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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.

Background: Sickle cell anemia (SCA) is a monogenic disease resulting in polymerization of hemoglobin in hypoxic conditions. This leads to red blood cell (RBC) membrane damage and sickling, causing vaso-occlusion and hemolysis. Continual, excessive release of lysed RBC contents within the vascular space can activate the inflammasome, a multiprotein oligomer that promotes maturation and secretion of pro-inflammatory cytokines, including interleukin 1-beta (IL-1β). The intravascular inflammation associated with SCA, e.g., increased serum c-reactive protein (CRP) and absolute counts of neutrophils and monocytes, is predictive of long-term morbidity and mortality. Inflammation is a major component of many of the clinical complications of SCA, including vaso-occlusive pain episodes, acute chest syndrome, vascular-endothelial dysfunction, renal disease and other forms of end organ damage. Standard of care for SCA is hydroxyurea, which augments fetal hemoglobin levels and may have some anti-inflammatory effects by reducing neutrophil and monocyte counts. Canakinumab is a fully human monoclonal antibody targeting IL-1ß and blocking its downstream pro-inflammatory activities with potential to ameliorate the inflammatory complications of SCA. Objective:To clinically validate in pediatric and young adult SCA patients the hypothesis that IL-1ß blockade by canakinumab is safe and provides clinical benefits. Methods: A multi-center, randomized, parallel group, double-blind, placebo-controlled trial recruited SCA patients (HbSS or HbS/ß0thalassemia) with history of ≥2 major pain episodes/year, screening baseline detectable pain (using pain e-diaries) and serum high sensitivity CRP level ≥1.0 mg/L. Patients were randomized with 1:1 ratio to receive six monthly s.c. injections of either canakinumab 300 mg (4 mg/kg for patients ≤40 kg) or placebo. The concurrent use of hydroxyurea was a stratification factor at randomization. Outcomes were measured at baseline and at weeks 4, 8, 12, 16, 20, 24, after which all patients moved to open label canakinumab treatment for additional 6 months. Electronic patient reported outcomes included daily pain intensity with a 0-10 cm visual analog scale, school/work absences secondary to SCA, fatigue and analgesic use. The primary outcome was change from baseline in the 4-week average daily pain intensity at week 12. Other secondary and exploratory outcomes included daily activity measured by wrist actigraphy, rate of hospitalization and adverse events, serious adverse events, transcranial Doppler velocities, percent oxygen saturation and laboratory markers of inflammation and hemolysis. Results: A planned interim analysis for futility and safety was performed on the first 30 enrolled patients (canakinumab, n=16; placebo, n=14), of whom 26 patients completed the Week 12 assessments (canakinumab, n=14; placebo, n=12), and 13 patients completed the Week 24 assessments. Enrolled patients (median age 17 years, range 12-20; 19 male, 11 female) were evenly distributed between treatment arms. All except one patient were maintained on a stable hydroxyurea regimen. Baseline overall disease activity levels (median, [range]) included average daily pain 3.93 [0.29, 6.57]; high sensitivity CRP 3.93 mg/L [1, 64.7]; transcranial Doppler velocities 85.0 m/s [23, 267]; hemoglobin 94.8 g/L [73.5, 121]. Futility criteria were not met and no canakinumab-associated safety issues were identified in this first interim analysis. Conclusions: Canakinumab was well tolerated and not associated with any major side effects in SCA. Results from a second interim analysis of study outcomes for all currently enrolled patients (n=49) completing the blinded, 24-week treatment period will be available in November 2019. Disclosures Rees: Agios: Other: Grants; TauRx (methylene blue): Other: Data monitoring committees; Astra Zeneca (ticagrelor): Other: Data monitoring committees; Novartis: Other: Strategic advisory role,Principal investigator,sickle cell disease2.6 Investigator; Emmaus: Other: Strategic advisory role; Celgene: Other: Strategic advisory role; Global Blood Therapeutics: Other: Strategic advisory role; Alnylam: Other: Principal investigator. Dampier:Micelle Biopharma: Consultancy, Research Funding; Merck: Research Funding; Hudson Publishing Company: Consultancy; Global Blood Therapeutics: Consultancy; Ironwood: Consultancy; Epizyme: Consultancy; Modus Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mahlangu:Sanofi Genzyme: Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Baxalta: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Biomarin: Research Funding; uniQure: Research Funding; Spark: Consultancy, Speakers Bureau; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Freeline Therapeutics: Research Funding; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; World Federation of Haemophilia: Speakers Bureau. Mortier:Novartis Pharma AG: Employment. McNamara:Novartis Pharma AG: Employment. Li:Novartis Pharma AG: Employment. Oliver:Novartis Pharma AG: Employment, Equity Ownership. OffLabel Disclosure: canakinumab use in the treatment of sickle cell anemia.

Introduction: Challenges to the transition of care for adolescents and young adults with bleeding disorders negatively impact clinical outcomes. Transition of care is a Healthy People 2020 measure, and many Hemophilia Treatment Centers (HTCs) in the United States are developing a systematic approach based on the Got TransitionTM framework, which includes six core elements designed to aid patients and their families during this vulnerable period. To improve the quality of care delivered to transition-aged individuals with hemophilia, we developed a quality improvement initiative (QI) to track and monitor transition, to assess transition readiness, and to provide education based on patient-centered goals. Our global aim is to improve transition readiness and rate of successful transfer to an adult hemophilia provider by age 18-21y. We report results for the specific aim to increase the percentage of transition-aged individuals who complete transition readiness assessments and receive patient-centered goals education at annual comprehensive clinic appointments over a six-month cycle from 0 to 80%. Methods: We developed metrics and reports in Epic (electronic health record system) to track patients with hemophilia aged 12y and older who are eligible to begin the transition process. We also developed a Transition Readiness Assessment and a 15-question hemophilia-specific Skills Practicum to be completed by the patient in EPIC during their appointment. Based on responses to the Transition Readiness Assessment, patients select 2-3 goals for the year. Each selected goal generates a corresponding education handout. The tools are completed by patients with hemophilia between the ages of 12-21y at the time of rooming by the medical assistant for the annual comprehensive clinic appointment. Patients are excluded if they have significant developmental delays. During the appointment, the child life specialist for the HTC reviews the results of the Skills Practicum with the patient, and the HTC nurse reviews the Transition Readiness Assessment and the education handouts with the patient. Descriptive statistics were used to analyze the population and the results. Results: During the QI cycle, 20 of 43 transition-aged patients attended a comprehensive clinic visit and 17/20 (85%) completed all age-appropriate assessments. Patient characteristics and transition readiness results are shown in Table 1. The most frequently selected patient goals were "know my doctors' and nurses' names and roles" (29%), "know my doctor's phone number and call my doctor's office to make or change an appointment" (65%), and "have access to MyChart account and check MyChart" (47%). Four questions on the Skills Practicum test how to read a prescription. Five patients (29%) correctly answered all four questions. Conclusions: In summary, the Epic transition tools were successfully integrated into the HTC comprehensive clinic workflow, and 85% of eligible patients completed the assigned assessments. Utilization of MyChart is low, and access to MyChart was a frequently selected goal. Further work is underway to increase MyChart utilization which would facilitate workflow changes such that assessments may be completed in MyChart before the visit and educational and other resources can be accessed in MyChart. Achievement of patient goals, improvements in knowledge (e.g. how to read a prescription), and successful transfer are being tracked over time. Disclosures Thornburg: Sanofi Genzyme: Other: Data Safety Monitoring Board; Sanofi Genzyme: Research Funding; NovoNordisk: Research Funding; Genentech: Speakers Bureau; Bluebird bio: Other: Data Safety Monitoring Board; Ironwood: Other: Data Safety Monitoring Board.

Introduction: FVIII and FIX have a well-established pivotal role in the promotion and maintenance of hemostasis. There is emerging evidence, however, for a role of FVIII and FIX in regulating processes beyond thrombin generation, such as bone health and macrophage function affecting wound healing. Previous studies on bone mineral density (BMD) and fractures have primarily investigated persons with hemophilia A (PwHA) and hemophilia B (PwHB), but not hemophilia carriers. It has been estimated that 35% of hemophilia carriers have FVIII and FIX levels below 40IU/dL. However, it is not known if hemophilia carriers have a similar potential to develop decreased BMD and poor wound healing as PwHA or PwHB. This study aims to assess the prevalence of bone health issues and wound healing among women who are hemophilia carriers comparing them to control women in the general population. Methods: A commercial database (Explorys Inc, Cleveland, OH, USA), an aggregate of electronic health record data from 26 major integrated US healthcare systems, was queried for data, using Systematized Nomenclature of Medicine (SNOMED) clinical terms or codes. Cases were defined as female patients of any age, with a diagnosis of Hemophilia carrier. Controls were defined as female patients of any age, with at least one medical encounter, and who did not have a diagnosis of Hemophilia Carrier. The prevalence rates of osteoporosis, osteoarthritis, fractures and wound dehiscence among cases and controls were estimated based on binomial distribution theory. The prevalence rates of the comorbidities were compared in the Hemophilia Carrier group and control group using chi-square or Fisher's exact test, and relative risk calculations for bone health issues were adjusted for age > 50, as the risk of osteoporosis and osteoporotic fractures is higher in post-menopausal women above the age of 50. Results: Our database search identified 740 hemophilia carriers and 34,129,790 women in the control group (Table 1). Among the hemophilia carrier group, there was increased prevalence of osteoporosis (7% vs 3.6%, p Conclusions: Our study suggests an association between hemophilia carrier state and poor bone health and wound healing. Prospective studies are required to confirm these findings, including the role of factor levels in these patients in relation to bone turnover markers and macrophage function. This data may also have relevance for the importance of exposure to factor in the era of emerging non-factor therapies in hemophilia. Disclosures Ahuja: Genentech: Consultancy; Biovertiv Sanofi: Consultancy; Bayer: Consultancy; Rainbow Children's Foundation: Research Funding; XaTexk Inc.: Consultancy, Patents & Royalties, Research Funding.

Introduction: The main goal of Hemophilia A treatment has been to restore secondary hemostasis, whether through direct factor VIII replacement or through a combination of bypassing agents and immune tolerance induction in cases of inhibitor activity. In pediatric populations, these treatments are frequently given through a central venous access device (CVAD) for ease of access, convenience, and mitigation of pain. However, these devices carry the risk of infection and thromboembolism (Cost & Journeycake, 2011). The new Hemophilia treatment emicizumab (Hemlibra) has the benefits of less frequent dosing (weekly to every 4 weeks) and does not require central venous access since it is given subcutaneously. There have been cases in the literature of patients developing thromboemboli when using both emicizumab and high doses of inhibitor bypassing agents such as activated prothrombin complex concentrate (aPCC) (Weyand, Dorfman, Shavit, & Pipe, 2019). There have been no reported cases of patients developing thromboemboli who were on emicizumab alone. We present a patient with severe Hemophilia A with no inhibitor who developed a central line-associated venous thromboembolism (VTE) while on emicizumab. Case Summary: A nine-year-old boy with Hemophilia A, factor VIII activity Management: The femoral CVAD was removed, and the patient received two doses of recombinant factor VIII during the admission. The patient was started on enoxaparin titrated to a therapeutic anti-Xa level while continuing emicizumab. At approximately one month of follow up, the venous ultrasound showed resolution of the acute portion of his VTE and persistence of chronic VTE. Thereafter, patient was to continue eight more weeks of enoxaparin prior to further venous ultrasound imaging. This patient's family then moved, and the patient was transferred to another hemophilia treatment center. Conclusions: Patients with central venous catheters on emicizumab alone without may develop clinically significant thromboemboli. We propose that guidelines should be developed for patients with CVAD receiving emicizumab. Patients transitioned to emicizumab with central lines in place may require more urgent removal. Furthermore, standardized therapy for anticoagulation is needed for patients on emicizumab who develop VTE. References 1. Cost, C. R., & Journeycake, J. M. (2011). Deep venous thrombosis screening in patients with inherited bleeding disorders and central venous catheters. Haemophilia,17(6), 890-894. doi:10.1111/j.1365-2516.2011.02515.x 2. Weyand, A. C., Dorfman, A. L.,Shavit, J. A., & Pipe, S. W. (2019).Emicizumab prophylaxis to facilitate anticoagulant therapy for management of intra‐atrial thrombosis in severe haemophilia with an inhibitor. Haemophilia,25(3). doi:10.1111/hae.13721 Disclosures No relevant conflicts of interest to declare.

Introduction Acquired hemophilia (AH) is a rare disorder due to the production of autoantibodies against factor VIII or IX procoagulant function. The development of these autoantibodies results in hemorrhagic symptoms in patients without previous coagulopathy. The typical clinical manifestations of the acquired hemophilia are: extensive cutaneous purpura and internal hemorrhages while hemarthrosis are not common. Acquired hemophilia is less frequent than the inherited form of the disease, with an estimated incidence of 2 to 4 cases/million inhabitants/year, value that increases with age, but is extremely infrequent in children (0.045 cases/million/year). It affects all ethnic groups and has a biphasic distribution with a peak incidence in subjects between 20 and 30 years and another peak between 60 and 80 years. Objective To report a case of AH in a 2-year-old child. Clinical data: Hematoma in the left iliac flank, forearm and legs.Personal history: Otherwise healthy 2-year-old boy with a twin brother and both parents without a history of bleeding disorders. Prior to the onset of bruising, the patient suffered an important trauma on one foot without bleeding complications. A short time after this episode he presented a hematoma in the gluteus that was interpreted as result of a slight trauma due to a fall. Subsequently, he presented multiple spontaneous hematomas that motivate the consultation. • Laboratory upon admission: Hemoglobin: 12.8g/dL; PT: 11" (Control: 11"); APTT:>180" (Control: 30"). Plt: 543000/mm3 • Clinical evolution: With the suspicion of bleeding reactivation, he was referred to the Rosario Hemophilia Foundation to be evaluated. Reactivation of bleeding was ruled out and imaging had shown subcutaneous bleeding without muscle involvement. The presence of an inhibitor to Factor VIII was detected. The patient was commenced on Prednisolone 1mg/kg/day to eradicate the acquired antibody. • Laboratory Results: Hb: 12.6 g/dL, Plt: 575000/mm3, PT: 12" (11") (Innovin), APTT: 76" (30") (Actin FSL) which does not normalize after addition of normal plasma and potentiate when was incubated 2 hours at 37°C, TT: 14"(14") (Trombin), FVIII Conclusions AH is a rare autoimmune disease first described in 1940 and is extremely infrequent in children younger than 16 years. Although it is usually associated with other autoimmune disorders, in our patient, we have not found other autoimmunity markers. We should suspect this pathology in all patients who begin with cutaneo-mucosal bruising without a previous history of bleeding, with prolonged APTT that does not correct with the addition of normal plasma and whose prolongation potentiates after incubating the mixture for 2 hours at 37˚C. These results are usually associated with PT and normal platelets count. The FVIII inhibitor can be quantified by the Bethesda-Nijmegen method. Although the title of the Inhibitor does not correlate well with the clinical severity of the patient, its value is useful in monitoring the immunosuppressive therapeutic response. Finally, although AH is unusual in pediatrics, it must be taken into account among the differential diagnoses. Disclosures No relevant conflicts of interest to declare.

Introduction Incidence of hospital-acquired venous thromboembolism (HA-VTE) in children has been increasing in the absence of proven effective preventative interventions. To decrease the incidence of HA-VTE, we must first identify children at the highest risk by creating a risk assessment model (RAM). Critically ill children, especially those with a central venous catheter (CVC), inflammatory condition and/or prolonged hospital stay have been identified as high-risk. To date, studies of HA-VTE in critically ill children have only been at single-center and have not been well-validated in diverse populations. The Children's Hospital-Acquired Thrombosis (CHAT) consortium established a large multicenter Registry to develop and validate pediatric RAMs for HA-VTE. This multicenter study aimed to derive a RAM for HA-VTE among critically ill children (RAM-ICU) performed upon admission/transfer to a pediatric intensive care unit (PICU). The CHAT Registry consists of retrospectively-identified, imaging confirmed cases of symptomatic HA-VTE and hospitalized controls (without HA-VTE) aged 0-21 years from eight U.S. centers. Controls were frequency-matched by year of admission and center. Details on demographics, medical history and hospital course were extracted from the medical record. For the RAM-ICU, only HA-VTE subjects and controls admitted/transferred into an ICU were included. Subjects who had a cardiac surgery up to 2 weeks prior to ICU admission were excluded. Fourteen variables that were present at or within 24 hours of ICU admission/transfer were evaluated by univariate logistic regression. These included demographics, medications, medical history, recent surgeries, mechanical ventilation, patient mobility and presence of a CVC. Those variables with p-values of Results Out of 1172 HA-VTE cases and 952 controls in the Registry, 535 cases and 188 controls met inclusion criteria for the RAM-ICU. With discrepant subject distribution as expected due to previously reported increased incidence of HA-VTE in critically ill children. Median age was 0.8 years (IQR 0.1-10.2) for cases and 2.6 years (IQR 0.2-8.35) for controls. Fifty-eight percent of cases and 50% of controls were male. The Table presents the unadjusted analysis which revealed eight variables associated with HA-VTE (P Conclusions With the increasing incidence of pediatric HA-VTE, there is an urgent need to identify children at high risk and incorporate risk reduction methods. The CHAT RAM-ICU represents the largest, multicenter pediatric study evaluating HA-VTE risk in children admitted/transferred to an ICU, with 535 HA-VTE cases and 188 controls. Recent placement of a CVC, congenital heart disease, and autoimmune disease or serious infection are significant, independent risk factors for HA-VTE in critically ill children. We will prospectively validate the RAM-ICU in a multicenter prospective study funded via the Hemophilia and Thrombosis Research Society. Disclosures Jaffray: CSL Behring: Research Funding. Mahajerin:Alexion: Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark: Speakers Bureau. Silvey:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Croteau:Spark Therapeutics: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Shire: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Octapharma: Honoraria. Young:CSL Behring: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria. Goldenberg:NIH: Other: research support and salary support.

Introduction: With many standard half-life (SHL) and extended half-life (EHL) recombinant factor VIII and factor IX products licensed in the US over the last 6 years, it is likely that previously treated patients (PTPs) will consider switching to a new EHL FVIII or FIX product. Although past product switching surveillance suggests no increased inhibitor development risk, there is the need for a real-world data on the incidence of inhibitor development following switching from SHL to EHL rFVIII or rFIX in PTPs with hemophilia A and B. Methods: A longitudinal, observational study of participants with Hemophilia A or B who switched to a rFVIII or rFIX concentrate licensed after Jan 1, 2013. The study included retrospective (switched within 50 exposure days (EDs) and prospective arms. Participants were recruited from ATHN-affiliated Hemophilia Treatment Centers (HTCs). The primary outcome measure was the development of a new inhibitor (i.e. neutralizing antibodies to factor VIII or IX) a 1 year or during the 50 EDs following the product switch. Plasma samples were collected at baseline, 10 EDs and 50 EDs. Inclusion criteria include moderate or severe hemophilia A/B currently on a plasma-derived or recombinant FVIII or FIX concentrate with planned or recent switch to an EHL FVIII or FIX concentrate approved after Jan 1, 2013. Participants with an active inhibitor at time of enrollment or undergoing ITI or switched to a non-factor product were excluded. Results: 303 hemophilia participants from 27 treatment centers were enrolled from 2015 to June 2019. The median age at enrollment was 17 years (IQR 10-32 years). 300 of 303 participants were male, Caucasian (72.6%) and had private insurance (44.9%). 74.3% were FVIII deficient and 25.7% were FIX deficient. Most had severe hemophilia A or B, 82.3% (n=237) and 12.8% (n=37) had a prior history of inhibitor but were negative at the time of enrollment. Prior to the switching, 92.1% (n=197) and 7.9% (n=17) of hemophilia A participants took standard rFVIII or pdFVIII respectively, while 87.8% (n=65) and 12.2% (n=9) of hemophilia B participants took standard rFIX or pdFIX, respectively. The three most frequent switching reasons were extended half-life consideration (n=192; 66.7%), a desire for a longer acting version (n=55; 19.1%) and less than expected clinical response to the current product (n=15; 5.2%). Among 214 participants with hemophilia A, 182 (85.0%) switched to FVIII EHL products while 23 (10.7%) switched to new SHL FVIII. For nine patients (4.2%) switching product information was not available. 72 out of 74 (97.3%) participants with hemophilia B that switched products, switched to an EHL rFIX. Eleven hemophilia participants (six A and five B) entered a second cycle of switching after the completion of the first switching cycle. Following that, four switched to FVIII EHL products, two to new SHL rFVIII and five to rFIX EHL products. A total of 193 (63.7%; 148 FVIII, 45 FIX) participants completed the clinical trial while 36 (11.9%; 26 FVIII, 10 FIX) did not complete the trial and 74 (24.4%) are ongoing in the trial. None of 303 (0%) enrolled participants developed an inhibitor, the primary outcome for this study, through data updated 6/2019. Variability was noted in per-site enrollment. The median enrollment per Hemophilia Treatment Center (HTC) was 10, the IQR was 7-16 with a range of 1-31. The types of factors associated with patients switches are summarized in the figure. Conclusion: No new inhibitors were noted among 303 moderate/severe hemophilia A/B PTPs without active inhibitors at entry, who switched factor VIII or IX products over 50 exposure days or 12 months. This result provides real-world evidence of the rarity of inhibitor development after a product switch in PTPs. The study also achieved a key logistical objective: to demonstrate feasibility of a prospective observational study across ATHN sites. Figure Legend: Factor types to which ATHN-2 patients switched during the study. Disclosures Sidonio: 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; 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; 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; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guelcher:Takeda: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board. Takemoto:genentech: Membership on an entity's Board of Directors or advisory committees; novartis: Other: DSMB membership. Tarantino:Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI, Speakers Bureau; Roche: Consultancy; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Grant Reviewer , Research Funding; Octapharma: Consultancy, Speakers Bureau. Neufeld:Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

Background: Hemophilia A is an X-linked congenital bleeding disorder caused by deficient or defective factor VIII (FVIII), characterized by spontaneous or traumatic bleeding into joints, muscles, and body cavities. The burden of disease is high, as prophylaxis for bleed prevention requires several weekly intravenous factor infusions which are expensive and inconvenient. By adulthood, fewer than 50% comply and many develop pain, joint degeneration, and disability. For the 30% who develop inhibitors, requiring bypass therapy, which is associated with poor response, frequent hospitalization, and high cost. The bispecific monoclonal antibody emicizumab is licensed to prevent bleeds in hemophilia A (HA) and HA with inhibitors (HA-I). While it mimics FVIII by bridging FIXa and FX, it differs from FVIII biochemically, with no phospholipid binding and limited self-regulation. Thus, whether bleed frequency and severity, long-term joint health, and quality of life are comparable to FVIII is unknown. Methods: We reviewed outpatient medical records of HA and HA-I cared for at Hemophilia Center of Western Pennsylvania, switched to emicizumab between November 2017 and May 2019. This was an expedited study approved by the University of Pittsburgh IRB, PRO1800098. Means, medians, and standard deviations or frequencies were determined for clinical variables, including age race, genotype, reason for switching, bleeding events, surgical events, and treatment rating. Group comparisons were by Student's t test for continuous data, or chi-square or Fisher's exact test for discrete data. A p-value of Results: A total of 42 patients initiated emicizumab during outpatient comprehensive clinic, including 18 (42.9%) HA and 24 (52.1%) HA-I. Of these, 17 (47.3%) were Discussion: This study indicates the majority of HA and HA-I switching to emicizumab experience low ABR, infrequent surgical bleeding, and subjective improvement in health. Postoperative thrombosis/TMA suggests FEIBA should be avoided for at least 6 months after emicizumab discontinuation, during which it may still be detected. Disclosures Xavier: Bioverativ/Sanofi: Research Funding. Seaman:Takeda: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy. Ragni:Alnylam/Sanofi: Other: Advisory Board, Research Funding; BioMarin: Other: Advisory Board, Research Funding; Bioverativ/Sanofi: Other: Advisory Board, Research Funding; OPKO: Research Funding; Sangamo: Research Funding; Shire/Takeda: Other: Advisory Board, Research Funding; Spark Therapeutics: Other: Advisory Board, Research Funding.

Introduction: Hemophilic bone disease is a pathology inherent to factor VIII (FVIII) and factor IX (FIX) deficiency present in both adult and pediatric persons with hemophilia (PWH). This pathology is also present in mouse models. We have previously demonstrated that FVIII replacement restores lost mineralization activity in osteoblast-like cells from FVIII-deficient mice. We hypothesized that bone disease in PWH is secondary to decreased thrombin generation in PWH. Methods: Murine bone marrow stromal cells isolated from FVIII knockout (FVIII-/-) and wild-type (FVIII+/+) C57BL mice and human osteosarcoma (HOS) TE85 cells were cultured in α-MEM with 0-10% FBS, 100 U/mL penicillin, 100 µg/mL streptomycin, and 25 µg/mL Amphotericin B. Ten millimolar ß-glycerophosphate and 50 µg/mL ascorbic acid were added to induce differentiation and mineralization. Mineralized deposits were stained with alizarin red. Alkaline phosphatase (ALP) activity and culture protein content were measured using colorimetric assays. Results: In , the addition of thrombin in serum-free conditions increases cell proliferation ~25% (p=5x10-4, ANCOVA) and decreases mineralization up to 84% (p=1x10-6) (Figure 1). Thrombin's effect on ALP activity in HOS TE85 cells is negative at low cell numbers and positive at high cell numbers (Figure 1). Osteoblast-like cells from FVIII-/- mice mineralize 70% less than those from FVIII+/+ cells (p=3x10-6). Administering FVIII to cells from FVIII-/- mice ameliorates the mineralization deficiency (Figure 1), while mineralization in cells from FVIII+/+ mice does not change (p=0.66). FVIII-/- cells express 30% lower levels of ALP activity than FVIII+/+ (p=3x10-4). FVIII+/+ cells proliferate 26% more rapidly than FVIII-/- cells (p=4x10-7, ANCOVA), but this is not affected by the addition of FVIII in vitro (p=0.45). The addition of FVIII causes a ~33% decrease in ALP activity in osteoblast-like cells from both FVIII-/- (p=2x10-4) and FVIII+/+ (p=5x10-5) mice. Although thrombin impacts osteoblast differentiation and function, it has paradoxical effects on their mineralization, suggesting thrombin deficiency is not the sole driver of reduced bone health in PWH. Deficient mineralization in cells from FVIII-/- mice compared to those from FVIII+/+ mice is corrected with FVIII replacement in vivo or in vitro, suggesting that circulating FVIII has a positive role in these cells' mineralization. More rapid proliferation in cells from FVIII+/+ mice likely contributes to the increase in mineralization, yet, as proliferation is unchanged by FVIII replacement, it appears unlikely that this effect occurs via the same mechanism. Thrombin causes increased proliferation of HOS TE85 cells, yet also causes a significant decline in mineralization activity (Figure 1). Whether this is a paradoxical effect present only in this transformed cell line is yet undetermined. ALP activity increases when HOS TE85 cells are given thrombin in vivo during the log phase of growth (Figure 1), indicating a positive effect on the osteoblast-like function of the cells. However, this notion is undermined by the decrease in mineralization. Identifying the role of FVIII, FIX, thrombin, and active protein C in bone mineralization in PWH is proving to be a challenging undertaking, yet it remains critical, especially as new drugs with the potential to supplant FVIII prophylaxis hit the market. Future experiments will include thrombin and a thrombin inhibitor, a PAR1 agonist and antagonist, a PAR2 antagonist, and an APC neutralizing antibody. Upcoming findings will be discussed. Disclosures Taylor: Baxalta: Research Funding; CTI BioPharma: Employment, Equity Ownership.

Introduction Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical development for the subcutaneous prophylactic treatment of hemophilia patients. We present exploratory analyses assessing the impact of concizumab prophylaxis on health-related quality-of-life (HRQoL) in hemophilia A and B with inhibitor (HAwI/HBwI) patients compared with recombinant activated factor VII (rFVIIa) on-demand treatment in a phase 2 trial (NCT03196284; explorer4). HRQoL is impaired in patients with hemophilia relative to the general population and this impairment is more pronounced among patients with inhibitors, including HBwI patients for whom treatment options are particularly limited. Methods HAwI and HBwI patients were randomized 2:1 to concizumab prophylaxis (n=17) or rFVIIa on demand (recombinant activated factor VII; n=9). Patients completed the 36-item Short Form Health Survey (SF-36v2; 4-week recall) questionnaire at baseline and at the end of the main phase of the trial (24 weeks). Scoring was conducted according to the SF-36v2 scoring software (version 5.0). The change in SF-36v2 scores after treatment onset from baseline to Week 24 was analyzed with an analysis of covariance (ANCOVA model) with regimen as factor and baseline score as a covariate. Improvement in SF-36v2 scores was assessed at both group and individual patient level. At group level, SF-36v2 score improvement was assessed based on minimally important difference (MID) criteria as recommended by the SF-36v2 manual (3rd edition; 2013) (Table 1). A responder analysis was also conducted to identify the proportion of patients who had an improvement in the Physical Component Summary (PCS) in terms of meeting the recommended individual level response threshold of 3.4 points (established based on the 2009 United States general population norms; SF-36v2 manual). Results Overall, improved HRQoL was observed in patients receiving concizumab prophylaxis as reflected by improvements (higher scores) in all SF-36v2 domain scores. At a group level, the difference in improvement from baseline for concizumab prophylaxis vs rFVIIa on-demand for the PCS score met the MID criterion (Table 1), as did the difference in improvement from baseline for the following SF-36v2 domains: Social Functioning, Vitality Score, Health Perception, Bodily Pain and Physical Functioning (Table 2). This difference in improvement between the two groups was not statistically significant, as the study was not powered to show significance for this endpoint. In addition, a larger percentage of patients on concizumab prophylaxis achieved an improvement that met or exceeded the response threshold on the PCS score scale compared with patients receiving rFVIIa on-demand treatment. Conclusions Hemophilia patients have been reported to have a worse HRQoL than members of the general population, particularly in relation to physical activity and pain. In results from the concizumab phase 2 explorer4 trial presented here, HAwI and HBwI patients on concizumab prophylaxis reported higher values for change from baseline in all SF-36v2 domain scores compared with patients receiving rFVIIa on demand after 24 weeks of treatment, indicating better functional health and well-being. A reduction in bleeding rate in these patients is likely to have a positive effect on physical function and reduce pain. In explorer4, there was a 78% reduction in the estimated annualized bleeding rate (ABR) among patients on concizumab prophylaxis vs those on rFVIIa on-demand treatment (Shapiro et al., ASH 2019; abstract submitted). The larger reduction in ABR observed with concizumab subcutaneous prophylaxis may have contributed to the larger improvement in HRQoL relative to the rFVIIa on-demand treatment arm. The potential beneficial effect of concizumab prophylaxis on HRQoL in all hemophilia patients will be investigated further in the phase 3 trials. Disclosures Lee: Novo Nordisk A/S: Employment. Cepo:Novo Nordisk A/S: Employment. Porstmann:Novo Nordisk Health Care AG: Employment, Honoraria.

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Octapharma: Membership on an entity's Board of Directors or advisory committees.

Introduction: Obesity is associated with endothelial dysfunction, hemostatic and fibrinolytic disturbances. The relationship between obesity and elevated Von Willebrand Factor (VWF) is complex and not fully elucidated. There is a significant knowledge gap regarding the impact of BMI on VWF levels. Given the proinflammatory effect associated with abdominal obesity, we hypothesized that there would be an increased prevalence of obesity among individuals with Low VWF (LVWF) compared to Type 1 Von Willebrand Disease (T1VWD) in the ATHN (American Thrombosis and Hemostasis Network) dataset. Methods: A retrospective review of de-identified patients included in the ATHN dataset as of March 2018 was performed. The dataset was queried for all patients with a diagnosis of "T1VWD," who were over 18 years of age when labs were drawn and when BMI was recorded, who had VWF Ristocetin cofactor (RCO) levels 40, extremely obese). Results: Of the 6939 patients with T1VWD in the ATHN dataset, 4754 patients had VWF RCO 3:1 (Table 1). BMI was treated as a continuous measurement and on bivariate analysis there was not a statistically significant difference (p=0.593), with mean BMI 28.2 (17.2-52) in T1VWD and 28.6 (15.3-55.4) in LVWF. Prevalence of obesity (BMI ≥30) was not significantly different between cohorts (T1VWF 32% vs. LVWF 36%, p=0.345, Table 1). The prevalence of obesity by age (18-39, 40-59, >60 years) was similar among both cohorts with the exception of a larger proportion of obese individuals over the age of 60 in the LVWF cohort (63% vs 25%). Mean FVIII level for LVWF cohort was significantly higher compared to that for T1VWD cohort (80% vs. 53%; p Among individuals with BMI≥30, there were increased rates for Black race (p=0.013), and Medicaid and Medicare rates (p=0.028) when compared to non-obese individuals (Table 3). While rates of obesity are known to vary regionally, no conclusions could be drawn as there was disproportionate geographic clustering in states with well-established hemophilia treatment centers. Conclusions: Our analysis identified that 34.8% of adults categorized as VWD in the ATHN data set are obese, with similar prevalence among T1VWD and LVWF. This finding, coupled with associated race, ethnic and socioeconomic risk factors can help prioritize prevention and weight management as a critical component of the comprehensive care model. Increasing degree of obesity may be associated with elevated FVIII, and should be studied prospectively in larger cohorts and the potential impact on cardiovascular risk. Limitations of this analysis include incomplete laboratory data, lack of longitudinal laboratory data, unknown potential confounders including pregnancy or medication effect, and non-uniform geographic distribution of patients. Further research is needed to evaluate the impact of obesity on bleeding phenotype, bleeding related complications, and management practices, as well as the effects of weight change on VWF and FVIII levels. Disclosures Schaefer: Siemens: Research Funding; Stago: Research Funding.

Introduction: Glanzmann thrombasthenia (GT) is a rare bleeding disorder (~1:1,000,000) caused by impaired function of platelet glycoprotein IIb/IIIa responsible for aggregation. This novel survey was designed to identify the burden of GT through better understanding of the management of the disorder and its psychosocial impact on patients and caregivers. Methods: Participants were recruited via a rare disease specialty recruiter from Comprehensive Health Education Services. Data were collected from January 31 through March 12, 2019, via a moderator-assisted online survey. On average, the survey was completed within 45 minutes. Information regarding demographics, diagnosis, treatment history, and quality of life was collected. Results: In total, 45 respondents (24 patients and 21 caregivers; 58% female) completed the survey. Many patients were born with significant bruising (76%) or bled extensively during circumcision (47%). As a result of their early symptoms, more than 50% of those surveyed were diagnosed prior to their first birthday. For others, the average time between experiencing initial symptoms and visiting a specialist was just over 1 year and to diagnosis was just over 2 years (average age, 2.6 years, range Conclusions: Many patients with GT are identified early in life owing to a severe phenotype, but diagnosis remains somewhat difficult. Patients with GT experience frequent bleeding episodes, commonly as bruises and nosebleeds, with 31% experiencing more than 100 bleeds per year. Additional support from outside the GT patient community is needed. Patients desire additional education for themselves and their HCPs, especially around menstruation, childbearing, and treatment options. Disclosures Duncan: Novo Nordisk Inc: Consultancy. Kellum:Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; BPL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Peltier:Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees. Cooper:Novo Nordisk Inc.: Employment. Saad:Novo Nordisk Inc: Employment.

Introduction: In Poland, the principles for the management of rare bleeding disorders as well as financing of medication are regulated by the National Program for the Management of Haemophilia and Related Bleeding Disorders. One objective of the Program for 2012-2018 was to include the financing of ITI for all haemophilia patients with inhibitor. The qualification for ITI was performed by a physician from a Haemophilia Treatment Centre (HTC). Goal: the aim of the study is/was prospective assessment of the efficacy of ITI in real life setting. Patients and Methods: The study comprised 30 patients with severe and one with moderate HA and HT FVIII inhibitors. Factor VIII activity (FVIII:C) was measured by one-stage clotting assay and Factor VIII inhibitors by a modified Nijmegen-Bethesda assay and expressed in Bethesda Units/ml (BU/ml). Cut-off level for positive inhibitor was ≥0.5BU/ml. The following data was collected: historical peak inhibitor titre (HPT), pre-ITI titre (measured 1 month prior to ITI), peak titre recorded during the course of ITI, time between inhibitor detection and ITI start, and ITI duration. During ITI course blood samples were collected every 4 weeks. Treatment regimen with dosing and type of FVIII concentrate was at the discretion of the physician in each HTC. ITI success was defined as inhibitor titre below 0.5 BU/ml with FVIII half-life ≥6h and FVIII recovery ≥66% of normal. Partial response to ITI was defined as clinical response to FVIII therapy with no anamnestic response despite the presence of FVIII inhibitor or FVIII half-life Results: 31 patients with HA and inhibitor were divided into two groups: Group 1 comprised 12 adults with severe HA, median age 36 years (mean 40.1±15.1 and Group 2 included 19 boys, ( The median (mean) duration of ITI was 24 months (30.8±31.7) (1-120) in Group 1 and 28 months (33.4±21.4) (6-84) in Group 2. The median (mean) peak titre during ITI was 40 BU/ml (225.7±185.7) in Group 1 and 85 (160±171.7) in Group 2. Immune tolerance to FVIII (success) was achieved in 3/11 adult (27.3%) and in 6/16 paediatric patients (37.5%). Median HPT, median time between inhibitor detection and ITI start, median peak inhibitor titre during ITI and median duration of ITI in patients who achieved immune tolerance were 380 BU/ml, 120 months, 8 BU/ml, 33 months in Group 1 and 22.5 BU/ml, 9.5 months, 205 BU/ml, 25 months in Group 2, respectively. No partial response to ITI was observed in our patients. The most common initial ITI regimen in both groups was 100 IU/kg/d of FVIII (50 - 200 IU/kg/d). In 28/31 (90.3%) patients only plasma derived FVIII concentrates were used which contained various amounts of von Willebrand factor. In two patients recombinant FVIII was administered. Recombinant, plasma derived and EHL FVIII concentrates were used in the case of one boy. In two patients immunosuppressive therapy (prednisone or rituximab) was concomitantly applied. Conclusions: it is our belief that the presented real-life data reflects i) the challenge of ITI therapy in clinical practice and ii) wide variety of approaches to ITI strategy in individual haemophilia treatment centres. Disclosures Windyga: Octapharma: Honoraria, Research Funding; Rigel Pharmaceuticals: Honoraria, Research Funding; Ferring Pharmaceuticals: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Werfen: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Baxalta/Shire (a Takeda company): Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Siemens: Honoraria, Research Funding; Sobi: Honoraria, Research Funding.

Background: Acute heavy menstrual bleeding (HMB) is common for adolescent females, with about a quarter of menstruating females seeking care for HMB over a 3-year time period (O'Brien et al, Blood 2018). Inherited bleeding disorders are common in this adolescent population, identified in 24.6% referred for hematologic evaluation (Zia et al, Blood 2016). The timing and contents of the hemostatic workup for acute HMB in adolescents is extrapolated from adults, although the causes of acute HMB varies significantly between adult women and adolescents. A consensus statement by the American College of Obstetrics and Gynecology recommends obtaining a variety of hemostatic tests including CBC, von Willebrand studies, factor VIII, prothrombin time, partial thromboplastin time, fibrinogen, and thyroid stimulating hormone at the time of presentation (Committee Opinion 557, ACOG 2011). Factor VIII and Von Willebrand studies are known to be increased in the setting of physiologic stress and supplemental estrogen use, questioning their diagnostic accuracy in the setting of acute bleeding. Repeat testing is often required for diagnosis of von Willebrand disease A von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor level over 100IU/dL has been shown to have a negative predictive value (NPV) of 95%.(Doshi et al, ASH 2018). Methods: As part of a quality improvement initiative to improve the evaluation and management of adolescents with HMB at Children's Healthcare of Atlanta (CHOA), we instituted an acute HMB protocol for emergency department (ED) and inpatient use. This protocol was implemented at all CHOA emergency departments in metropolitan Atlanta. Subjects were included if they presented with acute HMB as determined by an adapted Philip Menorrhagia Screening Tool. Subjects with a previously diagnosed bleeding disorder, ITP, active rheumatologic disease, cancer, or anticoagulant use were excluded. Descriptive statistics were used to summarize demographics and clinical characteristics. Patients with a positive Philip screen underwent a uniform bleeding inventory and a standardized set of laboratory tests based on the adult consensus statement. Inpatient and outpatient treatments were standardized by hemoglobin level and symptomology. Follow up with hematology and gynecology was encouraged for all. Data was extracted using various heavy menstrual bleeding ICD-10 codes from January 1, 2017 to December 31, 2018. Individuals with von Willebrand studies at baseline and follow up were identified. T-tests and Wilcoxon rank sum tests were utilized to compare VWF:Ag, VWF:RCo and Factor VIII as baseline and follow up. Results: Over a 2-year period, 232 adolescent girls were seen in CHOA EDs for acute HMB with 88 (37.9%) requiring admission and 6 (2.6%) requiring intensive care. The population was primarily African American (63%) with a median age at presentation of 14.8 years (IQR 13.1-16.7). The majority of adolescents had the core hemostatic labs drawn (55.6%) as described per protocol. Thirty-six individuals had baseline and follow up VWD studies. Those with repeat VWD studies were younger (median 13.2 years vs 15.0 years), more commonly white (44.4% vs 21.2%), were more likely to have been admitted (83.3% vs 29.6%) and more likely to have had a hematology follow up appointment (63.4% vs 7.8%). Mean and median VWF:Ag, VWF:RCo and Factor VIII were significantly higher at presentation with HMB than at follow up. Of those with a baseline VWF:Ag and/or VWF:RCo >100, there was a 96.4% NPV for the diagnosis of VWD. For individuals whose initial VWF:Ag and VCWF:RCo were both >100, there was 100% NPV. Conclusions: Among the adolescents cared for at our institution with acute HMB who had confirmatory VWD testing, initial VWF:Ag and VWF:RCo >100 ruled out VWD based on repeat testing. However, poor adherence with hematology or gynecology follow-up may give false reassurance against a diagnosis of VWD. Further improvements of our quality improvement initiative will include a limited hemostatic workup at presentation with a focus on improved adherence to follow up and subsequent hemostatic evaluation. Disclosures White: National Hemophilia Foundation: Other: Shire Clinical Fellowship Program. Sidonio:Kedrion: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; 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; Genetech: 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; Grifols: 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; Uniqure: Membership on an entity's Board of Directors or advisory committees.

BACKGROUND. Tissue factor (TF) is critical for hemostasis. However, TF also plays a pathogenic role in a multitude of diseases, including: thrombosis, coagulation-associated inflammation, multi-organ failure associated with infections, tumor growth, angiogenesis and metastasis. Tissue Factor Pathway Inhibitor (TFPI), the regulator of TF actions, produces FXa-dependent feedback inhibition of the FVIIa/TF catalytic complex, directly inhibits FXa, and suppresses cellular signaling by FVIIa/TF/FXa complexes. In man, TFPI is expressed as isoforms TFPIα and TFPIβ. The pathophysiologic impacts of the individual α and β isoforms have yet to be elucidated. Mouse models have been used extensively to provide insight into human physiology and disease, including abnormalities concerning hemostasis and TF-associated diseases. Like man, mice express TFPI α and β, but unlike man, mice express a third transcript encoding TFPIγ. In fact, we recently reported that the vast majority (98%) of TFPI in mouse plasma is derived from TFPIγ. We also reported that anti-TFPI antibodies enhance in vitro thrombin generation in hemophilia mouse plasma that contains only the TFPIγ isoform, which demonstrated that TFPIγ possesses anticoagulant activity. RESULTS. We report herein that, while complete TFPI gene deletion is 100% embryonic lethal, TFPIγ only mice [TFPIαβ(-/-)] are viable and reproduce. Offspring genotypes from parents with intact TFPIγ(+/+) exons and TFPIαβ(+/-) were 33 TFPIαβ(+/+), 57 TFPIαβ(+/-) and 34 TFPIαβ(-/-) at weaning. Also, TFPIγ only mice produced similar numbers of pups per litter as wild type mice. The viability of TFPIγ only mice proves endogenous mouse TFPIγ possesses substantial functional activity. TFPIα is considered to be a much more potent anticoagulant than TFPIγ. Our preliminary thrombin generation assay data suggests that the sum total anticoagulant activity of the endogenous low level (0.07 nM) of TFPIα is similar to the sum total anticoagulant activity of the endogenous high level (3.5 nM) of TFPIγ. The presence of active TFPIγ in mice, not found in man, confounds attempts to translate results from wild type mouse studies to the human condition. The extents to which TFPIγ influences the various wild type mouse models of human diseases are unknown. The presence of mouse TFPIγ also precludes our ability to properly distinguish the roles of TFPI α and β isoforms independently. Deletion of the TFPIγ exon eliminates this confounder. Fortunately, in TFPIαβ mice the levels, properties and location of TFPIα and TFPIβ in mice reflect those in man. Importantly, we can now report that our CRISPR-Cas9-generated TFPIγ KO strains - TFPIαβ mice, TFPIα only mice, and TFPIβ only mice are viable and reproduce. To illustrate the potential influence of TFPIγ in a mouse model, we used a tail vein-rebleeding assay to assess bleeding in TFPI isoform-specific mice in a FVIII KO background. Reported as mean number of clots per 15 minutes, results were: 4.8 for hemophilia controls; 25.4 for controls with FVIII replacement; 4.2 for TFPIα KOs; and 13.5 for TFPIβγ KOs. (The S.E.M. of each group was 0.5 vs controls), whereas deletion of TFPIβ and γ improves hemostasis ( P CONCLUSIONS. 1.) Endogenous mouse TFPIγ possesses significant functional activity. 2.) TFPIγ confounds the extrapolation of results in wild type mouse models to human diseases. 3.) The TFPIγ KO mouse possesses a TFPIαβ profile that is similar to man. 4.) For essentially all studies of human TF-associated diseases in mouse models, it would be prudent to delete TFPIγ. Disclosures No relevant conflicts of interest to declare.

61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) -- DEC 07-10, 2019 -- Orlando, FL, WOS:000577160400199, [No Abstract Available], Amer Soc Hematol

Introduction: Recurrent joint bleeding in patients with congenital hemophilia causes progressive arthropathy, characterized by reduced range of motion, synovial proliferation and osteochondral damage. Chronic hemophilic arthropathy remains a leading disabling complication affecting activity and quality of life. Clinical scoring systems, such as the Hemophilia Joint Health Score (HJHS), along with semi-quantitative imaging modalities (radiographs, magnetic resonance, ultrasound) can aid in the evaluation of joint health. However, scores exhibit ceiling effects and lack the opportunity to provide tissue measurements reflecting subtle dynamic changes of intra-articular structures that may be important in monitoring progression of hemophilic arthropathy. Point-of-care (POC) musculoskeletal ultrasound (MSKUS) has emerged as a rapid and sensitive imaging modality to evaluate not only acute bleeding episodes but also the extent of hemophilic arthropathy at the tissue level in the clinic setting. The Joint Tissue Activity and Damage Exam (JADE) has been developed as a concise, quantitative (not semi-quantitative) MSKUS protocol, validated per Outcomes Measures in Rheumatology guidelines for accurate tissue recognition, with high intra/inter-rater and inter-operator reliability, to quantify (1/10th of millimeter) soft tissue expansion, osteochondral alterations and cartilage thickness in hemophilic joints. We aimed to explore to what extent measurable structural intra-articular tissue changes, evaluated by JADE, correlate with clinical and functional joint assessments. If the value of JADE can be established in this context, such information would enable the use of JADE as a POC precision imaging tool to guide management of hemophilic arthropathy. Methodology: From May 2016 to April 2019, we assessed baseline joint characteristics in a prospective multicenter study in patients with congenital hemophilia and arthropathy (age ≥18 years; n=44 patients; n = 264 joints [bilateral elbows, ankles and knees]). HJHS (a clinical assessment tool) and total arc (a functional assessment tool measuring the sum of flexion and extension degrees of motion) were also evaluated. Each joint was examined using the MSKUS JADE protocol. We analyzed the association between joint HJHS and each JADE variable (comprising measurements of soft tissue expansion, osteochondral alterations and cartilage thickness in validated sentinel positions), and between total arc and each JADE variable, by fitting random intercept models that accounted for intra-individual correlation. The outcomes were transformed to ensure normal residuals, and when necessary polynomial terms were added to fit the curve associations between outcomes and JADE variables. Results: A wide range of joint HJHS values (Elbow: 0 - 13, Knee: 0 - 14; Ankle: 0 - 18 [normal=0; highest abnormal 20]) and total arc values (Elbow: 48 - 158, Knee: 22 - 160; Ankle: 5 - 76) were recorded in the cohort, enabling analyses over a broad range of arthropathic changes. Increasing HJHS and declining total arc were associated with increasing age which is consistent with deteriorating joints. Worsening arthropathy (increasing HJHS or declining total arc) of each joint were associated with JADE measurements in the expected direction including increasing soft tissue expansion, increasing length of osteochondral alterations and decreasing cartilage thickness. This is exemplified for the elbow in Figure 1, showing the associations of worsening HJHSs and arcs with increasing osteochondral alterations and decreasing cartilage thickness. Conclusions: This study demonstrated convincing relationships between direct ultrasonographic measurements using the JADE protocol, clinical HJHS and functional arc in a broad range of arthropathic manifestations in hemophilic patients. Interestingly, changes in arc, limiting joint flexion and extension, appeared often to be closer related to ultrasound tissue measurements than HJHS, highlighting the relevance of JADE towards joint function, a parameter of particular patient interest. These findings confirm the clinical value of POC ultrasonographic direct joint tissue measurements as a precision tool to guide timely changes in the management of hemophilic arthropathy. Disclosures von Drygalski: University of California San Diego: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UniQure, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Founder.

Patients with Sickle Cell Disease (SCD) frequently present for emergency care with pain or fever. The rate of emergency visits/year is between 2-4 per patient every year with 12% of patients visiting the emergency 4 or more times/year1. National medical organizations in Canada and the United States recommend pain therapy within 30 minutes of arriving to the emergency department2,3. Feedback from patients in Canada reflected a lack of awareness of the medical community regarding the disease and optimal management. As a response Canadian Haemoglobinopathy Association2 (CanHaem), created the "Sickle Cell Disease Emergency Wallet Cards" which were inspired from the successful Hemophilia "Factor First Card4". The goal of the cards was to provide simple care instructions to an emergency responder and facilitate timely care for patients in crisis. These wallet cards have recommendations for treatment of pain and fever within 30 minutes, patient's diagnosis, program contact details, and patient's individual pain plan. The cards have been in circulation for 4 years. The purpose of this study was to determine if the cards are used by parents and patients as intended. Research Questions: 1.Are the CanHaem Cards used by patients and families? 2. Do patients find the card helpful in facilitating their care delivery? Methods: The surveys were administered to patients and/or proxies. Prior to survey distribution three parents/patients have verified the utility of the questions, the content and the readability of the survey. The survey was translated into French/Arabic by two independent translators per language. It was distributed in Alberta and British Columbia, Canada in specialty clinics known to use the cards. The University of Alberta Ethics Board deemed the project a quality improvement initiative and the ARECCI tool: A pRoject Ethics Community Consensus Initiative was completed prior to quality improvement project start. Results: 140/184 participants completed the survey. The response rate: 76%. Demographics: 91% province of Alberta. Proxy: 49%; Patients: 51%. The majority of respondents were female: 54%, median age: 37 years (range 16-84 years). See graphs 1-4 below: 72.3% felt the card was helpful in their care. 78.6% carry the physical card (purse, wallet, and diaper bag), while 10.7% have a picture on their phone, 9.3% don't carry the card, 7.1% state they never received a card. The majority (63.6%) show the card at first contact in emergency, 48.9% felt staff read the card. Total of 68 comments. 67.6% of comments were positive: "Sense of security"; "Get us in to see the doctor faster..." Neutral comments (22%) ranged from requests for lamination to provider response to the card being variable "sometimes it is faster and sometime(s) doesn't really change anything". Finally, 10% were negative reflecting long wait times "Good concept, the idea itself is great. Execution... could be improved greatly", and requests for more information on the card. Conclusion: In Canada, SCD is an uncommon disease and many healthcare providers may not be aware of national and international guidelines regarding acute presentations. To help facilitate knowledge transfer and to aid communication with emergency services, CanHaem created wallet cards as a Canada-wide initiative. This survey demonstrates the patient/parent perspective of the emergency cards. Eighty-nine percent of patients/proxies carried the card (either digitally or physically) and 63% showed the card in the acute care setting. The discrepancy between those who carry the card and those who show it may reflect that numerous respondents stated they had not required emergency care since receiving the card as well some respondents were "carried away by the pain and forget to use the card". Comments revealed a sense of security and patient's appreciation for having the card available to them indicating the value of card to patients. The card demonstrates a simple and low cost intervention to facilitate emergency care for hemoglobinopathy patients. References: 1. Paulukonis ST et al. Emergency department utilization by Californians with sickle cell disease. Ped Blood and Ca 2017. doi: 1002/pbc.26390 2. CanHaem https://www.canhaem.org/healthcare-professionals/ 3. Evidence-Based Management of Sickle Cell Disease: Expert Panel, 2014. 4. Canadian Hemophilia Society. Stop the Bleeding. https://www.hemophilia.ca/files/ER%20CARD%20E_%20Jan%2009.pdf Figure Disclosures Ezzat: Novartis: Honoraria, Speakers Bureau; ApoPharma: Research Funding.

Introduction Hemophilia is one of the most common inherited bleeding disorders. This study aims to estimate associated diagnoses, healthcare utilization, and mortality in hospitalized pediatric and adult patients with hemophilia A and B and evaluate outcome improvement trends. Methods The 2016 Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (HCUP-NIS) was utilized for the analysis. The NIS uses a stratified probability sample of 20% of all inpatient discharges (representing more than 97% of the US population). We applied sampling weights to represent all hospital discharges for hemophilia identified using ICD-10 codes D66 and D67 and generate nationally representative estimates. For comparative historical data, we used 2007 data from a prior published study [Goel et al., Hemophilia (2012), 18, 688-692]. Results In 2016, there were n=10,840 hospital discharges with hemophilia A or B as one of all listed diagnoses (n=1600 as principal diagnosis). Of these, 2445 were children, and 8395 were adults. The median age (interquartile range) was 52 (33-68) years for adults and 5 (1-11) years for children. Associated Diagnoses (Table 1a) The most common associated diagnoses in adults with hemophilia were hypertension (34.7 ± 1.2%), Type 2 diabetes (21.1 ± 1.2%), and hyperlipidemia (18.8 ± 1.0%). Other noteworthy ones include hepatitis C (16.4 ± 1.1%), coronary artery disease (13.3 ± 0.9%), and congestive heart failure (11.1 ± 0.8%). In pediatric hemophilia cases, central line infection and fever (13.5 ± 1.5%), hemarthrosis (10.4 ± 1.3%), and anemia (8.6 ± 1.3%) were the most common discharge diagnoses. HIV/AIDS and hepatitis C were not reported in children and listed in 5.9 ± 0.6% and 16.4 ± 1.1% of adults, with the youngest age at reported diagnosis being 32 and 21 years, respectively. Mortality (Table 1b) The all-cause in-hospital mortality was 1.9% for hemophilia related admissions, which was comparable to all NIS hospitalizations at 1.9%. The median age at death in years (interquartile range) for hemophilia patients was 72 (57-78) and comparable to 73 (61-83) for all hospitalizations. The most common diagnoses associated with mortality included respiratory failure, "do not resuscitate" status, and sepsis. There was no inpatient mortality reported in children, and the youngest age for in-hospital death was 27 years. Health Care Utilization 96.0% of all hemophilia admissions had insurance coverage with the distribution as follows: Medicare: 33.4%, Medicaid: 28.8%, private insurance: 28.6%. For all NIS hospitalizations, 96.1% had coverage (Medicare: 39.6%, Medicaid: 23.1%, private insurance: 30.1%). The median hospital stay length per hemophilia admission was 3 days (2-6) and was similar to all hospital stays at 3 days (2-5). The median hospital charge per hemophilia admission was $50,662 as compared to $25,261 for all hospital admissions. 2007 Comparison When we compared our data to 2007, serving as a near-decade long follow-up, insurance distribution, inpatient mortality rate, and length of stay were relatively unchanged. Amongst the most common diagnoses for adults with hemophilia were hypertension (up from 28.1% to 34.7%), hepatitis C (down from 21.8% to 16.4%), congestive heart failure (up from 8.1% to 11.1%), and HIV/AIDS (stable at 5.6% and 5.9% respectively). In both 2007 and 2016, there were no HIV or hepatitis C cases amongst children with hemophilia. Notably, in 2007, there were more bleeding related diagnoses, such as hematuria and hemorrhages. There was no inpatient mortality for children in 2016, while there were 15 day of life zero deaths (7% mortality rate) in 2007. The median age at death was also greater in 2016 (72 and 68.3 years). Discussion/Conclusions Adult hemophilia hospitalizations were in large part related to non-bleeding complications and age-related co-morbidities. In contrast, catheter-related infections and bleeding remain the top reasons for pediatric admissions. Most hemophilia patients had insurance coverage. The median hospital charge for those with hemophilia was nearly twice that of all-cause hospitalizations. Advancements in hemophilia treatment and outcomes are continuing, as evidenced by the improved mortality rate and median survival range approaching those from all hospitalizations. These changes all cumulatively demonstrate significant treatment and health care advancements in hemophilia management. Disclosures Takemoto: Genetech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Other: DSMB for aplastic anemia trial.

Introduction: Patient reported outcome measures (PROMs) are questionnaires completed by patients or caregivers without interpretation by healthcare professionals. As such, they allow patient concerns about a variety of healthcare issues to be identified and addressed in an efficient and actionable manner. PROMs can be generic, with questions relevant to multiple disease groups or disease-specific, with questions targeting the symptoms, limitations, and feelings common to the disease group. This systematic review identified generic and disease-specific PROMs for monitoring symptoms and health-related quality of life (HRQoL) in 4 pediatric non-malignant hematologic disease groups: thalassemia, hemophilia, immune thrombocytopenia (ITP), and sickle cell disease (SCD). Methods: Databases (MEDLINE, Embase, HaPI, CINAHL, and PsycTESTS) were searched to identify publications that either validated or used PROMs as an outcome measure in the four disease groups. Articles were excluded when Results: The search identified 1176 unique records, with 902 records remaining for title and abstract screening after removal of 274 hemophilia articles published prior to the systematic review. Including hemophilia records identified from the 2017 review, 217 articles met inclusion criteria incorporating 107 generic and 20 disease-specific PROMs. Of the generic tools, the most frequent categories identified include psychological well-being (26 tools), general quality of life (19 tools), and family impact (19 tools). The most frequently used tool was the PedsQL 4.0 Generic Core Scales (66 studies), appearing 33 times in SCD, 25 times in thalassemia, 5 times in ITP, and 3 times in hemophilia. Other commonly used generic tools include the Short Form Health Survey, Child Health Questionnaire, PROMIS Health Measures, and Child Behaviour Checklist (Table). Disease-specific tools identified in the review include the PedsQL SCD Module, Kids ITP Tool, Haemo-QoL, CHO-KLAT, and TranQol (Table). In addition, 10 studies reported on pain diaries and 9 of these studies were SCD focused, the other being hemophilia focused. Conclusion: This systematic review identified several generic and disease-specific PROMs that have been used in pediatric non-malignant hematology. Although generic tools have been used more frequently, many disease-specific tools have been validated and are available for use in the clinical environment. We are currently conducting focus groups with patients, parents, and clinicians to determine the optimal choice of tools for monitoring symptoms and HRQoL in the pediatric non-malignant clinical environment. Disclosures No relevant conflicts of interest to declare.

Introduction Emicizumab is a recombinant humanized monoclonal antibody that bridges factor IXa and Factor X and is administered via subcutaneous injection. It provides protection against bleeding in patients with hemophilia A (HA) with and without inhibitors of all ages. Since licensure, the use of emicizumab has increased across hemophilia treatment centers (HTCs). Management of patients on this drug who require procedures has not been well established. The objective of this study was to report peri-procedural hemostasis management as well as bleeding and thrombotic outcomes in a heterogenous group of patients with HA on emicizumab requiring interventional procedures. Methods We conducted a multi-center observational study at 3 federally funded Hemophilia Treatment Centers: Children's Hospital of Philadelphia, Virginia Commonwealth University and Children's National Health System. Inclusion criteria included patients with HA initiated on emicizumab prior to May 15th 2019 that underwent a surgical, dental or interventional procedure prior to July 15, 2019. Data extraction included: demographics, diagnosis, inhibitor, emicizumab dosing data, surgery type, factor used during surgery, and bleeding or thrombotic complications during or after surgery. Results There were a total of 19 procedures in 19 subjects during the study period. 18 were male and all had severe HA. Age at initiation of emicizumab in this cohort ranged from 5 weeks to 27 years; median 5.7 (IQR) yrs. There were 6 patients with an active inhibitor at the time of emicizumab initiation. All patients received emicizumab 3.0 mg/kg weekly x 4 loading doses, followed by either weekly (8), every other week (10), or monthly (1) dosing. There were 18 minor procedures during the study period (14 port removals and one of each of the following: PE tube removal, laparoscopic inguinal hernia repair, arthroscopy, and dental extraction) and one major procedure (intracranial ventricular shunt revision )(Table 1). Of the 14 port removals, 5 patients (1 with inhibitor) did not receive pre-procedure factor replacement; the other 7 received rVIIa or factor VIII pre-procedure and 2 of these patients received a subsequent dose as part of their plan. Three of the 14 patients that underwent port removal (one with inhibitor) were noted to have swelling and hematoma at the surgical site 1-2 days post-op and received 1-2 doses of subsequent factor to treat these bleeding events; only one of these patients did not receive pre-procedure factor. The patient who underwent major surgery received multiple doses of FVIII (to keep FVIII levels >50% x 1 week) and did not have bleeding complications. There were no thrombotic complications. Conclusions In general, the 19 patients with HA who required procedures while on emicizumab did well. Port removal was the most common procedure, which was not surprising given the transition from intravenous to subcutaneous prophylaxis. There was variation in practice, particularly in regard to the need for clotting factor prior to port removal. Most patients did well with 0-1 treatments prior to minor procedures, and no additional replacement. Although 3 of the 14 patients required 1-2 unplanned infusions of clotting factor post port removal, there was no clear relationship between pre-procedure factor replacement and post-procedure port hematoma. This observational study provides useful information for providers who manage patients with HA on emicizumab, although larger studies are clearly needed to help determine best practice. Disclosures Guelcher: Takeda: Other: Advisory Board; Octapharma: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board. Butler:Hema-Biologics: Consultancy; pfizer: Other: Advisory board; genetech: Other: Advisory board. Guerrera:Bioverativ: Consultancy; Novo Nordisk: Consultancy; Pfizer: Other: Advisory Board; Bayer: Other: Advisory Board; Shire: Other: Advisory Board; Kendrion: Other: Advisory Board; Genetech: Other: Advisory Board. Raffini:Roche: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board.

The genetics of blood coagulation has been an ongoing area of research; and with the advent of next generation sequencing panels, there is a significant increase in the number of variants identified in coagulation factor genes. Several published reports and online databases document the variants observed in patients with bleeding disorders; however, the clinical interpretation of these variants is not always straight-forward. To enable gene-specific variant interpretation in coagulation factor deficiency disorders, the National Institutes of Health (NIH)-funded effort, Clinical Genome Resource (ClinGen), has developed the Coagulation Factor Deficiency Variant Curation Expert Panel (CFD-VCEP). The CFD-VCEP is comprised of expert clinicians, genetic counselors, clinical laboratory diagnosticians and researchers working toward the goal of developing and implementing standardized protocols for sequence variant interpretation for coagulation factor genes. The CFD-VCEP adapts the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for precise and consistent variant classification to genes involved in blood coagulation deficiencies. These guidelines recommend the use of 28 criteria codes based on the evidence category and the strength of the evidence (see Figure below). The first two genes under the purview of CFD-VCEP are F8 (OMIM: 300841) and F9 (OMIM: 300746). Pathogenic variants in the F8 and F9 genes resulting in the loss of protein function cause Hemophilia A and B, respectively. Owing to the similarity between these two genes with respect to their role in the coagulation cascade as well as the resulting phenotype, specification of variant curation guidelines for both genes has been undertaken simultaneously. With the completion of guideline specification for F8 and F9, the CFD-VCEP will subsequently continue this effort for other coagulation factor genes, while also curating F8 and F9 variants reported in ClinVar and other variant databases. Modifying the ACMG/AMP guidelines involves gene- and disease-informed specifications of the recommended criteria codes. This includes identifying which codes are applicable and which are not, defining gene- and disease-specific cut-offs such as for population frequency, and making code strength adjustments when appropriate. The specified guidelines are further refined based on their performance on a set of pilot variants (n = 30) for each gene compared to existing assertions of variant classification in ClinVar and by diagnostic laboratories represented in the CFD-VCEP. F8 and F9 variants classified by the CFD-VCEP will be submitted to ClinVar at the 3-star review status, with the tag of "FDA-recognized database", and the CFD-VCEP plans to begin this process by the second quarter of 2020. The considerations by the CFD-VCEP in the guideline-specification process and results from the pilot analysis will be discussed. This effort will lead to the standardized use of evidence criteria for the evaluation of variants in F8 and F9, which will reduce the number of variants of uncertain significance and those of conflicting interpretations, making genetic testing results more informative for providers and patients. The CFD-VCEP also encourages sharing de-identified data on variants among laboratories, which enables accurate and consistent curations. Figure Disclosures Lee: UNC Hemophilia Treatment Center: Employment. Carcao:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kemball-Cook:European Association for Haemophilia and Allied Disorders: Other: Freelance . Leebeek:CSL Behring: Research Funding; uniQure BV: Consultancy, Research Funding; Baxalta/Shire: Research Funding. Miller:Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention: Consultancy.

Introduction Hemophilia is an inherited disorder that causes a deficiency of a blood clotting factor resulting in a lifelong bleeding diathesis. People with hemophilia (PWH) may experience significant morbidity including potentially life-threatening hemorrhages and accumulation of joint damage and require burdensome and costly chronic treatment with factor replacement therapies. Gene therapies aimed at providing endogenous production of the missing clotting factor have the potential to yield significant health benefits for PWH. Economic evaluation is an important component for the commissioning and funding of new treatments like gene therapies. In economic evaluation, quality-of-life (QoL) is measured using health state utility valuations (HSUV). However, people with inherited and long-term health conditions may adapt to their given health state and adjust their expectations, therefore biasing the estimates of QoL/HSUV (i.e., disease state adaptation (DSA) or "disability paradox"; Albrecht and Devlieger, 1999). Here, we describe the first stages of research to evaluate DSA experienced by PWH. Methods To facilitate the selection of research methodology, a systematic litearure review (SLR) was performed to examine existing studies on QoL/HSUVs for PWH. A SLR was conducted to identify full-text studies by searching electronic databases (e.g. MEDLINE, Web of Science, Cochrane Library). Studies were included in the review using predefined inclusion/exclusion criteria for population, study type, language (English). Additionally, a manual search (last three years) for conferences abstracts was performed to capture the most up-to-date research. Findings from the SLR informed the conceptualisation of a study framework. The proposed research approach was then discussed with an expert panel consisting of clinicians, patient advocacy representatives, and Health Technology Assessment (HTA) specialists. Results The SLR identified 32 studies reporting HSUVs in hemophilia. The studies identified applied a mix of direct and indirect HSUV elicitation techniques. Two studies applied direct time trade-off methodology and the remaining 30 studies adopted indirect valuation methodologies. Utility values were found to vary by disease severity, musculoskeletal damage, bleed frequency, inhibitors, hemophilia subtype, treatment regimen, and adherence. Interestingly, HSUVs derived from valuations from the general public were found to be valued lower than those derived from PWH for the same health states. For example, in Carlsson et al. (2017), general public participants consistently rated significantly lower HSUVs for hemophilia disease states compared to PWH (range: 0.54-0.60 vs. 0.67-0.73), suggesting DSA might exist for PWH. Based on SLR findings, an expert panel discussed the feasibility and acceptability of an approach for conducting a preference elicitation study to directly evaluate DSA in PWH. Preference elicitation is an established research framework that is widely used in health economics. A comparative preference elicitation study was proposed to describe and quantify DSA by comparing responses from PWH, caregivers of PWH, and the general public. Conclusion Based on the SLR and expert panel inputs from clinicians, patients and HTA experts, an agreement was achieved about the research methodology for a new study directly assessing DSA experienced by PWH. Experts agreed that a comparative preference elicitation approach among PWH, caregivers of PWH, and the general public was fit-for-purpose for this research. The impact of DSA on QoL/HSUV should be characterized within economic evaluations of novel treatments with transformative impact on patients' lives, such as gene therapies. Disclosures Martin: HCD Economics: Employment. Mulhern:HCD Economics: Consultancy. Shaikh:HCD Economics: Employment. Asghar:HCD Economics: Employment. O'Hara:HCD Economics: Employment, Equity Ownership. Pedra:HCD Economics: Employment. Sawyer:uniQure Inc.: Employment. Li:uniQure Inc.: Employment.

Introduction : As the first in a new class of substitutive, non-factor hemophilia A therapy, acceptance of emicizumab by patients with hemophilia is unclear. Impact of emicizumab on treatment adherence, pursuit of athletic activity, psychosocial connection to the hemophilia patient community, and patient satisfaction have not been assessed. Additionally, reasons for choosing to initiate or not initiate emicizumab in patients who have been offered it have not been evaluated. This patient survey study addresses these questions. Methods : A voluntary, anonymous 22-item survey was electronically distributed to hemophilia patients throughout the United States through hemophilia treatment centers and the National Hemophilia Foundation. Recipients were instructed to take the survey only if they were a patient with hemophilia A who has been offered bleeding prophylaxis (or the parent of such a patient under age 18). Skip logic was employed such that individual respondents answered 15 or fewer items based on their familiarity with and use of emicizumab. Results to items utilizing a 5-point Likert scale were converted to weighted average scores (ranging from 1, lowest to 5, highest) for comparison between groups of respondents. Results : 126 respondents (67 adults and 59 parents of children age Conclusions : Most U.S. hemophilia A patients requiring prophylaxis are familiar with emicizumab. Regardless of inhibitor status, patients with higher ABR and worse compliance with infusion-based prophylaxis are more likely to use emicizumab. From the non-inhibitor patient perspective, ease of administration with subcutaneous dosing ≤1 time per week was at least as important as effectiveness and safety of the drug in their decision to switch to emicizumab, whereas this was much less important to inhibitor patients. Patients using emicizumab were highly satisfied with their decision to switch to this agent. Patients choosing not to switch to emicizumab are concerned about safety, unknowns with a new treatment, and lack of lab monitoring, although one-third of patients felt they lacked the information to decide whether to use it. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Croteau:Octapharma: Honoraria; Bayer: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Spark Therapeutics: Research Funding; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding.

Hemophilic arthropathy is characterized by vascular abnormalities in the joint soft tissue that may cause rebleeding and progressive joint destruction. Defective thrombin generation in hemophilia leads to impaired activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI). Activated TAFI (TAFIa) is a carboxypeptidase that cleaves C-terminal Lysine from fibrin or cell plasminogen receptors, thereby diminishing fibrinolysis or pericellular plasmin generation. In addition, TAFIa inactivates pro-inflammatory (i.e. C3a, C5a, bradykinin) and anti-angiogenic (i.e. VEGF-A, SDF-1α) substrates. We have recently shown that TAFI-gene deficiency causes vascular abnormalities in the mouse joints that phenocopy those in hemophilic arthropathy, either after joint bleeding or spontaneously with aging. Based on these mechanistic insights, we evaluated treatment with TAFI for its ability to mitigate bleeding-induced vascular abnormalities and associated bleeding susceptibility in the FVIII KO mouse joint. Knee joint bleeding in FVIII KO mice was induced by a subpatellar puncture injury that was standardized to cause severe bleeding as defined by a hematocrit (Hct) drop from 47 ± 2 % at baseline (BL) to 29 ± 11 % two days after injury. The vascular abnormalities formed in the hemophilic mouse joint 2 weeks after injury capture those in patients with hemophilic arthropathy: i.e. increased vascular permeability and abnormal vessel enlargement. Hydrodynamic gene delivery was used in mice for continuous treatment with human wild type TAFI (hTAFI-WT). To compensate for lower TAFI activation in hemophilia, two TAFI mutants were tested with extended enzymatic stability: hTAFI-CYQ (8-fold increased) and hTAFI-CIIYQ (180-fold increased). The TAFI constructs had comparable antigen expression profiles (reaching a similar level as in human plasma at day 2 and gradually returning to BL by week 2). Treatment efficacy to reduce vascular permeability, however, differed according to TAFIa's enzymatic stability in FVIII KO mice 2 weeks after injury. Without treatment, Evans blue-BSA extravasation in the joints was increased (1.8-fold compared to the contralateral joint; p= 0.0001 vs BL). hTAFI-WT overexpression initiated 2 days after injury had no effect, whereas hTAFI-CYQ and hTAFI-CIIYQ overexpression reduced the vascular permeability to 1.5-fold (n= 10; p= 0.10 vs untreated) and 1.3-fold (n= 8; p= 0.0032 vs untreated), respectively, indicating that hTAFI-CIIYQ was most effective. Histology at week 2 confirmed that hTAFI-CIIYQ reduced the number of excessively enlarged CD31+ vessels (with ≥ 20 µm diameter) by 3-fold (n= 6; p= 0.0011 vs untreated). To determine whether the protective effect of TAFI overexpression on bleeding-induced vascular abnormalities was associated with inhibition of the plasminogen activation system, continuous administration of tranexamic acid (TXA; 50 mg/ml in drinking water) or antibody-mediated blockage of uPA's proteolytic activity (mU1; 60 mg/kg; 2x weekly) was initiated in FVIII KO mice 2 days after injury. Histology at week 2 showed mU1, but not TXA, reduced vessel enlargement to the same extent as hTAFI-CIIYQ. Finally, the joint bleeding model was adopted to appreciate functional consequences of hypervascularity to changes in bleeding susceptibility. Aged TAFI KO mice (8 months) were used for their spontaneously (3-fold) increased number of enlarged vessels (≥ 40 µm diameter; p= 0.0076) in the joint that correlates with Power Doppler (PD) signal. A mild injury was optimized to cause minimal bleeding and showed that PD signals in joints of aged TAFI KO mice correlated negatively with the Hct 2 days after mild injury with injection of a FVIII inhibitor (r= -0.53, p= 0.024; n= 18), supporting hypervascularity as a major contributor to hemophilic joint bleeding. Furthermore, the same mild injury caused minimal bleeding in naive FVIII KO mice with low BL vascularity (median Hct 46 % vs 48 %; p= 0.81 vs BL; n= 7), but excessive bleeding in FVIII KO mice injured 2 weeks previously with vascular abnormalities (median Hct 38 %; p= 0.021 vs BL; n= 7). hTAFI-CIIYQ effectively reduced bleeding severity upon re-injury (median Hct 47 %; p> 0.99 vs BL; n=5). Our data provide an experimental link between vascular abnormalities and bleeding susceptibility in hemophilic joints and conclude that the vascular abnormalities were alleviated by increasing TAFI levels or inhibiting uPA activity. Disclosures von Drygalski: University of California San Diego: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UniQure, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Founder. Mosnier:The Scripps Research Institute: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Background: The child's diagnosis of a chronic genetic disease such as haemophilia is life-changing and impacts not only the child, but also the parents (Khair & Chaplin, 2016). Alloantibodies to factor concentrates occur in 25-30% previously untreated patients (PUPs), and usually develop within the first 50 exposure days (EDs) and can cause anxiety in parents of children with haemophilia. Risk factors include ethnicity, genotype, family history of inhibitors and product type. Moreover, the daily management of the disease can cause a great burden to these parents. Aim: Evaluation of caregiver's burden in parents caring for toddlers and young children with severe haemophilia from a single centre in Germany. Methods: Caregivers of recently diagnosed PUPs with severe haemophilia A or B (< 0,01 IU/ml FVIII or FIX) from the GZRR were included in this study. Haemophilia-specific caregiver's burden was evaluated using the 'HEMOphilia associated Caregiver Burden scale' (HEMOCAB), comprising 54 questions in 13 domains, of which nine domains build the sum score FREQUENCY of burden ranging from 'never' to 'always' and four domains build the sum score INTENSITY of burden ranging from 'not at all' to 'very much'. High values imply high burden (von Mackensen et al., 2015). Clinical data were collected from patient records. Results: Twenty-eight caregivers with a mean age of 35.92±8.6 years participated, most of them were mothers (71.4%) and hold the primary responsibility in the management of their children's disease (50%). Eighty-seven percent of the caregivers were married and 95.2% lived with a partner and had a median number of 2 children (range 1-4). Most of them had a high school education (47.6%) and were working full- or part-time (56.5%); 52.9% were not working full-time due to caring for their haemophilic child. Most of the families lived in a big city (60.9%). Half of the caregivers reported that haemophilia affected their family life and 28.6% had an economic impact. They were caring for 21 children with severe haemophilia with a median age of 2.11 years (range 0.45-8.7). 85.7% of the children had haemophilia A, none had a target joint, reduced range of motion, a concomitant disease or an inhibitor; 68.4% had a high-risk mutation. One third of the children received home treatment (33.3%) and were mainly infused by a physician at the centre (63.2%) and all had a peripheral venous access. Two out of 21 children had not yet started treatment, while all children who received treatment were on primary prophylaxis, mainly every 10 days (31.6%), with plasma-derived products and a median of 60 EDs (range 0-229). In general, all PUPs at the GZRR when starting their treatment receive 20 IU/kg every 10 days until 20 EDs, thereafter the dosing and frequency will be escalated individually up to 40 IU/kg up to 4x/week depending on their bleeding tendency. Two children underwent a surgical procedure (circumcision, phimosis). In average children had 3.0±3.6 total bleeds in the past 12 months and 0.43±0.8 joint bleeds. Caregiver's overall burden was 27.95±13.2 with highest impairments in the domains 'emotional stress' (M=39.17±20.0), 'perception of your child' (M=35.85±22.8) and 'work' (M=34.44±36.8). Forty-seven percent 'always/often' asked themselves "if my child's condition will be better in the future", 40.3% were "afraid that my child could get injured in an accident and I cannot help him" and 30% thought "my child needs more attention and affection"; 33.3% thought that 'quite a bit/very much' "the choice of their job depends on a location close to my child's day care/school". Conclusion: Ninety-one percent of the PUPs had started with an early low-dose prophylaxis with plasma-derived products, no inhibitors occurred so far although the critical benchmark of 50 EDs has been exceeded and resulted in good bleed protection with few joint bleeds. Caregivers reported highest burden in the domain 'emotional stress' which might be caused by the permanent conflict situation; on the one hand, they want their child to grow up as normal as possible (without stigmatization), on the other hand, they want to protect their child from bleeding. To understand how such demands impact on caregivers of children with haemophilia who live with the daily threat of bleeding can help health professionals to provide effective support to parents and families. Disclosures No relevant conflicts of interest to declare.

Introduction Current adeno-associated viral (AAV) vector-based gene therapy strategies for hemophilia rely on systemic administration of the vector. Durable expression of the transgene over the span of years has been reported from several trials, yet information on the clearance of vector material from bodily fluids is still limited and monitoring of "shedding" is required during trials despite lack of evidence of environmental or transmission risk. Here, we examined the magnitude and duration of the presence of vector DNA in participants from a Phase I/II study of an AAV5-hFIX wildtype construct (AMT-060; NCT02396342) and from a Phase IIb study utilizing the enhanced version, AAV5-hFIX Padua (AMT-061; NCT03489291). Methods Adult male participants with severe or moderately severe hemophilia B received a single intravenous infusion of either AMT-060 at 5x1012 genome copies(gc)/kg (low dose) or 2×1013 gc/kg (high dose), or AMT-061 at 2x1013gc/kg in one of two ongoing trials. Assessments in both trials included efficacy and safety outcomes as well as vector shedding in whole blood and semen. Vector shedding was also measured in nasal secretions, feces, urine, and saliva in participants receiving AMT-060. Vector shedding was analyzed using a validated quantitative real time polymerase chain reaction (qPCR) based assay measuring presence of vector DNA in the bodily fluids. Vector clearance was reached when vector DNA was either zero or below the limit of detection (LOD) for three consecutive measurements. The range in time to the first and the third consecutive negative measurement for each dose group are provided. Results Treatment with AMT-060 resulted in sustained improvement in FIX activity for up to 3.5 years [Mean FIX activity was 5.1% (low dose group at 3.5 years) and 7.5% (high dose group at 3 years)] and treatment with AMT-061 resulted in mean FIX activity of 45% over 36 weeks. AMT-060 and AMT-061 reduced the mean number of annualized bleeds by between 82% and 100% respectively. AMT-060 reduced the requirement for exogenous FIX administration by 86% and was abrogated with AMT-061. Both AAV5-hFIX and AAV5-hFIX Padua were safe and well tolerated and no unexpected TRAEs have been observed with longer-term follow up. Table 1 describes the time in weeks to the first and last of three consecutive measures of vector DNA of either zero or Conclusions Post-AMT-060 treatment, vector DNA was undetectable in all participants in the high dose group by 10 months and considered cleared by 16 months in all bodily fluids except blood. AMT-060 was cleared from the blood in 100% of participants in the low dose group at 3 years and 80% of participants in the high dose group by 2.5 years. As expected, AMT-061 vector DNA was detectable at 36 weeks in blood and in the semen of 1 of 3 participants, although clearance had not yet been established in the remaining participants. The presence of vector DNA in bodily fluids assessed was not associated with any adverse safety or efficacy findings. Disclosures Sawyer: Uniqure BV: Employment. Gielen:uniQure Biopharma: Employment. Twisk:uniQure Biopharma: Employment. Long:Uniqure BV: Employment. Gut:Uniqure BV: Employment.

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer 5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

The contact system produces the inflammatory peptide bradykinin and contributes to experimental thrombosis. C1 esterase-inhibitor (C1INH) deficiency or gain-of-function mutations in factor XII (FXII) cause hereditary angioedema, a life-threatening tissue swelling disease. C1INH is a relatively weak contact system enzyme inhibitor. Although α1-antitrypsin (α1AT) does not naturally inhibit contact system enzymes, a human mutation (M(358)R; α1AT-Pittsburgh) changes it into a powerful broad-spectrum enzyme inhibitor. It blocks the contact system, but also thrombin and activated protein C (APC), making it an unattractive candidate for therapeutic contact system blockade. We adapted the reactive center loop of α1AT-Pittsburgh (AIPR/S) to overcome these obstacles. Two α1AT variants (SMTR/S and SLLR/S) strongly inhibit plasma kallikrein, activated FXII, and plasmin. α1AT-SMTR/S no longer inhibits thrombin, but residually inhibits APC. In contrast, α1AT-SLLR/S residually inhibits thrombin, but no longer APC. Additional modification at the P1′ position (S→V) eliminates residual inhibition of thrombin and APC for both variants, while retaining their properties as contact system inhibitors. Both α1AT-SMTR/V and -SLLR/V are superior to C1INH in reducing bradykinin production in plasma. Owing to their capacity to selectively block contact system-driven coagulation, both variants block vascular occlusion in an in vivo model for arterial thrombosis. Furthermore, both variants block acute carrageenan-induced tissue edema in mice. Finally, α1AT-SLLR/V, our most powerful candidate, suppresses epithelial leakage of the gut in a mouse model of colitis. Our findings confirm that redesign of α1AT strongly alters its inhibitory behavior and can be used for the treatment of contact system-mediated thrombosis and inflammation.

Objectives: to investigate the ratio between arterial and venous thrombosis in patients with Hemophilia A or B in comparison with that of patients with von Willebrand Disease. Methods: analysis of a time unlimited survey of the literature together with an evaluation of personal records. Thrombotic events had to be proven by objective methods. Acquired forms were excluded. 222 patients were found to meet the inclusion criteria, 131 patients with Hemophilia A or B and 91 patients with von Willebrand Disease. Results: The ratios between arterial and venous thrombosis resulted to be 3.75, 1.12, 2.54 and 1.75, for Hemophilia A, Hemophilia B, combined Hemophilia A and B and von Willebrand Disease, respectively. The difference between Hemophilia A and von Willebrand Disease was statistically significant. Conclusions: The plasmatic defect present in the Hemophilias, especially in Hemophilia A, seems to protect more from venous rather than from arterial thrombosis. This pattern is less evident for von Willebrand Disease. The clinical significance and the pathogenetic implications of these findings are discussed.

A 32-year-old male with severe hemophilia presents for his annual evaluation. He has a history of multiple joint bleeds that he has always treated on-demand, that is, after they occur. You have recommended prophylaxis, that is, preventively, before they occur, to decrease his episodes of bleeding; however, he had been reluctant to comply in the past. He is having difficulty keeping up at work because of interruptions, pain, and lost time at work. He is willing to consider a trial of prophylaxis. You discuss the impact of hemophilia on his health-related quality of life (HRQOL) and consider measuring his HRQOL over time using a generic measure of HRQOL to determine whether prophylaxis will reduce interruptions, pain, and lost time from work and improve his HRQOL.

Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P.01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P.01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US$1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US$1000 for Swedish patients; (P.01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.

Gene therapy products for the treatment of genetic diseases are currently in clinical trials, and one of these, an adeno-associated viral (AAV) product, has recently been licensed. AAV vectors have achieved positive results in a number of clinical and preclinical settings, including hematologic disorders such as the hemophilias, Gaucher disease, hemochromatosis, and the porphyrias. Because AAV vectors are administered directly to the patient, the likelihood of a host immune response is high, as shown by human studies. Preexisting and/or recall responses to the wild-type virus from which the vector is engineered, or to the transgene product itself, can interfere with therapeutic efficacy if not identified and managed optimally. Small-scale clinical studies have enabled investigators to dissect the immune responses to the AAV vector capsid and to the transgene product, and to develop strategies to manage these responses to achieve long-term expression of the therapeutic gene. However, a comprehensive understanding of the determinants of immunogenicity of AAV vectors, and of potential associated toxicities, is still lacking. Careful immunosurveillance conducted as part of ongoing clinical studies will provide the basis for understanding the intricacies of the immune response in AAV-mediated gene transfer, facilitating safe and effective therapies for genetic diseases.

Hemophilia A (deficiency in factor [F] VIII) and hemophilia B (deficiency in FIX) are the most common serious congenital coagulation factor deficiencies. (Based on strong evidence) Hemophilia is a genetic disorder inherited in an Xlinked fashion. Both diseases cause similar bleeding diatheses, with the hallmark being hemarthroses. (Based on strong evidence) The optimal treatment is recombinant factor replacement to prevent bleeding; however, this treatment has many barriers. (Based on strong evidence) The most serious complication of treatment is the development of inhibitors to factor products. (Based on strong evidence) Care for patients with hemophilia is most appropriate in a comprehensive care setting. (Based on strong evidence).

Genetic correction of hemophilia A and B was long considered amenable to the available gene transfer technologies. This assumption has come to fruition with the recent results of a phase I/II trial for hemophilia B. Here we review the clinical application of gene therapy for the hemophilia's as a paradigm of the evolution of gene transfer science and technology. This review is not intended as comprehensive but rather to highlight current clinical developments of gene therapy for the hemophilias.

Background: Hemophilias A and B are X-linked bleeding disorders caused by mutations in the factor VIII and factor IX genes, respectively. Our objective was to identify the spectrum of mutations of the factor VIII and factor IX genes in Saudi Arabian population and determine the genotype and phenotype correlations by molecular dynamics (MD) simulation. Methods: For genotyping, blood samples from Saudi Arabian patients were collected, and the genomic DNA was amplified, and then sequenced by Sanger method. For molecular simulations, we have used softwares such as CHARMM (Chemistry at Harvard Macromolecular Mechanics; http://www.charmm-gui.org) and GROMACS. In addition, the secondary structure was determined based on the solvent accessibility for the confirmation of the protein stability at the site of mutation. Results: Six mutations (three novel and three known) were identified in factor VIII gene, and six mutations (one novel and five known) were identified in factor IX gene. The factor VIII novel mutations identified were c.99G>T, p. (W33C) in exon 1, c.2138 DelA, p. (N713Tfs*9) in eon14, also a novel mutation at splicing acceptor site of exon 23 c.6430 - 1G>A. In factor IX, we found a novel mutation c.855G>C, p. (E285D) in exon 8. These novel mutations were not reported in any factor VIII or factor IX databases previously. The deleterious effects of these novel mutations were confirmed by PolyPhen2 and SIFT programs. Conclusion: The protein functional and structural studies and the models built in this work would be appropriate for predicting the effects of deleterious amino acid substitutions causing these genetic disorders. These findings are useful for genetic counseling in the case of consanguineous marriages which is more common in the Saudi Arabia. J Clin Med Res. 2017;9(4):317-331 doi: https://doi.org/10.14740/jocmr2876w

Anti-inhibitor coagulant complex (AICC), an activated prothrombin complex concentrate, has been available for the treatment of patients with inhibitors since 1977, and thromboembolic events (TEEs) have been reported after infusion of AICC in patients with congenital or acquired hemophilia. With the aim of estimating the TEE incidence rate (IR) related to AICC exposure in these patients, a systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The IR of TEEs was estimated through a meta-analytic approach by using a generalized linear mixed model based on a Poisson distribution. Thirty-nine studies were included (1980-2016). Overall, 46 TEEs were reported; of these, 13 were reported as disseminated intravascular coagulations, 11 as myocardial infarctions, and 3 as thrombotic cerebrovascular accidents. The pooled TEE IR was 2.87 (95% confidence interval [CI], 0.32-25.40) per 100 000 AICC infusions (5.42 in retrospective studies [95% CI, 0.92-31.82]; 1.09 in prospective studies [95% CI, 0.01-238.77]). The TEE rate was 5.09 (95% CI, 0.01-1795.60) per 100 000 AICC infusions administered on demand, whereas no TEEs were reported with prophylaxis. Interestingly, the estimated IR in patients with congenital hemophilia was

Among bleeding disorders, hemophilia A, hemophilia B and von Willebrand diseases are the most commonly occurring, whereas deficiencies of other coagulation factors are rare worldwide. Unlike hemophilias, which are X-chromosome linked disorders, the inheritance pattern of the rare coagulation factor deficiencies is generally autosomal recessive. In literature, association of these factor deficiencies and congenital abnormalities are especially rare. In this study, we present our cases having both rare factor deficiencies and congenital abnormalities, including Cenani-Lenz syndrome and Duane retraction syndrome.

Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K–dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti–tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.

Individuals with severe hemophilia have benefitted from 5 decades of advances that have led to widespread availability of safe and efficacious factors VIII and IX, a multidisciplinary integrated care model through a network of specialized hemophilia treatment centers, and aggressive introduction of prophylactic replacement therapy to prevent bleeding and preserve joint health. Yet, there are remaining challenges and treatment gaps which have prevented complete abrogation of all joint bleeding, and progressive joint deterioration may continue in some affected individuals over the course of a lifetime. Some of these challenges can now be addressed with recombinant clotting factors with extended half-life that may improve adherence to prophylaxis regimens through more convenient infusion schedules, maintain higher plasma levels for longer when clinically necessary, and allow for better adaptation to individual phenotypic and pharmacokinetic variability. Real-world case studies will be presented that illustrate practical application of these newly approved therapies in clinical practice and the clinical trial data that have demonstrated the potential for improved clinical outcomes by implementing these strategies.

Wound healing requires interactions between coagulation, inflammation, angiogenesis, cellular migration, and proliferation. Healing in dermal wounds of hemophilia B mice is delayed when compared with hemostatically normal wild-type (WT) mice, with abnormal persistence of iron deposition, inflammation, and neovascularity. We observed healing following induced joint hemorrhage in WT and factor IX (FIX) knockout (FIX-/-) mice, examining also parameters previously studied in an excisional skin wound model. Hemostatically normal mice tolerated this joint bleeding challenge, cleared blood from the joint, and healed with minimal pathology, even if additional autologous blood was injected intra-articularly at the time of wounding. Following hemarthrosis, joint wound healing in hemophilia B mice was impaired and demonstrated similar abnormal histologic features as previously described in hemophilic dermal wounds. Therefore, studies of pathophysiology and therapy of hemophilic joint bleeding performed in hemostatically normal animals are not likely to accurately reflect the healing defect of hemophilia. We additionally explored the hypothesis that the use of a FIX replacement protein with extended circulating FIX activity could improve synovial and osteochondral wound healing in hemophilic mice, when compared with treatment with unmodified recombinant FIX (rFIX) in the established joint bleeding model. Significantly improved synovial wound healing and preservation of normal osteochondral architecture are achieved by extending FIX activity after hemarthrosis using glycoPEGylated FIX when compared with an equivalent dose of rFIX. These results suggest that treating joint bleeding only until hemostasis is achieved may not result in optimal joint healing, which is improved by extending factor activity.

For somatic gene therapy of hemophilia B, hepatocytes as the main cellular host for expression of hFIX are attractive targets. In gene therapy protocols, an efficient expression vector equipped with cis-regulatory elements such as introns is required. With this in mind, hFIX-expressing plasmids equipped with different combinations of 2 human β-globin (hBG) introns inside the hFIX-cDNA and Kozak element were used for bioengineering of HepG2 cells as a model for differentiated hepatocytes and CHO cells a cell line generally used to produce recombinant hFIX (rhFIX). In HepG2 cells, the highest hFIX secretion level occurred for the intron-less plasmid with 8.5 to 53.8- fold increases, while in CHO cells, the hBG intron-I containing plasmid induced highest hFIX secretion level with 2.3 to 14.3-fold increases as compared to other plasmids. The first hBG intron appears to be more effective than the second one in both cell lines. The expression level was further increased upon the inclusion of the Kozak element. The highest hFIX activity was obtained from the cells that carrying the intron-less plasmids with 470 mU/ml and 25 mU/ml for HepG2 and CHO cells respectively. Secretion of active hFIX by all constructs was documented except for hBG intron-II containing construct in both cell lines. HepG2 cells were able to secret higher hFIX levels by 0.6 to 112.2-fold increases with activity by 5.3 to 16.4-fold increases compared to CHO cells transfected with the same constructs. Presence of both hBG intron-I and II inside the hFIX-cDNA provides properly spliced hFIX transcripts in both cell lines. In conclusion, the advantages of hBG introns as attractive cis-regulatory elements to obtain higher expression level of hFIX particularly in CHO cells were demonstrated. Hepatocytes could be effectively bioengineered with the use of plasmid vectors and this strategy may provide a potential in-vitro source of functional hepatocytes for ex-vivo gene therapy of hemophilias and production of rhFIX in vitro.

Objective: To investigate the occurrence of ischemic stroke in patients with congenital bleeding disorders. Patients and Methods: Patients with congenital bleeding disorders who presented an objectively proven ischemic stroke were obtained by means of a time unlimited Pubmed search. Appropriate key words and Medical subject headings were used. Cross-checking of the references was also carried out. Results: There were four cases of Fibrinogen defects or Factor VII deficiency; seven patients had Hemophilia (6 hemophilia A and 1 hemophilia B); eight cases of FXI deficiency and six patients with von Willebrand Disease. One patient had a congenital platelet disorder. Age varied from 7 to 80 (mean age 38.6). 15 were male and 11 female. In four patients gender was not reported. The ratio of Myocardial Infarction to Ischemic stroke was 12.28 for the hemophilias, 7.83 for vW Disease and 2.75 for the Rare Bleeding Disorders. Risk factors were present in most patients, replacement therapy and old age being the most frequent. Conclusions: The differences in the prevalence of ischemic stroke vs coronary arterial disease seen in patient with congenital bleeding disorders indicate that clotting defects assure an uneven protection from atherothrombosis. Since the mechanisms underlying these differences are unknown, they represent a field of potential future investigation.

Recombinant FVIIa concentrate has been originally used in the treatment of hemophilia patients with inhibitors. Recently, its use has been expanded to a variety of off-label indications. Thrombosis is the most important side effect. This may occur especially in off-label use but also in hemophiliacs with inhibitors. The present study investigated the occurrence of thrombosis in congenital bleeding disorders other than hemophilias as gathered from personal files and from the literature. Fifteen patients (seven FVII deficiency, one fibrinogen defect, four FXI deficiency, one von Willebrand disease, and two Glanzmann's Thrombasthenia) have been evaluated. Thrombosis was arterial in eight instances, venous in six, whereas in one case the type of thrombosis was unspecified. In eight cases, associated risk factors were present. Two patients with FXI deficiency had inhibitors. Dosage was variable. There was at least one fatality but in five cases evolution was not reported. The remaining patients recovered with variable sequels.

To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)–derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A.

Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)–deficient plasma by an activated thrombin-activatable fibrinolysis inhibitor (TAFIa)–dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor–initiated fibrin formation and tissue-plasminogen activator–induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin-Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombin-Solulin complex were determined to be 1.53 and 0.02/μM/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses.

Economic evaluation in health care is increasingly used to assist policy makers in their difficult task of allocating limited resources. The high cost of care, including that for clotting factor concentrates, makes hemophilia a potential target for cost-cutting efforts by health care payers. Although the appropriate management of hemophilia is key to minimizing and preventing long-term morbidity, comparative effectiveness studies regarding the relative benefit of different treatment options are lacking. Cost-of-illness (COI) analysis, which includes direct and indirect costs from a societal perspective, can provide information to be used in cost-effectiveness and other economic analyses. Quality-of-life assessment provides another methodology with which to measure outcomes and benefits of appropriate disease management. Health care reform has implications for individuals with hemophilia and their families through changes in payment, insurance coverage expansion, and health care delivery system changes that reward quality and stimulate cooperative, team-based care. Providers will benefit from the expansion of insurance coverage and some financial benefits in rural areas, and from the expansion of coverage for preventive services. Accountable care organizations will potentially change the way providers are paid and financial incentives under reform will reward high quality of care.

The fourth edition of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) devoted only a single page to the rating of thrombotic and hemorrhagic disorders, based primarily on analogous impairments from other organ systems and impairments in the activities of daily living (ADLs). The AMA Guides, Fifth Edition, rated thrombotic disorders by the effects on the organ system; criteria for rating hemorrhagic and platelet disorders were based on the treatment required and interferences in ADLs. The sixth edition introduced significant changes, among which are the following: The ratings for hematological disorders were deliberately reduced, especially the highest ratings, because of the inevitable involvement of other organ systems. The goal is for evaluators to rate each organ system based on its defined criteria rather than combining multiple organ system difficulties into a single organ system rating. Also in the AMA Guides, Sixth Edition, separate tables are used to rate hemorrhagic conditions caused by platelet disorders, hemophilia, and clotting disorders. Further, major changes were required because of global methodological changes in this edition, including a significant expansion of the methodology used in rating clotting defects. Finally, the rating for the use of warfarin was altered, and thrombotic disorders are rated using the specific coagulation defect.