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Sickle-Cell Patients See Hope in CRISPR
The disease may be among the first to be treated with the novel gene-editing tool. https://www.technologyreview.com/s/608641/sickle-cell-patients-see-hope-in-crispr/
Hertz Nazaire is a soft-spoken artist who likes to paint in bright colors, with subjects like rainbow palm leaves and dancing women in twirling skirts. But one series of paintings he’s created is darker. Here, deep-red discs contrast with misshapen, bluish-purple ones against a black background. One canvas shows an African face drowning in the red and blue shapes, eyes streaming with tears, mouth agape in pain. The work reflects his lifelong struggle with sickle-cell disease.
Nazaire, a 43-year-old Haitian-American, figures he’s been hospitalized more than 300 times since he was a child. He and other sickle-cell patients will tell you that the worst part of the disease is the debilitating pain. “It’s a horrifying thing to have, because it’s extremely painful. It’s a major fight all the time,” he says.
Roughly 100,000 people in the U.S. have sickle-cell disease, most of them African-Americans and Latinos but also people of Middle Eastern, Asian, Indian, and Mediterranean descent. Compared with the average American, they live much shorter lives—about 40 to 60 years.
The cause of sickle-cell has been known for a century, but the disease has long been underserved by the medical establishment and the pharmaceutical industry. That may be about to change. Its genetic origin—a single, well-studied mutation—makes it an attractive candidate for treatment with the gene-editing tool CRISPR.
Temple native’s sickle cell case to be featured on Discovery program
Deidra Flowers-Williams ended up in Building 10 of the National Institutes for Health in 2015 because she was out of options.
Flowers-Williams had sickle cell anemia and the toll it had taken on her body over the years had left her in constant pain and too weak to walk from her bed to the bathroom.
After a stem cell transplant at the NIH hospital on Nov. 19, 2015, Flowers is free of the disease and has not had a sickle cell crisis since the procedure.
Her story, along with three other NIH patients, is the subject of the three-part documentary, “First in Human,” airing tonight on the Discovery Channel. Flowers-Williams’ story will be featured in the third segment on Aug. 24.
Narrated by Jim Parsons of the Big Bang Theory, the series follows the diverse patients as they participate in a “First in Human” trial — the initial time when a new therapy is tested in humans.
Deciding to pursue a spot in a medical trial can be daunting. There are lots of hoops to jump through to get accepted and there is always the chance that nothing will change or it might kill you, Flowers-Williams said.
She was willing to take the risk.
Tanisha Flowers, her sister, provided the stem cells. The sisters were a 100 percent match.
Sickle cell anemia is a disease in which the body produces abnormally shaped red blood cells. The cells are shaped like a crescent or sickle. They don’t last as long as normal, round red blood cells. This leads to anemia. The sickle cells also get stuck in blood vessels, blocking blood flow. This can cause pain and organ damage.
Flowers-Williams was No. 43 in the NIH clinical trial on using stem cells to cure sickle cell in adults. The first transplant took place about 13 years ago and that patient is alive and free of sickle cells.
Flowers-Williams returns to the NIH every six months for a checkup.
“On my last visit, everything was good,” she said.
She’s had to get all-new immunizations since her slate was swept clean when her sister’s stem cells took over.
The therapy couldn’t fix what was damaged before the stem cell transplant.
“You know I lived with sickle for 39 to 40 years and I’m so grateful to be here today,” Flowers-Williams said.
She said her success is hope for individuals with sickle cell anemia.
“There is medical work being done that can ease our suffering,” she said.
Flowers-Williams said she was excited about the series because it highlights the NIH and its work.
“Those scientists and researchers are working every day to cure diseases and sickle cell is only one of many,” she said. “I believe the stories of the four patients will touch people and bring focus to the institution.”
The research center has already come up with another treatment for sickle cell patients who don’t have a stem cell match, Flowers-Williams said.
“Prior to my treatments I had no prior knowledge of what they did,” Flowers-Williams said. “This has opened up a whole new world for me. I’m so happy the National Institutes of Health is getting this exposure.”
Flowers-Williams has a job, an impossibility for years. Her teenage children have a new mother.
“They have only known me as being sick,” she said. “We’re making new memories.”
Ethel Flowers, a nursing instructor at Temple College, her daughter and family were in Los Angeles recently to promote “First in Human.”
“Dee Dee was on a panel with the other patients discussing their experiences,” Flowers said. “They asked everybody on the panel questions, but I only focused on her.”
Flowers said the family has viewed bits and pieces of the series, but haven’t seen it in its entirety.
“The producers were supposed to send me the program on a DVD, because I told them I was old school,” Flowers said. As of Wednesday the DVD hadn’t arrived.
Her daughter is doing great, according to Flowers.
“She has normal people problems now, like arthritis,” she said.
Over a period of a year, film crews from the Discovery Channel were embedded within the hospital and followed four patients who volunteered to participate in experimental treatments in the hopes they will help them, or others in the future. The series also follows the doctors and nurses who carry out the research while caring for the patients.
New Online Resources
Two new online learning modules concerning sickle cell disease, and a third is going to launch within the month. These are free-of-charge, ACCME-accredited modules. Learners are required to create a user account at the website Partners in Bleeding Disorders Education, www.PartnersPRN.org. The activities are entitled:
- Hydroxyurea for the Treatment of Sickle Cell Disease
- Comprehensive Sickle Cell Disease Care for Adolescents and Young Adults
The third module will be about creating a transition program for AYAs transitioning into the adult model of care. We also have a CNE (nursing) accredited module, “A School Nurse’s Guide to Sickle Cell Disease” on the same website.
Articles in the Medical Literature
PLoS One. 2017 Sep 1;12(9):e0184076. doi: 10.1371/journal.pone.0184076. eCollection 2017.
Hematological changes can drive damage of endothelial cells, which potentially lead to an early endothelial dysfunction in patients with sickle cell anemia (SCA). An association may exist between endothelial dysfunction and several clinical manifestations of SCA. The present study aims to evaluate the links between changes in endothelial function and clinical and laboratory parameters in children and adolescents with SCA.
This study included 40 children and adolescents with stable SCA as well as 25 healthy children; aged 6-18 years. All study subjects were evaluated for endothelial function using Doppler ultrasonography. In addition, a number of laboratory assays were performed, including reticulocyte and leukocyte counts as well as measurement of circulating levels of total bilirubin, C-reactive protein (CRP), glucose, lipoproteins and peripheral oxyhemoglobin saturation. These parameters were also compared between SCA patients who were undertaking hydroxyurea (HU) and those who were not.
Flow-mediated vasodilation (FMD) values were found to be reduced in SCA patients compared with those detected in healthy controls. SCA individuals with lower FMD values exhibited higher number of hospital admissions due to vaso-occlusive events. Additional analyses revealed that patients who had decreased FMD values exhibited higher odds of acute chest syndrome (ACS) episodes. A preliminary analysis with limited number of individuals failed to demonstrate significant differences in FMD values between SCA individuals who were treated with HU and those who were not.
Children and adolescents with SCA exhibit impaired endothelial function. Reductions in FMD values are associated with ACS. These findings underline the potential use of FMD as screening strategy of SCA patients with severe prognosis at early stages.
J Pediatr Hematol Oncol. 2017 Aug 30. doi: 10.1097/MPH.0000000000000930. [Epub ahead of print]
Cardiac abnormalities have been described in echocardiograms of children with sickle cell disease (SCD). However, longitudinal studies investigating progression of echocardiographic abnormalities across the pediatric age spectrum in SCD are lacking.
A retrospective longitudinal analysis of 829 echocardiograms from pediatric patients with SCD at steady-state was performed. Left heart parameters included left ventricular end-systolic, end-diastolic diameters, fractional shortening, and mass. Right ventricular pressure was estimated by tricuspid regurgitation gradient. Tricuspid regurgitation gradient ≥25 mm Hg, a z-score ≥2 for LV parameters and ≤-2 for left ventricular fractional shortening were considered abnormal.
Kaplan-Meier analysis revealed that echocardiographic abnormalities were detected by 5 years of age, and the cumulative incidence progressively increased throughout childhood. Age, male gender, HbSS and Sβ thalassemia genotype, white blood cell count, platelet count, total bilirubin, admissions for pain crises and acute chest syndrome were positively, whereas hemoglobin was negatively associated with cardiac abnormalities.
Cardiac abnormalities began early in childhood and progressively increased with age. Our study highlights the high cumulative incidence of cardiac abnormalities in children with SCD, which could represent a marker of disease severity.
Clin Kidney J. 2017 Aug;10(4):475-478. doi: 10.1093/ckj/sfx027. Epub 2017 Apr 21.
Albuminuria is considered to be a relevant biomarker for the detection of early glomerular damage in patients with sickle cell disease (SCD). Improvements in our understanding of the pathophysiological processes and molecular mechanisms underlying albuminuria are required, because increasing numbers of patients with SCD are developing chronic kidney disease. The early recognition of sickle cell nephropathy (SCN) and studies of the natural course of this emerging renal disease are therefore crucial, together with identification of the associated clinical and biological risk factors, to make it possible to initiate kidney-protective therapy at early stages of renal impairment. The pathophysiological process underlying SCN remains hypothetical, but chronic haemolysis-related endothelial dysfunction and the relative renal hypoxia triggered by repeated vaso-occlusive crises have been identified as two potential key factors. The optimal preventive and curative management of albuminuria in the context of SCD is yet to be established, but recent studies have suggested that hydroxyurea therapy, the cornerstone of SCD treatment, could play a key role in reducing albuminuria. The place of conventional kidney-protecting measures, such as renin-angiotensin system inhibitors, in the treatment of SCD patients also remains to be determined.
PMCID: PMC5570022 Free PMC Article
Clin Kidney J. 2017 Aug;10(4):479-486. doi: 10.1093/ckj/sfx058. Epub 2017 Jul 12.
Sickle cell anemia (SCA) is considered a major risk factor for renal complications. The main goal of this study was to determine the frequency of macroalbuminuria and microalbuminuria in Congolese children <18 years of age suffering from Sickle cell anemia and to identify associated factors.
The cross-sectional study was completed in 150 hemoglobin-SS children (77 boys and 73 girls). Microalbuminuria was defined by a urine albumin:creatinine ratio of 30-299 mg/g.
The mean age of this group was 8.8 ± 4.3 years (range 2-18). Microalbuminuria was found in 27 children (18%). In multivariate logistic regression, only age emerged as a determinant of microalbuminuria odds ratio 1.11 (95% confidence interval 1.00-1.22); P = 0.042].
In our series, only age was a major determinant of the occurrence of microalbuminuria. These results confirm the need for early screening of microalbuminuria in Congolese children suffering from Sickle cell anemia in a context where access to renal and bone marrow transplant is nonexistent.
PMCID: PMC5569932 Free PMC Article
BMJ Open. 2017 Aug 28;7(8):e016727. doi: 10.1136/bmjopen-2017-016727.
Sickle cell disease is highly prevalent in Africa with a significant public health burden. Nonetheless, morbidity and mortality in sickle cell disease that result from the progression of organ damage is not well understood. The Organ Damage in Sickle Cell Disease Study (ORDISS) is designed as a longitudinal cohort study to provide critical insight into cellular and molecular pathogenesis of chronic organ damage for the development of future innovative treatment.
METHODS AND ANALYSIS:
ORDISS aims to recruit children aged 0-15 years who attend the Kumasi Centre for Sickle Cell Disease based at the Komfo Anokye Teaching Hospital in Kumasi, Ghana. Consent is obtained to collect blood and urine samples from the children during specified clinic visits and hospitalisations for acute events, to identify candidate and genetic markers of specific organ dysfunction and end-organ damage, over a 3 year period. In addition, data concerning clinical history and complications associated with sickle cell disease are collected. Samples are stored in biorepositories and analysed at the Kumasi Centre for Collaborative Research in Tropical Medicine, Ghana and the Centre for Translational and International Haematology, University of Pittsburgh, USA. Appropriate statistical analyses will be performed on the data acquired.
ETHICS AND DISSEMINATION:
Research ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals, and the key findings presented at national and international conferences.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Conflict of interest statement
Competing interests: None declared.
Blood Cells Mol Dis. 2017 Aug 8. pii: S1079-9796(16)30276-5. doi: 10.1016/j.bcmd.2017.08.010. [Epub ahead of print]
Sickle cell disease (SCD) is a common and life threatening inherited blood disorder, affecting over 300,000 newborns per year. Over 75% of SCD births occur in sub-Saharan Africa, where the lack of timely and accurate diagnosis results in premature death within the first few years of life for a majority of affected infants. Current methods to diagnosis SCD require expensive laboratory equipment and reagents, and adequately trained laboratory personnel. In addition, test results are often delayed due to transport and batching of samples in a central laboratory. Financial and technical limitations often preclude any form of SCD laboratory testing at the local level in regions where SCD is most prevalent. There has been a recent surge of interest in addressing the global burden of SCD, including improving and optimizing diagnostic capacities. Largely stimulated by a funding opportunity from the NIH, several point-of-care diagnostics have been developed for SCD with a focus on developing devices that are inexpensive, simple, and practical in limited resource settings. In this manuscript, we review the global burden of SCA, including the rationale for the development of POC assays, and carefully review the POC devices currently in development.
Copyright © 2017 Elsevier Inc. All rights reserved.
Int J Stem Cells. 2017 Aug 31. doi: 10.15283/ijsc17019. [Epub ahead of print]
Background and Objective:
Sickle cell disease (SCD) is quite common in eastern Saudi Arabia and Avascular necrosis of femoral head (ANFH) occurs in 30% of the young patients leading to early joint arthroplasty. This study was conducted to assess the benefits of injection of osteoblasts in the avascular lesions of the head of femur.
Patients and Methods:
A preset technique was used, 10 CC of bone marrow aspiration was performed under local anesthesia and aseptic technique. Osteoblasts were separated from the bone marrow cells. The avascular area was drilled and 10 million osteoblasts were transplanted at the lesion site. Patients were seen in the out patient clinic after two weeks for removal of the suture and addressed the questionnaire and examined for the range of movement. The follow up MRI was performed at 4 months.
The average age was 20.2±3.9 years. The mean hemoglobin S was 81.6±4.8 percent. Quality of Life Score for Chronic Hip Disease was assessed and found at 8.6 (1 being the severe limitation and 10 being normal), whereas Harris hip score improved from 41.7±5.1 to 88.93±3.6 (p＜0.001). MRI of pre and post osteoblast implantation showed robust new bone formation and disappearance of the avascular lesions.
The short term results were good and we believe the injection of osteoblast in the avascular lesion of head of femur is a less invasive procedure devoid of any untoward complications and merits such treatment in large patient group with longer follow up.
Pain Manag Nurs. 2017 Aug 23. pii: S1524-9042(17)30446-0. doi: 10.1016/j.pmn.2017.07.003. [Epub ahead of print]
Sickle cell disease (SCD) pain may have a neuropathic component. Adjuvant drugs used to treat neuropathic pain have not been studied for the treatment of adults with SCD. To determine the safety and feasibility of using pregabalin for chronic SCD pain. A randomized, controlled, double-blind pilot study. Based on random assignment, participants were treated with pregabalin or placebo control for 3 months with monthly follow-up visits. Participants were recruited from the University of Illinois Hospital and Health Sciences System outpatient SCD clinic. Participants/Subjects: A total of 22 participants with SCD (21 African American, 1 other) were included 16 women aged 18-82 (mean age 33.1 ± 9.9). PAINReportIt, Leeds Assessment of Neuropathic Signs and Symptoms, Neuropathic Pain Symptom Inventory, and Short Form 36 Health Survey were completed. Adverse effects were minimal. Mean scores for average pain intensity, composite pain index, and neuropathic pain revealed a reduction for pregabalin and placebo control groups. Although the between-group differences were not significant, sustained reduction in pain over time within the pregabalin group indicated promising effects of pregabalin for SCD pain. Mean quality-of-life scores increased slightly over time (representing better quality of life) in 7 of 8 domains for the pregabalin group and decreased in 4 of 8 domains for the placebo control group. Small sample size made it difficult to interpret quality-of-life findings. This pilot study provided sufficient evidence that further investigation of pregabalin’s potential efficacy for treatment of chronic SCD pain in adults is warranted.
Copyright © 2017 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.
Transfusion. 2017 Aug 24. doi: 10.1111/trf.14282. [Epub ahead of print]
Red blood cell (RBC) alloimmunization occurs at a high frequency in sickle cell anemia (SCA) despite serologic matching for Rh (C/c, E/e) and K antigens. RBC minor antigen genotyping allows for prediction of antigens and RH variants that may lead to alloimmunization.
STUDY DESIGN AND METHODS:
RBC antigen genotyping was performed on chronically transfused pediatric SCA patients, using PreciseType human erythrocyte antigen (HEA), RHCE, and RHD BeadChip arrays. All patients received C/c, E/e, and K serologically matched units (Category 1); patients with prior RBC antibodies were also matched for Fya , Jkb , and any antibodies (Category 2). The RBC genotypes of all leukoreduced (LR) units transfused over a 12-month period were determined by the prototype HEA-LR BeadChip assay.
There were 2320 RBC units transfused to 90 patients in 1135 transfusion episodes. Thirty-five (38.9%) patients had homozygous or compound heterozygous RH variants. Seven new alloantibodies were detected, with alloantibody incidence of 0.706 in 100 units for Category 2 transfusions and 0.068 in 100 units for Category 1 (p = 0.02). Three patients on Category 2 transfusions formed new anti-Jsa and had a higher rate of exposure to Jsa than those who did not form anti-Jsa (20.4 vs. 8.33 exposures/100 units, p = 0.02). The most frequent mismatches were S (43.9%), Doa (43.9%), Fya (29.2%), M (28.4%), and Jkb (28.1%).
Alloimmunization incidence was higher in those with prior RBC antibodies, suggesting that past immunologic responders are at higher risk for future alloimmunization and therefore may benefit from more extensive antigen matching beyond C/c, E/e, K, Fya , and Jkb .
© 2017 AABB.
Rehabil Psychol. 2017 Aug;62(3):249-257. doi: 10.1037/rep0000158.
Youth with sickle cell disease (SCD) are at an increased risk for executive dysfunction and simultaneously have increased self-management needs compared to typical adolescents. This unique combination may contribute, in part, to difficulties during transition to young adulthood. Current measures assessing adaptive skills do not assess the executive components (e.g., initiation, prospective memory) of SCD-related self-care tasks. Modeled on the KKIS-Spina Bifida (Jacobson et al., 2013), the Kennedy Krieger Independence Scales-Sickle Cell Disease (KKIS-SCD) is a new caregiver-report measure that assesses independence with self-management of SCD-specific demands as well as routine daily activities in adolescents with SCD. Research Method/Design: Thirty-three youth with SCD and their caregivers participated in this preliminary validation study examining the construct validity of the KKIS-SCD total and composite scores (Initiation of Routines, Prospective Memory) and exploring relationships of this measure with intellectual functioning, demographic factors, illness severity, and age.
The KKIS-SCD exhibited generally good internal consistency (Cronbach’s alpha = .733 to .803), and demonstrated evidence for construct and discriminant validity when compared to an existing measure of adaptive function. The KKIS-SCD was significantly associated with caregiver-report of executive behaviors but not with intellectual functioning, demographic factors, illness severity, or age.
Results provide preliminary support for the KKIS-SCD as a reliable and valid tool for the assessment of executive components of self-care management skills for youth with SCD. Identifying specific weaknesses in executive function related to self-care management skills might assist in guiding intervention and individualizing transition planning in these at-risk youth. (PsycINFO Database Record
(c) 2017 APA, all rights reserved).
J Opioid Manag. 2017 May/Jun;13(3):143-156. doi: 10.5055/jom.2017.0382.
A subset of adults with sickle cell disease (SCD) heavily utilizes the emergency department (ED) and hospital. The objective of our study was to determine the efficacy of a multidisciplinary strategy to address unmet needs in highly utilizing adults with SCD.
In a prospective study, adults with SCD with ≥10 admissions per year were assessed by a multidisciplinary team for gaps in medical, social, and psychological care. Thereafter, the team decided upon the subject’s predominant domain that drove admissions and instituted an interventional plan. All plans included an opioid management strategy. Preintervention and postintervention admission rate, as well as opioid use, was compared.
Twelve subjects were enrolled. Median rate of ED and hospital admissions preintervention was 25 per year. The predominant domains identified were social needs (n = 6), psychological disorder (n = 1), and substance use disorder (n = 5). Multifaceted interventional plans were developed to address a wide range of gaps in care, but an opioid management strategy was the only intervention successfully completed. Even so, when the preintervention versus postintervention admission rate was compared, regardless of the domain, there was a 40 percent decline in hospital admissions (p = 0.03). Consistent with the successful implementation of an opioid management plan, the decrease in admissions was accompanied by a 37 percent decrease in intravenous opioid use (p = 0.02) and 10 percent decrease in oral opioid use (p = 0.04).
An opioid management strategy, as part of a larger effort to improve care for high-utilizing adults with SCD, decreased rate of admissions and opioid use.
J Dev Behav Pediatr. 2017 Aug 4. doi: 10.1097/DBP.0000000000000486. [Epub ahead of print]
Studies of early child development in sickle cell disease (SCD) have found modest associations between disease-related risks and developmental status in infants and toddlers, but such associations are evident by early elementary school. We screened 4-year-old children with SCD using 2 screening strategies to assess if biomedical risk factors for neurologic disease are related to developmental screening outcomes at this intermediate age.
Seventy-seven 4-year-old children with SCD (M = 4.5 yrs, SD = 0.3 yrs) completed developmental screenings at routine hematology visits using child testing (Fluharty Preschool Speech and Language Screenings Test, 2nd edition) and parent-report (Ages and Stages Questionnaire, 2nd edition) procedures. Genotype and other biomedical variables were coded from medical records.
Children with higher-risk SCD genotypes (n = 52) showed lower performance than children with lower-risk genotypes (n = 25) on a measure related to neurologic disease risk in older children (syntactic processing); genotype risk was also related to rates of positive screenings on parent-reported developmental milestones (52% positive screenings in high-risk genotypes vs 12% in low-risk genotypes). Screening outcomes were also related to transcranial Doppler ultrasound findings assessing cerebral blood flow.
Developmental screening at age 4 may be a useful target age for identifying preschoolers with sickle cell-related neurodevelopmental concerns. Parent report of developmental milestones and behavioral testing each may have a role in screening for children in need of follow-up services to address potential neurodevelopmental effects from SCD.
Pharmacoepidemiol Drug Saf. 2017 Aug 16. doi: 10.1002/pds.4291. [Epub ahead of print]
Opioid analgesics are commonly used to treat vaso-occlusive pain episodes in sickle cell disease (SCD), but comprehensive evidence characterizing opioid use in this patient population is limited. Our objective was to characterize opioid use patterns among SCD patients using a large nationwide database.
A large, US medical claims database was utilized to identify a cohort of 3882 SCD patients, and characteristics of opioid use were analyzed. Clinical variables including age, gender, medication use, health care utilization, and medical history were evaluated for correlations with opioid use.
Forty percent of patients took opioid medications during a 12-month span, and the prevalence of any opioid use was highest for 20 to 29-year-old patients (58%). The median daily opioid dose was 1.85 mg (interquartile range: 0.62-10.68 mg) oral morphine equivalents (OME). While most opioid users took between 0 and 5 mg OME daily, 3% of pediatric patients and 23% of adult patients used more than 30-mg OME daily. High-dose opioid use was associated with older age, hydroxyurea therapy, nonsteroidal anti-inflammatory drug (NSAID) use, and frequent inpatient hospitalizations. In multivariable-adjusted analyses, patients with vaso-occlusive complications such as pain crisis (OR = 3.8, 95% CI 2.7-5.3) and avascular necrosis (AVN) (OR = 3.7, 95% CI 2.7-5.1) were associated with high-dose opioid use.
Our study showed that only 40% SCD patients were on opioid analgesics during a 12-month span. However, a non-trivial number of patients used a much higher dose of opioids despite a relatively low average daily opioid dose among SCD patients, particularly with vaso-occlusive complications.
Copyright © 2017 John Wiley & Sons, Ltd.
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2003 Sep 15 [updated 2017 Aug 17].
Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ system, including the bones, spleen, liver, brain, lungs, kidneys, and joints. Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. In children, the spleen can become engorged with blood cells in a “splenic sequestration.” The spleen is particularly vulnerable to infarction and the majority of individuals with SCD who are not on hydroxyurea or transfusion therapy become functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections. Acute chest syndrome is a major cause of mortality in SCD. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation. Individuals with the highest rates of hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg ulcers but may be relatively protected from vaso-occlusive pain.
SCD encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant resulting in abnormal hemoglobin polymerization. Hb S/S (homozygous p.Glu6Val in HBB) accounts for 60%-70% of SCD in the United States. Other forms of SCD result from coinheritance of HbS with other abnormal β-globin chain variants, the most common forms being sickle-hemoglobin C disease (Hb S/C) and two types of sickle β-thalassemia (Hb S/β+-thalassemia and Hb S/β°-thalassemia); rarer forms result from coinheritance of other Hb variants such as D-Punjab, O-Arab, and E. The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal β-globin chain variant by hemoglobin assay or by identification of biallelic HBB pathogenic variants where at least one allele is the p.Glu6Val pathogenic variant (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing. All states in the US have included newborn screening for SCD since 2005. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. A few newborn screening programs confirm results with molecular testing.
Treatment of manifestations: Management of pain episodes includes hydration, anti-inflammatory agents, and pain medication. Pain episodes are additionally managed with a multi-model approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). Fever and suspected infection is treated with appropriate antibiotics. Life-threatening or severe complications (e.g., severe acute chest syndrome, aplastic crisis, and stroke) are often treated with red blood cell transfusion. Splenectomy may be necessary for splenic sequestration. Severe priapism may require aspiration and irrigation. Prevention of primary manifestations: Maintain hydration and avoid climate extremes. Chronic red blood cell transfusion in children at risk for stroke and individuals with pulmonary hypertension, chronic renal failure, recurrent acute chest syndrome, and severe end-organ damage. Hydroxyurea can decrease the frequency and severity of vaso-occlusive processes, reduce transfusion needs, and increase life span. Glutamine has received FDA approval for the prevention of acute complications in individuals with SCD age five years and older. Stem cell transplantation may be an option in selected individuals. Prevention of secondary complications: Aggressive education on the management of fevers; prophylactic antibiotics, including penicillin in children; immunizations; folic acid supplementation; and iron chelation therapy for those with iron overload. Surveillance: Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and routine dental care. Annual CBC and reticulocyte count, assessment of iron status, liver and renal function tests, urinalysis, LDH, and vitamin D level. Annual transcranial Doppler to determine risk of stroke in all children with Hb S/S and Hb S/β°-thalassemia and ophthalmologic evaluation in all with sickling disorders. There should be a low threshold to evaluate for end-organ damage including chest x-ray, ECG, abdominal ultrasound, and iron overload. Due to the high frequency and severity of cardiopulmonary complications there should be a particularly low threshold to obtain an echocardiogram, pulmonary function tests, and sleep study in individuals of any age with cardiac or pulmonary concerns. Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, recreational drugs with vasoconstrictive or cardiac stimulation effects, and meperidine. Evaluation of relatives at risk: Early diagnosis of at-risk family members allows education and intervention before symptoms or end-organ damage are present. Pregnancy management: Women with SCD who become pregnant require close follow up and monitoring by a hematologist and obstetrician; an increased risk for preterm labor, thrombosis, infectious complications, and acute painful episodes has been reported during pregnancy; hydroxyurea should be discontinued during pregnancy.
SCD is inherited in an autosomal recessive manner. If one parent is a carrier of the HBB HbS pathogenic variant and the other is a carrier of any of the HBB pathogenic variants (e.g., HbS, HbC, β-thalassemia), each child has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for common forms of SCD is most commonly accomplished by isoelectric focusing or HPLC. Prenatal diagnosis for pregnancies at increased risk for SCD is possible by molecular genetic testing if the HBB pathogenic variants have been identified in the parents.
Copyright © 1993-2017, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.
Free Books & Documents
Sickle Cell Conferences and Events
ASH Sickle Cell Disease Coding Webinar – September 5
Providers treating patients with sickle cell disease (SCD) continually struggle with inefficient reimbursement which can ultimately impact access to care. The Current Procedural Terminology (CPT) codes and the Diagnosis-Related Group (DRG) codes assigned for these patient visits have a significant impact on reimbursement. However, there is often a disconnect between a clinician’s documentation and the resulting CPT and DRG codes assigned by a coder. On September 5, 2017 from 3:00PM – 4:00PM ET, the American Society of Hematology will host a webinar, Coding for Sickle Cell Disease, to outline best practices for documentation of patients with SCD, and the many major comorbidities and complications for which these patients frequently present. The webinar will feature Dr. Michael DeBaun, a leading expert in the care of children with SCD, and Ellen Riker, an expert in public and private insurance reimbursement and coverage policies. Click here to register.
On behalf of Sickle Cell Partners of the Carolinas, please accept our invitation to the conference, “Sickle Cell Disease… Let’s Talk About It,” sponsored by Sickle Cell Partners of the Carolinas, a support group for patients and families affected by sickle cell disease. The annual conference will be held on Saturday, September 9, 2017 at Friendship Missionary Baptist Church from 8am to 2pm.
6th Annual Sickle Cell Disease Therapeutics Conference
The 6th Annual Sickle Cell Disease Conference, a forum to discover the latest advancements and future trends for sickle cell disease and drug development is scheduled for September 14, 2017, in New York, NY. Conference attendees will hear from innovative industry leaders, patients, physicians, and clinical-stage companies. To register for the conference, please visit www.SCDconference.com.
11th Annual Sickle Cell Disease and Thalassemia Conference
The 2017 Annual Scientific Conference on Sickle Cell and Thalassemia is a three-day conference aimed at all those with a common interest in sickle cell disease and thalassemia. It will be held in London on October 11-13, 2017. There will also be sessions on genetics and genomic progress, curative therapies and emerging services, as well as abstract and poster presentations. For more information and to register click here.
Join Sickle Cell Partners of the Carolinas for the 4th annual conference, “Sickle Cell Disease…. Let’s Talk About It”
Saturday September 9, 2017 | 8 am to 2 pm | Charlotte, NC
Friendship Missionary Baptist Church Conference Center 3400 Beatties Ford Road, Charlotte NC 28216
This day conference will feature a myriad of topics designed to engage patients, families and the at-large community and to build broader awareness about the challenges of sickle cell disease and how patients and families may be able to get beyond those challenges. Keynote Luncheon Speaker: Howard University President, Wayne A.I. Frederick, M.D., MBA.
Friendship Missionary Baptist Church Conference Center Charlotte, North Carolina. Cost is $5 for participants.
Pediatric Sickle Cell Mini Symposium: The School-Aged Child
Saturday, September 9, 2017 7:45 a.m. to 3:15 p.m. Atlanta,GA
Who Should Attend:The conference will benefit pediatricians, family practice physicians, advanced practice providers (NP’s, PA’s), nurses, fellows, and residents. Other healthcare professionals involved in the care of pediatric patients with sickle cell disease mayfind the information useful and are welcome to attend.
The purpose of this symposium is to update pediatricians and family practitioners
on the most current research and clinical guidelines related to pediatric sickle cell
disease, particularly in the school-aged child, and to discuss key considerations
when caring for these patients.
Location & Accommodations Emory Health Sciences Research Building
1760 Haygood Drive NE Atlanta, Georgia 30322
For more information, contact email@example.com.
SCDAA 45th Annual National Convention on Sickle Cell Disease
With over 447 researchers, physicians, nurses, socials workers, individuals living with SCD & SCT and more we are excited to reunite with you again on October 25-28, 2017
The SCDAA Annual Convention is a four-day conference designed to address the multi-factorial aspects of Sickle Cell Disease. This year the event will be held in Atlanta, Georgia, a city near and dear to the sickle cell community! https://www.sicklecelldisease.org/2017/03/07/45th-annual-national-convention/
The 11th Sickle Cell in Focus Conference
26-27, October 2017 Kingston, Jamaica
We are pleased to announce that Sickle Cell in Focus (SCiF) will be held for the first time in Kingston, Jamaica on October 26-27, 2017. This year, SCiF will be co-hosted by the National Heart, Lung, and Blood Institute and the University of West Indies, Jamaica. SCiF is a two-day, intensive, educational update on sickle cell disease. This year’s conference will focus on the latest clinical trials, the science and mechanisms for new therapeutic targets, and curative therapies. This two-day intensive educational conferences includes both clinical and scientific lectures, aimed at clinicians, academics, and other healthcare professionals involved in sickle cell disease around the world. Contact Rusinel Amarante| firstname.lastname@example.org |