylaxis; Group 2 - ITI with Nuwiq ® , octanate ® or wilate ® and emicizumab prophylaxis and aPCC/rFVIIa if needed to treat BEs or during surgery; Group 3 - routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI and aPCC/rFVIIa if needed to treat BEs or during surgery. Patients will not be randomised to a treatment group and may change groups during the study., Conclusions: It is planned to enrol 120 patients who will be followed for up to 5 years. Optional sub-studies will explore factors that may influence ITI results as well as the impact of different treatment approaches on important aspects of patient health, including joint and bone health and the risk of thrombotic events., Competing Interests: Conflict of interest statement: CEE has acted as a consultant, received speaker’s fees and/or received research funding from the following companies: Alnylam, Bayer Healthcare, Biomarin, Biotest, CSL Behring, Freeline, Grifols, Kedrion, LFB, Novo Nordisk, Octapharma, Roche/Chugai, Sobi, Takeda. RFS Jr. has acted as a consultant and/or received research funding from the following companies: Octapharma, Genentech, Biomarin, Uniqure, Kedrion, Grifols, Bayer, Pfizer, Novo Nordisk, Bioverativ, Hema Biologics, Shire., (© The Author(s), 2021.)

Hemophilia A and B predominantly attracts clinical attention in males due to X-linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and <0.40 IU/ml, 0.01-0.05 IU/ml, and <0.01 IU/ml, respectively), symptomatic and asymptomatic HC (FVIII/IX ≥0.40 IU/ml with and without a bleeding phenotype, respectively). This new nomenclature is aimed at improving diagnosis and management and applying uniform terminologies for clinical research., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

As we pass the nearly 9 month mark of the coronavirus virus disease 2019 (COVID-19) pandemic in the United States, we sought to compile a brief multi-disciplinary compendium of COVID-19 information learned to date. COVID-19 is an active viral pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that confers high morbidity and mortality. COVID-19 has been associated with: pulmonary compromise and acute respiratory distress syndrome, thrombotic events, inflammation and cytokine, and post-infectious syndromes. Mitigation of these complications and expeditious therapy are a global urgency; this is brief summary of current data and management approaches synthesized from publications, experience, cross-disciplinary expertise (Figure 1)., (© 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Heavy menstrual bleeding (HMB) is often the first bleeding symptom for female individuals with inherited bleeding disorders. Guidelines recommend performing the hemostatic evaluation at HMB presentation. Von Willebrand factor (VWF) levels increase with stress, making it unclear if VWF studies during acute bleeding are beneficial in diagnosing von Willebrand disease (VWD)., Objectives: To determine the utility of testing for VWD during acute HMB., Patients/methods: This retrospective cohort study evaluated VWF levels of individuals presenting to the emergency department (ED) with HMB from January 1, 2017, to December 31, 2018, after prospective implementation of a clinical practice guideline recommending hemostatic evaluation in the ED. We compared VWF and factor VIII (FVIII) levels between acute presentation and follow-up visit after bleeding resolution. We compared the diagnostic accuracy of initial and follow-up labs., Results: During the study period, 221 individuals were seen in the ED for acute HMB, and 39 had VWD testing at both time points. Median FVIII and VWF levels were higher during acute bleeding than at follow-up. The difference in VWF levels between visits was negligible when initial FVIII value was normal. Overall incidence of VWD was 7.5%; 69% of those with VWD had low VWF levels during acute HMB., Conclusion: VWD testing during acute HMB detects the majority of individuals with VWD but also leads to elevated levels of VWF, potentially limiting at the accuracy of diagnostic labs during acute bleeding episodes. Delayed testing until resolution of anemia and active bleeding may provide more accurate diagnostic evaluation for VWD., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Introduction: In the network of U.S. comprehensive haemophilia treatment centres (HTCs), von Willebrand disease (VWD) is the most common bleeding disorder other than haemophilia. Estimates of the size and characteristics of the VWD population receiving treatment are useful for healthcare planning., Aim: Estimate the prevalence and incidence of VWD among males and females receiving care at U.S. HTCs (HTC-treated prevalence and incidence)., Methods: During the period 2012-2019, de-identified surveillance data were collected on all VWD patients who visited an HTC including year of birth, sex, race, Hispanic ethnicity, VWD type, and laboratory findings and used to calculate period HTC-treated prevalence by VWD type and sex. Data from patients born 1995-1999 were used to estimate HTC-treated incidence rates., Results: During the period, 24,238 patients with a diagnosis of VWD attended HTCs; for 23,479 (96.9%), VWD type was reported or could be assigned. Age-adjusted HTC-treated prevalence was 8.6 cases/100,000 (7.2/100,000 for Type 1, 1.2/100,000 for Type 2 and 1.7/million for Type 3) and was twice as high in women as men (4.8 vs. 2.4 cases/100,000) for Type 1 and similar by sex for Type 2 and Type 3. HTC-treated Type 1 incidence increased over the period, averaging nearly threefold higher for women than men (26.2 vs. 9.9/100,000 live births). Sex differences were less for Type 2 (2.2 vs. 1.4 cases/100,000 births) and slight in Type 3., Conclusion: Prevalence and incidence of HTC-treated VWD differ by sex and type and are likely strongly influenced by differences in rates of diagnosis., (© 2021 John Wiley & Sons Ltd. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Gene therapy has the potential to overcome many of the limitations of prophylactic hemophilia therapies. Several clinical trials evaluate investigational adeno-associated virus (AAV)-mediated gene transfer approaches for the treatment of hemophilia A and B. The practical application of these approaches is nuanced by differences in AAV serotypes, transgene modifications, manufacturing, dosing, administration, and approach to follow-up. This guide explores mechanisms of AAV gene transfer, identification of appropriate candidates for clinical trial participation, anticipated trial events that follow infusion of an investigational gene therapy including outcomes to be monitored, and future considerations. Patient-accessible infographic summaries of these topics are included to serve as potential visual aids that healthcare providers may choose to utilize or adapt to guide informed consultation. The fundamentals of AAV-mediated, liver-directed gene transfer for hemophilia are reviewed, to facilitate discussion between healthcare providers, patients, and their families and advocates if considering a trial of investigational gene therapy., (Copyright © 2020. Published by Elsevier Ltd.)

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.

Background: The majority of patients with hemophilia A with inhibitors who undergo immune tolerance induction (ITI) achieve successful tolerance and transition to factor VIII (FVIII) prophylaxis. A portion of these patients have switched to emicizumab for bleeding prevention. However, the risk of inhibitor relapse on emicizumab is unclear., Objective: To evaluate the inhibitor status of patients with hemophilia A and inhibitors who achieved successful/partial tolerance after ITI and transitioned from FVIII prophylaxis to emicizumab., Methods: This is a single-institution, retrospective review of pediatric patients with severe hemophilia A who have completed ITI with FVIII and switched to emicizumab., Results/conclusions: Seven successfully tolerized and five partially tolerized patients were identified. Three patients continued intermittent FVIII infusions on emicizumab at 50-70 IU/kg twice weekly, once weekly, or every other week due to concerns for inhibitor relapse or loss of recent FVIII tolerance by the treating provider. Eleven of 12 patients (92%) maintained negative inhibitor titers at a mean follow-up of 14.2 ± 6.1 months. One individual had an inhibitor relapse with a peak titer of 2.5 BU/mL. Five of the 11 patients (45%) with negative inhibitor titers had detectable nonneutralizing anti-FVIII IgG4 antibodies, but none of the patients had detectable IgG1 antibodies. There were no inhibitor recurrences in a subset of six patients after FVIII re-exposure for bleeding events or surgery. Given that the presence of an inhibitor significantly impacts factor product choice for bleeding management, ongoing inhibitor monitoring in tolerized patients with hemophilia A who transition to emicizumab is strongly recommended., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Emicizumab is a bispecific antibody that recognizes FIX(a)/FX, and mimics FVIIIa cofactor activity. Due to its unique characteristics including longer half-life and subcutaneous injectability, treatment for haemophilia A dramatically improved regardless of the presence of FVIII inhibitor. Protection from pathological change in joints, avoidance of inhibitor development and intra-cranial haemorrhage could be expected by introduction of emicizumab in early childhood. Applications in mild/moderate patients should be also considered. Clinical assessment tool should be standardized; however, since there are limitations to conventional ABR-based assessment. Laboratory monitoring is another practical issue due to the mode of action of emicizumab. Chromogenic assays and global assays could be utilized. The other emicizumab-related practical issue is immune tolerance induction for the inhibitor patients, since ITI remains the only effective means to inhibitor eradication. With the recently introduced Atlanta protocol, emicizumab prophylaxis is given in combination with 50-100 IU/kg FVIII three times a week. A single manuscript has been published, and multiple clinical trials are open to address the efficacy of this strategy. Whether the Atlanta protocol will be fully embraced is yet to be seen, but there is widespread consensus about attempts to tolerize every haemophilia A patient with an inhibitor., (© 2020 John Wiley & Sons Ltd.)

Background Thrombosis is common in infants undergoing staged surgeries for single-ventricle congenital heart disease. The reported incidence and timing of thrombosis varies widely, making it difficult to understand the burden of thrombosis and develop approaches for prevention. We aimed to determine the timing and cumulative incidence of thrombosis following the stage I Norwood procedure and identify clinical characteristics associated with thrombosis. Methods and Results We analyzed data from the Pediatric Heart Network Single Ventricle Reconstruction trial from 2005 to 2009 and identified infants with first-time thrombotic events. In 549 infants, the cumulative incidence of thrombosis was 21.2% (n=57) from stage I through stage II. Most events occurred during stage I (n=35/57, 65%), with a median time to thrombosis of 15 days. We used a Cox proportional hazards model to estimate the association of clinical variables with thrombosis. After adjusting for baseline variables, boys had a higher hazard of thrombosis (adjusted hazard ratio [HR], 2.69; 95% CI, 1.44-5.05; P =0.002), non-hypoplastic left heart syndrome cardiac anatomy was associated with a higher early hazard of thrombosis (adjusted HR, 3.93; 95% CI, 1.89-8.17; P <0.001), and longer cardiopulmonary bypass time was also associated with thrombosis (per 10-minute increase, adjusted HR, 1.07; 95% CI, 1.01-1.12; P =0.02). Lower oxygen saturation after the Norwood procedure increased the hazard for thrombosis in the unadjusted model (HR, 1.08; 95% CI, 1.02-1.14; P =0.011). Conclusions Thrombosis affects 1 in 5 infants through Stage II discharge, with most events occurring during stage I. Male sex, non-hypoplastic left heart syndrome anatomy, longer cardiopulmonary bypass time, and lower stage I oxygen saturation were associated with thrombosis.

With licensure of extended half-life (EHL) factor products and the changing landscape of available hemophilia products, patients and providers have options for less treatment-intense prophylaxis. The impact of these products in clinical practice to date remains understudied. We aimed to quantify the use of EHL products in prophylaxis in the US using the ATHN-dataset, a database of 145 ATHN-affiliated hemophilia treatment centers (HTCs). Further, we aimed to quantify the impact of EHL on key hemophilia indicators including annualized bleed rates (ABRs), hemophilia joint health scores (HJHS) and quality of life (QOL) metrics. The use of EHL vs standard half-life (SHL) products in severe hemophilia was compared between June 2018 and March 2019 using the ATHN-dataset. A cohort of patients was also recruited from seven participating HTCs in order to compare ABR, HJHS and QOL between product classes. By March 2019 the number of individuals with severe Hemophilia A (SHA) receiving EHLs remained relatively stable (28.4%), whereas the number of prescribed non-factor products increased to 7.1%, with a diminishing majority of patients (64.0%) continuing to receive SHLs. The majority of patients with severe hemophilia B (SHB) received treatment with EHLs including 57.5% by March 2019. There was a trend toward lower ABR with use of EHLs in SHA and SHB, although this did not result in improved HJHS nor QOL. EHL use in the United States in severe hemophilia continues to increase, although at a slower rate in SHA with the availability of non-factor therapy. The impact of the EHL therapies in clinical practice should continue to be examined prospectively., (© 2020 Wiley Periodicals, Inc.© 2020 Wiley Periodicals, Inc.)

Aim: Haemophilia A (HA) is a male-predominant disorder, yet women and girls can have factor VIII (FVIII) deficiency with bleeding events requiring treatment. This study aimed to identify and characterize female patients with HA., Methods: Administrative claims dated 01 January 2012-31 July 2016 were accessed for patients with 18 months' coverage by commercial or Medicare Advantage with Part D insurance. Patients were included by HA diagnoses or treatments and/or bleeding-related diagnoses or procedures, and excluded by haemophilia B or qualitative platelet disorder diagnoses. A sample of charts was examined for bleeding history, HA therapies and bleeding treatments. All-cause healthcare utilization and costs were also described., Results: Among 353 patients meeting initial inclusion criteria, 86 charts were procured, with 8 patients identified as having HA. Their mean age was 60 ± 17 years and most were Medicare-insured. The mean Charlson Comorbidity Index score was 2.50 ± 2.56; the most prevalent comorbid conditions involved coagulation/haemorrhage, fluid/electrolyte balance and non-traumatic joint disorders. Over 18 months, a mean of 54 ambulatory visits and 120 pharmacy fills were observed; mean medical costs were $86 694 and pharmacy costs were $25 396., Conclusions: Identifying females with HA is challenging using healthcare claims, because diagnostic nomenclature is unclear for female patients treated for bleeding events. Although chart abstraction enhanced claims data, very few female patients were identified with HA. Nevertheless, even in a small sample, sizeable burden in comorbidity and healthcare use was observed. Improved nomenclature and coding for HA diagnoses for women and girls is key to improving research and treatment., (© 2020 John Wiley & Sons Ltd.)

Introduction: The number of women and girls (WG) with bleeding disorders cared for at hemophilia treatment centers has increased dramatically over the last 30 years, owing to improved recognition of bleeding symptoms specific to WG. However, basic epidemiologic data of this population remain elusive. The ATHNdataset (American Thrombosis and Hemostasis Network) is a surveillance tool for people with bleeding disorders in the United States, providing demographic as well as bleeding symptom and treatment information. The aim of this study was to characterize the female cohort within the ATHNdataset. Methods: In this retrospective cohort study, the ATHNdataset was queried for demographic data, bleeding disorder diagnosis, bleeding symptoms, and treatment. Descriptive statistics were used. Results: As of December 31, 2017, 8,820 WG with a congenital bleeding disorder were enrolled in the ATHNdataset, comprising 24.5% of the entire ATHNdataset cohort (35,945). The most common reported diagnosis was von Willebrand disease (VWD), accounting for 62.9% of the population. Reproductive tract bleeding was reported in 15.8% of participants older than 15 years. Conclusions: The ATHNdataset describes the largest cohort of WG with bleeding disorders to date. VWD is the most common diagnosis in WG with bleeding disorders. Symptoms specific to WG, such as heavy menstrual bleeding, are underreported in this data set compared with other data sources. Ongoing efforts are needed to improve diagnosis, treatment, and surveillance of WG with bleeding disorders.

Background: Despite the high prevalence of overweight and obesity in the United States, few studies have assessed the impact of obesity on haemophilia-specific outcomes or experiences/perceptions of healthcare providers (HCPs) treating haemophilia., Aim: The Awareness, Care and Treatment In Obesity maNagement to inform Haemophilia Obesity Patient Empowerment (ACTION-TO-HOPE) study was designed to identify HCP insights on the unique challenges of patients with haemophilia and obesity/overweight (PwHO) and the barriers to chronic weight management., Methods: An online survey collected data from haemophilia treatment centre-based HCPs. Respondents included 10 adults and 29 paediatric haematologists, 27 nurses/nurse practitioners/physician assistants, 22 physical therapists and 17 social workers., Results: Almost all HCPs rated obesity of moderate/high concern and reported that weight significantly affects future health and has an impact on life expectancy, yet fewer than 60% reported discussing the impact of weight on health with their patients. HCPs reported that few PwHO tried to lose weight; not many were 'successful'. HCPs perceived a desire to feel better physically and joint pain as top motivating factors. HCPs believe that PwHO would have less joint bleeding and pain and greater mobility if they lost weight. HCPs viewed lack of exercise and food preferences/habits as the biggest barriers to initiating/maintaining weight loss and therefore recommended increasing exercise and healthier eating to their patients. However, physical activity in this patient population is limited and requires advice and support., Conclusions: Most HCPs appreciated the impact of obesity on joint bleeding, pain, and function and quality of life. Reduced food intake and increased activity are the most commonly recommended weight-loss strategies but the least likely to be successful. HCPs desire additional education/materials to understand weight management for PwHO., (© 2019 John Wiley & Sons Ltd.)