Autoantibody Formation and Alloimunization in Sickle Cell Disease Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4099-4099
Author(s):  
Marcia C.Z. Novaretti ◽  
Eduardo Jens ◽  
Thiago Pagliarini ◽  
Andreia L. Rodrigues ◽  
Pedro E. Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Study Group ◽  
Cell Disease ◽  
The One ◽  
Design And Methods ◽  
The Impact ◽  
Transfusion History ◽  
Autoantibody Formation

Abstract Background: Alloantibody and autoantibody formation to red blood cell (RBC) antigens is one of the observed complications in sickle cell disease patients (SCD). The incidence of alloimmunization and autoantibodies in this selected group of patients is particularly high, although the clinical implication of autoantibodies in sickle cell disease patients is not clear. The purpose of this study is to evaluate the rate of alloantibody and autoantibody formation in SCD patients. Study design and methods: A retrospective analysis of transfused sickle cell disease patients followed at Fundacao Pro-Sangue Hemocentro de Sao Paulo between 1988 and 2004 were retrieved. Data on transfusion history, were correlated with development of alloantibodies and autoantibodies. Results: The study group was composed by 43 sickle cell disease patients followed for a mean of 89 months (22–116). The number of RBC units transfused (mean) was 64 (4–208). The development of the first alloantibody was detected after a mean of 40 months (1–107) after the first transfusion in our institution. Out of these patients, 31 (72.1%) were identified with RBC alloantibodies; 9 of these patients (21%) had both allo and autoantibodies to RBC antigens, whereas 5 (55.6%) developed autoantibodies after alloimmunization. The one remainder had only autoantibodies. Conclusion: The alloimmunization rate was extremely high (72.1%) and can be partially explained because of the extended time of follow-up (mean of 89 months). Different from the literature the development of autoantibodies preceeded alloantibodies in 44.4%. The impact of this observation in clinical practice warrants further investigation.

Transcranial Doppler Screening Program Is Effective in Preventing Stroke in Children with Sickle Cell Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 714-714 ◽  
Author(s):  
Henrietta Enninful-Eghan ◽  
Renee H Moore ◽  
Rebecca Ichord ◽  
Janet L Kwiatkowski
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Transcranial Doppler ◽  
Screening Program ◽  
Treatment Protocol ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
Neurological Event ◽  
The Impact

Abstract In the Cooperative Study of Sickle Cell Disease the incidence of stroke in SCD-SS was estimated to be 0.61 per 100 patient-years. Since that study, the use of transcranial Doppler ultrasonography (TCD) has become routine to detect children at high risk of stroke and regular transfusions have been shown to reduce the risk of stroke by over 95% in those with abnormal TCD studies. The impact of TCD screening on the overall incidence of stroke in children with SCD has not been studied extensively. We sought to determine the impact of our TCD screening and treatment protocol on the incidence of first stroke in a cohort of children followed at our Sickle Cell Center. Routine TCD screening was instituted at our Center in Oct, 1998. Our protocol includes annual TCD studies for children with normal TCD results (<170 cm/s), repeat study every 3 to 6 months in those with conditional results (170–199 cm/s), and within 1–4 weeks for children with abnormal results (≥200 cm/s). Chronic transfusion therapy is recommended for patients with confirmed abnormal TCD velocities. In the current study, the rate of stroke in the 8-y period prior to TCD screening (Sept 1, 1990-Aug 31, 1998 – Pre-TCD) was compared to the rate in the 8-y period after TCD screening began (Sept 1, 1998 – Aug 31, 2006 – Post TCD). Eligible subjects were patients less than 22 years old with a diagnosis of SCD-SS or SCD-Sβ0-thalassemia. Subjects with a history of stroke prior to Sept, 1990 or before enrollment in our Center were excluded. Cases of stroke or other neurological event were identified from our clinical database. The study neurologist reviewed all clinical data and radiological studies for each neurological event and classified events into one of the following categories: overt stroke - ischemic (neurological deficit conforming to a vascular territory with neuroimaging studies corresponding to the clinical deficit) or hemorrhagic not overt stroke (other neurological event), and indeterminate. Incidence rates for stroke were calculated and compared between the Pre and Post TCD groups using a test of binomial proportions. Subjects were followed until they had a stroke or neurological event, turned 22 years old, the end of the 8-y period or until the last clinic date. The pre-TCD group included 475 children with a total follow-up time of 3,137 person-years. Twenty-one patients had overt stroke, 3 had other neurologic events (1-seizure, 1-transient ischemic attack/syncope, 1-behavioral changes) and 2 were indeterminate. The post-TCD group included 530 children with 3,578 person-years follow-up. Two patients had overt stroke, 6 had other neurological events [1-diffuse encephalopathy with viral syndrome, 1-febrile seizure, 3-dizzy and/or syncope (one with hgb=2.7), 1-headache with <30 min arm/leg weakness – all with acute punctate infarcts whose location did not correspond to clinical presentation], and 1 was indeterminate. The incidence of overt stroke in the pre-TCD period was 0.67 per 100 person-years, compared with an incidence of 0.06 per 100 person-years in the post-TCD period (p < 0.001). The first stroke case in the post-TCD period was a 3.4 year-old with ACA velocities > 200 cm/s but no abnormal velocities in the ICA/MCA and the second occurred in a 1.2 year-old, prior to the age that screening is started. Thus, our TCD screening and treatment program has been successful in reducing the rate of first overt stroke, although small vessel ischemia, particularly in the setting of an additional insult such as severe anemia, may not be prevented. Further modifications such as the addition of ACA velocity to treatment criteria, earlier screening, or the addition of other neuroimaging studies might further reduce the risk of first stroke.

Declining stroke rates in Californian children with sickle cell disease

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 336-339 ◽  
Author(s):  
Heather J. Fullerton ◽  
Robert J. Adams ◽  
Shoujun Zhao ◽  
S. Claiborne Johnston
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Stroke Prevention ◽  
Incidence Rates ◽  
Cell Disease ◽  
Stroke Incidence ◽  
The Impact ◽  
Discharge Database ◽  
High Risk Children

Abstract Although the Stroke Prevention Trial in Sickle Cell Anemia (STOP) demonstrated the efficacy of blood transfusions for primary stroke prevention in high-risk children with sickle cell disease (SCD) in 1998, the impact of this trial on public health has not been studied. Our objective was to determine whether stroke rates in Californian children with SCD have declined since 1998. Using a California-wide hospital discharge database, we identified all first admissions for stroke in children with SCD from 1991 through 2000. Annual stroke incidence rates were calculated as the number of admissions divided by the estimated population of Californian children with SCD in that year. For 1991-2000, 93 children with SCD were admitted to Californian hospitals with a first stroke during 12 030 person-years of follow-up; 92.5% were ischemic and 7.5% hemorrhagic. Overall, the rate of first stroke was 0.77/100 person-years. For the study years 1991-1998, the rate for first stroke was 0.88/100 person-years compared to 0.50 in 1999 and 0.17 in 2000 (P &lt; .005 for trend). Since the publication of the STOP study in 1998, annual rates of admissions for first stroke for Californian children with SCD have declined. (Blood. 2004;104:336-339)

Arterio-Venous Fistula Is an Applicable Vascular Access for Erythracytapheresis in Patients with Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4856-4856
Author(s):  
Marianne Delville ◽  
Sandra Manceau ◽  
Nassim Ait Abdallah ◽  
Jan Stolba ◽  
Sameh Awad ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Access ◽  
Cell Disease ◽  
Sickle Cells ◽  
Increased Risk ◽  
Before And After ◽  
Venous Fistula ◽  
Transfusion History

Abstract Introduction Erythracytapheresis (ER) can improve outcome in patients with sickle cell disease (SCD). A good vascular access is required but can be difficult to obtain for sickle cells patients. Arterio-venous fistula (AVF) has been suggested for ER in SCD supported by limited evidence. We report the largest cohort of ER performed with AVF from three French sickle cell disease reference centers. Methods Data of SCD patients undergoing ER with AVF in the French SCD reference center were retrospectively collected. The inclusion criteria were: SS or Sβ-Thalassemia and AVF surgery for ER. AVF for hemodialysis were excluded. SCD-related complications, transfusion history, details about AVF surgical procedure, echocardiographic data before and after AVF, AVF-related surgical and hemodynamical complications were collected. Results Twenty-six patients (mean age 20.5 years; median follow-up 68 months [11; 279]) were included. Twenty-three patients (88.5%) required a central vascular access before AVF. Fifteen AVF (58%) were created on the forearm and 11 (42%) on the arm. Nineteen patients (73%) had stenotic, thrombotic or infectious AVF complications. The median AVF lifespan was 34 months [13; 66]. One patient with severe pulmonary hypertension worsened after AVF creation, and died. Conclusions We report the first series of SCD patients with AVF for ER demonstrating AVF could be considered as a potential vascular access for ER. Patients with increased risk for hemodynamic intolerance of AVF must be carefully identified, in order to consider alternative vascular accesses. Disclosures Ribeil: Bluebirdbio: Consultancy; Addmedica: Research Funding.

scholarly journals Impact of TCD Screening Protocol on the Incidence of Hemorrhagic Stroke in Children and Young Adults with Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3402-3402 ◽  
Author(s):  
Julie Kanter ◽  
Janet Kwiatkowski ◽  
Heather J. Fullerton ◽  
Jenifer Voeks ◽  
Ellen Debenham ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Stroke Prevention ◽  
Hemorrhagic Stroke ◽  
Cell Disease ◽  
Increased Risk ◽  
The Mean ◽  
The Impact

Abstract Background: Primary hemorrhagic stroke is a rare complication of sickle cell disease (SCD) that usually occurs in adults. 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 patients with abnormal TCD as standard of care. Despite a notable improvement in the incidence of infarctive stroke in children with SCD after the introduction of TCD screening protocols, it is unclear how this protocol will affect the rate of hemorrhagic stroke. Presumably, early TCD screening and subsequent initiation of CRCT in high risk patients will prevent the progression of cerebral vasculopathy, which should decrease the risk of hemorrhagic stroke; however this has not been proven. Using the large multicenter cohort of children who participated in STOP and/or STOP 2 trials, we sought to assess whether the rate of hemorrhagic stroke was impacted by the use of TCD screening and/or CRCT. 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 3835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 required at least a single screening TCD for randomization. Patients on STOP 2 also had an observational arm for children started on CRCT who had an abnormal TCD. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both of trials. For all participants the date of their last encounter in STOP/2 was defined as the start of their Post-STOP period. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3539 (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 including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two separate neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results adjudicated all suspected strokes. Results: Follow-up data were available for 2850 of the 3539 subjects (81%). Twelve children who had a stroke during the STOP study period were further excluded from this analysis resulting 2838 subjects. The mean age at the start of Post-STOP was 10.5 years and mean duration of follow-up after exiting STOP/2 until time of last medical encounter was 9.1 years. A total of 31 patients had a primary hemorrhagic stroke during the Post-STOP observation period (incidence 0.12 per 100 pt years). The mean age at time of stroke was 16.2+5.6 (median 15.3 range (4.8-30.2) years of age. Of those 31 patients, only 52% had a TCD during Post-STOP prior to the event. Seven of those children who underwent screening had documentation of an abnormal TCD prior to the event (5 during STOP era and/or 3 Post-STOP). However, only 1/7 patients (14%) were documented on CRCT at the time of the stroke (4 patients were receiving HU and 2 patients had unknown treatment). Discussion: Although less common than infarctive stroke, patients with SCD are at increased risk for hemorrhagic stroke. There is an increased risk of mortality for patients who suffer from hemorrhagic stroke (up to 26% in some reports in the 2 weeks after the event). It is unclear if TCD screening and subsequent initiation of CRCT will impact the rate of hemorrhagic stroke in the long term. In our results, a similar incidence of primary hemorrhagic stroke was noted although the patients were overall younger than previously reported (16.5+/- 5.5 years versus 20-29 years in Cooperative Study of Sickle Cell Disease). Many patients who had a hemorrhagic stroke (48%) had not undergone TCD screening during the Post-Stop period. Additionally, although a safe stopping point for CRCT has not been established in patients who have had an abnormal TCD, only 1 patient was documented on CRCT at the time of the event (14%). Thus, it is unclear at this time whether TCD screening and subsequent, lifelong continuation of CRCT could have prevented these other events. Clearly, these results demonstrate that improved implementation of STOP protocol is needed as well as further evaluation of the impact of this protocol on the incidence of hemorrhagic stroke. Disclosures No relevant conflicts of interest to declare.

Evaluation of Treatment Adherence of Sickle Cell Pediatric patients in Use of hydroxyurea

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4757-4757
Author(s):  
Celia M. Campanaro ◽  
Annemeri Livinalli ◽  
Debora Lourenço Souza ◽  
Vanessa Rocha Varizano ◽  
Heder Frank Gianotto Estrela
Keyword(s):  
Sickle Cell Disease ◽  
Treatment Adherence ◽  
Sickle Cell ◽  
Pediatric Patients ◽  
Adherence Rate ◽  
Cell Disease ◽  
Good Adherence ◽  
Short Period ◽  
The Impact

Abstract Abstract 4757 Background: Sickle cell disease is a genetic and chronic disease prevalent in Brazil. It is believed that about 2500 to 3000 brazilians born a year with sickle cell disease. The most common clinical complication is the vessel occlusive crisis, the blockade of microcirculation, sickling of red blood cells, local hypoxia and ischemia of tissues, resulting in acute painful crises. To control this situation, treatment with analgesics, red blood cell transfusion and hydroxyurea (HU) are recommended.The HU administration has shown excellent results through the significant increase in the hemoglobin F levels, thus contributing to decrease in vessel occlusive crises, reducing the frequency of transfusion and potentially preventing organ damage. The treatment adherence is crucial to maintain the serum level of the drug and achieve the best therapeutic results. Adherence is defined as degree of agreement between the person's behavior in relation to guidance provided by physician or other healthcare professional.Several factors influence adherence and understand them allows the professional to develop tools to assist the patient in understanding its importance.The purpose of this study was to quantify the adherence to treatment with HU and identify related causes to non-adherence in pediatric patients with sickle cell disease. METHODS: quantitative, descriptive and retrospective study involving pediatric patients 3 to 18 years seen at GRENDACC- Jundiai-SP.The information was obtained from a questionnaire applied to 19 caregivers and pharmacotherapeutic follow-up recording form (PH) available at the pharmacy for the period from may/2010 to september/2010.PH served as an instrument to measure adherence by the method pill count. Each patient has a form that is filled with information: date and amount of medication dispensed and dosage.At each visit to pharmacy, the caregiver has the bottle for refill and pill count.During the research, the form provided information to apply the formula to verify the adherence rate: quantify dispensed – number on the bottle/treatment period × 100.It was considered a good adherence who have demonstrated a adherence rate of ≥ 90%. RESULTS: The caregivers were represented mostly by mothers (68%).The caregiver's educational level varied from illiterate (1/19), complete or incomplete elementary (10/19), complete or incomplete secondary (7/19) and university (1/19). Asked about the administration of HU, 95% of caregivers reported giving the medication in correct schedule and 42% forgot to give the medicine sometime during the treatment, the reason was accumulation of tasks and concerns with other family members. In the evaluation of adherence 17 PH were viable and showed that 58.8% (10/17) of patients had an rate ≥90%. The lowest rate was 63% and ocurred in only 1 patient. CONCLUSIONS: Although there is no consensus regarding the optimal rate to consider a good adherence, the papers present that rates below 80% is worrying and needs intervention. In the group evaluated, 82% presented more than 80% adherence. Pharmacotherapeutic follow-up allows rapid detection of drug related problems, with immediate intervention through guidance, and if necessary, medical or psychosocial intervention. Although there are few studies about this issue in pediatric patient, the small group of subjects studied and the short period of assessment, we believe the results support the importance of a rigorous monitoring pharmacotherapeutic by visits to pharmacy to follow-up consultations. We suggest further studies with a larger sample and longer period to confirm the importance of monitoring pharmacotherapeutic tool in improving the adherence, evaluate the impact and variables that affect the non-adherence. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Variability of Prognostic Results Based on Biological Parameters in Sickle Cell Disease Cohort Studies in Children: What Should Clinicians Know?

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 143
Author(s):  
Julie Sommet ◽  
Enora Le Roux ◽  
Bérengère Koehl ◽  
Zinedine Haouari ◽  
Damir Mohamed ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Sickle Cell Disease ◽  
Cohort Studies ◽  
Statistical Methods ◽  
Sickle Cell ◽  
Biological Parameters ◽  
Analysis Method ◽  
Cell Disease ◽  
Statistical Analysis Method

Background: Many pediatric studies describe the association between biological parameters (BP) and severity of sickle cell disease (SCD) using different methods to collect or to analyze BP. This article assesses the methods used for collection and subsequent statistical analysis of BP, and how these impact prognostic results in SCD children cohort studies. Methods: Firstly, we identified the collection and statistical methods used in published SCD cohort studies. Secondly, these methods were applied to our cohort of 375 SCD children, to evaluate the association of BP with cerebral vasculopathy (CV). Results: In 16 cohort studies, BP were collected either once or several times during follow-up. The identified methods in the statistical analysis were: (1) one baseline value per patient (2) last known value; (3) mean of all values; (4) modelling of all values in a two-stage approach. Applying these four different statistical methods to our cohort, the results and interpretation of the association between BP and CV were different depending on the method used. Conclusion: The BP prognostic value depends on the chosen statistical analysis method. Appropriate statistical analyses of prognostic factors in cohort studies should be considered and should enable valuable and reproducible conclusions.

scholarly journals Implementation of an Educational Intervention to Optimize Self-Management and Transition Readiness in Adolescents with Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3536-3536
Author(s):  
Cecelia Calhoun ◽  
Regina Abel ◽  
Hai Anh Pham ◽  
Shomari Thompson ◽  
Allison A King
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Psychosocial Development ◽  
Sexual Development ◽  
Independent Living ◽  
Self Management ◽  
Cell Disease ◽  
Adult Care ◽  
Transition Readiness

Abstract Background: The transition from the pediatric setting to adult care is a challenge for many adolescents with chronic disease. Patients with sickle cell disease (SCD) represent a unique cohort as the timing of psychosocial development of adolescence often coincides with worsening end organ damage. Previously, we used the Adolescent Autonomy Checklist (AAC) modified to include SCD specific tasks that patients with SCD need to practice in order to transition to adult healthcare and independent living. This study sought to use the AAC to measure the effects of skill based educational handouts on improving self-management and transition readiness in adolescents with SCD. Methods: This was a single center, retrospective study approved by the Washington University Institutional Review Board. Inclusion criteria were patients with SCD, age 13-21 years, and completion of pre and post assessments. As standard care, patients from a pediatric hematology clinic completed the AAC-SCD. The AAC-SCD assesses skill level in twelve domains (Table). The tool includes 100 items, and users check "can do already" or "needs practice" for each item. After review with the coordinator, participants were given skill-based handouts based on up to five noted deficits. Patients completed the AAC-SCD at the subsequent clinic visit. In addition to baseline and follow up AAC-SCD data, medical and demographic data were collected via chart abstraction. All data were entered into SPSS for statistical analysis, including descriptives, paired sample T-tests, and bivariate Pearson's correlations. Results: A total of 61 patients completed baseline and follow up. Of those participants, 49.2% were female. The mean age was 15.4 (+ 2.2) years. The genotypic distribution was as follows: 67.2% HbSS, 19.7% HbSC, 3.3% HbS-beta-thal+ and 9.8% HbS-beta-thal0. The majority of patients received healthcare coverage via Medicaid (52.5%), private insurance (45.6%) and 1.6% had no insurance coverage. Twenty-five patients (42.0 %) had a history of stroke or silent cerebral infarct and 34 (55.7%) were currently taking or were previously prescribed hydroxyurea. Formal academic support (IEP or 504 Plan) was reported for 20 (32.8%) of patients. At baseline, patients needed the most help with skills in the kitchen, housekeeping, personal care and leisure. Statistically significant improvements (p< 0.05) occurred in skills related to laundry, housekeeping, healthcare, sexual development and living arrangements. Modest sized and statistically significant correlation between the receipt of the educational handouts and decreased number of items marked "needs help" occurred in the areas of money management (r=-0.27, p=0.044), vocational skills (r=-0.27, p=0.046;) and laundry (r=0.32, p=0.015). A post hoc analysis by age groups 13-15 (n= 34),16-18 (n=24) and 19-21 (n=3) showed a decreased amount of items marked "needs help" in the areas of sexual development for both 13-15 year olds (r=0.42, p=0.024) and 16-18 year olds (r=0.93, p=0.001) as well. Conclusion: Transition skills improved over time among adolescents with SCD. While we cannot say for certain if gains in knowledge occur with age as development progresses or if a formal transition program can be credited, providing educational materials on transition related skills within a clinic setting was associated with significant improvements in three of the domains. Our preliminary data offers insight into what skill deficits may be most amenable to educational interventions based on age group. As is the case with medical management, the development of a multimodal intervention is needed to prepare adolescents with SCD to transition to adult care and independent living. Clinic based education is a simple intervention that could be one component of future approaches to transition. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Sickle Cell Disease Model Mice Lacking 2,3-Dpg Show Reduced RBC Sickling and Improvements in Markers of Hemolytic Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Kelly M. Knee ◽  
Amey Barakat ◽  
Lindsay Tomlinson ◽  
Lila Ramaiah ◽  
Zane Wenzel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Organ Damage ◽  
Complete Elimination ◽  
Cell Disease ◽  
The Impact ◽  
2,3 Dpg

Sickle cell disease (SCD) is a severe genetic disorder caused by a mutation in hemoglobin (b6Glu-Val), which allows the mutant hemoglobin to assemble into long polymers when deoxygenated. Over time, these polymers build up and deform red blood cells, leading to hemolytic anemia, vaso-occlusion, and end organ damage. A number of recent therapies for SCD have focused on modulating the mutant hemoglobin directly, however, reduction or elimination of 2,3-DPG to reduce Hb S polymerization and RBC sickling has recently been proposed as a therapeutic strategy for SCD. Current clinical studies focus on activation of pyruvate kinase to reduce 2,3-DPG, however, direct targeting of the enzyme which produces 2,3-DPG; Bisphosphoglycerate Mutase (BPGM) may also be possible. In this study we evaluate the impact of elimination of 2,3-DPG on SCD pathology by complete knockout of BPGM in Townes model mice. Animals with complete knockout of BPGM (BPGM -/-) have no detectable 2,3-DPG, while animals that are heterozygous for BPGM (BPGM -/+) have 2,3-DPG levels comparable to Townes mice. Western Blot analysis confirms that BPGM -/- animals completely lack BPGM, while BPGM -/+ animals have BPGM levels that are nearly equivalent to Townes mice. As expected from the lack of 2,3-DPG, BPGM -/- animals have increased oxygen affinity, observed as a 39% decrease in p50 relative to Townes mice. Complete elimination of 2,3-DPG has significant effects on markers of hemolytic anemia in BPGM -/- mice. Mice lacking 2,3-DPG have a 60% increase in hemoglobin (3.7 g/dL), a 53% increase in red blood cell count, and a 29% increase in hematocrit relative to Townes mice. The BPGM -/- mice also have a 57% decrease in reticulocytes, and a 61% decrease in spleen weight relative to Townes animals, consistent with decreased extramedullary hematopoiesis. Consistent with the reduction in hemolysis, BPGM -/- animals had a 59% reduction in red blood cell sickling under robust hypoxic conditions. BPGM -/+ animals had hemoglobin, RBC, and hematocrit levels that were similar to Townes animals, and a similar degree of RBC sickling to Townes mice. Liver phenotype was similar across all variants, with areas of random necrosis observed in BPGM -/-, BPGM -/+ and Townes mice. Higher percentages of microcytic and/or hyperchromic RBCs were observed in BPGM -/- animals relative to BPGM -/+ or Townes animals. These results suggest that modulation of 2,3-DPG has a positive effect on RBC sickling and hemolytic anemia, which may have therapeutic benefits for SCD patients. However, the lack of improvement in organ damage suggests that modulation of 2,3-DPG alone may not be sufficient for complete elimination of SCD phenotypes, and further investigation of this therapeutic avenue may be necessary. Disclosures No relevant conflicts of interest to declare.

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