ALBERT

Description: Type 2 von Willebrand disease (VWD) includes a wide range of qualitative abnormalities of von Willebrand factor (VWF) function and structure resulting in various bleeding phenotypes. Variants 2A, 2B and 2M are mainly related to abnormal interaction of VWF with platelets and/or the subendothelium. Mucocutaneous bleeds such as epistaxis, menorrhagia and gastro-intestinal bleedings are the most frequently reported in these subtypes, while in patients with type 2N VWD characterized by a defective binding of VWF to FVIII, a phenotype with symptoms suggestive of mild/moderate hemophilia A is common. Are type 2 VWD female patients' bleeding score, clinical phenotype and impairment of Quality of Life (QoL) more severe than the males' ones? To answer this question, we report here results of VWD type 2 patients enrolled in the French Heath related Quality of Life study: WiSH-QoL. This study is conducted with the French Reference Centre for von Willebrand Disease (CRMW). Clinical phenotype such as bleeding score (Tosetto score), biological profile and genotype are documented. Clinical characteristics and therapeutic approach are also recorded. Patients are treated with WILFACTIN®, triple-secured plasma-derived VWF with a low factor VIII content. Information on socio-demographic and resources consumption are gathered by patients in their diary. HRQoL is assessed with the generic SF-36 (for adults), the chronic-generic DISABKIDS Short Form (for children and adolescents), the VWD-specific HRQoL questionnaire VWD-QoL (for adults, children, adolescents and parents with a proxy version), the VWD-specific treatment satisfaction assessment VWD-Sat (for adults and parents with a proxy version). The Impact on Family (IOF) Scale is dedicated to caregivers of children with VWD. At least 350 patients will be followed during 2 years. During the recruitment period (Oct. 2014 - Nov. 2017), 357 patients were enrolled. At the time of this analysis, data at inclusion on 355 patients were evaluable. Focus was made on the 226 type 2 VWD patients: 141 (62.4%) females and 85 (37.6%) males, median age and range at study entry 32.7 (1-78) and 26.4 (1-83) years, respectively. The majority of them were adults with 101 (71.6%) females and 49 (57.6%) males. 76 patients were below 18 years (40 (28.4%) females and 36 (42.4%) males). In the female subgroup, 81 were women of child-bearing age (15-50 y.o), 27 under 15 years with 21 prepubertal children and 33 above 50 years. The median age at diagnosis was 11.5 years (range 0-78) associated with a family history of VWD in the majority of patients (178, 78.8%), earlier in males' life (6 y) than in females (15 y). The first substitutive treatment by VWF was administered at a median age of 19.0 years (range 0-78), with 13.0 years for males compared to 23.5 y for females. At baseline, 23 (10.2%) patients (12 females and 11 males) had reported GI manifestations. The patients were 64 patients with type 2A, 52 with type 2B, 68 with type 2M, 12 with type 2N and 30 with type 2 unspecified. The median Tosetto bleeding score (BS) reported for 202 patients was +7.0 (range -1 to 25), higher +8.0 (range -1 to 25) in female compared to +5.0 (range 0 to 21) in male patients. It was also able to distinguish disease severity by variants as shown in table1. Whatever the variants (2A, 2B, 2M and 2N VWD,) the women of child-bearing age group had the highest BS. At enrollment, 62 female patients (44.0%) have already received a concomitant treatment with Iron, oral contraceptive, intra-uterine device. In the group of 64 women who had experienced a total of 136 deliveries (mainly vaginal deliveries (107, 78.7%) and C. Section (29, 21.3%)), the mean number of childbirth was 2.1 (range 1-5). Post-Partum Hemorrhages occured in 42 of these cases (31.3%), mainly within 48 hours after giving birth in 27 cases (67.5%) out of the 40 cases with available data. Were also found differences in both Physical and Mental Component Score of the generic SF-36 with higher impairments in HRQoL in adults females than in males (PCS 54.04 vs 55.22) MCS (44.71 vs. 47.85). The same tendency was seen with the Normalized Global score VWD-Specific in adults with higher score in females than in males (17.26 vs 13.91). This study with HRQoL results will bring a deeper insight into type 2 VWD patients' real daily life. These findings may teach us what would be the best care for VWD patients and especially for females who need definitely specific health care throughout their fertile life. Disclosures Borel-Derlon: Octapharma: Other: Clinical Research Investigator; LFB: Membership on an entity's Board of Directors or advisory committees; Shire: Other: Principal investigator; Novonordisk: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Desprez:LFB: Other: Investigator. Volot:LFB: Other: Investigator. Pan-Petesch:LFB: Other: Investigator. Chatelanaz:LFB: Employment. Doriat-Robin:LFB: Employment. Veyradier:LFB: Other: Investigator. Von Mackensen:LFB: Membership on an entity's Board of Directors or advisory committees.

Description: We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

Description: Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 1% in the general population. VWD results from a deficiency in or a dysfunction of von Willebrand factor which is a protein that is necessary for normal platelet adhesion and protection of factor VIII from proteolysis in the circulation. Nevertheless, prevalence of the most symptomatic forms such as bleeds requiring replacement treatment and /or hospitalization is about 0.01%. Although VWD affects both genders, there is a higher proportion in females than in males.VWD seems to be more symptomatic in women because of their reproductive life. Women with VWD have an increased bleeding risk in numerous situations including anemia, menorrhagia, bleeding during pregnancy, postpartum hemorrhage and impairments in their quality of life (QoL).The prevalence of menorrhagia in women with VWD is 74-92%. According to the Francecoag Network, the referral-based prevalence of moderate-to-severe VWD patients is about 1,750 cases in France. Aim: Since the disease and its treatment can affect every-day life of patients and their families, a French HRQoL Study (WiSH-QoL) exploring this impact started 22 months ago. Methods: This non-interventional 5-year study evaluates patients HRQoL and costs of care in France. At least 350 patients will be followed for 24 months in minimum 30 centers. HRQoL is assessed with the generic SF-36 and the disease-specific VWD-QoL questionnaires. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Results: Since October 2014, 245 patients have been included. We present here the first interim analysis with a focus on the female group. At the first interim analysis, data from 140 patients were documented: 91 adults with a median age of 40.0 years [18.3-78.0] and 49 children with a median age of 10.1 years [2.9-17.5]. VWD Types were already identified for 122 (87%) of these patients: 33 with VWD type 1 (27%) including 5 type 1 Vicenza; 76 type 2 (62%) and 13 type 3 (11%). The median Tosetto bleeding score reported for 124 patients (males and females) was +7 ranging from -1 to +28. From the 95 female patients, 70 were aged ≥18 years, 21 were adolescents between 8-17 years and 4 were girls below 4 years of age. Median age was 29.4 (range 4.3-78.0) years. A total of 25 women had type 1 VWD (31%), 49 had type 2 VWD (60%), and 7 had type 3 VWD (9%), for 14 patients VWD type is undetermined. The median Tosetto bleeding score of the female group was +8 ranging from -1 to +28. Out of 95 patients, 45 patients (47.4%) have received a concomitant treatment due to menorrhagia, such as iron therapy, oral contraceptive, levonorgestrel intrauterin system: 5/21 patients in the group between 8 and 17 years and 40/70 in the group ≥18 years. Out of the 60 women of childbearing potential defined as age between 15-50 years, 6 women were pregnant at time of inclusion. A total of 46 patients, aged 18 years or more have had obstetrical history prior to study inclusion. The mean number of childbirth was more than 2 i.e 2.39 range (1-8) per woman, 75% of these deliveries were natural delivery and 25% were caesarean section. Out of 108 deliveries, 28 (26%) were experienced with post-partum hemorrhages. Conclusions: With the results of the WiSH-QoL study, the first prospective study of von Willebrand disease conducted in France, especially the VWD-specific evaluation of HRQoL and treatment satisfaction a deeper insight will be gathered into the patients' daily life, their perception of well-being and their specific health care needs. With the additional domain 'pregnancy' included in the French version of the VWD-QoL questionnaire for female adult patients, it will possible to better understand how women may be affected by VWD during childbearing years. Disclosures Borel-Derlon: LFB: Other: Reference expert and national coordinator for VWD; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee; Shire - Baxalta: Research Funding. Chatelanaz:LFB Biomedicaments: Employment. Doriat-Robin:LFB Biomedicaments: Employment. von Mackensen:SOBI: Research Funding; Shire: Research Funding.

Description: Abstract 1213 Introduction: The proportion of inhibitors is lower (5–10%) in mild/moderate hemophilia A (MM-HA) than in severe HA (20–35%) and the associated risk factors have been less studied. FVIII deficiency is due to a missense mutation of F8 gene in most of MM-HA patients (pts). Several studies showed that specific mutations are associated with a higher incidence of FVIII inhibitor. On the other hand, two recent studies performed in limited populations of pts identified intensive replacement therapy and age over 30 years as risk factors of inhibitor in MM-HA. An open multicenter prospective cohort of hemophilia pts was launched in France in 1994 and extended to all Hemophilia Treatment Centers (HTC) through the FranceCoag Network (FCN) in 2003 - see http://www.francecoag.org/ for protocol and participating centers. 5615 male hemophilia pts were included and the objective of the present study was to better identify environmental risk factors of FVIII inhibitor in MM-HA by studying this large cohort. Methods: Clinical and biological data were collected and transmitted via Internet for each patient every year or less frequently if irregular follow up. All information was checked automatically and monitored on a regular basis in HTC. Severity of HA was defined according to FVIII:C level (moderate 1–5; mild 6–40 IU/dL). Positive inhibitor was defined by two consecutive samples with titer 〉0.6 Bethesda Unit (BU). All unclear cases were reviewed on a collegial basis. The duration exposure from the initiation of FVIII treatment was analyzed and the associations between four fixed factors and the development of FVIII inhibitor were assessed. Results: In July 2011, 2924 MM-HA pts were recorded in FCN including 2055 (70%) who had been previously treated with FVIII. The median duration of exposure was 12.8 years (IQR: 4.0–23.8), including 4.4 years (IQR: 1.0–7.4) after inclusion in the FCN, and corresponding to 30,620 and 10,517 person-years respectively. An inhibitor was diagnosed in 99 pts, including 40 with a high titer (〉5BU). These inhibitors occurred at a median age of 31.7 years (IQR: 9.0–50.8), a median period of 6.8 years (0.4–24.3) following the first infusion of FVIII and a median number of 30 Cumulative Exposure Days (CED) (17–55). The FVIII inhibitor occurred at an earlier age in moderate HA pts (n=56) compared to the 43 mild HA pts (Table 1), but after a longer exposure time and a higher number of CED. The cumulative incidence of inhibitor was 4.5% after 20 years of exposure (95%CI: 3.5–5.8). The incidence of inhibitor was significantly higher in moderate HA pts and those whose treatment has been initiated after 1990 (Table 2). Age and type of FVIII concentrate at the first infusion don't appear to be associated with the incidence of inhibitor. Disclosures: d'Oiron: Bayer, Baxter, CSL Behring, Novonordisk: Funding for participation to congresses; Fees for participation as speaker at symposium; Fees for participation to boards. Calvez:LFB: Funding for participation to congresses. Conclusion: The apparent increase in incidence of inhibitor in MM-HA pts who were treated by FVIII after 1990 could be related to an evolution of practices (i.e. greater frequency of invasive procedures and/or more intensive treatment) and/or more frequent testing for inhibitor. These time-varying factors systematically recorded in the FCN will be analyzed taking into account only the observation period after enrolment in the cohort. In addition, the F8 gene defect is now recorded in all pts of the FCN, and this should allow us to better evaluate the respective role of genetic and environmental risk factors in the development of FVIII inhibitor in MM-HA.