Oxidative stress and haemolysis-associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). Microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin-1 and haematological parameters were compared between patients with SS and SC. Vascular function, oxidative and nitrosative markers were also measured in healthy (AA) children. SS and SC had increased plasma advanced oxidation protein products (AOPP), malondialdehyde, plasma antioxidant activities and NO end products, compared to AA. SC had lower catalase activity compared to AA and SS. Haemolytic rate, glutathione peroxidase and nitrotyrosine concentrations were significantly increased in children with SS compared to SC and AA. SS and SC had impaired microvascular reactivity compared to AA. In SS, the plateau phase of the response to local thermal heating was negatively associated with nitrotyrosine and AOPP. No association between vascular function parameters and oxidative stress markers was observed in SC. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress and could explain the better preserved microvascular function in this group. Abstract source Full text

Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease (SCD) who receive chronic or episodic red blood cell transfusions. Iron-induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging (MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long-term (over the 5 years prior to enrolment) mean serum ferritin (MSF), spot-ferritin values and liver iron content (LIC) measured using MRI and liver biopsy. Thirty-two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long-term MSF and spot-ferritin values significantly correlated with LIC by MRI-R2* (r = 0·77, P < 0·001; r = 0·82, P < 0·001, respectively). LIC by MRI-R2* had strong positive correlation with LIC by liver biopsy (r = 0·98, P < 0·001) but modest inverse correlation with cardiac MRI-T2* (r = -0·41, P = 0·02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression. Abstract source Full text

Erythrocytapheresis (ER) can improve outcome in patients with sickle cell disease (SCD). A good vascular access is required but frequently it can be difficult to obtain for sickle cell patients. Arterio-venous fistulas (AVFs) have been suggested for ER in SCD supported by limited evidence. We report the largest cohort of ER performed with AVFs from three French SCD reference centers. Data of SCD patients undergoing ER with AVFs in the French SCD reference center were retrospectively collected. The inclusion criteria were: SS or Sβ-Thalassemia and AVF surgery for ER. SCD-related complications, transfusion history, details about AVF surgical procedure, echocardiographic data before and after AVF, AVF-related surgical and hemodynamical complications were collected. Twenty-six patients (mean age 20.5 years, mean follow-up 68 months [11-279]) were included. Twenty-three patients (88.5%) required central vascular access before AVF. Fifteen AVFs (58%) were created on the forearm and 11 (42%) on the arm. Nineteen patients (73%) had stenotic, thrombotic or infectious AVF complications. A total of 0.36 stenosis per 1,000 AVF days, 0.37 thrombosis per 1,000 AVF days and 0.078 infections per 1.000 AVF days were observed. The mean AVF lifespan was 51 months [13-218]. One patient with severe pulmonary hypertension worsened after AVF creation and died. We report the first series of SCD patients with AVF for ER, demonstrating that AVFs could be considered as a potential vascular access for ER. Patients with increased risk for hemodynamic intolerance of AVFs must be carefully identified, so that alternative vascular accesses can be considered. Abstract source Full text

BACKGROUND: Although a blood genetic disease, sickle cell disease (SCD) leads to a chronic vasculopathy with multiple organ involvement. We assessed arterial stiffness in SCD patients and looked for associations between arterial stiffness and SCD-related vascular complications. METHODS: The CADRE (Coeur Artères et Drepanocytose, ie, Heart Arteries and Sickle Cell Disease) study prospectively recruited pediatric and adult SCD patients and healthy controls in Cameroon, Ivory Coast, Gabon, Mali, and Senegal. Patients underwent clinical examination, routine laboratory tests (complete blood count, serum creatinine level), urine albumin/creatinine ratio measure, and a measure of carotid-femoral pulse wave velocity (cf-PWV) and augmentation index (AI) at a steady state. The clinical and biological correlates of cf-PWV and AI were investigated by using a multivariable multilevel linear regression analysis with individuals nested in families further nested in countries. RESULTS: Included were 3627 patients with SCD and 943 controls. Mean cf-PWV was lower in SCD patients (7.5±2.0 m/s) than in controls (9.1±2.4 m/s, P<0.0001), and lower in SS-Sβ(0) than in SC-Sβ(+) phenotypes. AI, corrected for heart rate, increased more rapidly with age in SCD patients and was higher in SCD than in control adults. cf-PWV and AI were independently associated with age, sex, height, heart rate, mean blood pressure, hemoglobin level, country, and hemoglobin phenotype. After adjustment for these correlates, cf-PWV and AI were associated with the glomerular filtration rate and osteonecrosis. AI was also associated with stroke, pulmonary hypertension, and priapism, and cf-PWV was associated with microalbuminuria. CONCLUSIONS: PWV and AI are deeply modified in SCD patients in comparison with healthy controls. These changes are independently associated with a lower blood pressure and a higher heart rate but also with the hemoglobin phenotype. Moreover, PWV and AI are associated with several SCD clinical complications. Their prognostic value will be assessed at follow-up of the patients. Abstract source Full text

We report a case of subarachnoid hemorrhage in a 38-year-old patient with sickle cell anemia. This case highlights the limitations of non contrast computed tomography in the diagnosis of subarachnoid hemorrhage in patients with sickle cell disease as well as the special needs of this patient population in addressing the treatment of stroke. Abstract source Full text

Background: Sickle cell disease is a group of disorders characterized by deformation of erythrocytes. Renal damage is a frequent complication in sickle cell disease as a result of long-standing anemia and disturbed circulation through the renal medullary capillaries. Due to the improvement in life expectancy of people with sickle cell disease, there has been a corresponding significant increase in the incidence of renal complications. Microalbuminuria and proteinuria are noted to be a strong predictor of subsequent renal failure. There is extensive experience and evidence with angiotensin-converting enzyme (ACE) inhibitors over many years in a variety of clinical situations for patients who do not have sickle cell disease, but their effect in people with this disease is unknown. It is common practice to administer ACE inhibitors for sickle nephropathy due to their renoprotective properties; however, little is known about their effectiveness and safety in this setting. This is an update of a Cochrane Review first published in 2013.   Objectives: To determine the effectiveness of ACE inhibitor administration in people with sickle cell disease for decreasing intraglomerular pressure, microalbuminuria and proteinuria and to to assess the safety of ACE inhibitors as pertains to their adverse effects.   Search Methods: The authors searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Hameoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 03 June 2015.   Selection Criteria: Randomized or quasi-randomized controlled trials of ACE inhibitors designed to reduce microalbuminuria and proteinuria in people with sickle cell disease compared to either placebo or standard treatment regimen.   Data Collection and Analysis: Three authors independently applied the inclusion criteria in order to select studies for inclusion in the review. Two authors assessed the risk of bias of studies and extracted data and the third author verified these assessments.   Main Results: Five studies were identified through the searches, only one met our inclusion criteria. The included study randomized 22 participants (seven males and 15 females) having proteinuria or microalbuminuria with sickle cell disease and treated the participants for six months (median length of follow up of three months) with captopril or placebo. The overall quality of the outcomes reported was high, since most aspects that may contribute to bias were regarded to be of low risk, although allocation concealment was not reported. At six months, the study reported no significant difference in urinary albumin excretion between the captopril group and the placebo group, although the mean urinary albumin excretion in the captopril group was lower by a mean difference of -49.00 (95% confidence interval -124.10 to 26.10) compared to that of placebo. However, our analysis on the absolute change score showed significant changes between the two groups by a mean difference of -63.00 (95% confidence interval -93.78 to -32.22). At six months albumin excretion in the captopril group was noted to decrease from baseline by a mean of 45 ± 23 mg/day and the placebo group was noted to increase by 18 ± 45 mg/day. Serum creatinine and potassium levels were reported constant throughout the study. The potential for inducing hypotension should be highlighted; the study reported a decrease of 8 mmHg in systolic pressure and 5 mmHg in diastolic and mean blood pressure.   Authors' Conclusions: There is not enough evidence to show that the administration of ACE inhibitors is associated with a reduction of microalbuminuria and proteinuria in people with sickle cell disease, although a potential for this was seen. More long-term studies involving multiple centers and larger cohorts using a randomized-controlled design are warranted, especially among the pediatric age group. Detailed reporting of each outcome measure is necessary to allow a clear cut interpretation in a systematic review. One of the difficulties encountered in this review was the lack of detailed data reported in the included study. Abstract source Full text

Children and adults with sickle cell anemia (SCA) have a higher risk of strokes compared to age- and race-matched peers. Velocity in the middle cerebral or distal internal carotid artery as measured by transcranial Doppler ultrasound is a recognized method to identify children but not adults with SCA at high-risk for first stroke. For both children and adults with SCA that have had a stroke, no methods clearly identify individuals at highest risk of recurrent strokes or an initial silent stroke, the most common neurological injury. Methods to assess cerebral hemodynamics in SCA have been utilized for decades but often required radiotracers making them not feasible for screening and longitudinal follow-up. MRI approaches that do not require exogenous contrast have been introduced and are appealing in both clinical and research scenarios. Improved neuroimaging strategies hold promise for identifying individuals with SCA at increased risk of initial and recurrent infarcts, justifying more aggressive risk-based therapy. We review the epidemiology of stroke in SCA, the impact of strokes, stroke mechanisms, and potential imaging strategies including regional and global oxygen extraction fraction, cerebral blood flow, and vessel wall imaging to identify individuals at high-risk of stroke. Abstract source Full text

Background: Sickle cell disease is an inherited autosomal recessive blood condition and is one of the most prevalent genetic blood diseases worldwide. Acute chest syndrome is a frequent complication of sickle cell disease, as well as a major cause of morbidity and the greatest single cause of mortality in children with sickle cell disease. Standard treatment may include intravenous hydration, oxygen as treatment for hypoxia, antibiotics to treat the infectious cause and blood transfusions may be given. This is an update of a Cochrane review first published in 2010.   Objectives: To assess the effectiveness of blood transfusions, simple and exchange, for treating acute chest syndrome by comparing improvement in symptoms and clinical outcomes against standard care.   Search Methods: We searched The Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings.Date of the most recent search: 25 April 2016.   Selection Criteria: Randomised controlled trials and quasi-randomised controlled trials comparing either simple or exchange transfusion versus standard care (no transfusion) in people with sickle cell disease suffering from acute chest syndrome.   Data Collection and Analysis: Both authors independently selected trials and assessed the risk of bias, no data could be extracted.   Main Results: One trial was eligible for inclusion in the review. While in the multicentre trial 237 people were enrolled (169 SCC, 42 SC, 15 Sβ⁰-thalassemia, 11Sβ(+)-thalassemia); the majority were recruited to an observational arm and only ten participants met the inclusion criteria for randomisation. Of these, four were randomised to the transfusion arm and received a single transfusion of 7 to 13 ml/kg packed red blood cells, and six were randomised to standard care. None of the four participants who received packed red blood cells developed acute chest syndrome, while 33% (two participants) developed acute chest syndrome in standard care arm. No data for any pre-defined outcomes were available.   Authors' Conclusions: We found only one very small randomised controlled trial; this is not enough to make any reliable conclusion to support the use of blood transfusion. Whilst there appears to be some indication that chronic blood transfusion may play a roll in reducing the incidence of acute chest syndrome in people with sickle cell disease and albeit offering transfusions may be a widely accepted clinical practice, there is currently no reliable evidence to support or refute the perceived benefits of these as treatment options; very limited information about any of the potential harms associated with these interventions or indeed guidance that can be used to aid clinical decision making. Clinicians should therefore base any treatment decisions on a combination of; their clinical experience, individual circumstances and the unique characteristics and preferences of adequately informed people with sickle cell disease who are suffering with acute chest syndrome. This review highlights the need of further high quality research to provide reliable evidence for the effectiveness of these interventions for the relief of the symptoms of acute chest syndrome in people with sickle cell disease. Abstract source Full text

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation. Abstract source Full text Full text (PMC)

BACKGROUND/AIMS: Neuropathic pain is a known component of vaso-occlusive pain in sickle cell disease; however, drugs targeting neuropathic pain have not been studied in this population. Trials of acute pain are complicated by the need to obtain consent, to randomize participants expeditiously while optimally treating pain. We describe the challenges in designing and implementing the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study (NCT01954927), a phase II, randomized, double-blind, placebo-controlled trial to determine the effect of gabapentin for vaso-occlusive crisis. METHODS: In the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study, we aim to assess the analgesic effect of gabapentin during vaso-occlusive crisis. Difficulties we identified included avoiding delay of notification of study staff of potential participants which we resolved by automated notification. Concern for rapid randomization and drug dispensation was addressed through careful planning with an investigational pharmacy and a single liquid formulation. We considered obtaining consent during well-visits to avoid the time constraints with acute presentations, but the large number of patients and limited duration that consent is valid made this impractical. RESULTS: In all, 79% of caregivers/children approached have agreed to participate. The trial is currently active, and enrollment is at 45.8% of that targeted (76 of 166) and expected to continue for two more years. Maintaining staff availability after-hours remains problematic, with 8% of screened patients missed for lack of available staff. LESSONS LEARNED: Lessons learned in designing a trial to expedite procedures in the acute pain setting include (1) building study evaluations upon a standard-of-care backbone; (2) implementing a simple study design to facilitate consent and data capture; (3) assuring ample, well-trained study staff; and (4) utilizing technology to automate procedures whenever possible. CONCLUSION: This study design has circumvented many of the logistical barriers usually associated with acute pain trials and may serve as a prototype for future studies. Abstract source Full text