Abstract: Currently, it is unknown which patient‐reported outcomes are important for patients with autosomal inherited bleeding disorders. Therefore, the purpose of this study is to systematically review the available literature assessing patient‐reported outcomes and their measurement methods in autosomal inherited bleeding disorders. Methods The Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar databases were searched from inception until 14 August 2020. Studies on patient‐reported outcomes in patients with von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies were included. Results Twenty‐one articles met the inclusion criteria. Three studies were assessed as having poor quality, and therefore a high risk of bias. Nineteen studies had fair quality rating. Different measurements methods were used, ranging from predefined to self‐developed questionnaires. The majority of included studies focused on von Willebrand disease. Patients with von Willebrand disease reported lower health‐related quality of life compared to the general population. Overall, this trend was especially visible in the following domains: vitality, physical and social functioning and pain. Women with inherited bleeding disorders scored lower on health‐related quality of life compared to men, especially women with heavy menstrual bleeding. Patients with joint bleeds or heavy menstrual bleeding reported an increased level of pain. Conclusion Patients with autosomal inherited bleeding disorders report lower health related quality of life, especially those with joint bleeds or heavy menstrual bleeding. Numerous measurement methods are used in patients with autosomal inherited bleeding disorders, highlighting the need for studies using established, standardized measurement methods.

Abstract: Background: In sickle cell disease (SCD), hemoglobin S (HbS) polymerizes upon deoxygenation, reducing red blood cell (RBC) deformability. RBC deformability can be measured over a gradient of oxygen tensions (pO2) with the Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics). Oxygen gradient ektacytometry generates 3 key parameters: 1) EImax, RBC deformability at normoxia; 2) EImin, minimum RBC deformability upon deoxygenation; and 3) the point of sickling (PoS): the oxygen tension at which a 5% decrease in deformability is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1A). Previously we showed that oxygen gradient ektacytometry-derived biomarkers correlate with measures of SCD disease severity and hemolytic rate (Rab et al. Blood 2018), and is associated with vaso-occlusive crisis (VOC) frequency (Rab et al, Blood 2019). In this study, we confirm these observations in 2 independent cohorts and extend it to occurrence of acute chest syndrome (ACS), stroke including silent cerebral infarction (SCI), and transcranial Doppler (TCD) outcome. Methods: We analyzed 2 cohorts of SCD patients; an adult patient cohort of 53 SCD patients, enrolled at either University Medical Center Utrecht, The Netherlands (UMCU, n=25) or Hospital Lyon France (LIBM, n=28), and a pediatric patient cohort of 190 SCD patients enrolled at Texas Children's Hospital, USA (TCH). Subjects were HbSS or HbS/β-thalassemia, with a substantial number of subjects on hydroxyurea (HU) therapy (adult cohort 66% and pediatric cohort 86%), and not on chronic transfusion therapy. Correlations between oxygen gradient ektacytometry-derived biomarkers and the clinical complications of stroke or silent infarcts (SCI), ACS, VOC were assessed in both pediatric and adult patients. Patient groups generally did not significantly differ significantly by age, gender or HU treatment in the adult cohort except for age, which was lower in the ACS+ group (25.3years (y) compared to 32.0y) and also lower in the VOC+ group (27.1y compared to 35.8y). In the pediatric cohort, patient groups differed significantly in the ACS+ group compared to the ACS- group by age (ACS- group 8.37, ACS+ group 10.9y) and HU treatment (ACS- group 76%, ACS+ group 93%). Similarly, age was significantly higher in the Stroke+ group compared to the Stroke- group (14.0y compared to 9.3y), which was also found when studying VOC (VOC+ group 11.6y, VOC- group 8.2y). Results: In the pediatric cohort, PoS was significantly higher in patients with ACS (mean 40.3 compared to 34.9 mmHg, p=0.0001, Figure 1B). In the adult cohort, PoS was also higher in those with ACS although this did not reach significance (p=0.053, Figure 1C). In the pediatric cohort, PoS was higher in patients with stroke or SI (mean 43.0 mmHg compared to mean 37.3 mmHg, p & lt;0.05), Figure 1D). This finding was replicated in the adult cohort (p & lt;0.05, Figure 1E). EImin and EImax in both cohorts were significantly lower in patients who experienced stroke or SCI (all p & lt;0.05). PoS was higher and EImin and EImax lower in subjects with elevated TCD measurements (all p & lt;0.01, Figure 1F and G). In the adult and pediatric patient cohort, PoS was higher in patients with recent VOC (both p & lt;0.05, Figure 1H and I). Differences in mean PoS between pediatric and adult patient cohorts could be due to differences in treatment, age, genetic background or technical differences between Lorrca devices. Lower significance levels found in the adult patient cohort could be due to smaller sample size. Conclusion: We show that oxygen gradient ektacytometry provides functional, clinically relevant next generation biomarkers that are associated with ACS, stroke and VOC. This study therefore further validates the clinical usefulness of these biomarkers, in particular in relation to cerebral vasculopathy. Since our results merely describe an association and not causality further validation is warranted to establish how well oxygen gradient ektacytometry can assess disease severity. However, its parameters could already provide the clinician with information about patient RBC characteristics and sickling propensity that could aid in clinical decision making. Our results provide a rationale for further development of these biomarkers in the evaluation of novel therapies as part of clinical care, or clinical trial endpoints. Disclosures Rab: RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Cnossen:Takeda: Research Funding; Shire: Research Funding; Baxter: Research Funding; Bayer: Research Funding; Sobi: Research Funding; CSL behring: Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Wijk:Agios Pharmaceuticals Inc.: Research Funding; RR mechatronics: Research Funding. Sheehan:Emmaus: Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. van Beers:Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Abstract: Background: In sickle cell disease (SCD), hemoglobin S (HbS) polymerizes upon deoxygenation, reducing red blood cell (RBC) deformability. RBC deformability can be measured over a range of oxygen concentrations using a Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics, Zwaag, the Netherlands) with Oxygenscan module. The Oxygenscan measures 3 key parameters: 1) EImax, RBC deformability at normoxia; 2) EImin, RBC deformability upon deoxygenation; and 3) the point of sickling (PoS): the oxygen tension at which a 5% decrease in normoxic EI is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1A). Previously we showed that Oxygenscan parameters correlate with measures of SCD disease severity and hemolysis (absolute reticulocyte count, %fetal hemoglobin, %HbS, total Hb, %dense RBC, (Rab et al. Blood 2018). In this study, we investigated the relationship between oxygenscan parameters and incidence of vaso-occlusive crisis (VOC), and we tested the ability of the Oxygenscan parameters to assess response to hydroxyurea (HU) and chronic transfusion (CTF) in patients with SCD. Methods: We analyzed 2 cohorts: a European cohort (EUC) of 62 SCD patients (all HbSS or HbS/β-thalassemia), enrolled at either University Medical Center Utrecht (UMCU, n= 42) or Hospital Lyon (LIBM, n=20), and a US cohort (USC) of 97 SCD patients enrolled at Texas Children's Hospital (TCH). Differences in Oxygenscan parameters in SCD patients without/with VOC (requiring a doctor's evaluation) in the past 2 years were measured in 46 adult EUC SCD patients and 80 pediatric USC SCD patients. EUC patients without VOC (n=18, median age 40.6 years (y); 11 female (F), 44% on HU, 6% on CTF, 28% on both treatments), were compared to patients with a positive history of VOC (n=28, median age 23.9y, 13F, 39% on HU, 11% on CTF and 11% on both). Patients without VOC in the USC (n= 34, median age 8.0y, 15F, 53% on HU, 15% on CTF and 21% on both treatments) were compared to patients with VOC (n=46, median age 11.8y, 20F, 74% on HU, 13% on CTF and 11% on both treatments). To establish treatment related Oxygenscan parameter changes, we analyzed RBCs from 9 SCD patients from UMCU (median age 19y, 5F), before and during HU treatment (measurements performed at baseline, and 1, 3 and 6 months after starting HU), 7 SCD patients from UMCU (median age 26.7y; 6F) before and after transfusion and 17 SCD patients from TCH (median age 10.8y; 6F) on HU before and after transfusion. Results: In the EUC, PoS differed significantly between patients without VOC in the last 2 years (median 41.6mmHg) and patients with VOC in the last 2 years (median 53.7 mmHg, p 〈 0.001, Figure 1B). In the USC, PoS was also lower in patients without VOC compared to those with a VOC in past 2 years (p 〈 0.05, Figure 1C). EImin in both cohorts was significantly lower in patients who experienced VOC (p 〈 0.05). EImax did not show a significant difference in both cohorts. Correlation of PoS with VOC episodes was significant in the EUC (r=0.447, p 〈 0.01, Figure 1D) and USC (r=0.228, p 〈 0.05), indicating that RBCs start to sickle at a higher pO2 in patients where VOC occur more often. Differences found in median PoS between EUC and USC could be due to differences in treatment (EUC 30% no treatment, USC 5% no treatment), difference in age (EUC median age 28.5y, USC median age 11.6y), genetic background or technical differences between Oxygenscan devices. Transfusion improved EImax, EImin, and PoS (USC: p 〈 0.001, p 〈 0.0001, and p 〈 0.01, EUC: all parameters p 〈 0.05 Figure 1E). HU treatment improved all parameters after 3 and 6 months compared to baseline (p 〈 0.05 and p 〈 0.0001 Figure 1F). Conclusion: Our results show that RBC from SCD patients without VOC in the last two years were able to tolerate lower oxygen concentrations before sickling (PoS). RBCs from patients without VOC were also more deformable when deoxygenated (EImin) compared to patients who had experienced one or more VOCs in the last two years. In contrast, RBC deformability, when oxygenated (EImax) was not different in patients with or without VOC in the last two years. All 3 Oxygenscan parameters significantly improved with standard of care SCD treatments, namely CTF and/or HU. We therefore conclude that the PoS, EImax and EImin are useful biomarkers of clinical severity and treatment response, and may be essential in monitoring novel SCD treatments as part of a clinical trial as a surrogate endpoint. Disclosures Rab: RR Mechatronics: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Nur:Novartis Pharmaceuticals: Consultancy. Cnossen:NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018; Roche: Other: Travel Grants; Takeda: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Baxter: Other: Travel Grants, Research Funding; Sobi: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Bayer: Other: Travel Grants, Research Funding; Pfizer: Other: Travel Grants, Research Funding. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding.

Abstract: Silent cerebral infarcts (SCIs) are the most common neurological complication in children and adults with sickle cell disease (SCD). In this systematic review, we provide an overview of studies that have detected SCIs in patients with SCD by cerebral magnetic resonance imaging (MRI). We focus on the frequency of SCIs, the risk factors involved in their development and their clinical consequences. Methods The databases of Embase, MEDLINE ALL via Ovid, Web of Science Core Collection, Cochrane Central Register of Trials via Wiley and Google Scholar were searched from inception to June 1, 2019. Results The search yielded 651 results of which 69 studies met the eligibility criteria. The prevalence of SCIs in patients with SCD ranges from 5.6 to 80.6% with most studies reported in the 20 to 50% range. The pooled prevalence of SCIs in HbSS and HbSβ 0 SCD patients is 29.5%. SCIs occur more often in patients with the HbSS and HbSβ 0 genotype in comparison with other SCD genotypes, as SCIs are found in 9.2% of HbSC and HbSβ + patients. Control subjects showed a mean pooled prevalence of SCIs of 9.8%. Data from included studies showed a statistically significant association between increasing mean age of the study population and mean SCI prevalence. Thirty-three studies examined the risk factors for SCIs. The majority of the risk factors show no clear association with prevalence, since more or less equal numbers of studies give evidence for and against the causal association. Conclusions This systematic review and meta-analysis shows SCIs are common in patients with SCD. No clear risk factors for their development were identified. Larger, prospective and controlled clinical, neuropsychological and neuroimaging studies are needed to understand how SCD and SCIs affect cognition.

Abstract: While multiple studies have examined the cost of health care for one aspect of sickle cell disease care, few have focussed on the overall cost of comprehensive care for sickle cell disease. Methods We conducted a retrospective cohort study of children with sickle cell disease treated in a comprehensive care centre from 1 January 2015 to 31 December 2016. Health care utilisation of included patients was based upon data from two main sources. The clinical practice guideline was used to determine the expected resource use of routine comprehensive care (planned elective care), and the financial claims database was used to estimate real‐world resource use associated with acute and inpatient care (additional care). Results A total of 125 children with sickle cell disease were analysed. Expenditures for these patients averaged €5049 [standard deviation (SD) €1634] per child per year. Total yearly costs per patient varied considerably, ranging from €669 to €84 010, and less than 15% of patients were responsible for 50% of the health care costs. The majority (37%) of costs was associated with inpatient hospital care, which increased by age group, 27% with diagnostics, 19% with treatment, 11% with outpatients’ visits and 6% with emergency care. Conclusion We have described real‐world resource use and expenditures for children with sickle cell disease in a European comprehensive care centre. It seems that costs of a comprehensive approach with effective management in the outpatient setting is favourable when compared to episodic health care.

Abstract: In sickle cell disease (SCD), sickle hemoglobin (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These sickled RBCs have strongly reduced deformability, leading to vaso‐occlusive crises and chronic hemolytic anemia. To date, there are no reliable laboratory parameters or assays capable of predicting disease severity or monitoring treatment effects. We here report on the oxygenscan, a newly developed method to measure RBC deformability (expressed as Elongation Index ‐ EI) as a function of pO 2 . Upon a standardized, 22 minute, automated cycle of deoxygenation (pO 2 median 16 mmHg ± 0.17) and reoxygenation, a number of clinically relevant parameters are produced in a highly reproducible manner (coefficients of variation 〈 5%). In particular, physiological modulators of oxygen affinity, such as, pH and 2,3‐diphosphoglycerate showed a significant correlation (respectively R = ‑0.993 and R = 0.980) with Point of Sickling (PoS 5% ), which is defined as the pO 2 where a 5% decrease in EI is observed during deoxygenation. Furthermore, in vitro treatment with antisickling agents, including GBT440, which alter the oxygen affinity of hemoglobin, caused a reproducible left‐shift of the PoS, indicating improved deformability at lower oxygen tensions. When RBCs from 21 SCD patients were analyzed, we observed a significantly higher PoS in untreated homozygous SCD patients compared to treated patients and other genotypes. We conclude that the oxygenscan is a state‐of‐the‐art technique that allows for rapid analysis of sickling behavior in SCD patients. The method is promising for personalized treatment, development of new treatment strategies and could have potential in prediction of complications.

Abstract: In well-resourced countries, comprehensive care programs have increased life expectancy of patients with sickle cell disease, with almost all infants surviving into adulthood. However, families affected by sickle cell disease are more likely to be economically disenfranchised because of their racial or ethnic minority status. As every individual child has the right to the highest attainable standard of health under the United Nations Convention on the Rights of the Child, it is essential to identify both barriers and facilitators with regard to the delivery of adequate healthcare. Optimal healthcare accessibility will improve healthcare outcomes for children with sickle cell disease and their families. Healthcare professionals in the field of sickle cell care have first-hand experience of the barriers that patients encounter when it comes to effective care. We therefore hypothesised that these medical professionals have a clear picture of what is necessary to overcome these barriers and which facilitators will be most feasible. Therefore, this study aims to map best practises and lessons learnt in order to attain more optimal healthcare accessibility for paediatric patients with sickle cell disease and their families. Methods Healthcare professionals working with young patients with sickle cell disease were recruited for semi-structured interviews. An interview guide was used to ensure the four healthcare accessibility dimensions were covered. The interviews were transcribed and coded. Based on field notes, initial codes were generated, to collate data (both barriers and solutions) to main themes (such as “transportation”, or “telecommunication”). Through ongoing thematic analysis, definitive themes were formulated and best practices were reported as recommendations. Quotations were selected to highlight or illustrate the themes and link the reported results to the empirical data. Results In 2019, 22 healthcare professionals from five different university hospitals in the Netherlands were interviewed. Participants included (paediatric) haematologists, nurses and allied health professionals. Six themes emerged, all associated with best practices on topics related to the improvement of healthcare accessibility for children with sickle cell disease and their families. Firstly, the full reimbursement of invisible costs made by caregivers. Secondly, clustering of healthcare appointments on the same day to help patients seeing all required specialists without having to visit the hospital frequently. Thirdly, organisation of care according to shared care principles to deliver specialised services as close as possible to the patient’s home without compromising quality. Fourthly, optimising verbal and written communication methods with special consideration for families with language barriers, low literacy skills, or both. Fifthly, improving the use of eHealth services tailored to users’ health literacy skills, including accessible mobile telephone contact between healthcare professionals and caregivers of children with sickle cell disease. Finally, increasing knowledge and interest in sickle cell disease among key stakeholders and the public to ensure that preventive and acute healthcare measures are understood and safeguarded in all settings. Conclusion This qualitative study describes the views of healthcare professionals on overcoming barriers of healthcare accessibility that arise from the intersecting vulnerabilities faced by patients with sickle cell disease and their families. The recommendations gathered in this report provide high-income countries with a practical resource to meet their obligations towards individual children under the United Nations Convention on the Rights of the Child.

Abstract: Introduction Sickle cell disease (SCD) is an autosomally, recessive inherited hemoglobinopathy and multisystem disorder characterized by ongoing hemolytic anemia, episodes of vaso-occlusion and progressive organ failure with ultimately a shortened life expectancy. Despite intensive comprehensive care and improved rates of morbidity and mortality, SCD care is still marked by high utilization of medical resources. Until now, most cost-of care studies have focused on one or two care categories, such as hospitalizations and physician visits [1-4]. Also, few studies have evaluated healthcare expenditures exclusively in children. Estimating cost-of care is important as it can ensure sufficient allocation of resources. In addition, SCD expenditures can be used to raise awareness of disease severity and serve as an incentive for prevention and management of disease complications. Primary aims of this study were to (a) investigate the overall cost of healthcare for pediatric SCD patients and to (b) estimate major cost drivers. Methods All pediatric SCD patients visiting the Erasmus University Medical Center-Sophia Children's Hospital for routine or emergency care from January 1st to December 31st 2017 with a diagnosis of SCD were included. Retrospective data of this cohort were analyzed for 24 months during January 1st 2015 to December 1st 2016. Patients were grouped into four age categories; (A) 0-12 months, (B) 1-5 years, (C) 5-13 years and (D) 13-19 years. For patients born before January 1st 2015, each individual contributed two years of follow-up time. As some children were born during one of the two years during the study time period, the weighted average was calculated based on the time patients were potentially able to make costs. Healthcare utilization of included patients was based upon data from two main sources. The clinical SCD standard treatment guideline was used to determine the expected resource use of routine comprehensive care (planned elective care) and the Erasmus University Medical Center financial claims database was used to estimate real-world resource use associated with acute and inpatient care (additional care). The included items for the SCD guideline and financial claims database per cost category are summarized in Table 1. Results A total of 125 patients were analyzed. The mean age was 8.1 years (SD: 5 years) on December 31st 2015 and 9.9 year (SD: 5 years) on December 31st 2016. Expenditures for the 125 children with SCD averaged €4285.09 (SD: €820.36) per child per year. The majority (49%) of costs was associated with standard treatment (i.e. prophylactic antibiotics); 23% with diagnostics; 19% with inpatient hospital care and 9% with outpatients visits. Annual average costs per patient per age group are depicted in Figure 1. Total expenditures for children with SCD increased per age group, ranging from €2962 (category A), €3726 (category B), and €4087 (category C) to €5890 (category D). This was mostly explained by increases in admission costs. Discussion Although healthcare utilization and costs of pediatric SCD patients have been studied previously [5-7], studies from Europe comprehensive care centers are scarce and have been mostly based on only one aspect of care such as hospitalizations costs [2] . To our knowledge, this is the first study combining standard treatment costs with real world resource use. The total annual coast of healthcare for children with SCD, including inpatient care, outpatient care, diagnostics and treatment averaged €4285.09 per patient per year. This is much lower when compared to costs of healthcare for pediatric patients with SCD reported in other studies. Kauf et al. calculated total costs of healthcare for SCD patients aged 0-9 years to be $10.704 [7] . In addition, inpatient care accounts for a relatively small part of total costs in our study. This finding has been inline with previous research where comprehensive care has been suggested as a means of reducing costs associated with SCD care [8]. A comprehensive, multidisciplinary approach is necessary to address the physical, mental and social needs of each child and their family. Comprehensive care, with effective management in the outpatient setting is able to prevent hospital admission, and is essential for delivery of high quality cost-effective care in SCD. Disclosures Cnossen: Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Sobi: Research Funding; Baxter: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Takeda: Other: Travel Grants, Research Funding; Roche: Other: Travel Grants; NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018.