Background: All patients with HbSS (SCA) share the same genetic mutation but the clinical phenotype is variable and difficult to predict early in life. The only available cure for SCA is hematopoeitic stem cell transplant (HSCT). Early trials of HSCT in SCA patients revealed that SCA patients have higher complication rates which increase with age than other patients undergoing HSCT. If a reliable severity predictor existed, HSCT could be performed in those patients with SCA who are at highest risk of SCA complications prior to the onset of vasculopathy and organ damage. Objectives: The goal of this project was to systematically review the literature to determine which disease severity predictors have been validated in pediatric patients with SCA. Design/Method: A search of PubMed, Cochrane Clinical Trials Register, and Scopus was performed using the following terms: sickle cell anemia or disease, complications, mortality, classification, prognosis, severity of illness, predictive value of test, risk, proportional hazards model, stroke risk, hematopoietic stem transplantation methods. Data were extracted using a standardized data collection form. Results: The full text of 53 of the 590 (9.0%) references identified was reviewed based on the title/abstract. Thirty-three articles (62.3%) are included in this analysis; 20 articles were excluded based on pre-determined exclusion criteria. Fetal hemoglobin (HbF) and alpha globin gene number were the most commonly studied severity predictors (7 studies each) with hemoglobin (6), white blood cell count (5) and absolute reticulocyte count (4) rounding out the top 5 studied predictors in this systematic review. Nearly three quarters (5/7) of the HbF studies reported beneficial effects with increasing HbF levels; however, increased HbF levels were not associated with lower rates of hospitalization or stroke risk in two articles. Increasing ARC was positively associated with increasing risk of cerebro-vascular complications in all 3 of the reports in which it was studied, while alpha thalassemia trait was protective against stroke and abnormal TCD, but not rate of painful crisis. Conclusion: The ability to predict SCA complications was mixed for all studied variables, including HbF. More reliable predictors of disease complications are urgently needed to guide therapeutic decisions in pediatric patients with SCA. Abstract source

Background: Consensus guidelines recommend chronic transfusion therapy (CTT) for stroke prevention in patients with sickle cell disease (SCD) who have a history of overt stroke or abnormal transcranial Doppler (TCD) velocities, typically with the goal of maintaining baseline hemoglobin (Hb) S <30%. Observational studies report considerable variation in Hb S% in children on CTT, but outside of alloimmunization, reasons for such variability have not been well-studied. Objectives: We report the possibility of chronic splenic sequestration as a cause of poor Hb S control in 3 patients with SCD on CTT for stroke prevention and suggest consideration of splenectomy to optimize transfusion parameters in select high-risk children. Design/Method: Patients were ages 7-9 years with Hb SS disease managed with chronic, partial-exchange PRBC transfusions every 3-4 weeks following a standardized institutional protocol with poor Hb S control. Indications for CTT were prior stroke and abnormal TCD. Surveillance magnetic resonance angiography showed progressive CNS vasculopathy. Spleens measured 9.5-13.5 cms. There was no evidence of alloimmunization. After careful consideration, these patients underwent laparoscopic splenectomy. Mean hematologic parameters were compared by paired t-tests 6 months pre and post splenectomy. Results: Prior to splenectomy, mean pre-transfusion Hb was 7.4 gm/dL, reticulocyte count 20.7%, and Hb S 56%. Post splenectomy Hb was 9.5 gm/dL, reticulocyte count 3%, and Hb S 17%. Following splenectomy, there was a mean reduction in Hb S of 39.77% (95% CI 34.3-45.3, p<0.001). With a mean follow-up of 19 months, there were no perioperative or infectious complications. One patient appeared to have reduced iron burden with a mean reduction in baseline serum ferritin of 1,500 ng/mL, perhaps in part because his transfusions were spaced out due to improved Hb S control. Conclusion: This data suggest splenic sequestration may cause shortened red cell survival resulting in suboptimal Hb S control and increased risk of incident or recurrent stroke. Splenectomy may be a reasonable therapeutic option for select high-risk patients. Additional research is warranted into the causes of variable Hb S control in patients with SCD on CTT so that therapeutic options can be refined to reduce the risk of overt stroke. Abstract source

Background: Hemoglobin SOman results from double mutations in the β globin chain; the classic βS mutation (β6 Glu→Val), and a second mutation in the same chain (β121 Glu→Lys) identical to that of HbOArab. In the literature only 6 carriers have been described. HbS-Oman carriers can have severe clinical presentation matching sickle cell disease with frequent vaso-occlusive crises, acute chest syndrome and even cerebrovascular accidents. Objectives: Study the clinical phenotype, genotype and cell biology of both carriers of HbSOman and compound heterozygotes HbS-SOman. Design/Method: A cross sectional study that includes all identified carriers of HbSOman and compound heterozygotes. Demographic and clinical phenotype data were collected, including family pedigrees that were tracked to the same grandmother indicating a founder effect. Hematological parameters and HPLC were performed. β-globin chain haplotypes were done using RFLP. Next generation Exom sequencing for α-globin gene non-deletional mutations, β-gene mutations and other genetic modifiers including AHSP, BCL11a, KLF1, TAL1 and GATA1 was performed. Deletional α-thalassemia mutations were identified using α-gene scan. Samples were processed for non-electrolytic hemolysis test, K+ efflux by using radioactive tracer studies. Results: We identified 53 carriers, 27 males and 26 females and 6 HbS-SOman patients, 4 males and 2 females, age range between 2-75 years. Hemoglobin range was 7.5-14.7 g/dl (11.9+1.6), and SOman 9.5-25.3% (15.9+3.7) for carriers, while Hb ranged from 3.2-7.8 g/dl (5.2+2.4) and SOman 6-24.6% (11.6+6.6) for compound heterozygotes. Clinical severity index correlated with the SOman percent in the carriers with a cut-off value of 14% and with decreased production of α-chains due to deletional or non-deletional mutations; however, there were no such correlations in the compound heterozygotes who presented in early infancy with severe transfusion-dependence. Other genetic modifiers seem to have no effect. Activation of a deoxygenation-induced Cl--independent K+flux, i.e. Psickle-like permeability, a lack of Gardos channel activity and minimal activity of potassium chloride co-transporter was found in SOman carriers. Conclusion: HbSOman is a severe form of SCD; carriers can be severely symptomatic and compound heterozygotes present as thalassemia major with early transfusion dependence. Alpha thalassemia mutation is the main genetic modifier in carriers. SOman cells have increased sickling and hemolytic characteristics. Abstract source

Background: Sickle cell disease (SCD) is a chronic disorder with lifelong effects. Complications include: pain crises, chronic fatigue, organ damage, infections, acute chest syndrome and stroke. Research shows that health related quality of life suffers along with daily activities. Stem cell transplant is an option for eligible patients. Cure by transplant can markedly improve quality of life, but how patients perceive this benefit is not clear. Objectives: The goal of this study was to explore self-reports of the effects of SCD on work or school along with common themes regarding participants’ perspectives on life without SCD. The hypotheses were that patients (1) perceive greater disability of SCD as they age, and (2) recognize that transplant could relieve them of that disability. Design/Method: Mixed methods surveys were administered in person to patients seen at the UI Health Comprehensive Sickle Cell Center hospital, pediatric clinic, or adolescent transition clinic. Participant ages ranged from 10 to 40+. Exclusion criteria were: respiratory or contact isolation or extreme pain. Qualitative responses were examined using thematic analysis. Results: Themes identified by all ages about the effect of SCD on work and school included “Disability,” “School absence,” and “Motivation to disprove odds.” Thematic analysis identified that patients would live their lives differently if cured: “More energy to improve myself,” “New educational goals”, “Career aspirations.” The potential that stem cell transplant would relieve their disability was recognized by nearly all subjects. Older age correlated significantly (P< 0.02) with responses that as relieving their disability, and almost universally the patients would pursue more in their career or education if cured. Conclusion: Advances in transplantation for SCD can achieve cure for adults and often reduces disability from pain. Heightened perception of benefits by adults supports the important role of adult SCD transplant programs. This survey is the first to examine perception of disability among the factors that patients consider in their decision about stem cell transplant for sickle cell. Further, few studies include both adolescent and adult sickle cell patients in a single survey, and this opens the door on age-related differences in perception of stem cell transplantation. Abstract source

Dr. Darbari is a pediatric hematologist consultant at children’s national health system main hospital based in Washington as well as Laurel outpatient center in Maryland. She is engaged with various working departments of the hospital which includes such as Hematology (Blood Disorders), Center for cancer and blood disorders and Comprehensive sickle cell disease program. Dr. Darbari studies complications of sickle cell disease with emphasis on pain. She has been conducting clinical and translational studies directed to better understanding of sickle cell pain and its management. She has published many peer reviewed papers on the subject. Her work was first in the field showing presence of altered brain connectivity in patients with frequent hospitalization for pain.   Representative Publications: A phase 1 dose-finding study of intravenous L-citrulline in sickle cell disease: A potential novel therapy for sickle cell pain crisis Pain-measurement tools in sickle cell disease: Where are we now? Online profile

Dr. Zumberg is recognized as an outstanding clinician-educator in the division of haematology/oncology and the department of medicine. He serves as section chief for benign haematology and holds various medical directorships. He is chairman of the Shands Hospital Transfusion Committee. He is noted as a key clinical faculty member in the internal medicine residency training program and the division of haematology/oncology fellowship program. His clinical interest cover various diseases which includes anaemia, sickle cell anaemia, sickle cell anaemia – resources, sickle cell test, deep vein thrombosis, hemochromatosis, idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia. Dr. Zumberg also provides outpatient, new patient, and follow-up services at the outpatient Davis Cancer Center. He serves as the medical director of Therapeutic Aphaeresis for Lifesouth, the region's blood provider. He is also the medical director for the Shands-UF Outpatient Anticoagulation Clinic. He serves as chairman for the Transfusion Committee at Shands Hospital. His research interests are in ITP, sickle cell disease, and other areas of benign haematology. Online profile

Yogen Saunthararajah, MD, is a staff in the department of Hematologic Oncology and Blood Disorders at Cleveland Clinic, a professor of medicine, and co-leader of the developmental therapeutics program of the Case Comprehensive Cancer Center. His clinical and research interests include acute myeloid leukemia, myelodysplastic syndrome, sickle cell disease/anemia, thalassemia, leukemia, benign hematology, myelodysplasia, cancer, leukopenia, aplastic anemia. Dr. Yogen developed an Epigenetic Platform that has the potential to identify and eliminate the “road blocks” that prevent cancer cells from becoming specialized, non-dividing cells. According to him, the methodology can be applied to some of the most common and most debilitating genetic disorders in the world, including sickle cell disease and beta thalassemia. Online profile

Dr. Mary Hulihan is the Health Scientist at Centers for Disease Control and Prevention. She works on a CDC Foundation effort with CDC called the Sickle Cell Data Collection program. Dr. Mary Hulihan earned her master of public health degree from The George Washington University in Washington D.C. and her doctorate of public health from The University of Georgia. She joined the Centre for Disease Control and Prevention in 2008 and has served as project officer for the Registry and Surveillance System for Hemoglobinopathies and Public Health Research and Surveillance for Hemoglobinopathies. She is also serving as acting team leader for Red Cell and Iron disorders team. Di Hulihan has written many research articles on sickle cell disease like: - CDC Grand Rounds: Improving the Lives of Persons with Sickle Cell Disease - The accuracy of hospital ICD-9-CM codes for determining Sickle Cell Disease genotype Online profile

Edith Aimiuwu was trained as a registered general nurse (RGN) in Nigeria in 1985 and midwifery in 1987. She came to the UK in 1992 and joined The Whittington Hospital in 1993 following the completion of the nurse adaptation course. She qualified as a pediatric nurse in 1999 and joined the ward permanently in 2000 where she worked as a ward sister until February 2005. Edith then worked as a clinical nurse specialist for sickle cell at the North Middlesex Hospital from February 2005 to October 2006 and rejoined The Whittington Hospital as a Roald Dahl pediatric hemoglobinopathy clinical nurse specialist. As a sickle and thalassemia nurse, Edith has provided support for patients and their families within their home environments and with minimal disruption to school and family life. Online profile

Robert H. Broyles was founder and president of The Sickle Cell Cure Foundation. He earned a BS in chemistry and PhD in biochemistry from Wake Forest University and its medical Centre and obtained post-doctoral training with a National Institute of Health fellowship from Florida State University. Dr. Broyles has served as Senior Scientist at the National Institutes of Health in the haematology Program and the laboratory of chemical biology of NIDDK, as a lecturer in the embryology course of the Marine Biological Laboratory in Woods Hole, Massachusetts, and as Research Member of the Free Radical Biology & Aging Research Program at the Oklahoma Medical Research Foundation.   Research Interest: - Regulation of gene expression as applied to sickle cell disease, malaria, cancer, neurological & cardiovascular diseases, diabetes - Organ culture techniques, especially as applied to liver - Stem cell differentiation and molecular engineering by gene regulation therapy - Natural products & biological molecules as pharmaceuticals/nutraceuticals Online profile