scholarly journals Real-World Clinical Burden of Sickle Cell Disease in the US Community-Practice Setting: A Single-Center Experience from the Foundation for Sickle Cell Disease Research

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5856-5856
Author(s):  
Lanetta Bronté-Hall ◽  
Matthew Parkin ◽  
Courtney Green ◽  
Elsa Tchouambou ◽  
Lynn Huynh ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Real World ◽  
Research Funding ◽  
Organ Damage ◽  
Community Practice ◽  
Cell Disease ◽  
End Organ Damage ◽  
The Mean

Background Sickle cell disease (SCD) is a progressively debilitating monogenic disease characterized by unpredictable, acute, life-threatening episodes and chronic complications such as hemolytic anemia and end-organ damage. It presents with a range of severity resulting in significant morbidity, poor quality of life, and early mortality. Real-world data on treatments and clinical outcomes for patients (pts) with SCD are limited, particularly in the community clinical care setting. The objectives of this retrospective real-world study were to characterize clinical manifestations and management of pts with SCD treated at the Foundation for Sickle Cell Disease Research (FSCDR). Methods A retrospective longitudinal analysis of an electronic health records (EHR) database from the FSCDR, which captured laboratory testing, treatments, and records on outpatient, emergency, and inpatient visits, was conducted. All unique pts with SCD assigned a medical record number in the EHR (N=172) were considered. Data from external records were manually entered into the EHR to supplement the EHR database. To address limitations of a real-world database, medical records for all pts included were manually reviewed and validation was performed on 10% of the sample. Pt demographics, clinical characteristics, hydroxyurea (HU) treatment (as captured by prescriptions and usage notes), administration of red blood cell transfusions, vaso-occlusive crisis (VOC) events and acute chest syndrome (ACS) (based on physician assessment) were described. Annual VOC rates were summarized by dividing the number of events by the total follow-up duration in years. Results In total, 122 pts with SCD were included. Twenty-three pts were excluded as they were not actively seeking care and/or had no relevant clinical data from 01/01/15-07/19/19. Data for 27 pts <22 years of age were unavailable at time of analysis (results of this cohort will be included in the presentation). Among all pts, 76 (62.3%) were female and 118 (96.7%) were Black or African American. The mean age at time of analysis was 39.1 (standard deviation [SD] 12.3) years with 9 (7.4%) 22-24 year-olds, 67 (54.9%) 25-40 year-olds, 35 (28.7%) 41-55 year-olds, and 11 (9.0%) ≥ 56 year-olds. The most common genotypes were HbSS (77.0%) and HbSC (17.2%). Over a mean follow-up period of 2.9 (interquartile range: 2.0, 4.4) years, 27 (22.1%) pts were treated with HU and 66 (54.1%) pts received transfusions, of which 1 (1.5%) pt chronically received episodic transfusions (i.e., continuous monthly transfusions for ≥ 6 months). The mean total hemoglobin (Hb) was 8.3 (SD 1.7) for HbSS pts and 10.9 (SD 1.5) for HbSC pts. Among pts who never received HU or transfusions during follow-up, mean Hb was 9.4 (SD 1.7) for HbSS pts and 11.4 (SD 1.6) for HbSC pts. Among pts who ever received HU or transfusions, mean Hb was 7.7 (SD 1.3) for HbSS pts and 10.3 (SD 1.1) for HbSC pts. Eleven (9.0%) pts had ≥ 1 ACS whereas 97 (79.5%) pts had ≥ 1 VOC event. ACS and VOC events occurred mostly in pts 25-55 years of age (ACS: 9 [81.8%] pts aged 25-40 years and 2 [18.2%] pts aged 41-55 years; VOC: 54 [55.7%] pts aged 25-40 years and 29 [29.9%] pts aged 41-55 years). Annual rates of VOC are described in Figure 1. Conclusions This is one of the first studies to describe clinical characteristics and management of pts with SCD in a community practice setting. Higher Hb levels among pts who never vs ever received HU or transfusions during follow-up may be a reflection of who were selected for treatment and additional studies to take into account timing of treatment and Hb assessments and confounding factors need to be conducted. The study found high VOC rates particularly among pts aged ≤ 40 years. Lower VOC rates among older pts do not necessarily indicate less severe disease. One potential reason for lower VOC rates among older pts with SCD is that cumulative exposure to ischemia-related tissue injury and resulting end organ damage may decrease VOC-related pain over time. Further investigation to elucidate the rate of VOC decline observed in older pts is needed, including looking at underlying health and end organ damage. While limitations are inherent in real-world studies, these findings underlie the ability to and importance of studying SCD management and clinical outcomes in community care settings. This study highlights the clinical burden of SCD and possibly higher than expected unmet need in this community setting. Disclosures Bronté-Hall: bluebird bio: Research Funding. Huynh:bluebird bio: Research Funding. Puri-Sharma:bluebird bio: Employment. Chang:bluebird bio: Research Funding. Chawla:bluebird bio: Employment. Signorovitch:bluebird bio: Research Funding.

scholarly journals Impact of Alloimmunization in Patients with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3251-3251
Author(s):  
Dipanjan Debnath ◽  
Hedy P Smith ◽  
Cathy Conry-Cantilena ◽  
Valentina Baez Sosa
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Health System ◽  
Sickle Cell ◽  
Organ Damage ◽  
Cell Disease ◽  
Academic Health ◽  
End Organ Damage ◽  
The Mean

Abstract INTRODUCTION Blood transfusion is an essential therapeutic and prophylactic component in the management of sickle cell disease (SCD) and associated complications. Prolonged transfusion therapy can lead to the development of antibodies to the donor's RBC antigens (alloimmunization), causing complications such as delayed hemolytic transfusion reactions, hyperhemolysis, worsening vaso-occlusive episodes, and end-organ damage. There have been only a few case series highlighting the impact of RBC alloimmunization on SCD morbidity and mortality, proposing a pathway involving RBC alloimmunization and decreased survival associated with hemolytic reactions or difficulty obtaining compatible blood when needed. However, apart from the consequences of iron overload, there is no long-term data for alloimmunization highlighting the clinical consequences, multiorgan damage, or associated morbidity in sickle cell patients. AIM The primary aim is to investigate the incidence of alloimmunization in SCD patients in an academic health system. The secondary aim is to elucidate the differences in demographics, frequency of vaso-occlusive crisis, end-organ damage, and inflammatory markers between alloimmunized and non-alloimmunized SCD patients. METHODS We conducted a retrospective multicentric descriptive study, including all sickle cell patients treated in an academic health system from January 1st, 2009, to December 31st, 2020, in Maryland, Virginia, and Washington, DC. An exemption from the Institutional Review Board for obtaining individual subjects' consent was procured. Patients included in the study were older than 18 years and diagnosed with sickle cell disease. Patients who did not have sickle cell disease were excluded from the study. Statistical analysis was reported using means for descriptive data, t-test for continuous variables, and chi-square for categorical variables. RESULTS A total of 94 patients with sickle cell disease were included in the study. Of these, 24 (25.5%) patients were found to have alloimmunization, whereas 70 (74.4%) patients did not. Of the alloimmunized patients, the average age, BMI and BSA were 30.15 years (p=0.037), 23.15 kg/m2 (p=0.040), and 1.65 m2 (p=0.003) compared to 37.07 years, 26.17 kg/m2 and, 1.84 m2 respectively among the non-alloimmunized group. 83% of the alloimmunized patients had sickle cell anemia (Hb SS), and 17% had a sickle thalassemia phenotype (p=0.005). A lower baseline hemoglobin (Hb) value of 8.01 g/dL was seen among alloimmunized patients compared to a higher Hb value of 9.63 g/dL (p=0.001) among the non-alloimmunized. Alloimmunized patients had an average of 5.55 alloantibodies. The average number of vaso-occlusive crises per year and related hospitalizations was statistically significantly higher in the alloimmunized group with 4.82 and 3.78, respectively, compared to 2.34 (p=0.035) 1.01 (p=0.0005) in the non-alloimmunized group. Similarly, the incidence of other sickle cell-related complications were higher among the alloimmunized patients, such as priapism (29% vs. 9%; p=0.0139), pulmonary hypertension (38% vs. 9%; p=0.0038) with no statistical difference in the iron overload (25% vs. 11%; p=0.150) or ferritin levels (. 83% of alloimmunized patients had a history of narcotic use vs. 34% among the non-alloimmunized (p=0.0001). Higher use of disease-modifying therapies including hydroxyurea (71% vs. 31%; p=0.0009) and voxelotor (13%vs0; p=0.0029), were also seen among alloimmunized patients. While no statistically significant difference was seen in the mean number of lifetime transfusions, there was a difference in the mean number of lifetime exchanges (3.67 vs. 0.0; p=0.0208). CONCLUSION The prevalence of alloimmunization in sickle cell patients in our study population (25.5%) was higher than in the literature (7- 59%) and the general population (2%). An increase in alloimmunization was associated with an increased number of exchanges but not with simple transfusions. Independent from the iron overload, alloimmunization was associated with increasing end-organ damage and sickle cell complications such as priapism, pulmonary hypertension. Strategies to decrease alloimmunization are needed to prevent these complications. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Single Institution Study of Chronic Erythrocytapheresis for Secondary Stroke Prevention in Children and Young Adults with Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4754-4754
Author(s):  
Nadia L Cheek ◽  
Robert L Saylors ◽  
Raghu Ramakrishnaiah ◽  
Suzanne Saccente ◽  
Xinyu Tang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Stroke Prevention ◽  
Organ Damage ◽  
Secondary Stroke Prevention ◽  
Cell Disease ◽  
End Organ Damage ◽  
Children And Young Adults ◽  
The Mean

Abstract Abstract 4754 Introduction: The current standard of care for secondary stroke prevention in children and young adults with sickle cell disease and cerebral infarction is chronic simple transfusion (ST). Published data indicate that at least 18% of patients treated with chronic ST will experience a second overt infarct and at least 28% will experience additional silent infarcts. Since 1996, we have used chronic erythrocytapheresis (RCE) instead of chronic ST in our hospital to treat all patients with either overt infarction or abnormal transcranial doppler (TCD) with silent infarction. Here we present clinical, radiographic, and laboratory data from this group of patients treated with chronic RCE for secondary stroke prevention. Methods: This was a retrospective study of all patients treated with chronic RCE for either overt infarction or for an abnormal TCD with silent infarction at Arkansas Children's Hospital from 1996 through 2011. We reviewed clinical records and serial MRI/MRA scans and determined the time to progression from the time of the initial diagnosis of an overt or silent infarct to the time of the second overt or silent infarct. Events were classified as overt infarcts if the MRI demonstrated acute cerebral ischemia, based on increased signal intensity on T2-weighted images and restricted diffusion on diffusion-weighted images, and abnormal neurologic findings correlated with the abnormalities identified on MRI. Events were classified as silent infarcts if the MRI demonstrated new lesions 3 mm or greater in a single dimension with increased signal intensity on T2-weighted images and there were no corresponding abnormal neurologic findings. We also studied the pre-procedure hemoglobin S concentration (%S), pre-procedure ferritin levels, volume of blood transfused per kilogram, necessity for chelation medication, and presence of end-organ damage. Results: We identified 24 patients, ranging in age from 2 to 18 years at the initiation of chronic RCE, who were treated with 2539 RCE procedures during the study period. These patients were treated with RCE every two to six weeks with the goal of maintaining their pre-RCE %S at less than 30%. Progressive cerebral infarcts occurred in 42% (10 of 24) of the patients while receiving chronic RCE (Figure 1): 3 were overt (13%) and 7 were silent (29%). There were no additional infarcts observed after patients had been on chronic RCE for greater than 5 years. Eight patients (33%) experienced increased vasculopathy and 3 patients (13%) had an improvement in vasculopathy while on therapy. The mean pre-procedure %S concentration was 29%. The mean pre-procedure ferritin was 1188 ng/ml but approximately 60% of the patients had ferritin levels under 1000 ng/ml and only three patients required chelation. Patients received a mean of 45.5 ml/kg of packed red blood cells per procedure. There was no evidence of end-organ damage secondary to iron overload. Discussion: We determined that children with sickle cell disease and cerebral infarction experience additional silent and overt strokes despite intensive treatment with chronic RCE. The proportion of patients developing new overt infarcts in our study (13%) was slightly lower than that in a recent multi-institution study (18%; Hulbert et al, Blood 117:772, 2011) but the proportion of patients developing new silent infarcts in our study (29%) was no different (28%). Although patients receiving RCE have increased blood product utilization as compared with patients receiving ST, only three patients required chelation medication and none experienced end-organ damage secondary to iron overload. We conclude that chronic RCE is no more effective than chronic ST for secondary stroke prevention, that chronic RCE prevents the iron overload and need for chelation that is common with chronic ST, and that other forms of therapy are needed to prevent the progressive accumulation of cerebral infarcts in these patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Economic Burden of End Organ Damage Among Patients with Sickle Cell Disease in the US

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3388-3388
Author(s):  
Xue Song ◽  
Andrew D. Campbell ◽  
Ze Cong ◽  
Irene Agodoa ◽  
Diane Martinez ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Economic Burden ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Index Date ◽  
Organ Damage ◽  
Cell Disease ◽  
End Organ Damage ◽  
Ibm Watson

Introduction Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin polymerization and red blood cell sickling, leading to chronic anemia, hemolysis, and episodic vaso-occlusion. Anemia affects the brain, kidneys and cardiovascular system, and is associated with neurocognitive dysfunction, silent cerebral infarction, stroke, renal dysfunction, pulmonary hypertension, and mortality. Limited research has been conducted to quantify the economic burden of end organ damage among patients with sickle cell disease in the US. Methods Patients with ≥3 nondiagnostic SCD ICD-9/ICD-10 codes within 5 years (Jan 1, 2013-Dec 31, 2017) were identified in the MarketScan® Medicaid claims databases. The first date of SCD diagnosis was the index date. At least three months of continuous enrollment with medical and pharmacy benefits prior to the index date, and at least 1 month of continuous enrollment following the index date were required to be included. Each patient's post-index period was divided into a series of 3-month intervals. For each 3-month interval, patients' entire available claims history (as early as 1/1/2008) was checked to identify four types of end organ damage experienced by SCD patients including stroke (within 1st year and >1 year after an acute stroke event), chronic kidney disease (CKD), end-stage renal disease (ESRD), and pulmonary hypertension (PH). Total healthcare costs (plan paid and patient out-of-pocket payment) and healthcare resource utilization (HRU) information were determined for each 3-month interval. Patient characteristics, HRU, and costs were summarized descriptively by type of end organ damage. Three multivariate generalized linear models with loglink function and gamma error distribution (assuming the cost follows an exponential relationship to the weighted average of covariates) were employed to estimate the relative cost ratios of patients with vs. without end organ damage, controlling for patients' demographic and clinical characteristics. Annualized costs for adult patients with each type of end organ damage were estimated based on the regression results. Results A total of 10,784 patients with SCD on Medicaid were identified. Patients were followed for 3.35 years on average, contributing 152,455 intervals (age ≥18: 42.7%; female: 54.6%; urban: 84.4%). Approximately 20% of the intervals had end organ damage. Patients with end organ damage had more days in hospital, ER visits, outpatient visits, lab tests, and outpatient pharmacy claims per month than patients without organ damage (Figure). The mean (SD) cost per hospitalization for acute stroke was $55,314 ($76, 847). In multivariate regression model 1 (accounting for end organ damage only), patients with any end organ damage had significantly higher costs than those without these conditions. After controlling for patient demographic characteristics (model 2) and additional clinical characteristics (model 3), the results were similar. The costs of SCD patients in the first year after stroke are 4.68 times as high as the costs of patients without any organ damage (2.08 times if >1 yr after stroke; 2.32 times for PH; 2.19 times for CKD; and 3.40 times for ESRD) (Table). The transitional age group (18-30 years) had significantly higher costs than other age groups. Having other SCD complications such as avascular necrosis, gallstones, cholelithiasis, cholecystitis, leg ulcers, osteomyelitis, or priapism also significantly increased the total costs. Based on model 3, after controlling for patient demographics and clinical characteristics, the predicted mean annual costs for adult patients with SCD in the first year after a stroke is $285,816; $127,393 if more than one year after a stroke; $148,174, $135,492, or $209,172 if the patient had PH, CKD or ESRD, respectively. Patients with multiple SCD complications had even higher costs. For example, the predicted mean annual cost for adult patients with CKD and avascular necrosis is $270,513. Conclusions Sickle cell disease is associated with substantial economic burden. When patients experience end organ damage such as stroke, renal dysfunction, or cardiopulmonary conditions, this economic burden is significantly elevated. SCD management strategies that can potentially reduce the risks of end organ damage offer both clinical and economic values to patients and society. Disclosures Song: Global Blood Therapeutics: Other: Xue Song is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Campbell:Cyclerion: Consultancy, Research Funding; Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Martinez:Global Blood Therapeutics: Other: Diane Martinez is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Lew:Global Blood Therapeutics: Other: Carolyn Lew is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Black:Global Blood Therapeutics: Other: Danae Black is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Varker:Global Blood Therapeutics: Other: Helen Varker is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Chan:Global Blood Therapeutics: Other: Chris Chan is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Lanzkron:Pfizer: Research Funding; Ironwood: Research Funding; Global Blood Therapeutics: Research Funding; HRSA: Research Funding; NIH: Research Funding; PCORI: Research Funding.

scholarly journals Ischemic Stroke in Children and Young Adults with Sickle Cell Disease (SCD) in the Post-STOP Era

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 68-68 ◽  
Author(s):  
Janet L. Kwiatkowski ◽  
Julie Kanter ◽  
Heather J. Fullerton ◽  
Jenifer Voeks ◽  
Ellen Debenham ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
High Risk ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Stroke Prevention ◽  
Cell Disease ◽  
Clinical Series ◽  
The Mean

Abstract Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. To identify children at high-risk of stroke, annual TCD screening is recommended from ages 2 to 16 years, with more frequent monitoring if the result is not normal. A reduction in stroke incidence in children with SCD has been reported in several clinical series and analyses utilizing large hospital databases when comparing rates before and after the publication of the STOP study in 1998. We sought to determine the rate of first ischemic stroke in a multicenter cohort of children who had previously participated in the STOP and/or STOP 2 trials and to determine whether these strokes were screening or treatment failures. Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3,835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 ranged from a single screening TCD to randomization. STOP 2 also had an observational arm for children on CRCT for abnormal TCD whose TCD had not reverted to normal. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two vascular neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results, reviewed source records to confirm all ischemic strokes, defined as a symptomatic cerebral infarction; discordant opinions were resolved through discussion. For the first Post-STOP ischemic stroke, prior TCD result and treatment history subsequently were analyzed. Results: Of the 3,539 subjects, follow-up data were available for 2,850 (81%). Twelve children who had a stroke during STOP or STOP2 were excluded from these analyses resulting in data on 2,838 subjects. The mean age at the start of Post-STOP was 10.5 y and mean duration of follow-up after exiting STOP/2 was 9.1 y. A total of 69 first ischemic strokes occurred in the Post-STOP observation period (incidence 0.27 per 100 pt years). The mean age at time of stroke was 14.4±6.2 (median 13.8, range 3.5-28.9) y. Twenty-five of the 69 patients (36%) had documented abnormal TCD (STOP/2 or Post-STOP) prior to the stroke; 15 (60%) were receiving CRCT and 9 (36%) were not (treatment data not available for 1 subject). Among the 44 subjects without documented abnormal TCD, 29 (66%) had not had TCD re-screen in the Post-STOP period prior to the event; 7 of these 29 (24%) were 16 y or older at the start of Post-STOP, which is beyond the recommended screening age. Four of the 44 (9%) patients had inadequate TCD in Post-STOP (1 to 10.7 y prior to event). Six (14%) had normal TCD more than a year before the event (1.2 - 4 y); all but one of these children were younger than 16 y at the time of that TCD. Only 5 (11%) had a documented normal TCD less than 1 year prior to the event. Conclusions: In the Post-STOP era, the rate of first ischemic stroke was substantially lower than that reported in the Cooperative Study of Sickle Cell Disease, prior to implementation of TCD screening. Many (39%) of the Post-STOP ischemic strokes were associated with a failure to re-screen according to current guidelines, while only 11% occurred in children who had had recent low-risk TCD. Among those known to be at high risk prior to stroke, treatment refusal or inadequate treatment may have contributed. While TCD screening and treatment are effective at reducing ischemic stroke in clinical practice, significant gaps in screening and treatment, even at sites experienced in the STOP protocol, remain to be addressed. Closing these gaps should provide yet further reduction of ischemic stroke in SCD. Disclosures No relevant conflicts of interest to declare.

Timing of the Initiation of Hydroxyurea and Hematologic Outcomes in Patients with Sickle Cell Disease (SCD)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1004-1004
Author(s):  
Shaina Willen ◽  
Nirmish Shah ◽  
Courtney Thornburg ◽  
Jennifer Rothman
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Significant Relationship ◽  
Medical Center ◽  
Fetal Hemoglobin ◽  
Clinical Severity ◽  
Cell Disease ◽  
Younger Age ◽  
The Mean

Abstract Abstract 1004 Hydroxyurea (HU) is approved for use in adults with Sickle Cell Disease (SCD) and increases the production of fetal hemoglobin (HbF). Increased HbF is associated with decreased clinical severity in adults and children with SCD, such as decreased numbers of vaso-occlusive events, transfusions, and hospitalizations. Higher HbF at initiation of HU is predictive of HbF response, but association between age of hydroxyurea initiation and HbF response has not been investigated. We hypothesize that starting hydroxyurea at an early age may improve hematological and clinical response. In order to determine if younger age at hydroxyurea initiation affects the percentage of HbF achieved with hydroxyurea, we conducted a retrospective cohort study. We identified subjects enrolled in the Duke University Medical Center Comprehensive Sickle Cell program who initiated hydroxyurea when they were less than 17.99 years of age and were prescribed hydroxyurea for at least six months. The following data were abstracted from the medical record between December 1996 and April 2011: age, hemoglobin, percentage HbF, and mean corpuscular volume (MCV) at start of HU and at maximum tolerated dose (MTD) of HU therapy. The correlation coefficient and p-values for various parameters were calculated. Seventy-three patients (41 males and 32 females) were included in the analysis. The mean age at hydroxyurea initiation was 5.5 years (1.2–14.1). The mean hydroxyurea dose at MTD was 28.6 ± 3.2 mg/kg/day. At initiation, the mean hemoglobin was 8.2 ± 1.2 g/dL, the mean MCV was 83±7.4 fl and mean HbF was 10 ± 5.7%. At MTD, the mean hemoglobin was 9.4 ± 1.1 g/dL, the mean MCV was 99 ± 11.1 fl, and the mean HbF was 21.7 ± 9.4%. As expected, at MTD, an elevated MCV was correlated with elevated fetal hemoglobin (r2= 0.19, p= 0.0001) [Table 1]. There was a statistically significant relationship between the age at HU initiation and the HbF at MTD (r2= 0.08, p= 0.015) [Figure 1] as well as the age at HU initiation and the hemoglobin at MTD (r2= 0.19, p= 0.016). The relationship between the age at starting HU and the overall change in HbF (DHbF) was not statistically significant (r2= 0.01, p= 0.41). There was not a statistically significant relationship between age at HU initiation and the MTD of HU (r2= 0.003, p= 0.61). The 6 patients started on HU at age less than 2 years (mean 1.5 ± 0.3 years) maintained a mean elevated HbF of 19.1 ± 5% at last documented follow-up with follow-up ranging from 1.4–13 year of uninterrupted hydroxyurea use. Starting hydroxyurea therapy at a younger age appears to improve HbF response as measured at MTD, although there is variability in the level of fetal hemoglobin attained. There is not an association seen with the DHbF or dose at MTD and age at hydroxyurea initiation. In summary, starting hydroxyurea at a younger age, when HbF is >20%, leads to persistence of HbF production and overall improvement in hematological efficacy. This was not simply the result of achieving MTD at a younger age before physiologic decline of HbF. Disclosures: Off Label Use: Hydroxyurea for complications of sickle cell disease in pediatrics. Shah:Eisai: Research Funding; Adventrx: Consultancy.

Transfusional Iron Overload In An Adult Sickle Cell Disease Population: Epidemiology, Prevalence, and Management

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1005-1005 ◽  
Author(s):  
James Son ◽  
Hongyan Xu ◽  
Nadine J Barrett ◽  
Leigh G Wells ◽  
Latanya Bowman ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Organ Damage ◽  
Morbidity And Mortality ◽  
Genotype Distribution ◽  
Cell Disease ◽  
The Mean

Abstract Transfusional iron (Fe) overload remains a significant problem among patients with chronic, transfusion dependent anemias, especially in transfusion dependent ß-thalassemia (Thal) syndromes. If not treated vigorously with chelation, Fe overload in Thal is associated with significant organ damage, especially with chronic liver disease and cardiac abnormalities which can contribute to morbidity and mortality. In recent decades, the significance of Fe overload in sickle cell disease (SCD) has also been recognized especially among pediatric patients on chronic transfusion regimens predominantly for primary and secondary prevention of stroke. The prevalence and significance of this problem among adult SCD patients is less clear, although it is widely believed that episodic, mostly unnecessary transfusion practices play a more prominent role in this patient population. There have been reports of an association between iron overload and increased morbidity and mortality among adult SCD patients; it has also been speculated that the chronic inflammatory state that exists in SCD affords some degree of protection against severe organ damage through upregulation of hepcidin and sequestration of Fe in these patients. We performed a retrospective review of 635 adult SCD patients followed at our Center to define and ascertain the epidemiology, prevalence, etiology, and clinical correlates of transfusional Fe overload. Fe overload was defined as two consecutive serum ferritin values of > 1000 ng/ml. 80 patients (12.6%) met this criterion. Of these, 38 were male and 42 were female. Genotype distribution was: 73 SS, 3 S-β+ thal, 2 S-β0 thal and 2 SC. The mean age was 35.9 (range 18-69). Out of the 80 patients with transfusional Fe overload, 24 (30%) were/had been on a chronic transfusion regimen (23 for secondary or primary stroke prevention and one for childhood cardiomyopathy). Seventy percent of the patients (n=56) developed Fe overload from episodic transfusions predominantly performed at outlying community hospitals. The mean highest ferritin value was 4991 ng/ml (range 1,052-16,500). There was no correlation between ferritin levels and the number of hospitalizations or painful episodes (p=0.9). Thirty seven patients (46.2%) had a history of chelation therapy (with desferoxamine, deferasirox, or both). In 25 patients who have been on deferasirox for a period of 6 months or more, serum ferritin levels decreased from 4452.3 to 3876.6 ng/ml (p=0.3239). Our retrospective study shows that transfusional Fe overload is not rare among adults with SCD and develops predominantly as a result of episodic blood transfusions. This underscores the importance of the development and dissemination of evidence based guidelines, especially for episodic transfusions in SCD. A careful study of the extent and degree of organ damage associated with transfusional Fe overload in SCD and why less than half (46.2%) of patients are exposed to chelation therapy needs to be done. These studies should include liver iron concentration (LIC), cardiac iron and liver histology, when indicated, in parallel with serum hepcidin levels. The fact that the reduction in serum ferritin levels with deferasirox did not reach statistical significance in this cohort can be explained by the relatively small number of patients as well as by the short period (6 months) of exposure to chelation therapy. Disclosures: No relevant conflicts of interest to declare.

In Vivo Modeling Of Genetic Mechanisms Associated With Sickle Cell Disease Nephropathy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2224-2224
Author(s):  
Blair R Anderson ◽  
Erica E Davis ◽  
Marilyn J. Telen ◽  
Allison E Ashley-Koch
Keyword(s):  
At Risk ◽  
Sickle Cell Disease ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Organ Damage ◽  
Strong Linkage Disequilibrium ◽  
Wild Type ◽  
Cell Disease ◽  
Gene Suppression ◽  
End Organ Damage

Abstract End-organ damage in patients with sickle cell disease (SCD) has become an emergent clinical priority over recent decades due to the increased lifespan of affected individuals. Renal failure (ESRD), which occurs in 4-12% of SCD patients and is strongly associated with early mortality, has become a particular concern. The detection of SCD nephropathy (SCDN) relies on relatively late markers of the disease process, namely proteinuria and reduced glomerular filtration rate (GFR). Therefore, at-risk SCD patients cannot be identified prior to end-organ damage. A genomic region on human chromosome 22 containing two genes, MYH9 and APOL1, has been associated with non-SCD nephropathy, although the primary gene responsible has remained elusive due to strong linkage disequilibrium in this region. Our group demonstrated that both MYH9 and APOL1 are strong, independent genetic predictors of risk for proteinuria in SCD and interact to affect GFR (Ashley-Koch et al., 2011). We have now used zebrafish as a model to study the contribution of each gene (myh9 and apol1) to kidney function and filtration. To test independent effects of the knockdown of myh9 or apol1, we injected morpholino (MO) antisense oligonucleotides in wild-type zebrafish embryos; this resulted in generalized edema (64% [myh9-MO] and 58% [apol1-MO], both significantly different compared to 3% of control embryos) and reduced glomerular filtration (as measured by quantitative dextran clearance; myh9-MO p=0.047 and apol1-MO p=0.042 when compared to control embryos) for both gene suppression models. Each morphant phenotype was rescued significantly by co-injection of each respective wild type human MYH9 (p=0.001) and APOL1 (p=0.043) mRNA. Importantly, co-injection of human mRNA corresponding to other APOL gene family members did not significantly rescue the observed apol1-MO phenotype, suggesting that apol1 is indeed the functional ortholog to the human gene. Next, we investigated the possibility of a genetic interaction between MYH9 and APOL1 by co-suppression of each of the zebrafish orthologous genes. We observed no additive or synergistic effects due to the co-suppression. Instead, the double morphants were indistinguishable from the myh9 morpholino alone, and neither single morpholino could be rescued by the human mRNA of the other gene. These data suggest that MYH9 and APOL1 may function independently but converge on the same biological process to affect risk of SCDN. In addition to evaluating the effects of candidate gene suppression in wild-type models, we have begun to utilize anemic zebrafish models described previously (Shah et al., 2012). Our preliminary work suggests that the myh9 knockdown phenotype is exacerbated under anemic stress. Ongoing efforts are aimed at identifying novel genetic contributions to SCDN through genome-wide association analysis and exome sequencing of extreme phenotypes in SCD patients, with functional evaluation of putative genetic candidates in our zebrafish model. By offering new insights into the contribution of genes that regulate renal function, these results further our understanding of the pathogenesis of SCDN and may provide genetic markers for the identification of at-risk SCD patients prior to the onset of kidney dysfunction. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Emergency Department Encounters, Hospitalizations and ED Reliance Among Medicaid Eligible Patients with Sickle Cell Disease in North Carolina

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2113-2113
Author(s):  
Paula Tanabe ◽  
Nancy Crego ◽  
Christian Douglas ◽  
Emily Bonnabeau ◽  
Marian Earls ◽  
...  
Keyword(s):  
North Carolina ◽  
Sickle Cell Disease ◽  
Old Age ◽  
Sickle Cell ◽  
Research Funding ◽  
Claims Data ◽  
Age Group ◽  
Cell Disease ◽  
Old Patients ◽  
The Mean

Introduction: Sickle cell disease (SCD) is a complex disease for which pain is the hallmark. Pain from vaso-occlusive episodes is the number one reason for ED visits and hospital admissions. This paper reports Medicaid claims data from NC for individuals with SCD, including: 1) ED encounters and re-encounters within 7, 14 and 30 days; 2) hospitalization and re-hospitalization within 7, 14 and 30 days; and 3) ED reliance (EDR) score. Methods: We examined Medicaid claims data from for patients with a diagnosis of SCD (ICD 9 CM codes: 282.6x, ICD 10 CM codes: D57.0x, D57.1, D57.2x, D57.4x, D57.8x) in North Carolina. Data is reported for a cohort of 2,790 patients with a diagnosis of SCD, age 1 to 65+ and enrolled at least 11 months in NC Medicaid between March 1, 2016 and February 28, 2017. ED re-encounters and re-hospitalizations within 7, 14 and 30 days were identified using the time between the date of service listed on the ED or hospital claim and the next date of service in the subsequent claim. Individual ED Reliance (EDR) score was calculated as the total number of ED encounters divided by the total ambulatory visits (outpatient + ED encounters) per enrollee, (ambulatory visits reported elsewhere). Similar to Kroner et al, an EDR of >0.33 was considered a high score. Inpatient claims were identified using a category of service code indicating hospitalization. Results: The participants in the sample (n=2790) were majority female (57.92%), lived in metropolitan areas (77.63%) and had a mean age of 23.05 years old (SD=16.06). Of the 9,075 total ED encounters, 69.86% of the total sample had an ED encounter during the 12-month study period. There was a mean of 3.25 (SD=7.38) and median of 1 (IQR = 0 - 3) ED encounters per patient for the sample. Those who were 18-30 years old had the highest mean and median ED encounters per patient (4.98, SD= 9.34 and 2, IQR 1 to 5). The 31-45 year old group had the second most, with 4.82 (SD= 11.03) total ED encounters. The percentage of the sample with an ED re-encounter within 7, 14, and 30 days was also highest among the 18-30 year old group (29.17%, 33.98% and 40.89%) followed by those 31-45 years old (23.71%, 28.49%, and 34.80%), respectively. The 31-45 age group had the second most hospitalizations/patient and re-hospitalizations. The mean EDR was highest among 18-30 year old patients (0.35) and 46.48% of this age group had an EDR of 0.33 or greater. In the 31-45 year-old age group, the mean EDR was 0.28 and 35.18% had an EDR of 0.33 or greater. The overall sample had a mean of 1.30 (SD= 2.75) hospitalizations/patient. The 18-30 year old age group also had the highest mean total hospitalizations (2.08, SD= 3.72) and mean re-hospitalizations within 7 (0.16; SD=0.77), 14 (0.41; SD=1.68), and 30 (0.82; SD=2.79) days. The 31-45 age group had the second most hospitalizations/patient and re-hospitalizations (Table 1). Conclusions: Overall, increasing age coincided with increased ED and inpatient utilization, as well as with the period of transition from pediatric to adult SCD care. Furthermore, high EDR was most prevalent in the 18-30 age group. Our study further supports the need for increased focus on acute care utilization in the 18-45 year-old age group and considerations for improved care transition interventions. Disclosures Tanabe: NIH: Research Funding; AHRQ: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; GBT: Research Funding.

scholarly journals Three Months of Human Haptoglobin Treatment Decreases Iron Deposition in the Kidneys of Townes Sickle Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2163-2163
Author(s):  
Patricia A Shi ◽  
Erika Choi ◽  
Julia Nguyen ◽  
Xinhua Guo ◽  
Narla Mohandas ◽  
...  
Keyword(s):  
Treatment Group ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Urine Osmolality ◽  
Organ Damage ◽  
Iron Deposition ◽  
P Value ◽  
Cell Disease ◽  
Old Mice

Abstract Introduction: Haptoglobin (Hp), the scavenger for hemoglobin, and hemopexin (Hx), the scavenger for heme, are depleted in most patients with sickle cell disease due to chronic hemolysis. There is mounting evidence of the crucial role of free hemoglobin and/or free heme in mediating inflammatory and oxidative damage in sickle cell disease, including vaso-occlusion and acute chest syndrome. Purified Hp has been used in Japan for a variety of hemolytic conditions and has been proposed as a potential treatment for sickle cell disease. Although infusions of Hp or Hx have been shown to ameliorate vaso-occlusion, acute lung injury, and heme toxicity in sickle cell mouse models, no prior studies have examined the utility of chronic Hp treatment for amelioration of organ damage. We therefore studied the effect of 3 months of chronic Hp treatment in the Townes sickle mouse model. Methods: Male and female Townes mice (Stock number 013071, The Jackson Laboratory) were used for all experiments, starting at 1 or 3 months of age. SS genotype was confirmed by PCR and HPLC. Organ damage in the spleen, liver, and kidneys as previously described was confirmed. Human Hp solution was a kind gift from Bio Product Laboratory (BPL, Hertfordshire, UK). Hp or equivalent volume PBS control was administered intraperitoneally (IP) in the first cohort of 5 mice and then subcutaneously (SC) in the next two cohorts of 7 and 12 mice on a 48-72 hr dosing schedule of Monday, Wednesday, Friday for a period of 3 months. At the end of 3 months treatment, mice were evaluated by the following studies (with concurrent blinding to treatment group for most studies): plasma Hp (ELISA), plasma heme (QuantiChrom heme assay), urine osmolality (osmometer), urine albumin (ELISA), CBC (Advia 120), WBC differential (Advia 120 and manual count), red blood cell ektacyometry (ektacyometer), organ mass (percent of body weight), and organ histology. Results: Mouse Hp levels in SS Townes mice were confirmed to be markedly low compared to Townes AA mice (mean ± SD: SS 2 ± 1 versus AA 39 ± 4 ug/mL). Dose-finding experiments determined that a dose of 200-400 mg/kg IP or SC in SS mice resulted in a 24 hr peak concentration that was 5-14X supraphysiologic, variably physiologic at 48 hr, and absent or almost absent at 72 hr. Chronic dosing at the 400 mg/kg IP in SA mice showed no CBC or organ toxicity. Three successive cohorts of SS mice were treated with Hp (or equivalent volume of PBS): 200 mg/kg IP in 3-month old mice, 400 mg/kg SC in 3-month old mice, and 400 mg/kg SC in 1-month old mice. At the 400 mg/kg dosing levels, there was a significant decrease in iron deposition in the kidneys of both 4-month and 6-month old mice (treatment started at 1-month and 3 months, respectively) (Table 1). There was also a trend towards decreased liver infarction in 6-month old mice (Table 2). Discussion: Functional binding of the administered human Hp to the human Hb of the Townes mice likely occurred, as evidenced by the decrease in iron deposition in the kidneys, suggesting that formation of the complex prevents filtration of Hb into the kidneys. Surprisingly, kidney function as measured by urine osmolality or albumin excretion was not improved, which may be explained by continued heme-laden red cell microparticle filtration (Camus SM, Blood 2015). Encouragingly, however, a trend towards decreased liver infarction in older mice was observed. The less-than-expected effect of Hp on mouse disease severity may also be explained by: 1) continuous physiologic Hp concentrations not being maintained with the dosing frequency while continued hemolysis releases Hb every minute of the day, and 2) CD163-mediated uptake in mice seems to only account for a part of the Hb clearance as opposed to in humans (Etzerodt A, Antioxid Redox Signal 2013). Despite the limitations of the SCD mouse model, the current study suggests haptogobin infusions could be beneficial in SCD patients. Acknowledgment: The authors are grateful to Sandra Suzuka for performing the HPLC. Table 1. Table 1. Kidney iron deposition (scale 1-10) Treatment group 6-month old SS 4-month old SS 400 mg/kg Hp 4.0 ± 1.4 1 ± 1.1 PBS 9.3 ± 0.6 5 ± 2.9 p-value 0.002 0.02 Table 2. Liver infarction (scale 1-10) Treatment group 6-month old SS 4-month old SS 400 mg/kg Hp 2.6 ± 2.0 3.7 ± 2.8 PBS 6.3 ± 2.4 3.8 ± 2.3 p-value 0.07 0.91 Disclosures Belcher: Biogen Idec: Research Funding; Seattle Genetics: Research Funding; CSL Behring: Research Funding. Vercellotti:CSL Behring: Research Funding; Seattle Genetics: Research Funding; Cydan: Research Funding; Biogen Idec: Research Funding.

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