scholarly journals Impact of Human Leukocyte Antigen on the Risk of Stroke in Patients with Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4831-4831
Author(s):  
Huda Al-Harrasi ◽  
Murtadha Al-Khabori ◽  
Salam Al-Kindi ◽  
Yasser Ahmed Mohamed Soliman Wali ◽  
Mohamed Al Huneini ◽  
...  

Objectives: Sickle Cell Disease (SCD) is an inherited hemoglobinopathy with multiple complications including stroke. It is observed that siblings with SCD have an increased risk of stroke if there was a sibling in the family with SCD and stroke (Driscoll M C, Blood, 2003). Human Leukocyte Antigen (HLA) is extremely variable among individuals and certain HLA alleles have previously been associated with a number of diseases. It has been shown that HLA-DRB1*0301, HLA-DRB1*0302 and HLA-DQB1*0201 increase the risk of stroke and HLA-DRB1*1501 and HLA-DQB1*0602 lower the risk of stroke in patients with SCD (Styles L, Blood, 2000). These alleles are not common in all populations. We therefore planned to assess the impact of other HLA alleles on the risk of stroke in patients with SCD. Methods: This is a retrospective case-control study conducted at Sultan Qaboos University Hospital. We included all adult and pediatric patients with SCD and diagnosed with stroke using CT/MRI of the brain. The study included patients diagnosed during the period of 1995 to 2015. HLA typing was performed using molecular techniques. HLA alleles with a frequency of at least 5% were selected for analysis. Association studies were performed using Fisher Exact test. All statistical tests were performed using R program (version 3.1.2). Results: A total of 244 patients were included (66 patients with SCD and stroke [cases] and 178 patients with SCD with no stroke. The median age was 26 years (Interquartile Range [IQR]: 19-32) and 23 (IQR: 17-29 ) for cases and controls respectively. The median hemoglobin, mean corpuscular volume, hemoglobin S level and lactate dehydrogenase level was 9 g/dL, 70 fL, 70% and 400 U/L respectively for the cases, and 9 g/dL, 60 fL, 70% and 400 U/L respectively for the control. The most frequent HLA-A allele was HLA-A*02 (24%) which did not impact the risk of stroke (Odds Ratio [OR]: 1.59, 95% Confidence Interval [CI]: 0.84-3.02) as were the other tested HLA-A alleles (all CIs crossed OR of 1.00). The most frequent HLA-B allele was HLA-B*51 (15%) which did not impact the risk of stroke (OR: 0.89, 95% CI: 0.43-1.85) as were the other tested HLA-B alleles (all CIs crossed OR of 1.00). The most frequent HLA-C allele was HLA-C*04 (17%) which did not impact the risk of stroke (OR: 1.34, 95% CI: 0.67-2.65); however, HLA-C*06 (OR: 2.37, 95% CI: 1.01-5.54) increased the risk of stroke while HLA-C*07 protected from stroke (OR: 0.35, 95% CI: 0.13-0.93). None of the other HLA-C alleles were statistically significant (all CIs crossed OR of 1.00). The most frequent HLA-DRB1 allele was HLA-DRB1*16 (18%) which did not impact the risk of stroke (OR: 1.02, 95% CI:0.51-2.03) as were the other tested HLA-DRB1 alleles (all CIs crossed OR of 1.00). Conclusions: HLA-C*06 is associated with an increased risk of stroke in patients with SCD while HLA-C*07 is protective from stroke in these patients. Early identification of high-risk patients would be beneficial for preventive intervention, such as chronic transfusion or bone marrow transplantation. The impact of these HLA alleles should be validated in other populations. Disclosures Al-Khabori: Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Wally R Smith ◽  
Jane S. Hankins ◽  
Miguel R Abboud ◽  
Ze Cong ◽  
Jonathan Sorof ◽  
...  

Background: Patients with sickle cell disease (SCD) experience varied salient symptoms that impact their health-related quality of life, which incorporates illness severity, their level of distress and other aspects of impairment, and the impact of the illness on functional status. SCD symptoms may begin at an early age, and their severity varies over time and between patients. Although detection of changes in patients' self-assessed symptoms may be obfuscated by their lifelong symptoms, treating physicians with SCD expertise may be able to detect changes in a patient's status given their experience in treating the diverse symptoms across multiple patients. We evaluated the longitudinal impact of voxelotor (Oxbryta®) in the HOPE study using the single-item Clinical Global Impression of Change (CGI-C), a validated clinician-reported outcome analogous to the commonly used Patient Global Impression of Change (PGI-C), which provides expert clinical impressions that transcend symptom checklists. Methods: In the randomized, placebo-controlled, double-blinded HOPE study, participants with SCD aged 12 to 65 years were randomized to receive voxelotor (1500 mg or 900 mg dose administered orally, once daily) or placebo. Study participants had a hemoglobin (Hb) level 5.5 to 10.5 g/dL at enrollment and 1 to 10 vaso-occlusive crises in the past 12 months at screening. Clinicians were blinded to treatment assignment and to all central laboratory measures (eg, hematological parameters) throughout the 72-week study period. Clinicians rated the CGI-C at 24 and 72 weeks from baseline. CGI-C ratings used a 7-point scale ("very much improved," "moderately improved," "minimally improved," "no change," "minimally worse," "moderately worse," and "very much worse"). CGI-C outcomes were stratified by baseline Hb levels and baseline markers of hemolysis to identify measures predictive of assessment outcomes. Results: Trends of improvement from baseline in overall clinical status with voxelotor 1500 mg, as assessed by CGI-C scores, were observed as early as week 24. At week 72, patients receiving voxelotor 1500 mg were more often rated by the clinician as "very much improved" or "moderately improved" (74%; 39 of 53) compared with those who received placebo (47%; 24 of 51) (P<0.01, Figure 1). CGI-C score improvement was consistently greater in participants treated with voxelotor compared with placebo regardless of baseline Hb. Greater proportions of participants were rated "very much improved" or "moderately improved" with voxelotor 1500 mg than placebo regardless of baseline hemolysis markers (indirect bilirubin, percentage reticulocytes, absolute reticulocyte count). Conclusions: Treatment with voxelotor 1500 mg resulted in improved clinician-reported patient outcomes, as assessed using the CGI-C. Greater proportions of participants were rated "very much improved" or "moderately improved" regardless of baseline Hb levels and baseline markers of hemolysis. The CGI provides an overall clinician-determined summary measure that takes all available information into account, including the patient's history, psychosocial circumstances, symptoms, and behavior, as well as the impact of symptoms on the patient's ability to function. Therefore, a tool that provides a holistic assessment of a patient's well-being may be complementary in capturing changes in a patient's status, considering the substantial interpatient and intrapatient variability in SCD symptomatology. CGI-C assessments are being included in ongoing studies of voxelotor. Disclosures Smith: Emmaeus Pharmaceuticals, Inc.: Consultancy; Novartis, Inc.: Consultancy, Other: Investigator, Research Funding; Global Blood Therapeutics, Inc.: Consultancy, Research Funding; Shire, Inc.: Other: Investigator, Research Funding; NHLBI: Research Funding; Patient-Centered Outcomes Research Institute: Other: Investigator, Research Funding; Health Resources and Services Administration: Other: Investigator, Research Funding; Incyte: Other: Investigator; Pfizer: Consultancy; Ironwood: Consultancy; Novo Nordisk: Consultancy; Imara: Research Funding; Shire: Research Funding; GlycoMimetics, Inc.: Consultancy. Hankins:American Society of Pediatric Hematology/Oncology: Honoraria; UptoDate: Consultancy; Novartis: Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; LINKS Incorporate Foundation: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Abboud:Novartis: Consultancy, Honoraria, Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Crispr Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel support; Eli Lilly: Research Funding; Modus Pharmaceuticals: Research Funding. Cong:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sorof:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gray:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hoppe:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Telfer:Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria, Research Funding; ApoPharma: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2048-2048
Author(s):  
Ondine Walter ◽  
Pierre Cougoul ◽  
Julien Maquet ◽  
Pablo Bartolucci ◽  
Maryse Lapeyre-Mestre ◽  
...  

Abstract Introduction : Sickle cell disease (SCD) is an inherited disorder which affects 300,000 newborns per year. Vaso-occlusive episodes (VOEs) cause an important morbi-mortality and a decreased quality of life in patients with SCD. Some risk factors of VOE are well known, like infection, cold exposure, stress, pulmonary diseases and dehydration. Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in few case reports or series. However, no comparative study has been conducted to demonstrate this risk which is still debated, resulting in discrepancies among guidelines on SCD management. This study aimed to assess the risk of hospitalization for VOE associated with out-hospital exposure to systemic corticosteroids in patients with SCD in France. Methods : Data source was the French national health insurance system database, named SNDS (Système National des Données de Santé) between 2010 and 2018. The SNDS links sociodemographic, out- and in-hospital data for the entire French population (>66 million inhabitants). The study population consisted in all patients with SCD with at least one hospitalization for VOE during the study period, identified with a primary discharge diagnosis of VOE (D57.0 code of the international classification of disease, 10 th version; positive predictive value: 98.6%). All genotypes (homozygous SS-SCD and double-heterozygous SCD) were included. Because we assessed out-hospital exposure to corticosteroids, patients hospitalized during the three months before the first VOE were excluded. We performed a case-case-time-control study (Figure 1). This self-controlled design results in self-adjustment for time-independent confounders, including genotype. The outcome was the first hospitalization for VOE. The exposure to oral and injectable corticosteroids, identified using out-hospital reimbursement data, was assessed during a case period (28 days before the outcome) compared to the exposure during a control period (28 days, starting 84 days before the outcome). The same comparison was made among future cases (matched patients hospitalized for VOE the year after the given case), in order to adjust for the trend of exposure to corticosteroids (calendar variations of corticosteroid exposure). Results : Overall, 5,151 cases of VOEs were included in the main analysis. Median age at first VOE was 16.9 years; 317 (6.2%) patients were exposed to corticosteroids during the case period. In the main analysis, corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted Odds Ratio (aOR): 3.81, 95% confidence interval (95% CI): 2.44 to 5.61. In patients exposed to hydroxyurea, the aOR was 2.61, 95% CI: 1.07 to 6.39, compared with an aOR of 4.00, 95% CI: 2.53 to 6.30 in unexposed patients. In the subgroup analysis by age, the aOR was 2.81, 95% CI: 1.49 to 5.30 in children, and 4.45, 95% CI: 2.37 to 8.37 in adults. The results were consistent in all sensitivity analyses. Conclusion : This study showed an association between outpatient exposure to systemic corticosteroids with an increased risk of hospitalization for VOE, in both adults and children. Hydroxyurea may reduce this risk in adults. Figure 1 Figure 1. Disclosures Bartolucci: GBT: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3459-3459
Author(s):  
Rishi J Desai ◽  
Mufaddal Mahesri ◽  
Raisa Levin ◽  
Denise Globe ◽  
Krista McKerracher ◽  
...  

Introduction: There is limited contemporary evidence on clinical outcomes and healthcare use in sickle-cell disease (SCD) patients enrolled in US Medicaid. We aimed to provide contemporary estimates for rates of vaso-occlusive crises (VOC), mortality, and healthcare resource utilization (HRU) in SCD patients enrolled in US Medicaid. Methods: We conducted a cohort study using nationwide Medicaid insurance claims data (2000-2013). Patients were included based on ≥1 inpatient or ≥2 outpatient HbSS SCD diagnosis claims after 365 days continuous enrollment in Medicaid (or continuous eligibility since birth if age at diagnosis is <1 year). Patients were followed until Medicaid disenrollment, death, bone marrow transplant, or end of data availability (December 31, 2013). Outcomes included frequency of VOCs, event rates of HRU including emergency department (ED) visits, hospitalizations, outpatient visits, and blood transfusions, and all-cause mortality during the follow-up period. All outcomes were reported as annualized event rates (with 95% confidence intervals). VOCs were stratified by age-group (<1, 2-6, 7-12, 13-18, 19-35, 35+ years), VOCs at baseline (<2, 2-4, >=5), race (African American or not), and sex. The impact of VOCs on the risk of mortality was analyzed using an extended multivariable Cox model with VOCs modeled as time-varying and updated annually. Results: A total of 44,033 SCD patients were included in the analysis; 47% were female, 82% were African American, and a mean (SD) age of 15.7 (13.6). The average VOC rate was 3.71 (95% CI: 3.70-3.72) VOCs per person-year over an average follow-up period of 4.3 years. The rate of VOCs was substantially higher among patients aged 19-35 years and those with a higher VOC frequency at baseline (Table 1). Overall, the event rates (95%CI) per person year for other HRU outcomes were: 2.97 (2.97-2.98) ED visits, 2.39 (2.38-2.40) hospitalizations, 5.80 (5.79-5.81) outpatient visits, and 0.91 (95%CI: 0.90-0.91) blood transfusions. The mortality rate was 1.13 (95%CI: 1.08-1.17) events per 100 person-years overall, with the highest rate being 4.91 (95%CI: 4.58-5.25) events per 100 person-years among patients ≥ 35 years of age. Higher VOC burden in the preceding year was associated with an increased risk mortality: 2-4 VOC vs. 0 or 1 VOC: Hazard Ratio (HR)=1.36 (95%CI: 1.21-1.52); ≥ 5 VOC: HR= 1.56 (95%CI: 1.39-1.75). Conclusion: The burden of SCD in US Medicaid enrollees is substantial, especially during early adulthood, with markedly high rates of VOCs, mortality, and healthcare utilization. A higher VOC rate in the preceding year was associated with an increased risk of mortality suggesting a need for careful management of SCD patients with higher VOC burden. Table 1. Annualized rates of vaso-occlusive crises (VOC) among sickle cell disease patients enrolled in Medicaid. VOC, vaso-occlusive crises; CI, confidence interval. Table 1 Disclosures Desai: Merck: Research Funding; Bayer: Research Funding. Globe:Vertex Pharmaceuticals Incorporated: Employment. McKerracher:CRISPR Therapeutics: Employment. Mutebi:Vertex Pharmaceuticals Incorporated: Employment. Bohn:Bohn Epidemiology: Equity Ownership; Vertex Pharmaceuticals Inc: Consultancy. Achebe:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Schneeweiss:Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Aetion, Inc.: Consultancy, Equity Ownership; Whiscon LLC: Consultancy.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 317-317
Author(s):  
Brooke Allemang ◽  
Kate Allan ◽  
Colleen Johnson ◽  
Melina Cheong ◽  
Patrina Cheung ◽  
...  

Abstract Introduction: Adolescents and young adults (AYA) with sickle cell disease (SCD) and thalassemia transitioning from pediatric to adult health care experience a lack of engagement with adult care providers, are at high risk of loss to follow-up, emergence of psychosocial issues, morbidity and mortality. The shift from a pediatric to an adult setting can be challenging for AYA who are coping with multiple life transitions and are expected to acquire the necessary skills to manage their own care. Hypothesis: implementation of a comprehensive structured transition program with dedicated transition navigator (TN) in a pediatric and adult hemoglobinopathy comprehensive care center will reduce loss to follow-up and hospitalization, improve adherence to medication and attendance to appointments compared to an unstructured transfer from pediatric to adult program. Methods: A structured comprehensive transition program with a dedicated TN, based on a quality improvement framework with an iterative design to refine the intervention over time, was developed and deployed across a pediatric and adult hemoglobinopathy comprehensive care center (Hospital for Sick Children (HSC) and Toronto General Hospital (TGH) respectively) starting August 1, 2014. Prior to this, patients at age 18 were transferred without preparation. With the TN model, adolescents, from age 12 were followed at each visit by the TN and up to one year after transitioning. Prior to transition to the adult center, adolescents were seen jointly by pediatric and adult care providers and TN in a transition clinic. Patients were assessed for transition readiness and provided with tailored education at each appointment. This observational study compared all AYA with SCD or thalassemia who turned 18 years between August 1, 2013 and August 1, 2015. Patients in the cohort prior to the comprehensive transition program were compared to patients who transitioned through the formal program. Data from one year prior to last appointment at HSC and one year after the first appointment at TGH were collected. The effects of covariates on imaging/clinic/transfusion/subspecialist appointment attendance, medication adherence and hospitalizations were analyzed by multivariable regression. Results: 112 patients met the criteria for transfer/transition, of which 51 transferred prior to August 1, 2014 and 61 transitioned through the comprehensive transition program. No significant differences were observed in baseline demographics including age at transfer/transition, phenotype, distance from the center, medications, parental/guardian appointment attendance, immigration status, family structure, first language spoken or documented cognitive impairment. The youngest patient to undergo transition in the observation period was 16.6 years. The transition process significantly reduced the proportion of patients lost to follow-up from 29% (11/38) to 7% (4/57) (P = 0.0335, Figure 1). In patients who were on hydroxyurea or iron chelation, significant increase in the proportion of patients who maintained or improved their medication adherence to 4 or more days a week was observed in the transition cohort (P = 0.047, LR 4.668) and the presence of the transition program was independently associated with the improvement. A trend towards improvement or maintenance of ≥ 90% attendance to appointments was observed (P = 0.096, OR 2.254). Variations in appointment attendance can be explained by patient's age, distance from the comprehensive hemoglobinopathy center, and English as patient's first language. No independent predictor was found in frequency of hospitalization. No new overt strokes or deaths occurred in the year after moving to the adult center. Conclusions: Comprehensive structured transition program with dedicated transition navigator significantly reduced the number of AYA lost to follow-up, and significantly improved and maintained fair to good medication adherence. Further analysis of economic benefit and patient satisfaction will be conducted. A clustered randomized-controlled trial will be forthcoming to determine the effectiveness of this transition model of care on AYA patients with sickle cell disease on patient-important outcomes. Disclosures Allemang: Novartis: Other: Funding for the transition navigator program; ApoPharma: Other: Funding for the transition navigator program; Sickkids Foundation: Other: Funding for the transition navigator program. Kuo:Apotex: Other: Unrestricted education grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.


HLA ◽  
2017 ◽  
Vol 90 (4) ◽  
pp. 211-218 ◽  
Author(s):  
M. C. F. da Silva-Malta ◽  
P. S. Rodrigues ◽  
L. W. Zuccherato ◽  
F. C. B. de Souza ◽  
E. M. F. L. Domingues ◽  
...  

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4054-4054
Author(s):  
Ofelia A. Alvarez ◽  
Tally Hustace ◽  
Emmeline Lerebours ◽  
Nora St Victor Dely ◽  
Rony Saint Fleur ◽  
...  

Abstract Background: There are significant limitations in Haiti for the diagnosis and management of sickle cell disease (SCD), including the non-availability of universal newborn screening (NBS) and transcranial Doppler (TCD) ultrasound screening, and the lack of diagnostic laboratory resources, oral penicillin and hydroxyurea (HU). Methods: Beginning in September 2019, CSHSCD (R01HL149121), a 5-year NIH-sponsored observational comparative study of children with SCD from Haitian ethnicity in Miami and in Haiti compared to children of African American ethnicity with SCD, was designed to increase access to care in Haiti. The study aims are 1) to compare the incidence of SCD among newborns from Haitian and African American ethnicity in Miami, 2) to establish NBS programs for hemoglobinopathies in Haiti, and 3) to compare cohorts of children in SCD at the study sites. The participating sites are the University of Miami (UM, Miami, Florida), Hôpital Saint Damien (HSD, Tabarre, Haiti), Hôpital de l'Université d'Etat d'Haïti (HUEH, Port-au-Prince, Haiti), Hôpital Universitaire Justinien (HUJ, Cap Haitien, Haiti), and Hôpital Sacré Coeur (HSC, Milot, Haiti). HUJ and HSC use two NBS screening methods (isoelectric focusing and Sickle SCAN rapid test) and HSD and HUEH use isoelectric focusing only. CSHSCD supplies penicillin and HU and trains TCD examiners to implement stroke risk screening. Data are collected in REDCap. Results: During the first 2 years and despite the COVID-19 pandemic, we established NBS sites with a cohesive network of physicians and nurses trained in the care of children with SCD in Haiti. This capacity building will support sustainability of the program. We successfully identified at least 15 new cases of SCD via newborn screening, trained six TCD examiners, and enrolled 130 children with SCD in follow up, providing them with penicillin prophylaxis and hydroxyurea for severe cases according to local protocols . Implementation activities which have helped are close communications between the investigators, monthly Zoom meetings to coordinate efforts with enrollment updates every month, the availability of rapid tests (Sickle SCAN and Gazelle miniature cellulose acetate electrophoresis) for the diagnosis of SCD, especially when there is no laboratory equipment on site. Implementation challenges we have faced are mostly two. The first is the timely completion of DUNS and SAM registration for the two public hospitals, with one site achieving this after 9 months and the other site taking 18 months to complete. The reasons for the delay are the inability for the UM site to direct these efforts, following strict rules, and the Haitian hospital officers' lack of familiarity with website requirements. We were able to achieve these registrations with the assistance of one Haitian study staff who is very acquainted with internet navigation and became familiarized with requirements. Outsourcing materials to Haiti is another major challenge, with either gaps in the delivery of supplies because of multiple steps involved in ordering and shipping or with delays in releasing equipment once it is at the Port-au-Prince customs, resulting in gaps in NBS in one of the sites for 8 weeks. We have minimized these issues by opening a one-year ticket to order materials from the different companies involved. Also, Haiti's lack of infrastructure, available materials and medications, and political instability limit health care delivery. Conclusion: Since its inception, we have achieved major milestones, including capacity building and implementation of NBS, TCD training, and enrollment of children with SCD into the prospective cohorts despite the current COVID-19 pandemic. Material outsourcing challenges have been the major implementation problem we have faced due to systemic factors. We anticipate that these factors will be corrected or minimized as we have learned how to handle them. These problems were expected as part of conducting an international study in a low-resource setting. Acknowledgment: We acknowledge NHLBI for supporting this work. Disclosures Alvarez: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; GBT: Membership on an entity's Board of Directors or advisory committees. Romano: Genentech: Research Funding; Vycor: Current holder of individual stocks in a privately-held company; NovaVision: Consultancy.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 955-955
Author(s):  
Cristiane Maria de Souza ◽  
Carolina Lanaro ◽  
Irene Pereira dos Santos ◽  
Oladele Olatunya ◽  
Sara T Olalla Saad ◽  
...  

Abstract Extracellular vesicles (EVs) are submicron structures released in blood circulation by different cell types which have been found to be increased in sickle cell disease (SCD) and are associated with clinical complications. The most abundant EVs in SCD patients derive from platelets, endothelial cells, and red blood cells (RBCs) and EVs have been explored as biomarkers of clinical severity. Crizanlizumab is a monoclonal antibody against P-selectin, an adhesion molecule expressed in activated platelets and endothelial cells. P-selectin facilitates the formation of heterocellular aggregates and is implicated in the pathophysiology of vaso-occlusive episodes (VOEs) in SCD. This study aimed to investigate the circulating levels of EVs in patients with SCD on standard of care or treated with crizanlizumab. We collected peripheral blood samples from 20 adults with SCD (Non treated group: 7 patients on hydroxyurea treatment and 7 without it. Treated group: 6 patients undergoing treatment with crizanlizumab in combination with hydroxyurea). Patients received the last dose of crizanlizumab at least a month prior to the study. EVs were identified by lactadherin+calcein stain and quantified by flow cytometry to determine the immunophenotype of their parent cell (platelet, endothelial cell, and RBC, with CD41+; CD146+/CD45-; CD235+, respectively). EV quantification was calculated in number per ml of blood as previously described by our group (Olatunya et al., 2019). We found that patients on crizanlizumab had lower total circulating EV counts than patients not receiving the drug (62.670.000,00 ± 15.600.000,00 vs 13.100.000,00 ± 3.513.000,00/mL, respectively, p=0,0076). The difference was statistically significant in platelet-derived EVs levels (5.397.000,00 ± 953.875,00 vs 2.413.000,00 ± 745.165,00/mL, p=0,0169), but not in endothelium-derived or RBC-derived EVs (345714 ± 101817 vs 220000 ± 64291, and 2.189.000,00 ± 1.648.000,00 vs 1.013.000,00 ± 572775, respectively). Crizanlizumab therapy has been shown to reduce the incidence of VOEs in SCD. EVs have been recognized as bio-effectors involved in VOEs, contributing to a hypercoagulable state, chronic inflammation, and endothelial damage. Our findings show an association between the use of crizanlizumab and lower EV levels, particularly of the platelet-derived type. While the anti-P-selectin activity of crizanlizumab could be expected to help remove platelets from circulation, clinical studies have not reported a reduction in platelet counts in patients treated with crizanlizumab. Therefore, we speculate that crizanlizumab may decrease the release of EV by activated platelets, reduce platelet activation, or contribute to EV removal from circulation. Our findings suggest that crizanlizumab therapy may modulate EV levels in the plasma of SCD patients and provide, for the first time, data to support exploring the use of extracellular vesicles as biomarkers to monitor the clinical response to this drug in patients. Further studies on EV expression of P-selectin and how crizanlizumab interacts with EVs and platelets may help clarify this particular effect of this drug. Disclosures Benites: Novartis: Honoraria. Fertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Costa: Novartis: Consultancy.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Mitchell Knisely ◽  
Liliana Preiss ◽  
Eleanor Stevenson ◽  
...  

Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight academic and comprehensive SCD centers, and one data-coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p <0.0001) were taking hydroxyurea. Females had significantly worse reports of pain frequency and severity (p=0.0002 and <0.0001 respectively), more vaso-occlusive episodes (p=0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9 % vs. 25.5, p= 0.03). Males had significantly more skin ulcers and respiratory, musculoskeletal, genitourinary and cardiovascular complications while females had more anxiety, depression and autoimmune conditions. Males also had significantly higher creatinine, blood urea nitrogen, albumin and liver enzymes (alkaline phosphatase, aspartate and alanine aminotransferases). Females had higher fetal hemoglobin levels with and without hydroxyurea use. There were no statistical differences in ethnicity, marital and employment status. Conclusion Key differences in SCD presentation and occurrence of complications exist among males and females. Females had higher rates of depression and anxiety while males had more chronic end-organ complications that are life threatening. Our findings emphasize the need for stratification of data analysis by sex in future SCD studies. Disclosures Hankins: Global Blood Therapeutics: Consultancy, Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; Novartis: Research Funding. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy. King:Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company; RiverVest: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees. Glassberg:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy. Shah:Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau.


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