BACKGROUND: Pregnant women with sickle cell disease (HbSS, HbSC and HbSβThal) may require blood transfusion to prevent severe anaemia or to manage potential medical complications. Preventive blood transfusion in the absence of complications starting from the early weeks of pregnancy or blood transfusion only for medical or obstetric indications have been used as management policies. There is currently no consensus on the blood transfusion policy that guarantees optimal clinical benefits with minimal risks for such women and their babies. This is an update of a Cochrane review that was published in 2013. OBJECTIVES: To assess the benefits and harms of a policy of prophylactic versus selective blood transfusion in pregnant women with sickle cell disease. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 May 2016) and reference lists of retrieved studies. We did not apply any language or date restrictions. SELECTION CRITERIA: Randomised controlled trials evaluating the effects of prophylactic versus selective (emergency) blood transfusion in pregnant women with sickle cell disease (SCD). Quasi-randomised trials and trials using a cluster-randomised design were eligible for inclusion but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two review authors independently assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Out of six relevant reports identified by the search strategy, one trial involving 72 women with sickle cell anaemia (HbSS) met our inclusion criteria. The trial was at unclear risk of bias. Overall, there were few events for most of the reported outcomes and the results were generally imprecise. The included trial reported no maternal mortality occurring in women who received either prophylactic or selective blood transfusion. Very low-quality evidence indicated no clear differences in maternal mortality, perinatal mortality (risk ratio (RR) 2.85, 95% confidence interval (CI) 0.61 to 13.22; very low-quality evidence) or markers of severe maternal morbidity (pulmonary embolism (no events); congestive cardiac failure (RR 1.00, 95% CI 0.07 to 15.38; very low-quality evidence); acute chest syndrome (RR 0.67, 95% CI 0.12 to 3.75)) between the treatment groups (prophylactic blood transfusion versus selective blood transfusion). Low-quality evidence indicated that prophylactic blood transfusion reduced the risk of pain crisis compared with selective blood transfusion (RR 0.28, 95% CI 0.12 to 0.67, one trial, 72 women; low-quality evidence), and no differences in the occurrence of acute splenic sequestration (RR 0.33, 95% CI 0.01 to 7.92; low-quality evidence), haemolytic crises (RR 0.33, 95% CI 0.04 to 3.06) or delayed blood transfusion reaction (RR 2.00, 95% CI 0.54 to 7.39; very low-quality evidence) between the comparison groups.Other relevant maternal outcomes pre-specified for this review such as cumulative duration of hospital stay, postpartum haemorrhage and iron overload, and infant outcomes, admission to neonatal intensive care unit (NICU) and haemolytic disease of the newborn, were not reported by the trial. AUTHORS' CONCLUSIONS: Evidence from one small trial of very low quality suggests that prophylactic blood transfusion to pregnant women with sickle cell anaemia (HbSS) confers no clear clinical benefits when compared with selective transfusion. Currently, there is no evidence from randomised or quasi-randomised trials to provide reliable advice on the optimal blood transfusion policy for women with other variants of sickle cell disease (i.e. HbSC and HbSβThal). The available data and quality of evidence on this subject are insufficient to advocate for a change in existing clinical practice and policy. Abstract source Full text

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. Abstract source Full text

Despite the detailed characterization of the inflammatory and endothelial changes observed in Sickle Cell Disease (SCD), the hierarchical relationship between elements involved in the pathogenesis of this complex disease is yet to be described. Meta-analyses of gene expression studies from public repositories represent a novel strategy, capable to identify key mediators in complex diseases. We performed several meta-analyses of gene expression studies involving SCD, including studies with patient samples, as well as in-vitro models of the disease. Meta-analyses were performed with the Inmex bioinformatics tool, based on the RankProd package, using raw gene expression data. Functional gene set analysis was performed using more than 60 gene-set libraries. Our results demonstrate that the well-characterized association between innate immunity, hemostasis, angiogenesis and heme metabolism with SCD is also consistently observed at the transcriptomic level, across independent studies. The enrichment of genes and pathways associated with innate immunity and damage repair-associated pathways supports the model of erythroid danger-associated molecular patterns (DAMPs) as key mediators of the pathogenesis of SCD. Our study also generated a novel database of candidate genes, pathways and transcription factors not previously associated with the pathogenesis of SCD that warrant further investigation in models and patients of SCD. Abstract source Full text Full text (PMC)

We describe the case of a 27-year-old woman with a history of sickle cell trait (SCT) who presented with several months of hematuria and was found to have nutcracker syndrome (NCS). While SCT is a common cause of hematuria resulting from renal papillary necrosis, our patient had concomitant abdominal pain and anemia, prompting further evaluation and the subsequent diagnosis of NCS. Interestingly, the anoxia in the left renal vein from NCS predisposes patients with SCT to sickling. Our case highlights key clinical features of both NCS and SCT and the relationship between the two disease processes. Abstract source Full text

Sickle cell anaemia is a monogenetic disorder with a high incidence of stroke. While stroke screening procedures exist for children with sickle cell anaemia, no accepted screening procedures exist for assessing stroke risk in adults. The purpose of this study is to use novel magnetic resonance imaging methods to evaluate physiological relationships between oxygen extraction fraction, cerebral blood flow, and clinical markers of cerebrovascular impairment in adults with sickle cell anaemia. The specific goal is to determine to what extent elevated oxygen extraction fraction may be uniquely present in patients with higher levels of clinical impairment and therefore may represent a candidate biomarker of stroke risk. Neurological evaluation, structural imaging, and the non-invasive T2-relaxation-under-spin-tagging magnetic resonance imaging method were applied in sickle cell anaemia (n = 34) and healthy race-matched control (n = 11) volunteers without sickle cell trait to assess whole-brain oxygen extraction fraction, cerebral blood flow, degree of vasculopathy, severity of anaemia, and presence of prior infarct; findings were interpreted in the context of physiological models. Cerebral blood flow and oxygen extraction fraction were elevated (P < 0.05) in participants with sickle cell anaemia (n = 27) not receiving monthly blood transfusions (interquartile range cerebral blood flow = 46.2-56.8 ml/100 g/min; oxygen extraction fraction = 0.39-0.50) relative to controls (interquartile range cerebral blood flow = 40.8-46.3 ml/100 g/min; oxygen extraction fraction = 0.33-0.38). Oxygen extraction fraction (P < 0.0001) but not cerebral blood flow was increased in participants with higher levels of clinical impairment. These data provide support for T2-relaxation-under-spin-tagging being able to quickly and non-invasively detect elevated oxygen extraction fraction in individuals with sickle cell anaemia with higher levels of clinical impairment. Our results support the premise that magnetic resonance imaging-based assessment of elevated oxygen extraction fraction might be a viable screening tool for evaluating stroke risk in adults with sickle cell anaemia. Abstract source Full text Full text (PMC)

After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations. Abstract source Full text Full text (PMC)

PURPOSE: Approximately 200,000 individuals worldwide are born annually with sickle cell disease (SCD). Regions with the highest rates of SCD include Africa, the Mediterranean, and Asia, where its prevalence is estimated to be 2-6% of the population. An estimated 70,000-100,000 people in the United States have SCD. Due to enhanced newborn screening, a better understanding of this disease, and more aggressive therapy, many sickle cell patients survive into their adult years and present more frequently for surgery. SOURCE: The authors identified relevant medical literature by searching PubMed, MEDLINE®, EMBASE™, Scopus™, Web of Science, and Google Scholar databases for English language publications appearing from 1972-September 2016. Case reports, abstracts, review articles, and original research articles were reviewed-with particular focus on the pathophysiology and medical management of SCD and any anesthesia-related issues. PRINCIPAL FINDINGS: Perioperative physicians should be familiar with the triggers of a sickle cell crisis and vaso-occlusive disease. Sickle cell disease affects various organ systems, including the central nervous, cardiovascular, pulmonary, genitourinary, and musculoskeletal systems. Preoperative assessment should focus on end-organ dysfunction. Controversy continues regarding if and when sickle cell patients should receive transfusions and which anesthetic technique (regional or general) confers any benefits. Timely, appropriate, and sufficient analgesia is critical, especially when patients experience a vaso-occlusive crisis, acute chest syndrome, or acute postoperative pain. CONCLUSION: Effective management of SCD patients in the perioperative setting requires familiarity with the epidemiology, pathophysiology, clinical manifestations, and treatment of SCD. Abstract source Full text

Pain, the hallmark complication of sickle cell disease (SCD), is largely managed with opioid analgesics in the United States, but comprehensive data regarding the long-term use of opioids in this patient population is lacking. The pain medication prescription records from a cohort of 203 SCD patients were analyzed. Twenty-five percent were not prescribed opioid medications while 47% took only short-acting opioids, 1% took only long-acting opioids, and 27% took a combination of short-acting and long-acting opioids. The median (interquartile range) daily opioid dose was 6.1 mg (1.7-26.3 mg) of oral morphine equivalents, which is lower than the published opioid use among patients with other pain syndromes. The dose of opioids correlated with the number of admissions due to vaso-occlusive crisis (VOC) (r = 0.53, P < 0.001). When the patients were grouped into quartiles based on daily dose opioid use, a logistic regression model showed that history of avascular necrosis (AVN) (OR: 2.87, 95% CI: 1.37-6.02, P = 0.005), 25-OHD levels (OR: 0.59, 95% CI: 0.38-0.93, P = 0.024) and total bilirubin concentration (OR: 0.64, 95% CI: 0.42-0.99, P = 0.043) were independently associated with opioid use quartiles. In conclusion, doses and types of opioid medications used by adult SCD patients vary widely. Our findings implicate AVN and lower vitamin D levels as factors associated with higher opioid use. They also suggest an association of higher bilirubin levels, possibly suggesting higher hemolytic rate, with lower opioid use. Abstract source Full text

BACKGROUND: Sickle cell disease is one of the most common genetic disorders. Sickle cell crises in which irregular and dehydrated cells contribute to blocking of blood vessels are characterised by episodes of pain. Treatment is mainly supportive and symptomatic. In vitro studies with piracetam indicate that it has the potential for inhibition and a reversal of the process of sickling of erythrocytes. This is an update of a previously published Cochrane review. OBJECTIVES: To assess the effectiveness of piracetam for reducing the incidence of painful sickle cell disease crises. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Last search of the Group's Haemoglobinopathies Trials Register: 21 September 2015. SELECTION CRITERIA: Randomised controlled trials comparing orally administered piracetam to placebo or standard care in people, of all ages and both sexes, with sickle cell disease. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Trial authors were contacted for additional information. Adverse effects data were collected from the trials. MAIN RESULTS: Three trials involving 169 participants were included in the review. A limited amount of data addressing some of the primary and some of the secondary outcomes were provided, but data were incomplete and based on un-validated assumptions used in the evaluation of outcomes. One trial reported a reduction in the number of pain crises and their severity with active intervention than placebo but presented no data to confirm these results. A second trial presented a monthly global pain score based on the number of sickle cell crises and severity of pain but included no separate data for these primary outcomes. Although there was no significant difference between the piracetam and placebo periods for the number of days of hospitalisation (P = 0.87) in one trial, inconsistencies in the criteria necessary for hospitalisation during sickle crises did not permit accurate conclusions to be drawn. Two of the trials reported participant satisfaction with piracetam but provided no details as to how this satisfaction had been assessed. There were no reports of toxicity or adverse effects with piracetam other than one participant who experienced dizziness. AUTHORS' CONCLUSIONS: The small number of included trials and their poor methodological quality provided insufficient reliable evidence to support the routine use of this medication for preventing the incidence of painful sickle cell disease crises.We will continue to run searches to identify any potentially relevant trials; however, we do not plan to update other sections of the review until new trials are published. Abstract source Full text

OBJECTIVE: People living with sickle cell disease (SCD) experience severe episodic and chronic pain and frequently report poor interpersonal treatment within health-care settings. In this particularly relevant context, we examined the relationship between perceived discrimination and both clinical and laboratory pain. METHODS: Seventy-one individuals with SCD provided self-reports of experiences with discrimination in health-care settings and clinical pain severity, and completed a psychophysical pain testing battery in the laboratory. RESULTS: Discrimination in health-care settings was correlated with greater clinical pain severity and enhanced sensitivity to multiple laboratory-induced pain measures, as well as stress, depression, and sleep. After controlling for relevant covariates, discrimination remained a significant predictor of mechanical temporal summation (a marker of central pain facilitation), but not clinical pain severity or suprathreshold heat pain response. Furthermore, a significant interaction between experience with discrimination and clinical pain severity was associated with mechanical temporal summation; increased experience with discrimination was associated with an increased correlation between clinical pain severity and temporal summation of pain. DISCUSSION: Perceived discrimination within health-care settings was associated with pain facilitation. These findings suggest that discrimination may be related to increased central sensitization among SCD patients, and more broadly that health-care social environments may interact with pain pathophysiology. Abstract source Full text