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Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding. We aimed to compare recombinant VWF with tranexamic acid for reducing heavy menstrual bleeding in patients with von Willebrand disease.

•Pooled longitudinal efficacy and safety data for rFIXFc demonstrates sustained benefits in hemophilia B.•All evaluable target joints resolved during treatment, and no recurrence was reported in most (90%) baseline target joints during follow-up.

PUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar “pathogenic” variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar “pathogenic” variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10−6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar “pathogenic” variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar “pathogenic” variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFBand DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWFalso surpassed exome-wide significance in the gene burden analysis (P= 7.31 × 10−6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

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.

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.

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P < .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P = .40) and VWD type (P = .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P= .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P< .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P= .40) and VWD type (P= .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

What is this summary about?This is a plain language summary of a clinical research study called XTEND-1. The study looked into how safe and effective a medicine called efanesoctocog alfa is for people with severe hemophilia A. Hemophilia A is a genetic condition in which the body does not produce enough or makes dysfunctional clotting factor VIII (eight) – a protein that is essential for blood clotting. People with hemophilia A are prone to dangerous bleeding, particularly internally and into their joints and muscles.How was the research done?The XTEND-1 study compared two ways of using the medication to treat bleeding episodes: (1) injecting it once a week for 12 months as a prophylaxis (regular preventative) treatment, or (2) injecting it as needed for 6 months, followed by weekly prophylaxis treatment for a further 6 months.What did the research find out?People who had prophylaxis treatment with efanesoctocog alfa injections for one year saw a significant reduction in the amount of bleeding they experienced compared to their pre-study prophylaxis treatment. The effects of the treatment also lasted longer, with higher factor VIII levels for longer, than previous prophylaxis treatment and less frequent injections were needed. There was a significant reduction in the amount of bleeding in people taking once-weekly prophylaxis treatment compared to ‘as needed’ treatment.

•The prevalence of intracranial hemorrhage in ITs with hemophilia remains substantial.

•This report provides a post hoc analysis of males with severe hemophilia A who developed inhibitors in the PUPs A-LONG trial.•High-risk F8variants and factor dosing were associated with high-titer inhibitors (HTI) and low-titer to HTI progression, respectively.

Low von Willebrand factor (VWF) in adults is associated with significant bleeding, most notably heavy menstrual bleeding (HMB) and postpartum hemorrhage, although this has not been characterized in adolescents. The objectives of this analysis of a multicenter single arm observational cohort study in adolescents with low VWF–associated HMB were to describe the bleeding phenotype, HMB severity, and related complications. Eligibility criteria included postmenarchal females <21 years of age with HMB (Pictorial Blood Assessment Chart [PBAC] score >100) and low VWF (2 values of VWF activity ≥30 and ≤50 IU/dL). Patients diagnosed with other bleeding disorders were ineligible. Clinical phenotype data, including PBAC and Bleeding Assessment Tool (BAT) scores, laboratory data, and HMB management/outcome details, were extracted. Patient demographics and clinical characteristics were summarized as medians with minimum/maximum values or frequencies with percentages. Groups were compared using a Wilcoxon rank-sum test or Fisher’s exact test. A total of 113 patients met inclusion criteria, and 2 were excluded. Ninety four percent had a significant bleeding phenotype (BAT score >2), with predominantly mucocutaneous bleeding (32%-44%), postprocedural/surgical bleeding (15%), and severe HMB (BAT HMB domain score ≥2; 90%). Bleeding complications included iron deficiency (60%), anemia (21%), transfusion (12%), and hospitalization (10%). Desmopressin challenge response in subjects tested was good and sustained. Several (48%) required combined therapy for HMB (hormonal/hemostatic), and one third did not show improvement despite therapy. Our results suggest that adolescent females with low VWF have a significant bleeding phenotype and resultant complications warranting a focus on prompt diagnosis, appropriate therapy, and prevention of complications.

Low von Willebrand factor (VWF) in adults is associated with significant bleeding, most notably heavy menstrual bleeding (HMB) and postpartum hemorrhage, although this has not been characterized in adolescents. The objectives of this analysis of a multicenter single arm observational cohort study in adolescents with low VWF–associated HMB were to describe the bleeding phenotype, HMB severity, and related complications. Eligibility criteria included postmenarchal females <21 years of age with HMB (Pictorial Blood Assessment Chart [PBAC] score >100) and low VWF (2 values of VWF activity ≥30 and ≤50 IU/dL). Patients diagnosed with other bleeding disorders were ineligible. Clinical phenotype data, including PBAC and Bleeding Assessment Tool (BAT) scores, laboratory data, and HMB management/outcome details, were extracted. Patient demographics and clinical characteristics were summarized as medians with minimum/maximum values or frequencies with percentages. Groups were compared using a Wilcoxon rank-sum test or Fisher's exact test. A total of 113 patients met inclusion criteria, and 2 were excluded. Ninety four percent had a significant bleeding phenotype (BAT score >2), with predominantly mucocutaneous bleeding (32%-44%), postprocedural/surgical bleeding (15%), and severe HMB (BAT HMB domain score ≥2; 90%). Bleeding complications included iron deficiency (60%), anemia (21%), transfusion (12%), and hospitalization (10%). Desmopressin challenge response in subjects tested was good and sustained. Several (48%) required combined therapy for HMB (hormonal/hemostatic), and one third did not show improvement despite therapy. Our results suggest that adolescent females with low VWF have a significant bleeding phenotype and resultant complications warranting a focus on prompt diagnosis, appropriate therapy, and prevention of complications.

Background: One of the most devastating complications of Hemophilia A or B (HemA, HemB) is end-stage joint damage characterized by chronic pain and functional disability. Joint bleeding is the best predictor of joint damage in hemophilia. A wide range of new therapeutics from extended half-life factor (EHL) concentrates to non-factor therapies such as factor VIII mimetics, hemostatic rebalancers and gene therapy have been recently approved or are in late-stage clinical trials that hold the promise of decreased joint disease in severe hemophilia.

Background

Data are needed on minimal factor activity (FA) levels required to prevent bleeding in hemophilia. We aimed to evaluate associations between hemophilia type and FA level and joint bleeding and orthopedic procedures using longitudinal data. Data were collected over an 11-year period on males with nonsevere hemophilia A or B without inhibitors who were receiving on-demand factor replacement therapy. Data on the number of joint bleeds in the previous 6 months and data on procedures from clinical records were analyzed using regression models. Data were collected on 4771 patients (hemophilia A, 3315; hemophilia B, 1456) from 19?979 clinic visits. Ages ranged from 2 to 91 years and baseline FA level ranged from 1% to 49% with a mean of 9.4%. Joint bleeding rates were heterogeneous across the FA range and were highest among men age 25 to 44 years. Adjusted for FA level, the mean number of joint bleeds per 6 months was 1.4 and 0.7 for patients with hemophilia A and B, respectively (P < .001). Regression models predicted 1.4 and 0.6 bleeds per year for hemophilia A and B patients, respectively, at an FA level of 15%. Patients with hemophilia B were 30% less likely than those with hemophilia A to have undergone an orthopedic procedure. We conclude that joint bleed rates for any given FA level were higher among hemophilia A than hemophilia B patients, and target FA levels of 15% are unlikely to prevent all joint bleeding in US males with hemophilia.

Kids B-LONG was a multicentre, open-label, phase 3 study assessing the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) in previously treated paediatric patients younger than 12 years with severe haemophilia B.

Supplemental Digital Content is available in the text.

Hemophilia A is an X-linked recessive hereditary bleeding disorder resulting from a deficiency in coagulation factor VIII. Difficulties due to hemophilia and its management present challenges for patient's quality of life. Turoctocog alfa, a recombinant, B-domain truncated factor VIII, is a recent US FDA- and EMA-approved replacement therapy shown to be an effective and safe option for the treatment of individuals with hemophilia A. Data collected throughout two Phase 3, multinational, open-label, non-randomized, non-comparative trials demonstrated that individuals with hemophilia A, particularly young adults experienced improvements in health-related quality of life when switched from an on-demand to a prophylactic regimen of turoctocog alfa.

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128.

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P< .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.govas #NCT01181128.

PUPs A-LONG evaluated safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, Phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at study start, 20 (19%) had family history of inhibitors, and 82 (80%) had high-risk F8mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI]: 21.8%–41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI: 8.8%–24.7%). The median (range) time to high-titer inhibitor development was 9 (4–14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 non–treatment-related death due to intracranial hemorrhage (onset prior to first rFVIIIFc dose). The overall median (interquartile range) ABR was 1.49 (0.00–4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within expected range, although high-titer inhibitor development was on the low end of the range reported in literature. rFVIIIFc was well-tolerated and effective as prophylaxis and for treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).

Ragni: Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam/Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; ATHN: Research Funding; Sangamo: Research Funding. Seaman:Bayer: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy; Takeda: Consultancy. Acharya:Novonordisk: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Bayer Pharma Inc.: Research Funding. Wheeler:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees. Tarango:Takeda/Shire: Honoraria, Other; Bayer: Consultancy, Other; Sanofi: Honoraria, Other. Dunn:ATHN: Research Funding; Spire: Honoraria; Medscape: Honoraria; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy; Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding. Chitlur:Takeda: Honoraria; Biovertiv: Honoraria; Agios Pharmaceuticals: Research Funding; Pfizer: Honoraria; Novo Nordisk: Consultancy, Honoraria. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Malec:Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy; Takeda: Consultancy; Bayer: Consultancy; SOBI: Consultancy. Leissinger:Bayer: Consultancy; Kedrion: Consultancy; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; HEMA Biologics: Consultancy; Takeda: Consultancy; Uniqure: Consultancy; Spark: Consultancy. Carpenter:Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria; Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding. Knoll:NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Wang:Bioverativ Inc: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Biomarin: Honoraria; Genentech: Honoraria; Takeda: Honoraria. Young:Genentech/Roche, Grifols, and Takeda: Research Funding; Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Thornburg:Genentech: Speakers Bureau; Spark Therapeutics: Consultancy; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; American Thrombosis and Hemostasis Network: Research Funding; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; NovoNordisk: Research Funding; Biomarin: Consultancy, Speakers Bureau; Bayer Pharmaceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lucas:CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hwang:Shire: Honoraria; Takeda: Honoraria.

BACKGROUD

Curtis: USC Hemophilia Utilization Group Study (HUGS): Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy. Konkle:Pfizer: Consultancy, Research Funding; Roche: Consultancy; BioMarin: Consultancy; Sigilon: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Wu:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Tran:Takeda: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Bioverativ: Consultancy. Nichol:Global Blood Therapeutics: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Genentech Inc.: Research Funding; Baxalta US Inc., Bannockburn, IL (a Takeda Company): Research Funding; Pfizer: Research Funding.

Background:von Willebrand disease (VWD) is the most common inherited bleeding disorder. Questions remain regarding the impact of VWD related bleeding phenotype on healthcare utilization, joint health, and health-related quality of life (HRQoL) in the US.

Introduction:Among the most challenging complications of hemophilia A is inhibitor formation. A T-cell dependent B-cell response to exogenous factor VIII (FVIII), inhibitors result in a high burden of disease, with poorly controlled bleeding, twice the hospitalizations, 10-fold the cost, and 3.5-fold the mortality of non-inhibitor patients. Thus, a major goal of hemophilia management is to prevent and eradicate inhibitors. With the availability of novel therapies, including eloctate, a recombinant Fc-fusion protein (rFVIII-Fc) which induces regulatory T cells to promote FVIII tolerance, and emicizumab, a bispecific monoclonal FVIII mimetic, we designed the INHIBIT Clinical Trials Platform (X01HL143024), Fig.1. The platform is composed of two linked randomized phase III trials, the Inhibitor Prevention Trial(NCT04303559), comparing rFVIII-Fc vs emicizumab prophylaxis to prevent inhibitors, and the Inhibitor Eradication Trial(NCT04303572), comparing rFVIII-Fc immune tolerance induction (ITI) plus emicizumab vs rFVIII-Fc ITI alone to eradicate inhibitors. The platform uses adaptive design to incorporate historical data (Bayesian priors) on inhibitor formation to increase power and promote efficient use of rare data. Yet, there is equipoise regarding the optimal approach to inhibitor prevention and eradication, and, as clinical practice is changing, we aimed to test the feasibility of the INHIBIT trial design.

Introduction:Low von Willebrand factor (VWF) activity is prevalent in adolescents with heavy menstrual bleeding (HMB). There is a need to better genetically characterize these patients and improve our understanding of the pathophysiology of their bleeding risk.

Introduction: Scientific evidence increasingly suggests that, for many patients with severe hemophilia A, targeting higher sustained factor VIII (FVIII) levels is required to improve protection from bleeds, preserve joint health, and advance closer to the goal of a functional cure and health equity (Skinner MW, et al. Haemophilia. 2020). However, achieving high sustained factor activity levels with once-weekly dosing is not possible with currently approved FVIII therapies due to the FVIII half-life ceiling imposed by endogenous von Willebrand factor (VWF).

BACKGROUND:Dental extraction (DE) is one of the most common procedures in people with hemophilia A or hemophilia B (PWH-A, PWH-B), yet little is known about impact of the type of hemophilia, hemostatic therapies, and bleeding outcomes. To date, there is no standard protocol for how to treat PWH undergoing DE. Similar overall bleeding rates occur with pre- and postoperative factor replacement (FRP) therapy and single dose preoperative FRP (11.9% and 11.4%, respectively) (DE. Bajkin et al. Haemophilia 2020).