TBI therapy is closely linked to the development of DVT. Coagulopathy on admission is associated with hypercoagulability in the postinjury period, suggesting a patient phenotype with systemic coagulation dysregulation. Treatment was not associated with improved VTE outcomes, suggesting that pediatric protocols should emphasize VTE prevention and prophylaxis strategies.

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

Prophylactic replacement therapy in severe haemophilia prevents bleeds and associated arthropathy [1] and is considered standard of care [2]. The FDA-approved long-acting recombinant factor VIII Fc fusion protein, rFVIIIFc (Eloctate TM ), is safe and effective in prevention and treatment of bleeding events accomplished in two rather than three doses weekly, thereby simplifying treatment [3,4]. Prolonged protection is attributed to increased factor VIII (FVIII) half-life and areaunder-the-curve (AUC), resulting in longer time ≥0.01 IU mL À1 , the level below which spontaneous bleeds occur [5]. rFVIIIFc may also promote tolerance to FVIII, as shown in preclinical animal models [6] and in an inhibitor-prone child [7], as Fc suppresses immunoregulatory T cells to proteins to which Fc is attached [8]. Whether rFVIIIFc is effective in suppressing inhibitor formation in haemophilia patients with existing inhibitors has not been studied. Given its immunoregulatory potential, we hypothesized rFVIIIFc might shorten and simplify ITI, which involves highdose daily FVIII, which is costly, invasive and ineffective in up to 20%. We, therefore, describe the use of rFVIIIFc in induction of ITI in three patients with severe haemophilia A and anti-VIII inhibitors.Immune tolerance induction was initiated with rFVIIIFc (Eloctate) in three children with severe haemophilia A and an anti-FVIII inhibitor. This included two children who had not previously undergone ITI and one individual who underwent salvage ITI after failing to achieve tolerance due to noncompliance with a prior daily rFVIII ITI taper regimen (Table 1). No patient had previously received rFVIIIFC; patient 1 had received rFVIII (Advate) prior to ITI, patient 2 had received rFVIII (Advate) prior to and with his failed prior ITI attempt, patient 3 had been treated abroad with pdFVIII and rFVIII (specifics unknown) and was receiving rFVIII (Kogenate) prior to ITI initiation with rFVIIIFc. ITI was initiated in the two patients beginning initial ITI once the inhibitor titre was <10 Bethesta Units (BU). Utilization of rFVIIIFc was at the discretion of the treating physician after discussion with the family; rFVIIIFc was utilized instead of a standard half-life product for reasons including avoidance of CVAD, decreased frequency of dosing and possible novel mechanisms to induce tolerance. ITI was performed using rFVIIIFc alone; patients did not receive additional immunosuppressive agents and were not on prophylaxis with bypassing agents.Follow-up was scheduled every 4-8 weeks, per institutional standard, with planned determination of FVIII recovery and half-life once the anti-FVIII fell to <0.6 BU. Tolerance was a priori defined as achieving anti-FVIII <0.6 BU, FVIII recovery of at least 60% and half-life ≥6 h [9]. FVIII half-life was determined by one-stage FVIII:C assay on citrate samples drawn pre-and 10 min, 1, 2, 4 and 6 h postinfusion of a single dose of rFVIIIFc; half-life estimates were calculated based on 1 h peak recovery. Inhibitor titres were determined by modificat...

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Background von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anemia, high health cost, and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding Von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. Methods We conducted a survey of U.S. hemophilia treatment centers (HTCs) and a literature review using medical subject heading (MeSH) search terms “von Willebrand factor,” “menorrhagia,” and “von Willebrand disease” to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. Results Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1,321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid, and desmopressin were the most common first-line therapies for menorrhagia, while VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU/kg on day 1-6 of menstrual cycle. Conclusions This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

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

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