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Essentials Patients with von Willebrand disease were enrolled in our study. Type 2 VWD diagnoses were based on original test results. Repeat evaluation resulted in many patients receiving a different type 2 diagnosis. Some genetic variants were particularly likely to move type 2 subcategories. ABSTRACT: Introduction Type 2 von Willebrand disease (VWD) refers to patients with a qualitative defect in von Willebrand factor. Accurate diagnosis of type 2 VWD subtypes can be challenging. Aim of the study To compare the historical diagnosis of type 2 VWD with current laboratory testing. Methods Subjects were enrolled in the Zimmerman Program either because of a preexisting diagnosis of VWD (retrospective cohort) or from evaluation for bleeding symptoms or suspected VWD (prospective cohort). Original diagnosis was assigned by the local center and central diagnosis was based on central laboratory testing. Results Two hundred and seventeen index cases in the retrospective cohort and 35 subjects in the prospective cohort carried a local diagnosis of type 2 VWD (29% and 6% of enrolled index cases, respectively). In the retrospective cohort, the diagnosis was confirmed in 66% of cases with a preexisting diagnosis of 2A, 77% 2B, 54% 2M, and 72% 2N. In the prospective cohort, 31% were confirmed 2A, 60% 2B, 23% 2M, and 100% 2N. Several genetic variants were repeatedly implicated in subjects with changed diagnosis: p.M1304R, p.R1315C, p.R1374C, and p.R1374H. Conclusions Both the prospective and retrospective cohorts demonstrated consistent variation in subjects whose diagnosis changed between 2A, 2B, and 2M. The importance of accurately diagnosing type 2 VWD may be most significant in the 2B subtype given potential concerns with the use of desmopressin in type 2B VWD. Some genetic variants appear in multiple types of VWD, making specific diagnoses challenging.

Introduction Haemophilia A is an X-linked recessive bleeding disorder that primarily affects males. Emerging data support evidence for increased bleeding in female haemophilia A carriers despite factor VIII activity within the normal range. Aim Data regarding the effect of increased bleeding on health-related quality of life (HR-QOL) in haemophilia A carriers is sparse. We tested the hypothesis that haemophilia A carriers have reduced HR-QOL related to bleeding symptoms. Methods We conducted a cross-sectional study at Vanderbilt University. Case subjects were obligate or genetically verified haemophilia A carriers age 18–60 years. Control subjects were mothers of children with cancer who receive care at the Vanderbilt paediatric haematology-oncology clinic. Trained interviewers administered the Rand 36-Item Health Survey 1.0, a validated questionnaire evaluating eight health concepts that may affect HR-QOL, to each study participant. Mann–Whitney U-tests were used to compare median scores for the eight health domains between the case and control groups. Result Forty-two haemophilia A carriers and 36 control subjects were included in analyses. Haemophilia A carriers had significantly lower median scores for the domains of ‘Pain’ (73.75 vs. 90; P = 0.02) and ‘General health’ (75 vs. 85; P = 0.01) compared to control subjects. Conclusion Haemophilia A carriers in our study demonstrated significantly lower median scores on the Rand 36-item Health Survey 1.0 in the domains of ‘Pain’ and ‘General Health’ compared to women in the control group. Our findings highlight the need for further investigation of the effect of bleeding on HR-QOL in this population.

Haemophilia A carriers have historically been thought to demonstrate normal haemostasis. However, recent data demonstrates that despite normal factor VIII, haemophilia A carriers demonstrate an increased bleeding tendency. We tested the hypothesis that obligate haemophilia carriers demonstrate an increase in bleeding symptoms. A cross sectional study was performed comparing haemophilia A carriers to normal women. Questionnaire assessment included a general bleeding questionnaire, condensed MCMDM-1VWD bleeding assessment tool and Pictorial Bleeding Assessment Chart (PBAC). Laboratory assessment included complete blood count, prothrombin time, activated partial thromboplastin time, fibrinogen activity, FVIII activity (FVIII:C), von Willebrand factor antigen level, ristocetin cofactor, platelet function analyser-100™ and ABO blood type. 44 haemophilia A carriers and 43 controls were included. Demographic features were similar. Laboratory results demonstrated a statistically significant difference only in FVIII:C (82.5 versus 134%, p value < 0.001). Carriers reported a higher number of bleeding events, and both condensed MCMDM-1 VWD bleeding scores (5 versus 1, p value < 0.001) and PBAC scores (423 versus 182.5, p value = 0.018) were significantly higher in carriers. Haemophilia A carriers exhibit increased bleeding symptoms when compared to normal women. Further studies are necessary to fully understand the bleeding phenotype in this population and optimize clinical management.

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients. Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

Investigation for bleeding disorders in the context of suspected non-accidental injury (NAI) is inconsistent. We reviewed the hematologic evaluation of children who presented with symptoms of bleeding and/or bruising suspicious for NAI to determine the frequency of hematologic tests, abnormal hematologic laboratory results, and hematologic diagnoses. A retrospective cohort study design was employed at two freestanding academic children's hospitals. ICD-9 codes for NAI were used to identify 427 evaluable patients. Medical records were queried for the details of clinical and laboratory evaluations at the initial presentation concerning for NAI. The median age for the population was 326 days (range 1 day–14 years), 58% were male. Primary bleeding symptoms included intracranial hemorrhage (31.8%) and bruising (68.2%). Hematologic laboratory tests performed included complete blood cell count in 62.3%, prothrombin time (PT) in 55.0%, and activated partial thromboplastin time (aPTT) in 53.6%; fibrinogen in 27.6%; factor activity in 17.1%; von Willebrand disease evaluation in 14.5%; and platelet function analyzer in 11.7%. Prolonged laboratory values were seen in 22.5% of PT and 17.4% of aPTT assays; 66.0% of abnormal PTs and 87.5% of abnormal aPTTs were repeated. In our cohort, 0.7% (3 of 427) of the population was diagnosed with a condition predisposing to bleeding. In children with bleeding symptoms concerning for NAI, hemostatic evaluation is inconsistent. Abnormal tests are not routinely repeated, and investigation for the most common bleeding disorder, von Willebrand disease, is rare. Further research into the extent and appropriate timing of the evaluation is warranted.

Acute non-hemolytic transfusion reactions, consisting of both allergic and febrile reactions, are common occurring in up to 10.2% of transfused blood products [1], however anaphylaxis, or severe allergic reactions, are rare following transfusion. The incidence of anaphylaxis is more common after the transfusion of plasma containing products with estimations from 1:10,000–33,000units of platelets and 1:29,000–50,000units of fresh frozen plasma (FFP) compared with 1:50,000–200,000 units of red blood cells [1,2]. Despite the rare occurrence, the clinical significance of transfusion related anaphylaxis can be severe with 12 reported fatalities over a 5-year span [3]. We report a case of FFP related anaphylaxis in a patient anticipating orthotopic liver transplant (OLT) with a unique peri-operative treatment plan.

Abstract 2231 Background Child maltreatment is a frequent cause of injury in the United States, occurring in approximately 695,000 children per year. Bleeding disorders can exacerbate and be confused with non-accidental injury (NAI); both of these diagnostic errors are life altering for the child and family. Despite the high incidence of child abuse and the independent relative high incidence of bleeding disorders, the optimal hemostatic evaluation is unclear for children who may be victims of NAI. Expert hematologic opinion recommends a multi-tiered approach, first investigating for common bleeding disorders, and subsequently investigating for rare defects in the coagulation and fibrinolytic pathways, if necessary. Further research is needed to develop evidence-based guidelines for the evaluation of bleeding disorders in children who may be victims of NAI. Objectives To review and analyze a five-year history of the hematologic investigation of children who presented with bleeding and/or bruising that was suspicious for NAI at Vanderbilt Children's Hospital (VCH). Our hypothesis is that there is a lack of a systematic approach for the hemostatic evaluation of children who present with bleeding symptoms and concern for NAI. Methods A retrospective cohort study design was employed. ICD-9 codes for NAI (995.5, 995.50, 995.54, 995.55, 995.59) were used. 354 medical records from 2007 – 2011 were reviewed and screened for inclusion and exclusion criteria, resulting in 198 fully evaluable patients. Medical records were then queried for details of clinical and laboratory evaluation that occurred at the initial presentation concerning for NAI. We defined a basic hematologic evaluation as a CBC, PT and PTT; and a comprehensive hematologic evaluation as a CBC, PT, PTT, factor VIII, IX and XI activity and von Willebrand evaluation. Data was analyzed using SPSS; statistical analysis was performed using frequencies and Chi-Square analysis. Outcomes The mean age for the studied population was 445 days (max 4687 days, minimum 6 days); 37% were male. Bleeding symptoms included intracranial hemorrhage (ICH) (40%) and bruising (58% without associated ICH, 73% with and without associated ICH), with approximately 60% demonstrating additional non-hematologic symptoms (i.e. fractures, burns). Hematologic laboratory tests performed included CBC in 66%, PT in 58%, and PTT in 55%; factor activity levels in 12% (primarily consisted of factors VIII and IX); and von Willebrand disease evaluation in 12% of subjects. Table 1 shows the percentage of laboratory tests obtained in the patients based on symptoms at presentation. Abnormal coagulation labs were seen in 33% of performed PT and 55% of PTT tests; 55% of abnormal PTs and 44% of abnormal PTTs repeated. Our defined basic evaluation was completed in 79% of patients with ICH and 36% of patients without ICH (p Conclusion Complete hematologic evaluation of children who present with bleeding symptoms and concern for NAI is inconsistent. While some children with other findings diagnostic for NAI may not require a hematologic work-up from a medico-legal perspective, it is still prudent to consider common bleeding disorders as a potential contributing factor in the severity of symptoms. At VCH, laboratory evaluation was obtained with greater frequency in patients with hematologic symptoms only. Given the variability of tests obtained and the disparity between expert opinion and our historical evaluation, further investigation into the optimal evaluation of these patients is warranted at this time. A prospective cohort study would allow comprehensive evaluation of all children suspected of NAI resulting in a clear understanding of laboratory abnormalities and incidence of bleeding disorders. Disclosures: No relevant conflicts of interest to declare.

Abstract 3385 Introduction: Hemophilia A, the result of reduced factor VIII (FVIII) activity, is an X-linked recessive bleeding disorder affecting one in 5,000 males born in the United States (U.S.). Females are designated heterozygous or carriers. While bleeding symptoms have been fully characterized in male patients with Hemophilia A, less is known about the female Hemophilia A carrier bleeding phenotype. Previous reports in Hemophilia A carriers suggest an increased bleeding tendency regardless of residual FVIII activity. Further, small studies suggest that Hemophilia A carriers report excessive bleeding symptoms including, but not limited to menorrhagia, epistaxis, surgical bleeding and hemarthrosis. Objective: To determine the attitudes and understanding of Hemophilia A carrier testing from the perspective of both providers and affected patients. Our global hypothesis is that genetically verified Hemophilia A carriers with normal FVIII activity will have increased clinically relevant bleeding. Methods: We employed a cross-sectional study design, and developed an electronic survey that was emailed to physicians and nurses employed at U.S. Hemophilia Treatment Centers (HTC). The email list was generated from listed current HTC providers on www.cdc.gov. A similar electronic survey was developed and distributed to female Hemophilia A carrier members of Hemophilia Federation of America. Questions were derived from the Female Universal Data Collection project questionnaire, and focused on the clinical understanding and management of Hemophilia A carriers. In addition, questions were developed to assess attitudes regarding the timing and intensity of testing. Data was analyzed using SPSS with descriptive statistics, Wilcoxon rank sum test and Pearson test. Results: In the provider survey there was a 49%(42/85) response rate from the physicians and 37% response rate (30/80) from nurses. Combined, 64% (47/72) had >10 years of clinical experience, 94% (68/72) work in primarily within an HTC and 97% (69/71) offer carrier testing. In the survey aimed at Hemophilia A carriers, a total of 38 responses were analyzed. The mean age was 35 ± 11 years, 76% (29/38) had a biologic son with Hemophilia A with 65% (24/37), 22% (8/37) and 14% (5/37) being severe, moderate or mild in severity. Carrier testing was performed after the age of 14 in 82% of those queried. When asked about the optimal timing of carrier testing, 78% (31/41) of physicians and 68% (19/28) of nurses recommend testing after 14 years of age while 69% (24/35) of carriers prefer testing to be done prior to this age (p While 78% (28/36) of the carrier's affected hemophiliac relatives receive care at an HTC only 26% (9/35) receive regular Hemophiliac care, and 67% (6/9) of those receiving regular care are followed at the same location as their affected hemophiliac relative. When queried, 51% (36/51) of providers compared to 78% (28/36) of carriers believe that Hemophilia A carriers with normal FVIII activity have an increased bleeding tendency (p Conclusion: Hemophilia A carriers report a higher frequency of bleeding than previously acknowledged. In contrast to preferences of Hemophilia specialists, Hemophilia A carriers prefer to know their carrier status prior to 14 years of age and be cared for in the same location as their affected relatives. Under recognition of Hemophilia A carrier bleeding is common amongst HTC providers, and data collected in a prospective cohort with appropriate controls is warranted. Disclosures: No relevant conflicts of interest to declare.