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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.

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.

1. Amita Ghuman, MD* 2. Allison Close, MD† 3. Lynn Malec, MD, MSc‡ 1. *Department of Pediatrics and 2. †Division of Hematology/Oncology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 3. ‡Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI; Division of Hematology/Oncology, Departments of Medicine and Pediatrics, Medical College of Wisconsin, Milwaukee, WI A 15-year-old Caucasian boy with autism, global developmental delay, chronic constipation, and oral aversion presents to the emergency department with parental concerns for worsening fatigue, weakness, and gait instability. Symptoms have been slowly progressive and accompanied by weight loss over the past 6 months. Whereas he used to run and jump, he is now unable to stand independently. His long-standing feeding difficulties have been refractory to intensive feeding programs, yet he continued to feed orally (with no previous attempts at enteral/parenteral nutrition). His daily diet consisted only of 50 to 60 oz of whole milk and 25 to 30 individual servings of butterscotch pudding per day (1,680–1,880 calories per day, 0.7 mg of iron per day). On presentation he is afebrile, with normal blood pressure and respiratory rate for age. His heart rate is 118 beats/min. Growth parameters are at the 2nd and 25th percentiles for weight and height, respectively. On physical examination the patient is well-appearing, thin with coarse facial features, and nonverbal but cooperative. Conjunctival pallor is present. Cardiovascular, respiratory, gastrointestinal, and dermatologic examination findings are normal other than mild tachycardia. On neurologic examination he has increased tone with extension in his upper and lower extremities, decreased muscle bulk, 3/4 deep tendon reflexes, and narrow-based gait with valgus deformity of the right leg, along with difficulty with dorsiflexion of his feet when walking. He …

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.

Background 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. Methods 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. Results 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.

Introduction Acquired hemophilia A (AHA) is a severe bleeding disorder due to autoantibodies against factor VIII (FVIII) with high morbidity/mortality from bleeding and complications from immunosuppression. Outcomes could improve with adequate hemostatic prophylaxis in the outpatient setting and reduced immunosuppression. Emicizumab, a FVIII-mimetic bispecific antibody, has revolutionized prophylaxis for congenital hemophilia A, but the role in AHA is unknown with limited data. Methods 87 hematologists at different US hemophilia treatment centers (HTCs) were queried on the use of emicizumab for AHA. Pediatric hematologists were excluded given the negligible incidence of pediatric AHA. 10 respondents had experience with off label emicizumab for AHA and were prompted for de-identified data on AHA cases treated with emicizumab at their HTC. These responses were compiled into a central database at the University of Washington under IRB exemption. Results Of the 87 US HTCs queried, 32 reported experience treating AHA; combined, 358 patients with AHA were treated at the 32 HTCs within the last 5 years. 10 respondents (31%) used off label emicizumab for a total of 40 patients with AHA. HTCs that had not used emicizumab for AHA had seen fewer cases of AHA in the last 5 years (average 8 vs 17 patients). Most HTCs (86%) would consider emicizumab if safety data in AHA was available. Of the 10 respondents who used emicizumab for AHA, 7 submitted deidentified data for a total of 24 cases of AHA treated with emicizumab. The median age of subjects was 73 years (range 34-87), 10 were female. The majority (17) were Caucasian. 15 had conditions often associated with AHA: autoimmune disease (7, with 4 on immunosuppression), cancer (6), and peripartum (2). Additionally, one patient had mild congenital hemophilia A and developed an autoantibody to FVIII. Other comorbidities included metabolic syndrome (11), vascular disease (10), prior venous thrombosis (3, none on anticoagulation), alcoholic pancreatitis (1) and Alzheimer's dementia (1). 3 had no comorbidities. At time of diagnosis, 4 were on antiplatelet therapy and 2 on therapeutic anticoagulation, which were discontinued in all cases. The majority presented with bleeding (92%): 63% was spontaneous with most in soft tissue (67%), followed by hematuria (17%), hemarthrosis (8%), retroperitoneal (8%), gastrointestinal (8%), subdural hematoma (4%). At diagnosis, the median FVIII was Emicizumab was mostly started to improve bleeding prophylaxis and/or facilitate outpatient management (Table A). Dosing varied with most receiving the standard loading regimen used for congenital hemophilia A (Table A). Bleeding resolved in most after starting emicizumab (Table B). One patient had new ecchymoses after the first loading dose, which resolved after further doses. 3 patients had breakthrough bleeding on maintenance emicizumab: two had hematuria that resolved with hemostatic agents and in one case a procedure; another had severe gastrointestinal bleeding 4 months after starting emicizumab that required an endoscopy and hemostatic agents (Table B). The majority (95%) tolerated emicizumab without complications. One patient developed a lower extremity deep vein thrombosis (DVT) while on maintenance emicizumab 3 mg/kg every other week. This patient had no history of DVT, but was on apixaban for atrial fibrillation until AHA diagnosis. Anticoagulation was resumed after the DVT. Emicizumab was held for 4 weeks and restarted at 1.5 mg/Kg every other week with no additional adverse events. At the time of the survey, 4 patients had died, of whom 2 were on emicizumab. No deaths were attributed to emicizumab. Of the living patients, 8 remain on emicizumab with persistent inhibitors, with 6 off immunosuppression (Figure One). Conclusion Emicizumab could improve AHA outcomes by providing outpatient hemostatic prophylaxis with lower intensity immunosuppression. Additional safety and dosing data are needed to clarify the role of emicizumab in AHA. Figure 1 Figure 1. Disclosures 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. OffLabel Disclosure: 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.

Background The development of antibodies (inhibitors) to clotting factors compromises the treatment of people with Hemophilia A (HA) and B (HB), and results in ineffective clotting-factor therapy, higher risk of complications, and need for bypassing agents to achieve hemostatic control. Objectives To evaluate the association between presence of inhibitors and peri-operative hemostatic control, complications, and deviations from pre-surgery plans. Methods We conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database (1998 - 2019). Association between specified outcomes and inhibitor status at surgery was assessed using generalized linear models while controlling for patient and procedural characteristics. Results A total of 1,492 surgeries were conducted in 539 patients with HA or HB, 4.8%(72/1492) of which were conducted in 20 (15 HA; 5HB) patients with inhibitors. Of the 72 surgeries involving inhibitors, 30 were high-titer, 10 low-titer and 32 with unreported inhibitor titers. Adjusting for patient's age, hemophilia diagnosis, surgery setting, and surgery type, the risk of achieving perioperative hemostasis was lower in surgeries involving inhibitors compared to non-inhibitor surgeries (65.6% vs 91.4%; aRR=0.78; 95% CI= 0.61-0.99; p=0.038). Complications including hemorrhage, fever, pain, thrombosis, and infections occurred more frequently in surgeries involving inhibitors (31.7% vs 14.6%; aRR= 1.67, 95% CI= 1.07 - 2.63; p=0.025). Deviation from pre-surgical plans, usually due to the development of complications including lack of effective hemostatic control, also occurred more frequently in surgeries involving inhibitors compared to those without inhibitors (70.8 vs 39.5%; aRR= 1.63, 95% CI= 1.33 - 2.01; p Conclusion Procedures involving patients with inhibitors have increased risk of adverse perioperative outcomes compared to those without inhibitors. Key Words: Inhibitors, Hemophilia, Surgery, Perioperative outcomes, Database. Disclosures 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.

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. Study Design and Methods: ATHN Transcends is a longitudinal, natural history, observational cohort study being conducted at approximately 150 ATHN-affiliated sites (ATHN Affiliate Network). Participants will be followed for a minimum of 15 years. Specific data will be collected for participants enrolled in cohort-specific arms. Each participant will be assigned in a single cohort: Hemophilia, Von Willebrand Disease, Congenital Platelet Disorder, Rare Bleeding Disorders, Bleeding Not Otherwise Specified, Thrombosis/Thrombophilia, or Non-Neoplastic Hematologic Conditions (see Figure 1). Inclusion criteria include: any age, any congenital or acquired non-neoplastic hematologic disorder, having a bleeding phenotype with an unknown diagnosis, or having a connective tissue disorder with a bleeding tendency. Exclusion criteria include not qualifying for a cohort and the unwillingness or inability to give informed consent or assent. Data will be collected at baseline, every three months, annually and at study exit (Figure 2). Participant biologic samples will be collected at enrollment and yearly thereafter. Safety endpoints mirror those collected by the European Haemophilia Safety Surveillance and include allergic and other acute events, treatment-emergent side effects of therapy, transfusion-transmitted infections, inhibitor development, thrombosis and cardiovascular events, malignancies, neurologic events, and deaths. Adverse events of special interest including thrombotic microangiopathies, anti-drug antibodies, unanticipated bleeding, and hospitalizations will be collected. A panel of patient-reported outcomes (Table 1) will be collected at baseline and annually. Descriptive statistics will be calculated to analyze the primary and secondary outcomes. If there are questions involving multiple cohorts, given there is adequate power to make comparisons between cohorts, for a discrete outcome, we will report estimated difference in percentage between cohorts as well as the 95% confidence interval (CI) of such a difference. If the outcome measurement is a continuous variable, we will report the mean difference and its associated 95% CI. Discussion: The key advantages of an independent study conducted by the ATHN Affiliate Network include the ability to observe participants on a variety of treatment regimens regardless of regimen dosing, frequency, or time of initiation; the ability to observe participants on recently FDA-approved therapies as well as continued monitoring of well-established therapies; the ability to enrich the ATHNdataset; and the ability to be the initial cohort study involving potentially all ATHN-affiliated sites to provide the infrastructure for all congenital and acquired hematologic disorders-related sub-studies in cooperation with other funders, including federal, foundation, academic and industry sources. ATHN Transcends received central institutional review board approval in April 2020. The protocol is currently being rolled out throughout the ATHN Affiliate Network. Figure 1 Figure 1. Disclosures 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.

Despite treatment, women with von Willebrand disease (VWD) have lower von Willebrand factor (VWF) levels and greater blood loss at delivery than controls. Current weight-based dosing does not account for the ~1.5-fold increase in blood volume in pregnancy.To evaluate the feasibility of a trial to prevent postpartum hemorrhage (PPH), we reviewed pre-pregnancy and 8th month VWF levels in women with VWD with and without PPH following vaginal delivery, assessed VWF concentrate use at delivery by U.S. hemophilia treatment center physician survey, and reviewed thrombosis risk with VWF concentrate by literature review. We determined trial interest and acceptability by structured interviews of physicians and patients. Analysis was by Student's t-test for continuous data, and chi-square or Fisher's exact test for discrete data.PPH was associated with lower pre-pregnancy VWF:RCo, p0.005; higher pre-pregnancy, 8th and 9th-month weight, each p0.001; a family bleeding history, p=0.036; and VWF concentrate treatment, p=0.005. Surveyed physicians reported first-line therapy at delivery was VWF concentrate, at a mean dose 50IU/kg. A trial of a 1.5-fold volume-based dose increase was acceptable to physicians and patients, if it is safe and if costs and visits are minimized. A literature review determined thrombosis risk with VWF concentrate is low, 0.4%.This study suggests pre-pregnancy VWF:RCo may predict PPH, but 50-80IU/kg VWF concentrate dosing may not prevent PPH. If pharmacokinetic modeling confirms volume-based dosing achieves VWF levels comparable to pregnant controls, it may be possible to determine if volume-modified VWF concentrate dosing will reduce PPH in VWD.

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. Methods: To establish design feasibility, we conducted interviews with 30 hemophilia treatment center (HTC) physicians participating in the INHIBIT trials, to determine prophylaxis and tolerance regimens they prescribe and perceived barriers to the INHIBIT trials design. A 4-question survey was subsequently emailed to these physicians to ascertain the initial prophylaxis regimens they prescribe in previously untreated patients (PUPs) with severe hemophilia A, and the initial immune tolerance induction (ITI) they prescribe in high-responding inhibitor patients with severe hemophilia A; if new inhibitors had been observed during emicizumab prophylaxis, and willingness to participate in post-trial surveillance. Results: In interviews, HTC physicians indicated the issues that influenced choice of prophylaxis/ ITI regimen were patient preference, family history of inhibitors, infusion frequency, IV access, port requirement, and family fatigue. In the absence of clinical trials data in PUPs, there was general agreement that emicizumab prophylaxis, with it simpler subcutaneous (SQ) administration, might delay or potentially prevent inhibitors. Survey findings in Table 1 indicated 75% of physicians prescribe extended half-life (EHL) FVIII in a once-weekly prophylaxis regimen, as planned in the Prevention Trial, despite the persistent 27% inhibitor rate (ALong PUPs Trial, Königs et al, ISTH 2020) and potential risks with port use. There was support for the 1:3 preferential randomization to emicizumab in the Prevention Trial due to the simpler SQ route, despite concern it might delay rather than prevent inhibitor formation, although no inhibitors were reported by physician survey with emicizumab use alone. There was also concern that breakthrough bleeds requiring FVIII during emicizumab prophylaxis, might lead to immune activation and inhibitor formation. There was strong agreement, however, in 29 (97%) of physicians to participate in post-trial surveillance for long-term inhibitor outcomes. FVIII ITI was considered essential to eradicate inhibitors, despite the intensity of the infusion regimen. Notably, 60% prescribe emicizumab with FVIII ITI, as planned in the Eradicate Trial, although the every-other-day infusion was considered a potential barrier to participation. Omitting FVIII ITI was not favored due to the risk of inhibitor anamnesis if FVIII treatment was subsequently required for surgery or acute hemorrhages. Despite these concerns, there was agreement to participate in the trials. Discussion: Physician interviews and surveys confirm there is heterogeneity in current hemophilia clinical practice, specifically in initial prophylaxis regimens and in initial immune tolerance regimens, including agent choice and duration. However, there is physician consensus with the INHIBIT trial aims and with the proposed INHIBIT trial regimens to prevent and eradicate inhibitors. Disclosures 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. Methods: Available data through April 30, 2020 were analyzed for participants with severe HA (factor VIII Results: Twenty-six HTCs have enrolled 112 male participants with severe HA. FH regarding hemophilia is known in 94 (84%) and positive in 60 (64%). Patients with a positive FH compared to patients without a positive FH were diagnosed significantly earlier and were less likely to have circumcision (Table 1). Bleeding rate and factor exposure rate was similar within the first 30 days of life. Among 46 subjects who bled within the first 30 days of life, 6 (13.0%) bled due to circumcision (2 have a positive family history, and 4 have a negative family history); 34/46 (74%) had other bleeding events within the first 30 days. Conclusions: The interim analysis of PUPs born with severe HA between 2010-2019 demonstrates a majority have a FH of HA which is associated with an earlier age at diagnosis compared to those without a FH. Those without a FH of HA have higher rates of circumcision. Earlier identification of hemophilia could result in perinatal management strategies and avoidance of procedures such as circumcision that could result in bleeding. Disclosures 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 The recent introduction of new therapies for hemophilia A and B (HA and HB) mandates careful monitoring of the safety of these treatments as their use becomes more widespread. The American Thrombosis and Hemostasis Network (ATHN) collects information about the use of all HA and HB therapies through the more than 140 ATHN-affiliated hemophilia treatment centers (HTCs) in the United States (US). The primary aim of ATHN 7: A Natural History Cohort Study of the Safety, Effectiveness, and Practice of Treatment for People with Hemophilia is to monitor the safety of current hemophilia therapies. Secondary aims include assessment over time of real-world effectiveness and patient experience of current therapies. METHODS ATHN 7 is being sponsored by ATHN. It is a longitudinal, prospective cohort study being conducted at over 20 ATHN-affiliated sites in the US. The study is approved by central and local institutional review boards. Any person with a diagnosis of congenital hemophilia A or B (factor VIII or IX activity < 50%) who receives care at a participating site is eligible for inclusion. All participants and parents/guardians sign informed consents and assents prior to participation. Patients are excluded if they have any other known bleeding disorder. Adverse events, including those events designated by the European Haemophilia Safety Surveillance (EUHASS) group as well as other adverse events of special interest, are recorded and monitored. Demographic and clinical information are collected at baseline and at least quarterly through patient interview and medical record review. Health status is measured using the 5-level EuroQoL-5D questionnaire (EQ-5D-5L). Descriptive statistics of the baseline medical history and demographic data are used to characterize the study population. RESULTS The first participant consented to ATHN 7 in February 2019. As of 06/30/2020, a total of 367 subjects were enrolled in the study from 24 sites. Baseline demographics, clinical characteristics, and treatments are shown in Table 1. Most participants (69.9%) had severe HA. Approximately half of the participants were being treated with clotting factor as their primary therapy and half with a bispecific antibody. Adverse events reported to date include allergic reactions/redness at the injection site, rash unrelated to treatment, and a severe subdural hematoma due to a fall, all in patients receiving emicizumab (Table 2). At baseline, problems with mobility, self-care, and completing usual activities were reported by 32.9%, 13.0%, and 33.7% of participants, respectively. Problems with pain and anxiety were reported by 52.4% and 34.1% of participants (Figure 1). The average health status rating was 83.4 out of 100 (Figure 2). DISCUSSION These results demonstrate the capability of ATHN 7 to enroll a large cohort of subjects from multiple sites, monitor safety events, and assess outcomes related to living with and being treated for HA and HB. Adverse events attributed to any hemophilia therapy have been limited to minor skin reactions and have not led to product discontinuation. One subject experienced a trauma-related subdural hemorrhage, which provides important information on the risk of bleeding from severe/significant trauma in those receiving emicizumab. We provide a sobering picture of the high prevalence of difficulties with activities of daily living, pain, and mental health concerns. Despite many advances in therapy, hemophilia continues to have a real, everyday impact on the lives of our patients. CONCLUSIONS During the first 16 months of enrollment in the ATHN 7 study, we observed skin reactions, as well as one severe, unanticipated bleeding event due to trauma. At baseline, pain, anxiety/depression, and impaired physical function were concerns for a significant proportion of the individuals in the study. Disclosures Buckner: Tremeau Pharmaceuticals: Consultancy; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Takeda: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Spark: Consultancy; Genentech: Consultancy; Biomarin: 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; Shire: Research Funding; CSL Behring: Research Funding; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Honoraria; Kedrion: Honoraria; Novo Nordisk: Honoraria. Croteau:ATHN: Research Funding; National Hemophilia Foundation: Honoraria; Spark Therapeutics: Research Funding; Novo Nordisk: Research Funding; Bayer: Consultancy; Hemophilia Federation of America: Honoraria; CSL-Behring: Consultancy; Pfizer: Consultancy; Genentech: Consultancy; Sigilon Therapeutics: Consultancy. Cuker:Synergy CRO: Consultancy; Alexion: Research Funding; Bayer: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Spark Therapeutics: Research Funding; Takeda: Research Funding; Novartis: Research Funding. Kempton:Spark Therapeutics: Honoraria; Octapharma: Honoraria; Pfizer: Honoraria; Genentech: Honoraria; Novo Nordisk: Research Funding. Malec:SOBI: Consultancy; Bayer: Consultancy; Takeda: Consultancy; CSL: Consultancy; Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau. Raffini:XaTek: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board; HemaBiologics: Other: Advisory Board; Roche: Other: Advisory Board. Staber:Spark Therapeutics: Consultancy; Genentech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Bayer: Consultancy. Wang:CSL Behring: Honoraria; Biomarin: Honoraria; Genentech: Honoraria; Bioverativ Inc: Honoraria; Bayer: Honoraria; Takeda: Honoraria. Recht:Novo Nordisk: Consultancy, Other: personal fees, Research Funding; Spark: Research Funding; uniQure: Consultancy, Other: personal fees, Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; BioMarin: Research Funding; Pfizer: Consultancy, Other: personal fees; Genentech: Consultancy, Other: personal fees, Research Funding; CSL Behring: Consultancy, Other: personal fees.

rFVIIIFc (Eloctate) is an extended-half-life recombinant factor VIII-Fc fusion protein that may promote factor VIII (FVIII) tolerance through Fc immunoregulatory properties. Yet, little is known regarding its immunogenicity in patients with hemophilia A (HA) or in HA with inhibitors (HA-I), including tolerized, immune tolerance induction (ITI)-refractory, or ITI-naïve.We reviewed medical records of 60 patients, including 2 previously-untreated patients (PUPs) and 58 previously-treated patients (PTPs), cared for between 01/01/06 and 06/01/17, on whom anti-FVIII antibody data were available before and after initiating rFVIIIFc. Continuous data were analyzed by student's t-test, and discrete data by chi square or Fisher's exact test.After initiating rFVIIIFc, one of two HA PUPs developed a low-responding (LR) inhibitor after 10 exposures, which resolved (anti-VIII0.6 B.U.) within 8 additional exposures, while none of 41 HA PTPS developed an inhibitor. Among 19 HA-I PTPs with detectable inhibitors prior to rFVIIIFc, 5 developed an anamnestic response to rFVIIIFc, including 1 of 8 (12.5%) low-responding (LR), and 4 of 9 (44.9%) high-responding (HR), of whom 3 were ITI-naïve and 1 ITI-refractory. Inhibitors resolved in 4 HR within 2 months of continuing rFVIIIFc (median) but persisted in 1 LR at low titer. The remaining 11 HA-I PTPs, including 4 HR and seven LR, had no detectable inhibitor at the time of or after initiating rFVIIIFc.rFVIIIFc was immunogenic in HA PUPs and in HA-I PTPs persistently ITI-naïve or ITI-refractory, with inhibitor resolution in the majority. rFVIIIFc immunogenicity appears to be similar to other FVIII products.

The diagnosis of type 1 von Willebrand disease (VWD) presents a diagnostic challenge in children. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. We previously described a 4-variable composite score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children with known VWD when 2 of 4 criteria are positive: (1) Tosetto bleeding score ≥ 1; (2) family history of VWD; (3) personal history of iron deficiency anemia; and/or (4) positive James early bleeding score. The purpose of this study was to prospectively validate a composite score of ≥ 2 for identifying children with VWD.Children without a previously diagnosed bleeding disorder presenting for hematology evaluation were enrolled. Sensitivity, specificity, positive, and negative predictive value of the composite score was determined.A total of 193 subjects were enrolled from 12 participating centers were included in the analysis. Forty-seven children had type 1 VWD, including 11 with von Willebrand Ristocetin Cofactor (VWF):RCo < 30 IU/dL, 14 subjects with a VWF:RCo 30 to 39 IU/dL, and 22 with a VWF:RCo 40 to 49 IU/dL. Including all 4 variables, a composite score of ≥ 2 had a sensitivity of 63.6% to 76.0%, specificity of 33.5% to 35.1%, negative predictive value of 76.9% to 93.8%, and positive predictive value of 5.5% to 25%.The negative predictive value of the composite score was robust, especially at lower VWF:RCo suggesting that VWD testing could be eliminated in nearly a third of children referred for VWD testing.

Background Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague. Aim To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs. Methods Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months. Results Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%). Conclusion Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.

Background von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. Methods We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms ‘von Willebrand factor,’ ‘menorrhagia’ and ‘von Willebrand disease’ to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. Results Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011–2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33–100 IU kg−1 on day 1–6 of menstrual cycle. Conclusions This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

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.We constructed a decision tree to evaluate the direct and indirect costs, possible outcomes, and probabilities of ICH in neonates with hemophilia. We created 3 decision analysis models to evaluate the cost-utility of different screening modalities for ICH: ultrasound, computed tomography, and magnetic resonance imaging. Within each model, 3 different strategies were compared: screen all neonates; screen only neonates born by instrumented delivery; and not screen any neonates. A societal perspective was used for all models. The base case models were later reanalyzed in sensitivity analysis to account for uncertainties.Total costs for screening all neonates, screening only neonates born by instrumented delivery, and not screening any neonates were $9501, $9297, and $9347, respectively, for US, and $9761, $9351, and $9353, respectively, for CT. Screening instrumented deliveries using MRI had an incremental cost-effectiveness ratio of $12,440.Screening newborns born by an instrumented delivery appears to be the most cost-effective strategy irrespective of the imaging modality. Subsequent studies will require a longer time frame to factor in possible late effects of radiation, anesthesia, and the high cost of factor replacement and hospital admission.

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 need in 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. Methods: This is an NHLBI-funded U01 phase III multicenter, prospective, randomized, crossover trial in to compare IV rVWF vs. po TA in reducing menorrhagia in type 1 VWD, clinicaltrials.gov, NCT02606045. Women with type 1 VWD, VWF:RCo100 in at least one of the last two cycles, are eligible. Exclusions include hypothyroidism, past thrombosis, and renal disease. Subjects are randomized to rVWF 40 IU/kg IV day 1 vs. TA 1300 mg po three times daily days 1-5 in each of two consecutive cycles. The order of treatment is determined by randomization: in Group 1, rVWF is given in cycles 1 and 2, and TA in cycles 3 and 4; while in Group 2, TA is given in cycles 1 and 2, and rVWF in cycles 3 and 4. A rescue dose day of rVWF 40 IU/kg may be given day 2 of cycles in which rVWF is given. The primary endpoint is a 40-point reduction in PBAC, a validated measure of menstrual loss, after 2 cycles. As rVWF is a greater burden (IV, cost), to show it is superior to TA, it should improve PBAC 40 points more from baseline than TA. Secondary endpoints are cycle severity, cycle length, QoL (SF-36, Ruta, CDC-HRQ0L-14, CES-D), and satisfaction survey. Treatment response will also be compared with VWF assays and VWF genotype. Safety is assessed by number of rescue doses, other bleeding, thrombosis, and allergic reaction. Our research hypothesis is that rVWF will be superior, producing a greater improvement, by at least 40 points, in PBAC, than TA. We also hypothesize that rVWF will be as safe, tolerable, and acceptable as TA, and that VWF assays and VWF genotype will predict response to treatment. A sample size of 60 (inflated to 66 for 5% attrition) will provide 84% power to detect a difference in improvement of 40 points between rVWF and TA. Analysis will be by intent-to-treat analyses, with a two-tailed alternative hypothesis with type 1 error rate of 0.05, a 4-period 2-group (AABB/BBAA) crossover design, and an estimated between-subject standard deviation (SD) of 63 points and within subject SD of 100 points. Results: A total of 442 potential subjects have been identified at 19 participating HTCs, of whom 33 (7.5%) are eligible, and 2 enrolled. The most common reason for ineligibility is use of an IUD (15.6%), COCs (9.4%), age Discussion: In conclusion, rVWF is a high-purity VWF concentrate with a longer half-life than pdVWF. In this multicenter phase III trial, rVWF is being compared to the current non-hormonal standard, TA, to reduce menorrhagia in adult women with type 1 VWD. rVWF is safe and effective in prevention and treatment of bleeds, and this trial will determine if rVWF reduces menorrhagia to a degree sufficient to justify its IV route and cost. Disclosures 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. Objective: To characterize diagnosis, bleeding, and treatment patterns in children (2-11 years of age) and adolescents (12-17 years of age) with VWD. Methods: This retrospective database analysis utilized data from the IQVIA PharMetrics Plus Database of medical insurance claims for patients with VWD (ICD-9 286.4) from January 1, 2006 to June 30, 2015. Patients included had ≥2 medical claims for VWD and continuous enrollment for ≥2 years, to ensure a higher likelihood of definitive VWD diagnosis, before and after their 1st VWD claim. The pre-diagnosis period included 18 months of data before diagnosis. The post-diagnosis period included 7-24 months post-diagnosis data. Data from the first 6-month post-diagnosis period were excluded due to data variability, suggestive of treatment optimization. Descriptive statistics were used to summarize patient demographic and clinical characteristics, including types of bleeding episode (BE), rates, and outcomes; treating physician specialty; and type of VWD treatment, in both the pre- and post-diagnosis periods. Results: Of 1087 patients identified, 475 were children (43% female) with a mean (SD) age at VWD diagnosis of 6.9 (2.7) years, and 612 were adolescents (74% female) with a mean (SD) age at VWD diagnosis of 14.9 (1.6) years. The top 3 treating physician specialties seen by children in the pre- and post-diagnosis periods, respectively, were hospitalists (21% and 9%), primary care physicians (16% and 7%), and hematologists (11% and 3%). Adolescents were mostly seen by hospitalists (30% and 15%), primary care physicians (25% and 16%), and obstetrician gynecologists (19% and 15%). Only 11% of children and adolescents saw a hematologist prior to diagnosis, compared with 3% and 5%, respectively, post-diagnosis. A 17% vs. a 15% decrease in bleed claims in the pre- vs. post-diagnosis period was observed among children (40% vs. 23%) and adolescents (59% vs. 44%), respectively. The most common type of BE among children in the pre- and post-diagnosis periods was epistaxis (19% and 10%), and the trend was similar for boys and girls. Heavy menstrual bleeding was the most common BE type among adolescents overall in both the pre- and post-diagnosis periods (40% and 30%; in females 54% and 40%). Epistaxis was the second most common BE among adolescents overall in both the pre- and post-diagnosis periods (11% and 7%), and in females (9% and 5%), but the highest among males (17% and 12%). Of note, 3% of children had gastro-intestinal (GI) bleeds pre-diagnosis, reducing to 1% post-diagnosis. In adolescents, 1% had GI bleeds pre-diagnosis, rising to 2% post-diagnosis. Overall, VWD related treatment claims increased between the pre- and post-diagnosis periods for both children (12% vs. 23%) and adolescents (31% vs. 50%). The most prescribed treatments for bleed management in children were aminocaproic acid (ACA), desmopressin (DDAVP) and nasal cauterization (pre-diagnosis: 5%, 4% and 4%, respectively; post-diagnosis: 11%, 13% and 3%, respectively). For adolescents, the most prescribed treatments, pre- and post-diagnosis respectively, were oral contraceptives (22% [females 29%, males 0%] and 33% [females 45%, males 0%]), DDAVP (9% [females 8%, males 12%] and 19% [females 20%, males 14%]) and ACA (4% [females 4%, males 5%] and 11% [females 12%, males 7%]). Of note, 3% and 4% of children and 2% and 4% of adolescents received plasma-derived VWF concentrates pre- and post-diagnosis respectively. Conclusions: This analysis demonstrates a decrease in BE claims following VWD diagnosis and a rise in ACA and DDAVP treatment claims in both children and adolescents, and in oral contraceptive claims among female adolescents. Nevertheless, a considerable proportion of children and adolescents continue to experience BEs 6 months post-diagnosis. This emphasizes the need for treatment optimization and improvement in the care and management of patients in these age groups. Disclosures 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: 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. Aims: To characterize the use and performance of EHL-FIX in clinical practice at six hemophilia treatment centers (HTCs). Methods: An electronic survey regarding center specific use of EHL-FIX amongst patients with severe hemophilia B (HB) was sent in summer 2019, including 4 previously surveyed centers and 2 additional centers. Providers were asked if patients utilizing EHL-FIX for prophylaxis had experienced 1) spontaneous/minimally traumatic bleeding events at factor levels >10% or 2) poorly controlled bleeding events requiring more frequent/higher doses of EHL-FIX than anticipated in addition to patterns of EHL-FIX product switching. Results: Surveyed HTCs cared for 90 patients with HB including 67 (74%) who utilized EHL-FIX, including 26 (39%) recombinant factor IX (FIX) albumin fusion protein (rFIX-FP), 37 (55%) recombinant factor IX Fc fusion protein (rFIXFc), and 4 (6%) received glycopegylated recombinant FIX (rFIX-GP). All patients had severe hemophilia B with the exception of one smaller center also contributing data regarding moderate HB patients on prophylaxis. All centers reported having patients with unexpected spontaneous/minimally traumatic bleeding and poorly controlled bleeding which did not seem to be dependent on age (median age 14.5 years, range 1.4-44). This occurred in 18 patients on prophylaxis, including 16 of 26 (62%) patients using rFIX-FP, and 2 of 4 (50%) of patients using rFIX-GP. Conclusions: Although plasma FIX activity levels have driven prophylaxis and bleed management decisions, clinical experience suggests novel properties of EHL-FIX may impact hemostasis. Although achieving seemingly adequate FIX plasma troughs (>10%), limited clinical experience suggests patients with SHB may have a differential response to EHL-FIX, noted in our cohort with FIX-FP and rFIX-GP. Successful bleed prevention or control in SHB may be predicted by the distribution of FIX in circulation and extravascular space, and the presence of FIX in tissues at time of injury. These data demonstrate the importance of real-world monitoring of efficacy of new FIX products and suggest the need for more robust mechanisms to understand the hemostatic performance of products. Disclosures 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.

Given the increased incidence of venous thromboembolism (VTE) in pediatric patients, which has been associated with increased survival of medically complex patients and increased use of invasive supportive measures, it is important to understand treatment options and unique aspects of anticoagulant use in children. The objective of this mini-review is to outline the goals of treatment, treatment options, and adverse events associated with the use of anticoagulants in pediatric patients with VTE.

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. Methods:Subjects were recruited from seven U.S. Hemophilia Treatment Centers. Subjects with severe hemophilia A or B ≤ 30 years of age on prophylaxis or demand therapy were eligible for enrollment. Subjects excluded from study were those with a recent joint bleed (within the last 2 weeks) or those unwilling to complete all elements of the study. Data were collected during a one-time encounter concurrent with an appointment for clinical evaluation, including demographic information, treatment regimen, product type, frequency, location and severity of all bleeds, Hemophilia Joint Health Scores (HJHS), and Quality of life (QoL). Bleeding rates in subjects receiving prophylaxis were compared with those receiving on demand therapy by type treatment, EHL vs standard half-life (SHL), and by hemophilia type. Severity of bleeding events (mild, moderate, or severe) and HJHS were compared by prophylaxis groups. Results: A total of 67 patients were enrolled and eligible for analysis. This included 58 subjects with severe hemophilia A, and 9 subjects with severe hemophilia B. The mean age of the cohort was 15 years (median 12 years, IQR 8 - 21 years). For these patients whose race information was known, 89.1% were Caucasian, 3.3% African-American, 3.3% Asian, and 4.7% were of mixed or 'other' race. Eleven out of 61 (18.0%) subjects with known ethnicity were Hispanic. Among 59 patients whose treatment type were available, the majority were on prophylaxis (n=53; 89.8%) as compared to on demand therapy (n=6; 10.2%). The average annualized bleeding rate (ABR) was 2.8 amongst all individuals. As expected, the ABR was substantially lower in those receiving prophylaxis (ABR=1.0) as compared to on demand therapy (ABR=18.6) (p For patients with severe hemophilia A, the ABR was lower in those individuals receiving EHL (ABR= 0.5) versus SHL (ABR= 1.5), although this did not reach statistical significance (p=0.136). All subjects with severe hemophilia B enrolled to date receive EHL products (n=9) therefore no comparison of ABR could be made between EHL and SHL products; the ABR in this group was 0.9. In patients with severe hemophilia A, there was a higher HJHS for those receiving EHL (mean HJHS= 7.0) versus those receiving SHL (mean HJHS = 2.1) (p=0.053). For patients with severe hemophilia B, all of whom received EHL, the mean HJHS was lower than in the hemophilia A cohort (mean HJHS=1.2). Conclusions: We report real-world bleeding events and joint health in patients with severe hemophilia A and B utilizing EHL and SHL products across a wide U.S. geographic distribution. As anticipated, there is substantial bleed reduction with prophylaxis versus on demand therapy. In our severe hemophilia A cohort, the ABR for patients receiving EHL products was similar to ABRs reported in clinical trials, suggesting clinical trial data may be reflective of real world use. Patients with severe hemophilia A receiving EHL for prophylaxis had a lower ABR than those receiving SHL, although the early impact is not reflected in the HJHS score. Longer follow-up will be necessary to determine the impact of EHL on HJHS. Disclosures 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.

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. Methods: The ATHNdataset, a HIPAA compliant limited dataset sponsored by the American Thrombosis and Hemostasis Network (ATHN), was accessed as of June 30, 2018. The proportion of subjects with severe hemophilia on prophylaxis were compared to those on demand by age cohort. The proportion of subjects on prophylaxis was analyzed by race, ethnicity, insurance status, and hemophilia treatment center region. For each group receiving prophylaxis, the product (EHL versus standard half-life (SHL)), dose and frequency of treatment was analyzed. Results: ATHNdataset included 6,160 severe hemophilia patients using factor replacements, 5,234 individuals with hemophilia A and 926 individuals with hemophilia B. Overall, 76.0% (n=4,864) of patients with severe hemophilia are on prophylaxis whereas 24.0% (n=1426) are on demand; this included a total of 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B on prophylaxis. Treatment type (prophylaxis or not) had significant associations with age (p-value Among patients on prophylaxis, 30.8% (n=1,462) are prescribed EHL products including 27.4% of patients with hemophilia A and 50.4% with hemophilia B. In terms of dosing frequency (n=758), 73.8% of hemophilia A patients on prophylaxis receive EHL two times per week while 73.7% (n=1,906) receive SHL every other day (Table 2). Of hemophilia B patients using EHL products, 63.3% of patients receive prophylaxis once weekly, 12.7% every 10 days, and 15.0% every 2 weeks (Table 2). Discussion: The ATHNdataset highlights increased use of prophylaxis over the past 3 years in the U.S. with 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B currently receiving prophylactic therapy as compared to 63% and 55% of patients, respectively, in 2015. Further, the majority (83.7%) of patients are beginning prophylaxis according to the World Federation of Haemophilia recommendation to initiate prophylaxis by three years of age. There has been an uptake of the use of EHL factor products including a majority of patients (50.4%) with severe hemophilia B. Although not captured in the ATHNdataset, a plausible reason for the increased uptake of EHL in the hemophilia B population includes the data that 91% of patients are able to dose between weekly or less frequently. As the hemophilia treatment landscape continues to evolve, it is important to continue to understand the adoption of these new products into practice and to examine their real-world impact. Disclosures 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.

Summary Background Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune Tolerance Study, immune tolerance induction was equally effective with high-dose (HD) (200 IU kg−1 day−1) and low-dose (LD) (50 IU kg−1 3× per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels. Methods We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent. Results There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre-, during and post-ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti-FVIII

Inhibitor formation is among the most serious complications of hemophilia treatment. With the US FDA licensure of the novel long-lasting recombinant factor VIII (FVIII) Fc fusion protein, Eloctate, which prolongs FVIII half-life, we propose an innovative approach to prevent inhibitor formation. In this paper, we describe a multicenter, Phase II, single-arm, 48-week trial, the INHIBIT trial, to determine if Eloctate, begun before a bleed and continued as once weekly prophylaxis, will reduce inhibitor formation in children with hemophilia A. We hypothesize that avoiding ‘danger,’ that is, immune activation by a bleed at first factor exposure and prolonging FVIII half-life will prevent inhibitors and promote FVIII-specific T-cell tolerance. If successful, this approach will suggest a new paradigm in clinical practice.

Background Pediatric trauma patients are at high risk for development of venous thromboembolism (VTE). Our objective is to describe incidence, risk factors, and timing of development of VTE, anticoagulation complications, and long-term VTE outcomes in a critically injured pediatric population. Procedure We did a retrospective review of pediatric (0–17 years) trauma admissions to intensive care unit from 2005 to 2014. Our center employs VTE screening and prevention protocols for high-risk patients based on hypercoagulable history, age, injuries, and medical interventions. We collected demographics, VTE prevention measures, VTE incidence, therapeutic anticoagulant use, and outcomes including postthrombotic syndrome (PTS) and clot resolution. Analysis included Wilcoxon rank–sum, Fisher exact, and logistic regression modeling. Results Seven hundred fifty-three subjects were analyzed. No patients on chemical prophylaxis (21/753) developed VTE. Overall incidence of deep vein thrombosis (DVT) was 8.9%; pulmonary embolism (PE) was 0%. Time to diagnosis was median (interquartile range [IQR]) 10.5 (6.5–14.5) days, with 63% of clots being symptomatic. Risk factors for VTE development included severe traumatic brain injury (TBI), acute traumatic coagulopathy (defined by elevated admission international normalized ratio), age less than or equal to 3 or age 13 years or more, injury severity, and child abuse mechanism. At a median (IQR) follow-up of 13 (6–19) months, 52.1% had persistent clot and 15.8% had PTS. Therapeutic anticoagulation was not associated with clot resolution or prevention of PTS. Conclusion TBI therapy is closely linked to the development of DVT. Coagulopathy on admission is associated with hypercoagulability in the postinjury period, suggesting a patient phenotype with systemic coagulation dysregulation. Treatment was not associated with improved VTE outcomes, suggesting that pediatric protocols should emphasize VTE prevention and prophylaxis strategies.

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 Haemophilia 2015, 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). Methods: To establish trial feasibility: 1) we compared pre-pregnancy and 8th-month VWF levels in women with VWD with and without PPH (≥500 cc blood loss in the 1st 24 hours) following vaginal delivery; 2) we evaluated VWF dosing in women with PPH in the James study; 3) we assessed thrombosis risk and VWF concentrate dose by literature review; 4) we surveyed current practice regarding VWF concentrate use at delivery by U.S. hemophilia treatment center (HTC) MDs; and 5) we conducted structured interviews of MDs and VWD patients to determine trial acceptability. Analysis was by Student's t-test for continuous data, and Fisher's exact test for discrete data. Results:In the Retrospective VWD-PPH Study of 16 women with VWD (14 type 1; 2 type 2) undergoing vaginal delivery, PPH was associated with higher pre-delivery weight, pre: 88.1 vs. 67.6 kg; 8thmonth: 99.9 vs. 75.0 kg; and delivery: 104.0 vs. 78.6 kg, all p Conclusions: The findings of this feasibility study indicate that pre-pregnancy VWF:RCo may be a better predictor of PPH than 8thmonth VWF:RCo. High pre-delivery weight which is associated with high blood volume may increase PPH, possibly through dilution of VWF levels. A VWF dose of ~50 IU/kg, which is the first line of therapy at delivery and the current standard of practice, may not prevent PPH. Thrombosis risk with VWF in published studies is low even at doses >80 IU/kg. Drug safety, local obstetric collaboration, and coverage of staff, travel, and childcare costs are critical issues to address in trial design. Disclosures 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. Methods: Immune tolerance induction was initiated in three patients with severe hemophilia A and anti-VIII >5 B.U., in two as initial ITI (Pt. 1, 3), and one as salvage (Pt. 2) after failing to achieve ITI with standard rFVIII due to poor compliance. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to 6 hours. Once a t½ >6 hours was documented, incremental reduction to rFVIIIFc occurred. Patients continued to be followed by their local HTC as per standard of care. Results: ITI was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc every other day or three times weekly per MD discretion. The time to initial anti-FVIII 6 hours, at weeks 18 and 17, respectively, after initiation of ITI. Patient 3 has improved but is not yet fully tolerized, as evidenced by 57% recovery and a t½ of approximately 7 hours. Anti-VIII inhibitor titers remain negative at 15, 16 and 15 months, from the initiation of ITI in patients 1, 2, and 3 respectively. Patients 1 and 2 have been able to decrease their post ITI prophylaxis dosing regimen to 80 IU/kg and 65 IU/kg three times a week while maintaining a FVIII trough of >1%. No patients were maintained on bypassing prophylaxis during ITI and no patients have experienced hemarthroses or other major bleeding event since the initiation of ITI. Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. At a mean duration of follow up of 15.3 months, all patients achieved an anti-VIII inhibitor titer of 0 B.U. Repeat pharmacokinetics studies will be available at planned subsequent follow-up visit. To date, these data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in three children with inhibitors, and has provided durable and continuing immune tolerance to FVIII. Whether rFVIIIFc ITI will be successful and durable in a larger cohort of children with severe hemophilia A will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the Hemophilia Inhibitor Response to Eloctate (HIRE) Study, has begun recruitment. Disclosures 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.

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 preventing inhibitors. 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 hypothesized that 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. Methods: Following informed consent, heparinized tubes were drawn from four mothers of hemophilic children, two with and two without inhibitors, cared for at the Hemophilia Center of Western PA (HCWP). T-reg responses to factor VIII were quantitated by flow cytometry, and phenotyping was performed by staining with anti-CD4/Foxp3/CD3/CD25/CD39 monoclonal antibody markers. Functional characteristics of the T-regs were determined in a T-reg proliferation assay using autologous antigen presenting cells (DCs) in the presence or absence of FVIII. Results: CD4+ T cell proliferative responses to factor VIII (FVIII) were decreased in all four mothers (Figure 1). Mothers of hemophilic sons with inhibitors demonstrated a 1.36-fold decrease (Pt 001) and a 1.1-fold decrease (Pt 002), as compared with mothers of hemophilic sons without inhibitors, who demonstrated a 1.47-fold decrease (Pt 003) and a 1.45-fold decrease (Pt 005) in CD4+ proliferative responses, unlike the two healthy donors who showed minimal (or no) factor VIII response. Patients showed slightly less proliferation with Factor VIII vs. no antigen; healthy donors showed minimal (or no) Factor VIII response (Figure 1). Discussion: These preliminary results demonstrate lower T cell proliferative responses to FVIII in mothers of children with inhibitor patients than in mother of children without inhibitors. This suggests there is lack of tolerance to FVIII in mothers of children with hemophilia, with or without inhibitors. These responses would also imply these mothers have no tolerance to paternal FVIII, but further studies will be needed to confirm these findings and to characterize maternal T regulatory response to factor VIII, and, in particular, paternal FVIII. Figure 1. Percent CD4+ T Helper Cell Proliferation +/- Factor VIII (FVIII) Figure 1. Percent CD4+ T Helper Cell Proliferation +/- Factor VIII (FVIII) Disclosures 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.

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. Methods: Immune tolerance induction was initiated with rFVIIIFc (Eloctate) in three children with severe hemophilia A and an anti-FVIII inhibitor. Dosing was per MD discretion with family agreement, and performed by central venous access device or intravenous infusion via heplock. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to 6 hours. FVIII half-life was determined by one-stage FVIII:C assay on citrate samples drawn pre- and 10 minutes, 1, 2, 4, and 6 hours post-infusion of a single dose of rFVIIIFc. Once a t½ >6 hours was documented, incremental reduction to 50 IU/kg every other day or three times weekly, once there was evidence of maintenance of inhibitor neutralization and a >6 hour FVIII:C half-life. Results: Immune tolerance induction was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc via central venous access device every other day or three times weekly per MD discretion in three children with severe hemophilia A and in anti-FVIII inhibitor > 5 B.U. (Table 1). Two patients had F8 genetic testing. In two patients, Pt 1 and Pt 3, this was the initial ITI course, and in the third child (Pt 2) this was salvage ITI after failing to achieve tolerance due to noncompliance with daily rFVIII ITI taper regimen. In two rFVIIIFc ITI was begun when anti-FVIII was < 10 B.U. Historic peak titers were 16-422 B.U. The time to anti-FVIII tolerance was 4-12 weeks Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. There were no adverse effects. These data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in children with inhibitors. Whether ITI may be accomplished more rapidly with rFVIIIFc, and the optimal dose for ITI will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the H emophilia I nhibitor R esponse to E loctate (HIRE) Study, is underway. | Patient (Pt) | Hemophilia Severity | F8 Gene Mutation | Age at Anti-FVIII Detection | Peak Anti-FVIII Titer | Initial ITI Dose | Time to Anti-FVIII = 0 | Current Anti-FVIII | | ------------ | ------------------- | ------------------------ | --------------------------- | --------------------- | ----------------- | ----------------------------- | ------------------ | | 1

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. Methods: Following IRB approval, TGA was performed on thawed, re-calcified CTI /citrate plasma samples from the ITI repository, using re-lipidated tissue factor and a BioTek Synergy 4 fluorescence plate reader. TGA parameters, i.e. peak thrombin (peak T), estimated thrombin potential (ETP), maximum rate (MaxR), lag time (LAG), were compared by dose group, and repeated after F.VIII spike to neutralize the inhibitor and enhance TGA sensitivity. Significance was calculated by fitting generalized estimating equations linear models to account for serial measurements, with log-transformed TGA as outcome and dose group as predictor. Wilcoxon rank sum test was used to compare bleeds by dose group. Spearman correlation was used to compare TGA and bleeds, and TGA and inhibitor titer. The first TGA sample per subject was used in the analysis; and, separately, all TGA samples per subject. Sensitivity analysis was performed by 95% bootstrap confidence intervals to account for multiple measurements per subject. Total F.VIII antibody (NNA+NA) was analyzed by fluorescent immunoassay (FLI) and compared with anti-VIII (BU/ml) by Pearson correlation. Results: Samples (n=83) from 31 subjects, 14 LD and 17 HD, were available. There was no difference in peak T, ETP, MaxR, or LAG between LD and HD; after VIII spike (Table); nor between non-tolerized (n=56) and tolerized (n=27) subjects, all p>.05. There was no correlation between TGA and bleeding, nor between TGA and anti-VIII titer, all p>.05. In 19 subjects in whom anti-VIII fell to Figure 1 Figure 1. Discussion: Despite ITI, the majority of inhibitor patients have detectable non-neutralizing inhibitors. Further, TGA is detectable despite the presence of inhibitors, but does not predict bleeding by ITI dose arm, suggesting thrombin generated after F.VIII dosing may be too low or too short-lived to detect. Limitations include the small sample size and random post-F.VIII sampling. Future studies should evaluate TGA prospectively, early after dosing to determine if thrombin generation predicts bleeding in inhibitor patients. Disclosures No relevant conflicts of interest to declare.

Background 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. Methods 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. Results 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 Discussion 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. Disclosures: No relevant conflicts of interest to declare.

Background 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. Methods We designed and conducted a prospective validation study to determine the accuracy of the Composite Score for identification of children ( Results 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 Discussion 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. Disclosures: Kerlin: Bayer Healthcare US: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; NovoNordisk A/S: Consultancy, Honoraria.