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Background: Chronic red cell transfusion (CRCT) therapy is one of a few effective disease-modifying therapies for children with sickle cell anemia (SCA). CRCT is recommended for primary and secondary stroke prevention for at-risk children with SCA and is sometimes used for other disease-related complications. However, CRCT can be resource- and time-intensive for patients/families, providers, and organizations. This study was conducted to provide a comprehensive, multilevel examination of barriers and facilitators to transfusion therapy in children with SCA from health care provider and caregiver perspectives. Methods: A qualitative descriptive approach was used to conduct key informant interviews in a sample of 26 caregivers and 25 providers across the United States. Interviews were analyzed using directed content analysis with the Multilevel Ecological Model of Health as an initial coding framework and the constant comparison method. Results: Ten barrier themes and 10 facilitator themes emerged across all ecological levels. Themes most commonly occurred on the patient and organizational levels. Key barriers themes included Logistical Challenges, Obtaining and Maintaining Venous Access, Alloantibodies/Alloimmunization and Reactions, and Iron Overload and Adherence to Chelation Therapy. Key facilitator themes included Nursing and Non-nursing Staff Support, Positive Child/Family Experiences, Logistical Help and Social Resources, Blood Bank and Access to Blood, and Transfusion-Specific Resources. Discussion: The comprehensive understanding of multilevel barriers and facilitators to transfusion therapy, including the role of nursing, in children with SCA can inform strategies to improve CRCT for patients/families and providers and can also be applied by organizations seeking to implement transfusion services for SCA. [ABSTRACT FROM AUTHOR]

Summary: EXpanding Treatment for Existing Neurological Disease (EXTEND) investigated whether hydroxycarbamide lowers transcranial Doppler (TCD) velocities in Jamaican children with sickle cell anaemia (SCA) and elevated TCD velocity with or without previous stroke. Forty‐three children (age 2–17 years) with baseline maximum time‐averaged mean velocity (TAMV) ≥ 170 cm/s were stratified into three risk categories based on treatment status and stroke history: Group 1 (no history of stroke, on hydroxycarbamide, n = 12); and Groups 2 (no stroke, no hydroxycarbamide, n = 21) and 3 (previous stroke, no hydroxycarbamide, n = 10). Open‐label hydroxycarbamide at 20 mg/kg/day was commenced, with escalation to maximum tolerated dose (MTD) based on mild marrow suppression (average dose 25·4 ± 4·5 mg/kg/day). TCD was performed every six months with brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) at baseline and after 18‐months of hydroxycarbamide. The maximum TAMV decreased significantly compared to baseline (24 ± 30 cm/s, P < 0·0001), with similar declines in all groups. Clinical stroke occurred in five children, one in Group 1, none in Group 2, and four in Group 3, P = 0·0032, comparing group incidence rates. Brain MRI/MRA was stable in children without clinical stroke. EXTEND documents the feasibility and benefits of hydroxycarbamide at MTD to lower TCD velocities and reduce stroke risk in children with SCA and no history of primary stroke in low‐resource settings without transfusion management. [ABSTRACT FROM AUTHOR]

Background Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. Methods In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the "Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. Results In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. Conclusion This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study. [ABSTRACT FROM AUTHOR]

Summary: This study investigated the association of nutritional and haematological variables with maximum time‐averaged mean velocity (TAMV) measured by transcranial Doppler (TCD) velocity and the agreement of classification between two protocols. TCD categories included: normal (<170 cm/s), conditional (170–199 cm/s) and abnormal (≥200 cm/s) based on TAMV in distal internal carotid artery (dICA), middle cerebral artery (MCA), internal carotid bifurcation, anterior and posterior cerebral arteries. Of 358 children with sickle cell anaemia (SCA) examined, the mean age (±standard deviation) was 7·4 ± 2·7 years; 13·1% and 6·7% had conditional and abnormal velocities, respectively. Children with abnormal TCD velocities had higher prevalence of prior stroke (P = 0·006). Increased TAMV was associated with younger age (P = 0·001), lower weight (P = 0·001), height (P = 0·007) and oxygen saturation (P = 0·005). There was no association of TAMV with height‐age or body mass index (BMI) z‐scores. Adjusting for gender, BMI z‐score, age, previous stroke and oxygen saturation, mean corpuscular volume (P = 0·005) and reticulocyte count (P = 0·013) were positively associated with TAMV, while haemoglobin concentration (P = 0·009) was negatively associated. There was good agreement [99%; weighted Kappa 0·98 (95% confidence interval 0·89–1), P = 0·0001] in TCD classification using data from five vessels versus two vessels (dICA and MCA). Haematological variables, rather than nutritional status, may be useful markers that identify high‐risk children with SCA. [ABSTRACT FROM AUTHOR]

Objective. We conducted a needs assessment for patients with sickle cell disease (SCD) in South Carolina using statewide administrative data to examine acute care utilization during a defined 12-month period. The data were collected to provide information for state and regional service providers, managed care companies, and policy makers to identify demographic gaps in care and inform policy and educational efforts to improve care. Methods. We obtained records on emergency department visits and hospitalizations through patient-based uniform billing data. We stratified analyses of acute care utilization and 30-day readmission rates by patient age, region, and expected payer. Results. Young adults, those with public insurance, and those who resided in a region with the largest number of patients had the highest rates of acute care utilization and 30-day readmissions. Patients who resided in a largely rural area without access to comprehensive care also had high rates of acute care utilization and readmissions. The pattern of readmissions data suggested that data on 7- or 14-day readmission rates, in addition to data on 30-day readmission rates, could be used as benchmarks of quality of care for adult patients with SCD. Conclusion. Administrative datasets can provide important information on demographic gaps in care for patients with SCD. The results highlight both national and regional issues in the provision of health-care services for patients with SCD. [ABSTRACT FROM AUTHOR]

Hypercoagulability in sickle cell disease (SCD) is associated with multiple SCD phenotypes, association with stroke risk has not been well described. We hypothesized that serum levels of biomarkers of coagulation activation correlate with high transcranial Doppler ultrasound velocity and decreases with blood transfusion therapy in SCD patients. Stored serum samples from subjects in the Stroke Prevention in Sickle Cell Anemia (STOP) trial were analyzed using ELISA and protein multiplexing techniques. 40 subjects from each treatment arm (Standard Care [SC] and Transfusion [Tx]) at three time points—baseline, study exit and one year post-trial and 10 each of age matched children with SCD but normal TCD (SNTCD) and with normal hemoglobin (HbAA) were analyzed. At baseline, median vWF, TAT and D-dimer levels were significantly higher among STOP subjects than either HbAA or SNTCD. At study exit, median hemoglobin level was significantly higher while median TCD velocity was significantly lower in Tx compared to SC subjects. Median vWF (409.6 vs. 542.9 μg/ml), TAT (24.8 vs. 40.0 ng/ml) and D-dimer (9.2 vs. 19.1 μg/ml) levels were also significantly lower in the Tx compared to the SC group at study exit. Blood levels of biomarkers coagulation activation/thrombin generation correlated positively with TCD velocity and negatively with number of blood transfusions. Biomarkers of coagulation activation/thrombin generation were significantly elevated in children with SCD, at high risk for stroke. Reduction in levels of these biomarkers correlated with reduction in stroke risk (lower TCD velocity), indicating a possible role for hypercoagulation in SCD associated stroke. [ABSTRACT FROM AUTHOR]

The Stroke With Transfusions Changing to Hydroxyurea (SWiCH ) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging /magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ⩾ Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85% /79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities , which were associated with worse stenoses (incidence risk ratio [IRR] =5.1,P⩽.0001 and IRR = 4.1 ,p <.0001) than normal velocities ; only 2% to 1 2% had any conditional/abnormal velocity . Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard /8 alternative arm subjects) had substantial parenchymal injury /vessel stenosis.At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis .SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980. [ABSTRACT FROM AUTHOR]

The risk of stroke for a child with SCD is many times greater than that of a healthy child without SCD or heart disease. There is a technique that allows the identification of the children with SCD who have high risk even within this relatively high-risk group. And there is a highly effective preventive treatment. While this would on the surface appear to be a straightforward medical decision, it is not. One must weigh the benefits of preventing permanent brain damage against the risks of infection from transfused blood, iron overload, which is the result of the frequent transfusions, and rare transfusion reactions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Stroke is a major complication of sickle cell disease (SCD). In an era of chronic red cell transfusions for stroke prophylaxis in children and greater life expectancy, nationwide data on stroke rates among pediatric and adult patients with SCD are scarce. We evaluated recent time trends in stroke hospitalization among children (0–17years) and adults (>17years) with SCD in the United States. Methods: Data were obtained from the Nationwide Inpatient Sample. Pediatric (n=26,380) and adult (n=9,638,507) patients admitted to hospitals between 1997 and 2006 with a primary stroke discharge diagnosis (identified by the International Classification of Diseases, Ninth Revision procedure codes) were included. Time trends in the proportion of stroke patients with SCD were computed. Results: Pediatric stroke patients with co-morbid SCD constituted 8.7% in 1997 vs. 4.8% in 2006 (p=0.04), with 81 fewer actual hospitalizations. Adult stroke patients with SCD were 0.3% in 1997 vs. 0.5% in 2006 (p=0.01), with 157 more actual hospitalizations. Factors that changed substantially and significantly across the decade among pediatric stroke patients with SCD included a drop in ischemic stroke type (74.2% vs. 56.3%) and a rise in comorbid hypertension (1.5% vs. 11.5%), while among adult stroke patients with SCD there was a rise in other stroke type (20.4% vs. 35.6%). Conclusions: In an era of increasing prophylactic red cell transfusions, the proportion of SCD diagnoses among pediatric stroke patients significantly decreased in the United States. The rise in SCD diagnoses among adult stroke patients is possibly due to a cohort effect, but further study is needed. [Copyright &y& Elsevier]

Elevation of blood flow velocity in the large cerebral vessels is known to be of substantial pathophysiologic and prognostic significance in sickle-cell disease (SCD). Its precise cause is not established, but the two obvious proximal mechanisms are obstructive vascular stenosis and hemodynamic dilatation. Here we revisit this distinction by analyzing cerebrovascular reserve capacity. Forty-two patients with SCD underwent measurements of global cerebral blood flow in grey matter by the 133Xe inhalation method during normocapnia and hypercapnia to quantify cerebrovascular reactivity. Cerebral blood flow was significantly higher in SCD patients (120±31 ml/100 g/min) than in controls (76±20 ml/100 g/min). Reactivity was significantly lower in SCD patients (1.06±1.92 versus 2.16±1.15%/mm Hg). Stepwise multiple regressions within the SCD sample determined that normocapnic cerebral blood flow was largely predicted by hematocrit (r=−0.59; P<0.0001), whereas hypercapnic reactivity was only predicted by normocapnic flow across all subjects (r=−0.52; P<0.0001). None of the controls, but 24% of the SCD patients showed ‘steal’ (negative reactivity, χ2=6.05; P<0.02). This impairment of vasodilatory capacity, occurring at perfusion levels above 150 ml/100 g/min, may reflect intrinsic limitations of the human cerebrovascular system and can explain both the elevated blood flow velocities and the high risk of stroke observed in such patients.Journal of Cerebral Blood Flow & Metabolism (2009) 29, 803–810; doi:10.1038/jcbfm.2009.6; published online 11 February 2009 [ABSTRACT FROM AUTHOR]

Elevated velocity in the internal carotid artery (ICA) or middle cerebral artery (MCA), detected by transcranial Doppler (TCD) ultrasonography, predicts an increased risk of stroke in children with sickle cell disease (SCD). Although strokes also occur in an anterior cerebral artery (ACA) distribution, the significance of elevated velocity in this vessel has not been determined previously. We assessed the effect of elevated ACA velocity on stroke risk using the results of the first adequate TCD study performed on 1975 children as part of The Stroke Prevention Trial in Sickle Cell Anemia (STOP). Elevated ACA velocity (≥170 cm/s) was associated with an increased risk of stroke ( P = 0·0013) after adjusting for the ICA/MCA classification. Among subjects with normal ICA/MCA velocity, the risk of stroke was more than 10-fold greater in those with elevated compared with normal ACA velocity (2·13 and 0·20 per 100 patient-years, respectively, P < 0·001); risk more than doubled with elevated compared with normal ACA velocity in those already at high risk due to abnormal ICA/MCA findings (7·56 vs. 3·22 per 100 patient-years, P = 0·042). Few of the strokes in those with elevated ACA velocity occurred in an ACA distribution, suggesting changes in blood flow velocity in anterior vessels may be associated with diffuse arterial disease or, alternatively, manifest collateral flow from compromised middle cerebral vessels. [ABSTRACT FROM AUTHOR]

Sickle cell disease is associated with a high risk of stroke in the early years of childhood. The risk of a secondary stroke can be significantly reduced through chronic blood transfusions. Prevention of the first stroke (primary prevention) was made possible through the use of transcranial Doppler (TCD) US and demonstrated in a randomized clinical trial called the stroke prevention trial in sickle cell anemia (STOP). TCD results were classified as normal, conditional, abnormal or inadequate based on velocity readings in specific arterial segments. The MCA and ICA were carefully searched to find the highest velocity, and this was used to stratify patients as to stroke risk. Those with abnormal or high-risk TCD received either monthly blood transfusions or no transfusions, and those randomized to transfusion had a much better outcome in terms of stroke (one stroke, versus ten in the control group) and also fewer other medical problems while transfused. TCD screening is recommended for SCD patients to begin at 24 months of age and should be repeated every 6-12 months during early childhood. Transcranial Doppler imaging (TCDI) can be easier to use and learn and with a few adjustments can provide equivalent predictive power. Currently, TCD is the only recommended method for treatment selection for primary-stroke prevention. MRI and MRA can provide important information on the status of the brain and the blood vessels and, when abnormal, indicate greater risk. Although TCD cannot predict all strokes, TCD and TCDI offer an opportunity to apply an effective therapy for patients in this risk group and reduce many first-time strokes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Ischemic stroke occurs in at least 11% of patients with homozygous sickle cell anemia (SCD) by the time they turn 20 years old. High risk associated with distal intracranial internal carotid (ICA) and proximal middle cerebral artery (MCA) stenosis can be detected by transcranial Doppler (TCD). TCD screening offers the possibility of reducing the risk of first stroke significantly based on a paradigm tested and proven to be effective in a stroke prevention trial in sickle cell anemia (STOP). Children with high flow velocity in the ICA and MCA of 200 cm/s time average mean of the maximum (TAMM) or higher had a 10% per year risk of first stroke that was reduced to <1% with regular red cell transfusion (reduction of hemoglobin S <30%). The clinical application of the STOP results could be enhanced if criteria for treatment could be found that are based on peak systolic velocity (PSV), the measure more commonly used in vascular ultrasound practice.Objective: To compare PSV and end diastolic velocity (EDV) with TAMM for prediction of stroke and to derive PSV cutpoints for STOP protocol definitions of conditional and abnormal TCD. Using the STOP TCD and stroke outcome data to compare PSV and TAMM in terms of stroke prediction, PSV cutpoints comparable to those based on TAMM and used in STOP were derived. Because of their familiarity to the vascular ultrasound community, PSV cutpoints should be an important alternative to TAMM and may increase availability of screening and risk stratification for children with this disease.Materials and Methods: Data from 1,937 baseline TCD studies from STOP were correlated with stroke outcome in those not treated with transfusion. Stroke prediction was assessed with survival analysis using TAMM, PSV and EDV as continuous variables individually and then pair-wise in the same model, which contained 53 stroke events.Results: PSV and EDV were highly correlated to the TAMM velocity (r=0.94). The multivariate model for prediction indicated that TAMM velocity was a better predictor than EDV, and PSV and TAMM were approximately equivalent. PSV cutpoints defining the two relevant STOP risk categories--"conditional," which should lead to increased TCD surveillance, and "abnormal," which should lead to strong consideration for treatment according to STOP--were derived taking into consideration known differences in measurements between the dedicated Doppler systems (TCD) used in STOP and the transcranial Doppler imaging (TCDI) systems commonly used in clinical practice. The recommended PSV cutpoint for conditional TCD is 200 cm/s, and for abnormal TCD triggering consideration for treatment is 250 cm/s.Conclusion: Assuming TCDI equipment is used and the STOP protocol is applied, a PSV cutpoint of 200 cm/s is recommended as the threshold for increased TCD surveillance (comparable to a TCD TAMM of 170 cm/s in STOP); a PSV of 250 cm/s is recommended as the cutpoint at which, if confirmed in a second examination, chronic transfusion should be considered. Assuming the STOP scanning protocol is used, PSV is at least as good as TAMM and can be used to select children with SCD for treatment or increased surveillance to prevent first stroke. [ABSTRACT FROM AUTHOR]

Background: The phenotypic heterogeneity of sickle cell disease is likely the result of multiple genetic factors and their interaction with the sickle mutation. High transcranial doppler (TCD) velocities define a subgroup of children with sickle cell disease who are at increased risk for developing ischemic stroke. The genetic factors leading to the development of a high TCD velocity (i.e. cerebrovascular disease) and ultimately to stroke are not well characterized. Methods: We have designed a case-control association study to elucidate the role of genetic polymorphisms as risk factors for cerebrovascular disease as measured by a high TCD velocity in children with sickle cell disease. The study will consist of two parts: a candidate gene study and a genomewide screen and will be performed in 230 cases and 400 controls. Cases will include 130 patients (TCD ≤ 200 cm/s) randomized in the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study as well as 100 other patients found to have high TCD in STOP II screening. Four hundred sickle cell disease patients with a normal TCD velocity (TCD < 170 cm/s) will be controls. The candidate gene study will involve the analysis of 28 genetic polymorphisms in 20 candidate genes. The polymorphisms include mutations in coagulation factor genes (Factor V, Prothrombin, Fibrinogen, Factor VII, Factor XIII, PAI-1), platelet activation/function (GpIIb/IIIa, GpIb IX-V, GpIa/ IIa), vascular reactivity (ACE), endothelial cell function (MTHFR, thrombomodulin, VCAM-1, ESelectin, L-Selectin, P-Selectin, ICAM-1), inflammation (TNFα), lipid metabolism (Apo A1, Apo E), and cell adhesion (VCAM-1, E-Selectin, L-Selectin, P-Selectin, ICAM-1). We will perform a genomewide screen of validated single nucleotide polymorphisms (SNPs) in pooled DNA samples from 230 cases and 400 controls to study the possible association of additional polymorphisms with the high-risk phenotype. High-throughput SNP genotyping will be performed through MALDI-TOF technology using Sequenom's MassARRAY™ system. Discussion: It is expected that this study will yield important information on genetic risk factors for the cerebrovascular disease phenotype in sickle cell disease by clarifying the role of candidate genes in the development of high TCD. The genomewide screen for a large number of SNPs may uncover the association of novel polymorphisms with cerebrovascular disease and stroke in sickle cell disease. [ABSTRACT FROM AUTHOR]

Background: Transcranial Doppler (TCD) has been demonstrated to identify those at highest risk of stroke among children with sickle-cell disease. Based on a randomized clinical trial [Stroke Prevention in Sickle-Cell Anemia Trial (STOP)], which ended in 1997, the National Heart Lung and Blood Division of NIH has recommended TCD screening and chronic blood transfusion based on Nicolet TC 2000 dedicated Doppler (TCD). Studies performed using TCD imaging modalities need to be correlated to that used in the clinical trial to provide information for treatment decisions when screening with TCDI.Objective: To correlate transcranial arterial time-averaged mean velocities obtained from an Acuson Transcranial Doppler Imaging to those obtained using the TCD as the gold standard for treatment decisions based on STOP.Materials and Methods: A total of 29 children with sickle-cell disease, age 3-16 years, were studied at one of two scanning sessions using both techniques and a scanning protocol based on that used in STOP performed and read independently. The average difference in the measured velocities for each arterial segment was tested to determine difference from zero. Differences were compared before and after modifications to the TCDI technique were made to mimic the STOP protocol more closely.Results: TCDI velocities were generally lower than TCD velocities for the same segment, but the difference was reduced (from 15 % to 10% for the middle cerebral artery) by modifications to the TCDI protocol.Conclusions: Measurements using the Acuson system are modestly lower than those obtained with dedicated Doppler using the Nicolet TCD. [ABSTRACT FROM AUTHOR]

Discusses the approaches to treatment of stroke in patients with sickle cell disease. Blood transfusion therapy; Hydroxyurea therapy; Bone marrow transplantation.

A letter to the editor is presented which discusses a meta-analysis four different U.S. population-based cohort studies, which found that sickle cell trait is not linked woth an increased risk of heart failure or abnormalities of cardiac structure and function.

Stroke is a devastating complication of sickle cell anemia (SCA), occurring in 11% of patients before age 20 years. Previous studies of sibling pairs have demonstrated a genetic component to the development of cerebrovascular disease in SCA, but few candidate genetic modifiers have been validated as having a substantial effect on stroke risk. We performed an unbiased whole-genome search for genetic modifiers of stroke risk in SCA. Genome-wide association studies were performed using genotype data from single-nucleotide polymorphism arrays, whereas a pooled DNA approach was used to perform whole-exome sequencing. In combination, 22 nonsynonymous variants were identified and represent key candidates for further in-depth study. To validate the association of these mutations with the risk for stroke, the 22 candidate variants were genotyped in an independent cohort of control patients (n = 231) and patients with stroke (n = 57) with SCA. One mutation in GOLGB1 (Y1212C) and another mutation in ENPP1 (K173Q) were confirmed as having significant associations with a decreased risk for stroke. These mutations were discovered and validated by an unbiased whole-genome approach, and future studies will focus on how these functional mutations may lead to protection from stroke in the context of SCA. [ABSTRACT FROM AUTHOR]

Abstract: Sickle cell anemia (SCA) associated cerebrovascular disease includes vascular remodeling, abnormal cerebral blood flow (CBF) and infarction. We studied the relationships between plasma brain derived neurotropic factor (BDNF), platelet derived growth factors (PDGF-AA and -AB/BB) and high trans-cranial Doppler (TCD) velocity, an indication of CBF velocity. Baseline plasma samples from 39 children (19 SCA with abnormal/high TCD [SATCD], 13 SCA with normal TCD [SNTCD] and 7 healthy non-SCA), were assayed for BDNF, PDGF-AA and -AB/BB plus 11 other cytokines. The sensitivity, specificity and usefulness of these biomarkers for stroke prediction was investigated. All subject groups were of similar age and gender distribution. Mean BDNF was significantly higher among SATCD than SNTCD (p =0.004) as was mean PDGF-AA (p =0.001). Similarly, mean PDGF-AA was higher among SCA subjects who developed stroke than those who did not (p =0.012). Elevated BDNF and PDGF-AA were good predictors of the presence of abnormally high CBF velocity and were both associated with severity of anemia. Elevated PDGF-AA predicted risk for stroke development. Stroke incidence and high TCD velocity were associated with elevated BDNF and PDGF-AA. These findings suggest a role for BDNF and PDGF-AA in the patho-physiological mechanism of cerebrovascular disease in SCA. [Copyright &y& Elsevier]

Summary: Sickle-cell anaemia is the most common cause of stroke in children, and stroke is one of the most devastating complications of sickle-cell disease. Overt strokes are typically due to large-artery vasculopathy affecting the intracranial internal carotid arteries and proximal middle cerebral arteries, whereas silent strokes typically occur in the territory of penetrating arteries. The sickled red blood cell can contribute to the pathogenesis of stroke via abnormal adherence to the vascular endothelium and by haemolysis, which results in endothelial cell activation, a hypercoaguable state, and alterations in vasomotor tone. Red-blood-cell transfusion, the most common preventive measure for stroke in sickle-cell disease, is associated with iron overload in chronic disease. Therefore, interventions directed towards the potential mechanisms that promote vasculopathy and occlusion in sickle-cell anaemia should be investigated. Here we review the epidemiology, clinical spectrum, and pathophysiology of stroke in sickle-cell disease to identify potential therapeutic targets. [Copyright &y& Elsevier]