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Central venous access devices (CVADs) are essential for total parenteral nutrition administration in patients with short bowel syndrome (SBS). They are, however, fraught with complications including infection and venous thromboembolism (VTE), which increases associated morbidity and mortality in this population. There is evidence linking the development of CVAD-associated thrombosis and line-related infection. Thus, it has been postulated that prevention of catheter-related clot formation could minimize the risk of infection originating from the catheter. Recombinant tissue plasminogen activator (rtPA, alteplase), lyses clots by binding plasmin-bound fibrin in a clot and cleaving plasminogen to plasmin; moreover, it is widely used to clear occluded CVADs. Prophylactic rtPA lock therapy in children with SBS was evaluated as a single site pilot study to minimize line-associated VTE, infection, need for line replacement, and hospitalization at the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center. rtPA lock therapy was administered by parents/caregivers on a weekly basis over a 6-month time period in place of heparin lock therapy. Comparisons were made between line-associated complications in the cohort in the 6 months before study versus during the study period. Six out of 8 subjects completed the study over a 1-year time period. As a group, subjects experienced a significant decrease in the number of line-associated bloodstream infections from a mean of 1.9 infections in the 6 months before the study to a mean of 0.5 infections (P= 0.025). There was no change in the need for line replacement amongst subjects while on study. The primary outcome of VTE was not found in the cohort, and it is unclear whether rtPA lock therapy contributed to the lack of thrombosis development. Given the success of rtPA in this pilot study in reducing bloodstream infections, further investigation or rtPA lock therapy in patients with SBS is warranted.

Supplemental Digital Content is available in the text.

Intracranial hemorrhage (ICH) in the newborn period is a potential cause of serious morbidity and mortality in individuals with hemophilia. The incidence of ICH is estimated to be 2 to 4; however, depending on the mode of delivery, it may be considerably higher. Considering the varying sensitivities and costs of various imaging modalities, there remains controversy surrounding universal cranial imaging. Cost-utility analysis is the ideal tool to display the consequences of a decision made.

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.

Introduction: ATHN 8: U.S. Cohort Study of Previously Untreated Patients (PUPs) with Congenital Hemophilia is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at ATHN-affiliated sites in the United States. The ATHN 8: PUPs Study collects detailed demographic, diagnosis, treatment, bleed, and inhibitor data on children with moderate and severe hemophilia born on or after January 1, 2010 and followed at an ATHN-affiliated hemophilia treatment center (HTC). The endpoint for the overall study is inhibitor development or achieving 50 exposure days. A confirmed inhibitor is defined as two consecutive positive inhibitor titers (>0.5 Nijmegen Bethesda Units (BU) for hemophilia A and >0.3 Nijmegen BU for hemophilia B) which results in change in treatment. Available family history is also collected. For this interim analysis, we hypothesized that children with severe hemophilia A (HA) and a family history (FH) of hemophilia would have earlier age of diagnosis.

Thornburg: NovoNordisk: Research Funding; Genentech: Speakers Bureau; American Thrombosis and Hemostasis Network: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharmaceuticals: Research Funding; Spark Therapeutics: Consultancy; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; Biomarin: Consultancy, Speakers Bureau. Friedman:Alexion: Speakers Bureau; Instrumentation Laboratories: Consultancy; Alexion: Consultancy; Bayer: Consultancy. Guerrera:NovoNordisk: Consultancy, Speakers Bureau; Kedrion: Consultancy; Biomarin: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; Takeda: Consultancy. Malec:SOBI: Consultancy; Bayer: Consultancy; CSL: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau. Simpson:HEMA Biologics: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bioverativ/Sanofi: Research Funding. Tarantino:Spark: Membership on an entity's Board of Directors or advisory committees; HRSA: Membership on an entity's Board of Directors or advisory committees; CDC: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other; NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Grifols: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees. Carpenter:Novo Nordisk: Honoraria; Shire: Research Funding; Genentech, Inc.: Honoraria; Kedrion: Honoraria; CSL Behring: Research Funding; 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; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees.

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

Background:Clinical researchers affiliated with the American Thrombosis and Hemostasis Network (ATHN) conduct multi-institutional, observational cohort studies assessing the safety and effectiveness of various interventions for people affected by bleeding and clotting disorders. In parallel with the growth of ATHN's clinical studies, the number of new therapies for all congenital and acquired hematologic conditions, not just those for bleeding and clotting disorders, is increasing. Some of the recently FDA-approved therapies for congenital and acquired hematologic conditions have yet to demonstrate long-term safety and effectiveness. In addition, results from well-controlled, pivotal studies often cannot be replicated once a therapy has been approved for general use. With this explosion of potential new therapies on the horizon, it is imperative that clinicians and clinical researchers in the field of non-neoplastic hematology have a uniform, secure, unbiased, and enduring method to collect long-term safety and efficacy data. The overarching objective of ATHN Transcends (NCT04398628) is to characterize the safety, effectiveness, and practice of treatments for all people with congenital and acquired hematologic disorders in the United States.

Background

Poston: TeraImmune: Consultancy. von Drygalski: Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Parnes: Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman LaRoche: Research Funding; Sigilon: Membership on an entity's Board of Directors or advisory committees; Sunovion: Consultancy; I-mAb: Consultancy; Aspa: Consultancy; UniQure: Membership on an entity's Board of Directors or advisory committees. Walsh: Tremeau: Consultancy; Takeda: Consultancy; Biomarin: Consultancy; Genentech: Consultancy; Novo Nordisk: Consultancy. Kessler: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Janbain: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee member; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy. Kruse-Jarres: Biomarin: Consultancy; Genentech: Consultancy, Research Funding; Genentech/Roche: Speakers Bureau; CSL Behring: Consultancy; CRISPR: Consultancy; Pfizer: Consultancy.Emicizumab is FDA approved for congential hemophilia A and is a bispecific monoclonal antibody that binds coagulation factors IXa and X. We will discuss off label use for acquired hemophilia A.

Malec: HEMA Biologics: Consultancy; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; Pfizer: Consultancy; CSL Behring: Consultancy; Takeda: Consultancy. Recht: uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment.

Iorio: McMaster University: Current Employment; Bayer (funding to the institution): Research Funding; BioMarin (funding to the institution): Research Funding; NovoNordisk (funding to the institution): Research Funding; Octapharma (funding to the institution): Research Funding; Pfizer (funding to the institution): Research Funding; Roche (funding to the institution): Research Funding; Sanofi (funding to the institution): Research Funding; Sobi (funding to the institution): Research Funding; Takeda (funding to the institution): Research Funding. Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy. Matino: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Spark: Other: research grants; Octopharma: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: personal fees. Shapiro: Pfizer: Research Funding; Novartis: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; Daiichi Sankyo: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Glover Blood Therapeutics: Research Funding; Kedrion Biopharma: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Prometric BioTherapeutics: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; Agios: Research Funding; BioMarin: Research Funding; Takeda: Research Funding.

Malec: Bayer: Honoraria; Spark: Honoraria; CSL: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Octapharma: Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Callaghan:Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Alnylum: Equity Ownership; Bayer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau. Matino:Bayer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Bioviiix: Honoraria; Sanofi: Honoraria. Friedman:CSL: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Instrumentation Laboratory: Consultancy; Siemens: Consultancy. Sidonio:Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; 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; Kedrion: Research Funding.

Ragni: Sangamo: Research Funding; Alnylam/Sanofi: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Biomarin: Consultancy, Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Spark Therapeutics: Consultancy, Research Funding. Seaman:Spark Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Sidonio:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Octapharma: 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. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Malec:Hemostasis and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria; CSL: Honoraria. Rodgers:AstraZeneca: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy. Wheeler:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Von Willebrand disease (VWD) is the most common bleeding disorder found in children and adolescents. It has a varied clinical presentation, which likely contributes to challenges and delays in the correct diagnosis and the subsequent management of the disease.

Background:Factor IX (FIX) has distinct pharmacokinetic properties compared to factor VIII including significant distribution to the extravascular space. Extravascular distribution and binding to type IV collagen is important in hemostasis but not readily measureable in clinical practice for patients with hemophilia B receiving factor products. We previously reported data regarding use of EHL-FIX products in a cohort of patients who demonstrated issues with spontaneous bleeding and poorly controlled bleeding events; we now report data from an expanded cohort including performance of all EHL-FIX products available in US and Canada.

Roberts: Shire, a Takeda company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ: 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; Octapharma: Membership on an entity's Board of Directors or advisory committees; Spark: Membership on an entity's Board of Directors or advisory committees. Malec:Spark: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria; Takeda: Honoraria; CSL: Honoraria. Halari:Charles River Associates: Employment. Hale:Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Oladapo:Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Sidonio:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire, a Takeda company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; BioMarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; uniQure: Membership on an entity's Board of Directors or advisory committees.

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting 1% of the population, and characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, up to 80% have heavy menstrual bleeding (HMB), many of whom have depleted iron stores and iron deficiency anemia with reduced physical functioning, anxiety, depression, and poor quality of life. HMB is a serious problem causing significant health burden for those affected. The lack of effective therapies for menorrhagia is a major unmet healthcare needin women with VWD: in up to 30% desmopressin (DDAVP), combined oral contraceptives (COCs) hormones, or the recommended non-hormonal agent, tranexamic acid (Lysteda®,TA) may be ineffective or poorly tolerated. VWF concentrates, including plasma-derived VWF (pdVWF, Humate-P®) and recombinant VWF (rVWF, Vonvendi®) safely reduce bleeds in VWD, but few data exist on VWF use in menorrhagia, and no prospective trials are available to guide treatment. As rVWF has higher purity, potency, and a longer half-life than pdVWF, this phase III trial will compare rVWF with TA in reducing menorrhagia in women with type 1 VWD.

Malec: Bioverativ: Research Funding; Bayer: Consultancy; Bioverativ: Consultancy; Shire: Consultancy. Jaffray:Octapharma: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy, Research Funding. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Sidonio:Octapharma: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board; Kedrion: Research Funding; Biomarin: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board. Abshire:CSL: Consultancy; Shire: Consultancy; Novo Nordisk: Other: DSMB. White:Asklepios: Other: Scientific Advisory Board; Novo Nordisk: Consultancy; Shire: Other: Physician Leadership Group; Bayer: Other: GRAC; Bioverativ: Other: DSMB; Biomarin: Other: DSMB; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Ragni:CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Bioverativ: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

Malec: Shire: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy; Bioverativ: Research Funding. White:Biomarin: Other: DSMB; Bioverativ: Other: DSMB; Bayer: Other: GRAC; Shire: Other: Physician Leadership Group; Novo Nordisk: Consultancy; Asklepios: Other: Scientific Advisory Board; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Croteau:Biomarin: Consultancy; Bioveritiv: Consultancy; Catalyst Biosciences: Consultancy; CSL-Behring: Consultancy; Genetech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Ragni:Sangamo: Research Funding; CSL Behring: Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding; Alnylam: 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; Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

Background:Use of prophylaxis is the evidence-based strategy to prevent joint bleeds and reduce arthropathy for patients with severe hemophilia however, prophylaxis has not been universally adopted in the United States. Amongst patients with severe hemophilia enrolled in the ATHNdataset, the largest database of patients with disorders of hemostasis and thrombosis in the United States, as of 2015, 37% of patients with hemophilia A, and 45% of patients with hemophilia B do not receive prophylaxis. With the approval of extended half-life (EHL) factor products, patients and providers have options for less treatment-intense and burdensome prophylaxis. With the changing landscape of available hemophilia products, we aimed to quantify the number of patients treated at U.S. HTCs on prophylaxis utilizing the ATHNdataset with the objective determining the impact of EHL products on the proportion of patients with severe hemophilia receiving prophylaxis and to characterize use of prophylaxis according to age, race and ethnicity, geographic region, and payer.

Background:The hemophilia treatment landscape has evolved substantially in the last several years with the approval of extended half-life (EHL) products which reduce the burden of prophylaxis. Data reported from the American Thrombosis and Hemostasis Network (ATHN) as of June 2017 indicate that 21% of patients with moderate or severe hemophilia A, and 42% of patients with moderate or severe hemophilia B, receive prophylaxis utilizing an EHL. As new treatments become available and are adopted into practice, it is important to recognize the need for evaluation of efficacy, safety, and economic impact of their use outside of the clinical trial setting. We aimed to characterize the real world impact of EHL products by collecting detailed information on bleeding rates, joint health and quality of life amongst patients cared for at ATHN-affiliated Hemophilia Treatment Centers. We hypothesized that use of EHL products were utilized in at least 30% of patients and would lead to decreased ABRs and improved joint health. To date 67 of a planned 135 subjects have been enrolled, constituting this interim analysis.

Background:Inhibitor formation is a serious complication of hemophilia A, occurring in up to 30% with severe disease. It is associated with a T-cell response to infused factor VIII which neutralizes and renders it ineffective. Bypass therapy (rVIIa, FEIBA) is less effective, resulting in high morbidity and mortality. While immune tolerance (ITI) with high-dose FVIII neutralizes the inhibitor, it is costly, invasive, and unsuccessful in 30%. Basic studies suggest rFVIIIFc, Eloctate,is less immunogenic than standard recombinant FVIII, rFVIII, as the Fc portion contains regulatory T cells that promote tolerance. In the hemophilia mouse model, rFVIIIFc reduces inhibitor frequency, lowers titer, and shortens ITI, but little is known of its impact on inhibitor patients, as they were excluded from clinical trials.

BACKGROUND:Acquired copper deficiency in the pediatric population is a rare event but given the hematologic and potentially irreversible neurologic consequences, prompt recognition and treatment is important. Copper is an essential cofactor in enzymatic reactions essential to proper hematologic, skeletal, neurologic and vascular function. Copper is found in a variety of foods including meats, nuts, legumes, and whole grains while lacking in highly processed foods. Copper requirements in children over the age of 4 is 15 mg/day, which is readily acquired in a typical diet. Copper deficiency is known to occur in patients with the rare X-linked mutation in the ATP7A copper transport protein, known as Menkes Syndrome, and in older individuals with gastrointestinal bypass surgery who lose the ability to absorb copper through the duodenum and proximal jejunum, however, it is rarely reported in other conditions. Pediatric patients with autism spectrum disorders or developmental delay with a limited dietary repertoire are at risk for copper deficiency thus a high index of suspicion must exist in order to diagnose the disorder.

Ragni: SPARK: Research Funding; Genentech: Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding; Novo Nordisk: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Baxalta: Research Funding; Biogen: Consultancy, Research Funding; Biomarin: Consultancy; Shire: Consultancy; CSL Behring: Research Funding. James:Intramural University of Ghana Research Fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding. Malec:Biogen: Consultancy; Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding. Kessler:Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Kouides:CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy. Neff:Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: DSMB Chair for research study; ABIM: Other: Hematology Exam committee; CSL Behring: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Philipp:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: Data Safety Monitoring Board. Brooks:Gilead Sciences: Research Funding.

Introduction:The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy in patients with severe hemophilia A who develop inhibitors. The long-acting recombinant factor VIII Fc fusion protein, rFVIIIFc (Eloctate™), which is safe and effective in the prevention and treatment of bleeding events, may promote tolerance to FVIII as shown in preclinical animal models and an inhibitor prone child, as Fc suppresses immunoregulatory Tcells to proteins to which Fc is attached. We therefore previously hypothesized rFVIIIFc would provide effective ITI, specifically shortening and simplifying ITI, and have previously described successful inhibitor eradication in three patients. Long-term follow-up data after successful ITI in patients with severe hemophilia remains limited. In the International Immune Tolerance Induction study, at 1-year follow-up, 6 of 66 subjects who had achieved tolerance demonstrated evidence of relapse at a median of 9.5 months. Of these 6 subjects, 1 had a measurable inhibitor titer and 5 had reduced FVIII recovery. We aim to provide follow-up data on our cohort of patients who had successful inhibitor eradication utilizing rFVIIIFc for ITI.

Background:Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is characterized by deficient and/or defective von Willebrand factor (VWF) which results in spontaneous and traumatic mucosal bleeding. In women with VWD, pregnancy is associated with excess blood loss and poor quality of life. Recently, a prospective cohort study by James et al Haemophilia2015, determined that even when treatment is given, women with VWD had lower VWF levels, greater blood loss at delivery, and lower hematocrit than controls without VWD. The reason for this finding remains unknown. Current VWF dosing is weight-based, but does not account for the ~1.4-1.5-fold increase in blood volume during pregnancy. To address this, we conducted a feasibility study for a prospective, randomized phase III trial comparing weight-based, 50 IU/kg, with volume-based, 80 IU/kg, VWF to prevent postpartum hemorrhage (PREVENT PPH Trial).

Ragni: SPARK: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Malec:Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding; Biogen: Consultancy. Journeycake:CSL: Consultancy; Biogen: Consultancy; Baxalta/Shire: Consultancy.

Off Label Use: recombinant VWF and plasma-derived VWF for treatment of menorrhagia in VWD. Ragni:Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Bayer: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Dimension Therapeutics: Research Funding; CSL Behring: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Genentech Roche: Research Funding; Medscape, Web MD: Honoraria; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Ferring Pharmceuticals: Research Funding; Biomarin: Research Funding; Vascular Medicine Institute: Research Funding. Malec:Baxalta: Research Funding; Biogen: Research Funding. Coyle:Bayer: Membership on an entity's Board of Directors or advisory committees. Drygalski:Biogen: Consultancy; Baxalta: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Hematherix Inc: Equity Ownership; Biogen: Research Funding; Baxalta: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; CSL Behring: Speakers Bureau; Hematherix Inc: Membership on an entity's Board of Directors or advisory committees. James:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Jobe:Biogen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Konkle:Octapharma: Research Funding; Baxalta: Consultancy; CSL Behring: Consultancy; Baxalta: Research Funding. Kouides:CSL Behring: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Kedrion: Speakers Bureau. Ma:Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Nance:Patient Services, Inc.: Membership on an entity's Board of Directors or advisory committees. Neff:Alexion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Membership on an entity's Board of Directors or advisory committees. Philipp:Baxter: Research Funding. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees.

Background:von Willebrand disease (VWD) is the most common congenital bleeding disorder. In affected women, menorrhagia is the most common bleeding symptom. Combined oral contraceptives (COCs), the first choice therapy recommended by NHLBI 2007 guidelines, reduce menstrual loss by increasing coagulation factor levels, but at least 30% are unresponsive or intolerant. Non-hormonal options include the antifibrinolytic tranexamic acid (TA), reduces menstrual bleeding by 30-50%, but requires dosing three times a day. Intranasal desmopressin (Stimate) is simpler to use, but ineffective in ~20%. Effective treatment for menorrhagia, thus, remains the greatest unmet health need in women with VWD. Von Willebrand factor (VWF) is used typically when first-line and second-line treatments fail, but few data exist regarding its effectiveness in reducing menorrhagia.

Ragni: Alnylam: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Biogen: Research Funding; SPARK: Research Funding; Pfizer: Research Funding; Ferring Pharmceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Medscape, Web MD: Honoraria; Genentech Roche: Research Funding; Vascular Medicine Institute: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; CSL Behring: Research Funding; Dimension Therapeutics: Research Funding; Biomarin: Research Funding. Malec:Biogen: Research Funding; Baxalta: Research Funding. Seaman:Vascular Medicine Institute: Research Funding.

Malec: Baxter: Research Funding; Biogen: Research Funding. Ragni:Pfizer: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Dimension: Research Funding; Vascular Medicine Institute: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; SPARK: Research Funding; Biomarin: Research Funding; Genentech Roche: Research Funding; Bayer: Research Funding; Biogen: Research Funding; Alnylam: Research Funding. Journeycake:CSL, Baxalta, NovoNordisk: Consultancy; ATHN: Research Funding; Biogen: Speakers Bureau; ATHN: Membership on an entity's Board of Directors or advisory committees.

Background:Inhibitor formation is among the most serious complications of hemophilia A. These alloantibodies are directed against foreign infused factor VIII (FVIII) and occur in up to 25-30% of children with severe hemophilia A, after the first 9-10 exposures to FVIII. The inhibitor neutralizes infused FVIII, requiring alternative "bypass" therapy to treat bleeds, e.g. factor VIIa or FEIBA, to "bypass" the missing factor, and immune tolerance to suppress the inhibitor. Despite these approaches, bleeding is poorly controlled, resulting in 2-fold as many hospitalizations, 10-fold the cost, and 1.7-fold higher mortality. As the burden of disease is high, efforts have been directed at preventinginhibitors. There is increasing evidence that a specialized subset of T cells known as T-regs or CD4+/CD25+/FoxP3+regulatory T cells, may play a role in mediating immune response to FVIII. Differentiation and function of T-regs are controlled by the X-chromosome-encoded transcription factor, FoxP3, and are generated centrally in the thymus and peripherally in extrathymic tissues. In the inhibitor-prone hemophilia A mouse (FVIII exon 16 knockout) T-regs reduce or prevent immune response to factor VIII: this is presumed to occur through T-reg-mediated hyporesponsiveness of T helper cells to factor VIII. T-regs also mediate maternal tolerance to the fetus in normal pregnancy. In early pregnancy there is an increase in immunosuppressive T-regs, peaking during the second trimester, and declining postpartum. T-regs are hypothesized to modify maternal immune response to the fetal "allograft" to promote tolerance to foreign paternal-derived antigens in the developing fetus. We hypothesizedthat defects in maternal T regulatory response to factor VIII might be associated with lack of normal FVIII tolerance in their offspring, leading to an alloantibody response, i.e. inhibitor formation. We therefore sought to quantitate and functionally characterize T-regs in mothers of children with congenital hemophilia A with inhibitors, in order to determine if maternal lack of tolerance to FVIII is associated with inhibitor formation in their affected sons.

Introduction:Inhibitor formation affects approximately 30% of individuals with severe hemophilia A. The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy, although typically requires daily high-dose factor VIII via a port for up to a year. Extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc, Eloctate¨) has a half-life extension 1.5-fold longer than standard recombinant FVIII (rFVIII), reducing treatment frequency, and also induces regulatory T cell response to FVIII in animal models. We hypothesized that rFVIIIFc would provide more effective ITI, specifically shortening ITI, than rFVIII. We describe ITI with rFVIIIFc in three patients with severe hemophilia A.

No relevant conflicts of interest to declare.

Background:Among the most serious complications of hemophilia A is anti-VIII inhibitor formation, which occurs in ~25% of patients, typically in childhood within the first 20 exposures. Morbidity is high, hospitalization is frequent, and healthcare cost is high. Thus, immune tolerance induction (ITI), a program of regular F.VIII therapy, is used to eradicate the inhibitor. A landmark study demonstrated ITI was equally effective with high-dose (HD) (200 IU/kg/day) or low-dose (LD) (50 IU/kg 3x/week) F.VIII, but found a bleeding rate 2-fold greater in the LD arm. As the inhibitor neutralizes F.VIII, no difference in bleeding was expected. We hypothesized that thrombin generation assay (TGA), a global measure of tissue factor-induced thrombin generation that predicts bleeding in hemophilia better than F.VIII, might clarify this question.

Postpartum hemorrhage (PPH) is a cause of potentially serious morbidity and mortality in women of reproductive age. Prior data suggests that women with von Willebrand Disease (VWD) and other inherited bleeding disorders (OBD) experience PPH at a rate greater than the general population. Little published data exist regarding the incidence or predictors of PPH in women with VWD or OBD to guide obstetricians and hematologists in the management of these at-risk women.In order to evaluate the incidence of PPH, clinical characteristics and obstetric outcomes of women with VWD and other inherited bleeding disorders we analyzed data from the Pennsylvania Health Care Cost Containment Council (PHC4) database between January 1, 2007 and December 31, 2011. The council collects data from over 4.5 million inpatient hospital discharges and ambulatory/outpatient procedure records each year from hospitals and freestanding ambulatory surgery centers in Pennsylvania. Data from all women with VWD and OBD (including factor XI deficiency, hemophilia A carriers, hemophilia B carriers) as well as all women who experienced PPH was extracted from the database. Data elements, in addition to demographic factors, were identified by ICD-9 codes, including medical comorbidities, hospital length of stay, obstetric complications, and birth outcomes. We compared data from women with VWD and OBD, specifically in those with and without PPH. Differences between groups were analyzed using chi-square or Fisher’s exact tests for categorical variables and two-sample t-tests for continuous variables.Between 2007 and 2011, there were a total of 1,234 women with bleeding disorders, including 506 with VWD and 728 with OBD, who underwent delivery. Of these, 54 (4.4%) experienced PPH, including 28 (5.5%) with VWD and 26 (3.6%) with OBD. Among women with VWD, those with PPH were younger, 25.4 vs. 27.8 years (p=0.034), and nearly 2-fold more likely to have anemia, 27.6% vs. 14.2% (p=0.059), but had no greater frequency of caesarean section delivery (p=0.234) or pregnancy complications (p=0.678), including antepartum bleeding, preeclampsia, placental abruption, gestational diabetes, fetal growth restriction, preterm labor, or intrauterine fetal death. There were no differences in live births or mortality (all p≥0.999), nor in medical comorbidities (p=0.300), including diabetes, hypertension, obesity, and hyperlipidemia. Among women with OBD, those with PPH were over 5-fold more likely to have anemia, 48.1% vs. 8.6% (p<0.001), but had no higher rates of caesarean section delivery (p=0.234) or pregnancy complications, mortality or lower rates of live births (all p≥0.999).The incidence of postpartum hemorrhage (PPH) in women with VWD is 5.5% and 3.6% in those with OBD. Importantly, anemia appears to be a marker of PPH in women with bleeding disorders as it is present in over one-fourth (27.6%) of women with VWD and PPH and in nearly one-half (48.1%) of those with OBD. These data suggest that screening hemoglobin, along with standard screening of factor levels in late pregnancy, may help identify those with VWD or OBD at risk for PPH. Future prospective studies will be needed to confirm this hypothesis.No relevant conflicts of interest to declare.

The diagnosis of type 1 von Willebrand disease (VWD), the most common inherited bleeding disorder, presents a diagnostic challenge in children. In the absence of a prior hemostatic challenge in children, a VWD diagnosis may be missed by the Tosetto bleeding score, as it is based, in part, on bleeding symptoms, i.e. with surgery, menses, or childbirth, that may not occur until after childhood. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. Other bleeding scores, such as the James score, which assesses early life bleeding, e.g. cephalohematoma, macroscopic hematuria, and umbilical stump, post-circumcision, post-venipuncture bleeding, has been validated in children with VWD, but early life bleeding events are uncommon in VWD. We previously described a 4-variable Composite Score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children < 11 years of age, when at least two of four criteria are positive: 1) Tosetto bleeding score ≥ 1; 2) family history of VWD or bleeding; 3) personal history of iron deficiency anemia; and/or 4) positive James early bleeding score. The purpose of this study was to validate a Composite Score of ≥ 2 (i.e. at least 2 of 4 variables positive) for identifying children with VWD.We designed and conducted a prospective validation study to determine the accuracy of the Composite Score for identification of children (<11 years of age) with VWD. Following parental consent, children without a prior history of VWD undergoing VWD testing were enrolled, and survey data were collected including personal bleeding history (including Tosetto and James scores), history of iron deficiency anemia, and family history of VWD or bleeding. Results of VWD testing were collected, including VWF:RCo, VWF:Ag, and VIII:C in addition to VWF multimers, if performed. Survey data and bleeding scores were compared between those with and without VWD, defined by VWF:RCo <30 (NIH 2008 criteria), or <40, or <50 IU/dL. Prior to study, it was determined that a Composite Score ≥ 2 would have 90% power to identify VWD defined by VWF:RCo <0.30 IU/dL, and 80% power to identify VWD by VWF:RCo <40 IU/dL. Categorical variables were compared using chi-square or Fischer’s exact test. Continuous variables were compared using two-sample t-test or Wilcoxon’s rank sum test. Sensitivity, specificity, positive and negative predictive value of the Composite Score of ≥ 2 to diagnose VWD were determined.A total of 195 subjects were enrolled from 12 participating centers from 2010-2013, of whom 193 patients with no missing data were included in the analysis. A total of 81 (41.9%) children had type 1 VWD, including 11 (5.7%) with VWF:RCo <30 IU/dL (Group A), 24 (12.4%) with VWF:RCo <40 IU/dL (Group B), and 46 (23.8%) with VWF:RCo <50 IU/dL (Group C); the remainder with VWF:RCo ≥50 IU/dL were unaffected. There were no significant demographic differences between groups: overall 54.9% were male, 82.4% were Caucasian, and the mean age was 4.7 years. A composite score of ≥ 2 had 63.6%, 75%, and 67.4% sensitivity in diagnosing type 1 VWD in Groups A, B, and C respectively; 33.5%, 34.9%, and 34% specificity in diagnosing type 1 VWD, respectively; and 93.8%, 90.8%, and 76.9% negative predictive value, respectively. Based on the performance of the composite, with VWD being defined by a VWF:RCo of <30, <40, or <50 IU/dL, 31.6%, 30.6%, and 25.9% of subjects, respectively, had a negative composite score and therefore would not have required VWD testing.This is the first study to prospectively validate the Composite Score to identify children with type 1 VWD. Although the sensitivity and specificity of the Composite Score were lower than in the original study (above), the latter included only VWD subjects, while this validation study included all, VWD and non-VWD, undergoing testing. The negative predictive value of the Composite Score was robust, especially at lower VWF:RCo, and indicates that VWD testing could be eliminated in nearly a third of children referred for VWD testing. Given the difficulty of diagnosing VWD in children, the Composite Score may be an important screening tool for diagnosis of type 1 VWD in children.Kerlin: Bayer Healthcare US: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; NovoNordisk A/S: Consultancy, Honoraria.

Postpartum hemorrhage (PPH) is a cause of potentially serious morbidity and mortality in women of reproductive age. Prior data suggests that women with von Willebrand Disease (VWD) and other inherited bleeding disorders (OBD) experience PPH at a rate greater than the general population. Little published data exist regarding the incidence or predictors of PPH in women with VWD or OBD to guide obstetricians and hematologists in the management of these at-risk women.

The diagnosis of type 1 von Willebrand disease (VWD), the most common inherited bleeding disorder, presents a diagnostic challenge in children. In the absence of a prior hemostatic challenge in children, a VWD diagnosis may be missed by the Tosetto bleeding score, as it is based, in part, on bleeding symptoms, i.e. with surgery, menses, or childbirth, that may not occur until after childhood. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. Other bleeding scores, such as the James score, which assesses early life bleeding, e.g. cephalohematoma, macroscopic hematuria, and umbilical stump, post-circumcision, post-venipuncture bleeding, has been validated in children with VWD, but early life bleeding events are uncommon in VWD. We previously described a 4-variable Composite Score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children < 11 years of age, when at least two of four criteria are positive: 1) Tosetto bleeding score ≥ 1; 2) family history of VWD or bleeding; 3) personal history of iron deficiency anemia; and/or 4) positive James early bleeding score. The purpose of this study was to validate a Composite Score of ≥ 2 (i.e. at least 2 of 4 variables positive) for identifying children with VWD.