ALBERT

Description: Abstract 542 Introduction Von Willebrand Disease (VWD) is the most common inherited bleeding disorder worldwide. Men and women are equally likely to be affected, but in women VWD is more often clinically manifest because of bleeding associated with menstruation and childbirth. Most studies investigating the prevalence of gynaecological bleeding problems in women with VWD are small case series of women with mainly type 1 or mild VWD. These studies may be hampered by selection bias given the fact that patients seeking medical attention for bleeding and menorrhagia have predominantly been included. Objective The aim of our study was to assess gynaecological and obstetrical symptoms in a large unselected cohort of women with moderate and severe VWD, and to investigate whether gynaecological bleeding problems affect quality of life (QoL). Design National cross-sectional study with patients recruited from all 13 Haemophilia Treatment Centers covering the Netherlands (the Willebrand in the Netherlands, WiN Study). Setting and Participants For this analysis, all 423 women aged 16 years or above from the WiN cohort were included. Methods Participants completed a detailed questionnaire, including the SF-36 for QoL and Tosetto Bleeding Score for bleeding severity. Menorrhagia was defined as the occurrence of ≥2 of the following symptoms: subjective excessive menstrual bleeding, loss of blood clots during menstrual bleeding, requirement of iron or blood transfusion, heavy menstrual flow that interferes with daily life, menstrual period that lasts longer than 7 days. Results 274 out of 423 (65%) women had type 1 VWD, 135 (32%) type 2 VWD, 10 (2%) type 3 VWD, and in 4 (1%) type was not specified. Menorrhagia was reported by 79% of the women. The two most frequent symptoms were excessive menstrual bleeding (82%) and loss of blood clots (80%). Women with type 3 VWD compared to women with type 1 and 2 VWD had more days with heavy menstrual bleeding (5 days versus 4 and 3 days respectively, p=0.03) and needed iron suppletion or blood transfusion more frequently (70% versus 43% and 36% respectively, p=0.08). Compared to women without menorrhagia, women with menorrhagia had significantly lower VWF antigen levels (29 vs 34 U/dL, p=0.022) and VWF ristocetin-cofactor levels (17 vs 23 U/dL, p=0.005). Treatment for menorrhagia consisted mainly of oral contraceptives (68%) and/or tranexamic acid (31%). QoL scores of women with menorrhagia were similar to those of women without menorrhagia. However, the subgroup of women with severe menorrhagia (Tosetto Bleeding Score on the menorrhagia item 4), had significantly lower QoL scores compared to women with no menorrhagia (BSmenorrhagia 0) for all four physical domains, the vitality domain, the social functioning domain and the physical component summary. Two domains: bodily pain (difference -17 [CI -25,-8]) and general health perceptions (difference -11 [CI -18,-4]), were clinically relevant with effect sizes ≥ 0.5. For all affected QoL domains, women with menorrhagia who used oral contraceptives or antifibrinolytics had higher scores, reflecting better QoL, than those who were not treated. Of all VWD women, 20% underwent a hysterectomy. In the group of women 〉40 years even 28% underwent a hysterectomy. The occurrence of postpartum hemorrhage was strongly increased compared to the general Dutch population: 24% vs 4% for primary postpartum hemorrhage, and 4% vs 2% for secondary postpartum hemorrhage. In 52% of the women with VWD who reported pregnancy losses (elective abortions, spontaneous miscarriages and fetal deaths), additional curettage was needed because of bleeding. Conclusion Women with moderate and severe VWD frequently have menorrhagia and bleeding complications during childbirth or after pregnancy loss. These gynecological complaints are associated with a lower QoL. Treatment of menorrhagia with oral contraceptives and tranexamic acid may improve QoL. Disclosures: Mauser-Bunschoten: CSL Behring: Membership on an entity's Board of Directors or advisory committees. Meijer:CSL Behring: Membership on an entity's Board of Directors or advisory committees. Leebeek:CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Research Funding, round table meetings; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction Despite current ABO/RhD matching and strict antibody screening policies, still every year transfused patients experience life-threatening hemolytic reactions due to boostering of previously immunization to red blood cell (RBC) antigens. Prevention can be optimized by administering RBC units at least matched on the most immunogenic antigens to high risk patients. In this respect, we set out to assess the immunogenicity of RBC antigens. Methods We performed an incident new user cohort study among previously non-transfused, non-alloimmunized patients who received RBC transfusions between 2006 and 2013 in six Dutch hospitals. Patients developing alloantibodies were followed up until their first RBC alloantibody identification and all non-alloimmunized patients until the last negative screen. To compute dose-specific alloimmunization risks and thereby evaluate the immunogenicity of various RBC antigens, only antigen-positive units transfused to all patients lacking this antigen should be considered. Per definition, alloimmunized patients met this condition. RBC phenotypes of non-alloimmunized patients were however unknown since phenotyping is routinely limited to ABO and RhD antigens. For each RBC antigen we therefore randomly extracted a subgroup of non-immunized patients whose size was based on the known proportion of antigen-negative individuals in the Caucasian population. The given antigen-positive units transfused to these 'antigen-negative cohorts' functioned to estimate the number of antigen-positive units transfused to the true antigen-negative, non-alloimmunized individuals in the source population. Multiple imputation was used to complete the dataset regarding some missing donor antigen phenotypes. We then calculated cumulative immunization incidences for each RBC antigen according to the total number of mismatched (i.e. antigen-positive) units using Kaplan-Meier survival tables. Women under 45 years of age were analyzed separately as in the Netherlands they receive c, E and K matched blood. Results In 474 of 21,512 patients (2.0%), 537 first formed antibodies were detected, the majority against E and K antigens. Cumulative immunization incidences after 40 RBC units transfused increased to 7.6% (CI 4.8-11.2). Due to lower frequencies of Rh and K immunizations, women under 45 years, who received blood matched on these antigens, demonstrated significantly lower cumulative immunization incidences compared to the remainder of the study population (4.4% (CI 0.2-20.5) versus 7.6% (CI 4.8-11.2) after 40 units received, log-rank p 0.013). Anti-c was only formed by RhD-positive patients while the lack of RhD expression led to significantly less E immunizations (cumulative immunization incidences 1.7% (CI 0.0-32.0) and 3.7% (CI 1.4-7.9) after 40 RBC units received for RhD-negative and RhD-positive patients respectively (log-rank p

Description: Von Willebrand factor (VWF) levels vary over time and increase throughout life in both healthy individuals and patients with von Willebrand disease (VWD). Especially in type 1 VWD patients, this increase may result in normalization of VWF levels. It is not yet known if normalization of VWF levels ameliorates bleeding symptoms in VWD patients. We have recently shown that elderly type 1 VWD patients had similar bleeding tendency as younger adults.1 However, many elderly patients in this study had relatively low VWF levels and many younger adults had relatively high VWF levels.1 The aim of the current study was to investigate the association between normalization of VWF levels and the bleeding phenotype in type 1 VWD patients. We included patients from the nationwide cross-sectional "Willebrand in the Netherlands" Study, with lowest historical VWF antigen (VWF:Ag) and/or VWF activity (VWF:Act) ≤30 U/dL. At inclusion, blood was sampled for central measurement of VWF:Ag and VWF:Act and VWF to collagen binding (VWF:CB). Central measurements were available in 367 type 1 VWD patients. Based on these central measurements, patients were divided into three groups: definite VWD (central VWF:Ag and/or VWF:Act and/or VWF:CB ≤30 U/dL, n=152); low VWF (central VWF:Ag and/or VWF:Act and/or VWF:CB 31-50 U/dL , n=120) and historical VWD with presently normalized levels (central VWF:Ag and VWF:Act and VWF:CB ≥51 U/dL, n=95). Age differed between groups: median age was 43 years in definite VWD patients, 45 years in low VWF and 50 years in historical VWD patients (p

Description: Background Transfusion of red blood cells (RBC) is a common intervention to treat and prevent complications in sickle cell disease (SCD). However, frequent transfusions may lead to erythrocyte alloimmunization, thereby complicating donor matching procedures and posing patients at risk for hemolytic transfusion reactions. Little information is available about the risk of alloimmunization of sickle cell patients living in European countries. In the Netherlands extensive matching procedures to prevent alloimmunization were introduced a decade ago, but the effect on alloimmunization has not been evaluated yet. Aims The primary aim of this study is to evaluate the cumulative incidence of first alloantibody formation in a Dutch cohort of transfused SCD patients, and to compare this with a general Dutch RBC-transfused population. In addition, the effect of extended RBC matching protocols on the incidence of alloantibody formation in SCD and potential clinical determinants of alloimmunization will be assessed. Methods We conducted a retrospective cohort study and collected data on SCD patients (genotypes HbSS, HbSC, HbSβ0 and HbSβ+ thalassemia), diagnosed in three Dutch Sickle Cell Treatment Centers that received non-extended matched (ABO, RhD) RBC transfusions between 1984-2004 and extended matched (at least ABO, Rhesus phenotype, Kell) RBC transfusions between 2004-2011. In addition, we compared this population with a general population of 3 042 patients that received non-extended matched (ABO, RhD) RBC transfusions between 2005-2009 in the Leiden University Medical Center (Zalpuri et al. 2012). Cohorts were not matched for ethnicity. Alloimmunization risk was calculated as Kaplan-Meier incidence with cumulative number of transfusions as time variable. The association with the clinical determinants gender, SCD-phenotype and ethnicity was analyzed with Cox-regression analysis. Results A total of 291 SCD patients received 7 957 RBC units. Alloantibody formation occurred in 52 (17.9%) patients. The cumulative incidence of alloimmunization was 9% after 5 RBC units, 15% after 10, 24% after 20 and 34% after 40 RBC units. Multivariate analysis, correcting for the cumulative number of transfusions, demonstrated a significantly increased risk of alloantibody formation in our SCD cohort when compared to a general population of transfused patients (HR 7.5 (95% CI: 5.06-11.14), where the cumulative incidence of alloimmunization was 1.1% after 5, 2.4% after 10, 3.4% after 20 and 6.5% after 40 RBC units. No association could be demonstrated between alloantibody formation and clinical determinants such as gender, SCD-phenotype or ethnicity. However, a significant reduction in alloimmunization was observed in SCD patients that received their first transfusion from the year 2004 onwards, after preventive matching for Rhesus phenotype and Kell was introduced for SCD patients (HR 0.48 (95% CI: 0.24-0.97)). Conclusion The overall rate of first RBC alloantibody formation in our cohort was 17.9% and the risk of alloimmunization increased substantially with an increasing number of RBC transfusions. A unique comparison with a general cohort of Dutch transfused patients demonstrates a significantly higher risk of alloantibody formation in SCD, acknowledging earlier findings. This may partially be explained by differences in RBC antigens between patients of African descent and the predominantly Caucasian donors. Besides the number of RBC units, no other clinical risk factors for allo-immunization in SCD could be identified. The effectiveness of extended RBC matching protocols in the prevention of alloimmunization for chronically transfused patients in the participating centers was confirmed. Disclosures: No relevant conflicts of interest to declare.

Description: The clinical presentation of patients with Willebrand Disease (VWD) is highly variable, and not always predictable upon laboratory measurements. The mechanism of this clinical variability is unknown. Also the impact of VWD on the quality of life is highly variable between patients. This ongoing study aims to register and investigate all patients in the Netherlands with moderate and severe von Willebrand Disease to assess clinical presentation, treatment and related complications of treatment. One of the aims is to assess which factors influence the bleeding phenotype. Another goal is to investigate the influence of von Willebrand Disease on quality of life. We have identified 1071 eligible patients. All patients are known at 12 hemophilia treatment centers. Inclusion criteria are moderate or severe VWD defined as; VWF antigen or activity ≤ 30% and/or FVIII:C ≤ 40%. The patients will be sent a questionnaire and a blood sample will be obtained for plasma and DNA. The characteristics of the patients are the following: median age is 34 years (range 0–86) in males and 42 years (range 1–92) in females. 192 children are included (

Description: INTRODUCTION: Pathogen inactivation (PI) of platelet (PLT) concentrates shows good efficacy against a broad array of viruses, bacteria and parasites. Moreover, animal studies have shown that the technology reduces alloimmunization due to HLA alloantibody formation. As bleeding is considered to be the pivotal outcome for PLT transfusion trials, we conducted a trial comparing PI-treated PLT concentrates using the Mirasol technology (Terumo BCT, Lakewood, CO) with standard untreated PLT concentrates, with the percentage of transfusion episodes in which a 〉 grade 2 bleeding complication (World Health Organization grading) occurred as primary outcome. METHODS: The PREPAReS study was designed as a randomized multicenter non-inferiority study using a parallel arm design. Patients aged 18 years or older were eligible if they were expected to require at least two PLT transfusions. Exclusion criteria included: WHO bleeding grade 〉 2 at randomization, known immunological refractoriness to platelet transfusions, indications to use hyperconcentrates, prior treatment with pathogen-reduced blood products, pregnancy, microangiopathic thrombocytopenia, ITP, and known allergy to riboflavin or its photoactive products. Patients were assigned to the Control group receiving standard plasma-stored PLT concentrates, or the Study group receiving Mirasol-treated PLTs. Patients could be re-enrolled, thereby adding multiple transfusion episodes to the trial. A Transfusion Episode was defined as the time from randomization until the time the patient went off trial. PLT concentrates were prepared from pooled buffy coats, resuspended in plasma and leukoreduced by filtration. For pathogen reduction, 35 ml (500 µM) riboflavin was added within 8 hours of preparation of the platelets, and exposed to UV light. PLT products were stored with gentle agitation at 20-24°C up to five days in Canada and for a maximum of seven days in the Netherlands and Norway. The Intention To Treat (ITT) analysis included all bleeding episodes from the moment of randomization on, the Per Protocol (PP) analysis included only bleeding episodes that occurred after the first platelet transfusion. Patients who were actively bleeding on the day of the first transfusion, or received more than 25% off-protocol transfusions were excluded. The PREPAReS trial was powered to demonstrate non-inferiority in the ITT analysis. RESULTS: Between November 2010 and April 2016, 567 transfusion episodes were randomized (283 in the Control group and 284 in the Study group; 469 unique patients), of which 11 were excluded due to active bleeding at the time of randomization, or due to gross incompliance. For the PP analysis, 37 episodes were excluded due to active bleeding at the time of the first platelet transfusion (Control, 21, Study, 16), because the patient did not receive a platelet transfusion, or because more than 25% were off-protocol transfusions (Control, 38, Study, 56), rendering 425 episodes evaluable. The ITT and PP outcomes are shown in the Table. The primary endpoint was met in the ITT analysis, but not in the PP analysis. CONCLUSION: For Mirasol-treated platelets compared with untreated platelets with bleeding as primary study outcome, the non-inferiority criterion was met in the ITT analysis, but not in the PP analysis. Disclosures No relevant conflicts of interest to declare.