ALBERT

Description: Introduction Approximately 40% of children with a severe form of sickle cell disease (SCD) will develop cerebral white matter hyperintensities (WMHs), visible on magnetic resonance imaging (MRI). This may be associated with impaired neurocognitive functioning. It is unknown whether the volume of these WHMs is associated with the degree of neurocognitive dysfunction. Our objective was to investigate the association between volume of WMHs and neurocognitive functioning. Methods We prospectively included children with HbSS or HbS-beta(0)thalassemia aged 8-16 years. Exclusion criteria were prior stroke and chronic blood transfusion therapy. Volume of WMHs was calculated on MRI and patients were ranked by size of WMHs. Neurocognitive function was evaluated by testing intelligence (IQ, intelligence quotient), memory, visuo-motor functioning and executive functioning. Fatigue was measured using a validated questionnaire (Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, PedsQL Fatigue) in which lower scores indicate more symptoms of fatigue. For each neurocognitive outcome, univariate linear regression was used to identify which variables (age, sex and hemoglobin level) were confounders. The independent association of volume of WMHs on neurocognitive outcomes was analyzed by multivariate linear regression, adjusted for these confounders when appropriate. The explained variance (R2) refers to the independently explained variance of volume of WMHs on the neurocognitive outcome and the presented p-value corresponds to the unique contribution of volume of WMHs on the outcome, both adjusted for confounders when appropriate. Results We included 38 children; mean age was 12.5 ± 2.7 years, WMHs were present in 50%. Mean full-scale, verbal IQ, performal IQ and Processing Speed Index were all between 85 and 90; this is significantly lower compared to the mean norm scores of 100. Our patients had significantly more symptoms of fatigue compared to Dutch reference values. A higher volume of WMHs was significantly associated with lower scores on full-scale IQ, verbal IQ and Processing Speed Index (see table). In addition, higher volume of WMHs was associated with higher scores of total and cognitive fatigue. Standardized beta coefficients ranged from -0.350 to -0.461, indicating a substantial negative effect of an increasing volume of WMHs on neurocognitive outcome. The volume of WMHs could explain between 12.1% and 21.2% of the variance of these outcomes. Conclusion Our findings suggest that the volume of WMHs is an independent predictor of full-scale IQ, verbal IQ, Processing Speed Index and fatigue in children with SCD. As WMHs are mostly found in the frontal lobe, this could explain the association with processing speed, which is an executive function and thought to be located in the frontal lobe. The association between WMHs and measures of fatigue has not been investigated before. Our results suggest the PedsQL Fatigue could be a promising screening tool for larger studies as it is easy and quick to administer and has a high validity. We suggest that future studies should consider taking the total volume of WMHs into account as an independent predictor of neurocognitive outcome, instead of only the presence or absence of WMHs. Taking the volume of WMHs into account is an important approach for individualized diagnostic and treatment strategies that could be further explored in a clinical setting. Table Prediction model of neurocognitive outcome by volume of white matter hyperintensities ß R2 p Full-scale IQ -0.382 0.146 0.018 Verbal IQ -0.460 0.212 0.004 Performal IQ -0.170 0.029 0.314 Processing Speed Index -0.461 0.212 0.005 PedsQL Fatigue, Total Score -0.350 0.121 0.025 PedsQL Fatigue, General Fatigue -0.289 0.083 0.071 PedsQL Fatigue, Cognitive Fatigue -0.352 0.123 0.026 IQ, Intelligence Quotient; PedsQL Fatigue, Pediatric Quality of Life Inventory Multidimensional Fatigue Scale. Disclosures No relevant conflicts of interest to declare.

Description: The risk for inhibitor development in mild hemophilia A (factor VIII levels between 5 and 40 U/dL) is larger than previously anticipated, continues throughout life, and is particularly associated with certain mutations in F8. Desmopressin may reduce inhibitor risk by avoiding exposure to FVIII concentrates, but the heterogenous biological response to desmopressin, showing large interindividual variation, may limit its clinical use. However, predictors of desmopressin response have been recently identified, allowing the selection of the best candidates to this treatment.

Description: Key Points The inhibitor incidence in nonsevere hemophilia A patients with certain F8 mutations approaches the inhibitor incidence in severe patients. These findings are highly relevant for clinical practice, as they facilitate identification of high-risk patients based on F8 genotype.

Description: Introduction: Blood transfusions are an important treatment modality for patients with either acute or chronic onset anemia such as trauma, sickle cell disease, and hematological malignancies. Transfusion poses a risk for alloimmunization, which may lead to potentially lethal transfusion reactions. A promising strategy to prevent alloimmunization is extensive matching on blood groups, yet this is a costly procedure and should be reserved for patients at highest risk for alloimmunization. Identification of genetic variants that increase the risk for alloimmunization might help to identify high-risk patients and could be used as a screening tool for patients receiving multiple transfusions. Objectives: To summarize all available evidence on genetic risk factors for alloimmunization after blood transfusion. Design: Systematic review with meta-analysis of observational studies. Studies were only included in the meta-analysis if polymorphisms were tested at least 3 times, and if ethnic background of the population and the control populations were comparable between studies. Data sources: The online databases Embase, MEDLINE and the Cochrane Library were search for relevant articles with search terms: 1) transfusion, 2) alloimmunization 3) genetics. The search was last updated March 2018. Eligibility criteria: 1) Primary study that assessed the association of genetic polymorphisms with transfusion related alloimmunization, 2) a human population, 3) studies with at least 50 patients, 4) full text availability. Data extraction: Two reviewers independently screened articles for eligibility, extracted data using a standardized data extraction form. Extracted data included study setting, study population, participant demographics, baseline characteristics, study methodology, comparisons and outcome, and risk of bias. Primary outcome measure: Alloimmunization after one or more blood transfusions. Risk of bias assessment: The quality of the included studies was assessed by the Q-genie tool for genetic association studies. Results: A total of 2045 cases and 24084 controls were derived from 18 genetic case-control studies that were included in this systematic review. Most commonly studied disease group was sickle cell disease (SCD) (8 studies). Three studies included patients with different diseases and seven studies did not report the underlying disease. Eleven studies identified the association of HLA polymorphisms with alloimmunization and 8 studies focused on non-HLA variants. Overall quality of the included studies was moderate (11 studies), 2 studies were of high quality, and 5 studies were ranked as poor. HLA-DRB1*04 (Odds Ratio 7.16, 95%CI 3.87-13.22, P

Description: Inhibitory antibodies directed against factor VIII develop in a substantial number of patients with hemophilia A as a consequence of factor VIII replacement therapy. These antibodies usually recognize discrete epitopes within the A2 and/or the C2 domains of factor VIII. Here, we have characterized the antibodies present in the plasma of a patient affected by severe hemophilia A. The antibodies reacted readily with the metabolically labeled factor VIII light chain and fragments thereof when analyzed by immunoprecipitation. The inhibitory activity could be neutralized by the complete light chain, whereas only slight neutralization occurred with a fragment comprising the isolated C2 domain. Binding of the majority of antibodies to in vitro synthesized factor VIII fragments was dependent on the presence of amino acid residues Gln1778-Met1823, a region known to contain a factor IXa binding site. Functional characterization showed that purified IgG from the patient's serum inhibited binding of factor IXa to immobilized factor VIII light chain in a dose-dependent manner. These data indicate that human alloantibodies may inhibit factor VIII activity by interfering with factor IXa–factor VIIIa complex assembly.

Description: Abstract 9 Introduction: The rate of complications after surgery is increased in patients with Sickle Cell Disease (SCD) and pre-operative blood transfusion has historically been used to decrease this risk. Observational studies and one limited Randomised Controlled Trial (RCT) have suggested that in some patients, transfusion can safely be omitted. Since transfusion is associated with complications including alloimmunisation and increased post-operative infections, we performed a RCT to address whether overall peri-operative complications in SCD are reduced by pre-operative transfusion. Methods: TAPS was a Phase III multicentre, pragmatic, randomised controlled trial with a parallel group sequential superiority design, carried out between November 2007 and March 2011 at 22 sites in the UK, Netherlands and Canada. Eligible patients had HbSS or HbSβ°thal, were aged one year or more and were having low risk (eg adenoidectomy, dental surgery) or medium risk (eg joint replacement, cholecystectomy, tonsillectomy) elective surgery. Patients were excluded if they had a haemoglobin (Hb)

Description: One of the most devastating complications of SCD is cerebral infarction. Cerebral infarcts are present on MRI scans in one third of SCD patients at the age of 18 years, although most of them are not accompanied by overt, focal neurological deficits. These so-called silent infarcts appear to be associated with diminished neurocognitive functioning and an increased risk of new infarcts. The risk of infarction is commonly attributed to the hyperemia that is associated with anemia and reduces the cerebral vascular reserve. In patients with anemia, adequate oxygenation of the brain tissue is presumably preserved by vasodilatation of the cerebral vasculature. In this hyperemic state there is limited reserve for further vasodilatation to assure adequate oxygen supply to the brain if the arterial pressure falls or metabolic demands increase. The lack of reserve capacity and ensuing ischemia is thought to predispose to cerebral infarction. The regional cerebral blood flow (rCBF) can be measured non-invasively by continuous arterial spin labeling (CASL) MRI. Proximal to entry in the brain, protons in the arterial blood are labeled using a radiofrequency pulse and quantified in terms of tissue perfusion on distal images in the brain. We performed a study to evaluate whether CASL MRI could detect differences in rCBF when these regions appear unaffected on conventional 3T MRI. The purpose of this study was to examine rCBF in children with SCD and compare it to rCBF in healthy children. Neurologically normal patients with sickle cell disease (HbSS or HbS-β0-thalassemia) and normal flow on Transcranial Doppler Ultrasonography (TCD) and healthy children (HbAA, matched for ethnicity and age) underwent 3T MRI examination in a stable clinical situation between August 2006 and June 2007. Conventional MRI and MRA images were assessed by a standardized evaluation protocol by two independent observers (MW and CM), blinded to the clinical data. Cerebral infarcts, leukoareosis and vasculopathy were scored. From CASL MRI the rCBF was calculated for 6 vascular territories (left and right anterior, middle and posterior cerebral artery, respectively ACA, MCA and PCA). Left-right asymmetry in rCBF for the vascular territories within each patient was evaluated by calculating differences in flow between both hemispheres. Asymmetry was defined as 〉 11.7 ml/100g/min between the two hemispheres. Mean differences between patients and controls and 95% confidence intervals were calculated. The Chi-square test was performed to test the hypothesis that left-right asymmetry was equally distributed among the patients and controls. We enrolled 24 SCD patients (mean age 13.4 yr, SD 3.0) and 12 controls (mean age 13.4 yr, SD 3.5). The rCBF was of similar magnitude in SCD patients and controls in the frontal, middle and posterior territories (Table 1). A left-right asymmetry of rCBF in one or more vascular territories was present in the majority of SCD patients (58%), whereas this was absent in all controls. The difference in proportions of patients and controls with left-right asymmetry was statistically significant for the MCA and PCA territory (Chi-square test respectively p=0.005 and p=0.037). In contrast to previous studies we found no difference in CBF between patients and controls. We did observe an asymmetry in rCBF in the majority of patients with SCD that was not present in healthy controls. Table 1. rCBF (ml/100g/min) values of patients and healthy controls. Patients n=24 Healthy controls n=12 Mean difference 95% CI Territories Mean SD Mean SD ACA 73.2 17.4 71.5 14.4 −1.7 (−13.6–10.1) MCA 77.1 19.9 76.1 16.4 −1.0 (−14.5–12.5) PCA 89.6 16.4 84.5 16.6 −5.1 (−17.0–6.7) Right hemisphere 77.6 19.2 76.3 15.3 −1.3 (−14.3–11.5) Left hemisphere 77.5 17.7 76.6 16.1 −0.9 (−13.3–11.4) Total 77.6 17.4 76.4 15.6 −1.2 (−13.4–11.0)

Description: Background: The clinical picture in sickle cell disease (SCD) is highly heterogeneous. Knowledge of the determinants of a severe disease course will help us to unravel the pathophysiological mechanisms underlying the disease process and provide novel targets for therapeutic interventions. To generate this knowledge well designed etiological studies are needed, using a valid outcome measure for disease severity. Objective: The aim of this systematic review is to identify all indices used to discriminate SCD patients by their current disease severity and to evaluate the methodological foundations of the indices and utility for clinical research. Method: We performed a systematic search in MEDLINE (Pubmed) (1966- February 2006) using the search terms: anaemia, sickle cell/ [MeSH]; health status indicators/ [MeSH]; severity; severe and clinical spectrum. Reference lists of relevant studies and reviews were screened to identify additional articles. Information was extracted in duplicate by two independent reviewers (XT, KF). Results: The Medline search yielded 1346 abstracts from which we selected 91 articles. Reference tracking resulted in 20 additional articles. After evaluation of the full text of these 111 articles, 28 articles (27 in English) were included in the review. These 28 indices contained 50 different items, including age at diagnosis, symptoms, findings at physical examination, laboratory values, organ damage, treatments and socio-economic consequences. The five most frequently used items were painful vaso-occlusive crises (86% of the indices), central nervous system abnormalities (59%), aseptic/avascular necrosis of the bone (52% of the indices), acute chest syndrome (48% of the indices) and leg ulcers (48% of the indices). Many indices (37%) were calculated by adding up scores on individual items without making a difference in the weight of the constituent items. In indices that did differentiate between items by allocating scores differentially, the rationale for weighing of the items was not explained. There were no scores that clearly distinguished devastating complications from complications that leave no sequelae. Most severity indices (89%) were not validated. Conclusion: In order to increase our understanding of the pathofysiology of SCD and identify potential targets for new therapeutic interventions, we need to identify the determinants of a severe phenotype. For this purpose, consensus on the concept of severity in SCD and an instrument or index to measure it are necessary. This review reveals that there is no consensus on a definition of SCD severity and an index to measure it. Given the current state, efforts should be made to reach international consensus on a definition of SCD severity and a core set of items to measure this concept should be developed.

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.