Showing papers on "Sickle cell anemia published in 2009"

Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease

Abstract: Background Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease. Methods Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward. Results All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. M...

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

Abstract: Background Sickle cell disease is characterized by a hypercoagulable state as a result of multiple factors, including chronic hemolysis and circulating cell-derived micr oparticles. There is still no consensus on the cellular origin of such microparticles and the exact mechanism by which they may enhance coagulation activation in sickle cell disease. Design and Methods In the present study, we analyzed the origin of circulating microparticles and their procoagulant phenotype during painful crises and steady state in 25 consecutive patients with sickle cell disease. Results The majority of microparticles originated from platelets (GPIIIa,CD61) and erythrocytes (glycophorin A,CD235), and their numbers did not differ significantly between crisis and steady state. Erythrocyte-derived micr oparticles strongly correlated with plasma levels of markers of hemolysis, i.e. hemoglobin (r=-0.58, p 0.05). The extent of factor XI inhibition was associated with erythrocyte-derived micr oparticles (r=0.50, p=0.023). Conclusions

Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases.

Abstract: The innovation of reprogramming somatic cells to induced pluripotent stem cells provides a possible new approach to treat β-thalassemia and other genetic diseases such as sickle cell anemia. Induced pluripotent stem (iPS) cells can be made from these patients' somatic cells and the mutation in the β-globin gene corrected by gene targeting, and the cells differentiated into hematopoietic cells to be returned to the patient. In this study, we reprogrammed the skin fibroblasts of a patient with homozygous β0 thalassemia into iPS cells, and showed that the iPS cells could be differentiated into hematopoietic cells that synthesized hemoglobin. Prenatal diagnosis and selective abortion have been effective in decreasing the number of β-thalassemia births in some countries that have instituted carrier screening and genetic counseling. To make use of the cells from the amniotic fluid or chorionic villus sampling that are used for prenatal diagnosis, we also showed that these cells could be reprogrammed into iPS cells. This raises the possibility of providing a new option following prenatal diagnosis of a fetus affected by a severe illness. Currently, the parents would choose either to terminate the pregnancy or continue it and take care of the sick child after birth. The cells for prenatal diagnosis can be converted into iPS cells for treatment in the perinatal periods. Early treatment has the advantage of requiring much fewer cells than adult treatment, and can also prevent organ damage in those diseases in which damage can begin in utero or at an early age.

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

Abstract: Background Elevation of echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The definition, prevalence and clinical correlates of elevated jet velocity have not been established in pediatric patients. The present study tested the hypotheses that elevated jet velocity affects 10% of pediatric patients, is associated with both hemolysis and hypoxia, and has clinical correlates with acute chest syndrome, stroke, transfusion requirement and abnormal 6-minute walk test results.Design and Methods A prospective multicenter study of 310 patients aged 3–20 years old with sickle cell disease under basal conditions and 54 matched controls was conducted. A hemolytic index was generated by principal component analysis of the levels of lactate dehydrogenase, aspartate aminotransferase and bilirubin and reticulocyte count.Results Elevated jet velocity (defined as ≥2.60 m/sec based on the mean±2 SD in controls) occurred in 32 patients (11.0%) including one child of 3 years old. After adjustment for hemoglobin concentration, systolic blood pressure and left ventricular diastolic function, a 2 SD increase in the hemolytic index was associated with a 4.5-fold increase in the odds of elevated jet velocity (p=0.009) and oxygen saturation ≤98% with a 3.2-fold increase (p=0.028). Two or more episodes of acute chest syndrome had occurred in 28% of children with elevated jet velocity compared to in 13% of other children (p=0.012), more than ten units of blood had been transfused in 39% versus 18% (p=0.017) and stroke had occurred in 19% versus 11% (p=0.2). The distance walked in 6-minute walk tests did not differ significantly, but oxygen saturation declined during the tests in 68% of children with elevated jet velocity compared to in 32% of other children (p=0.0002).Conclusions According to a pediatric-specific definition the prevalence of elevated jet velocity in this population of young patients with sickle cell disease was 11%. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation. Further investigations should address whether elevated jet velocity may indicate future complications and whether early intervention is beneficial.

Red blood cell aggregation, aggregate strength and oxygen transport potential of blood are abnormal in both homozygous sickle cell anemia and sickle-hemoglobin C disease

Abstract: Background Recent evidence suggests that red blood cell aggregation and the ratio of hematocrit to blood viscosity (HVR), an index of the oxygen transport potential of blood, might considerably modulate blood flow dynamics in the microcirculation. It thus seems likely that these factors could play a role in sickle cell disease. Design and Methods We compared red blood cell aggregation characteristics, blood viscosity and HVR at different shear rates between sickle cell anemia and sickle cell hemoglobin C disease (SCC) patients, sickle cell trait carriers (AS) and control individuals (AA). Results Blood viscosity determined at high shear rate was lower in sickle cell anemia (n=21) than in AA (n=52), AS (n=33) or SCC (n=21), and was markedly increased in both SCC and AS. Despite differences in blood viscosity, both sickle cell anemia and SCC had similar low HVR values compared to both AA and AS. Sickle cell anemia (n=21) and SCC (n=19) subjects had a lower red blood cell aggregation index and longer time for red blood cell aggregates formation than AA (n=16) and AS (n=15), and a 2 to 3 fold greater shear rate required to disperse red blood cell aggregates. Conclusions The low HVR levels found in sickle cell anemia and SCC indicates a comparable low oxygen transport potential of blood in both genotypes. Red blood cell aggregation properties are likely to be involved in the pathophysiology of sickle cell disease: the increased shear forces needed to disperse red blood cell aggregates may disturb blood flow, especially at the microcirculatory level, since red blood cell are only able to pass through narrow capillaries as single cells rather than as aggregates.

A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia.

Abstract: Background Hydroxyurea improves laboratory parameters and prevents acute clinical complications of sickle cell anemia (SCA) in children and adults, but its effects on organ function remain incompletely defined. Methods To assess the safety and efficacy of hydroxyurea in young children with SCA and to prospectively assess kidney and brain function, 14 young children (mean age 35 months) received hydroxyurea at a mean maximum tolerated dose (MTD) of 28 mg/kg/day. Results After a mean of 25 months, expected laboratory effects included significant increases in hemoglobin, MCV and %HbF along with significant decreases in reticulocytes, absolute neutrophil count, and bilirubin. There was no significant increase in glomerular filtration rate by DTPA clearance or Schwartz estimate. Mean transcranial Doppler (TCD) velocity changes were −25.6 cm/sec (P < 0.01) and −26.8 cm/sec (P < 0.05) in the right and left MCA vessels, respectively. At study exit, no child had conditional or abnormal TCD values, and none developed brain ischemic lesions or vasculopathy progression by MRI/MRA. Growth and neurocognitive scores were preserved and Impact-on-Family scores improved. Conclusions These pilot data indicate hydroxyurea at MTD is well-tolerated by both children and families, and may prevent chronic organ damage in young children with SCA. Pediatr Blood Cancer 2009;52:609–615. © 2008 Wiley-Liss, Inc.

Elevated IL-8 levels during sickle cell crisis

Abstract: The vaso-occlusive process (VOC) in sickle cell disease is of a complex nature. It involves intricate interactions between sickle red blood cells, endothelium and probably also leukocytes. As these interactions are regulated by cytokines, we analyzed the role of the potent neutrophil chemokine IL-8 by measuring serum levels in sickle cell patients during sickle cell crisis. These results were compared to nonsymptomatics and healthy controls. In patients having a vaso-occlusive crisis both HbSS and HbSC patients showed significantly enhanced serum IL-8 levels compared to healthy controls. Several of these patients showed extremely elevated serum IL-8 levels which were independent of the crisis inducing factor. Furthermore, a sickle cell patient with VOC as a complication of rhGM-CSF treatment similarly showed high IL-8 serum levels at crisis onset. Nonsymptomatic sickle cell patients serum IL-8 levels were comparable to healthy controls. These results implicate a role for IL-8 at or during (the initiation of) sickle cell crisis.

Hydroxyurea in sickle cell disease--a study of clinico-pharmacological efficacy in the Indian haplotype.

Abstract: There is clinical variability in the presentation of sickle cell disease among Indians. Vaso-occlusive crisis is common among non-tribal patients. Hydroxyurea, induces fetal hemoglobin (HbF) synthesis and reduces the clinical severity of sickle cell disease but individual patients have a variable response. This study was undertaken to investigate the efficacy and safety of hydroxyurea in Indians with severe manifestations where the beta(s) gene is linked to the Arab-Indian haplotype and is associated with higher HbF levels. Seventy-seven patients (29 adult sickle homozygous, 25 pediatric sickle homozygous, 23 adult sickle beta-thalassemia) selected for hydroxyurea therapy were evaluated for clinical, hematological, biochemical and genetic parameters and were followed for 24 months. Ninety-eight point seven percent of the sickle chromosomes were linked to the Arab-Indian haplotype, 27% of patients had associated alpha thalassemia and 65% were Xmn I +/+. Seventy-eight percent of the patients had no further crises after starting hydroxyurea. This effect was accompanied by a significant increase in HbF (p<0.001), but this increase was variable in individual cases. There was also an increase in gamma gene mRNA expression in the few cases so studied. Hemoglobin levels increased significantly (p<0.001) resulting in the cessation of blood transfusions. Leucopoenia was observed in one patient. Hydroxyurea was effective in reducing the clinical severity in Indian patients who initially had higher HbF levels and the presence of ameliorating factors, such as alpha-thalassemia and the Xmn I polymorphism. Hydroxyurea therapy with careful monitoring can thus change the quality of life of Indians with sickle cell disease.

Hematologic, biochemical, and cardiopulmonary effects of L-arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy.

Abstract: Objectives Fetal hemoglobin (HbF) induction involves NO-cGMP signaling pathways L-arginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU

Pain syndromes in sickle cell disease: an update.

Abstract: Objective. Pain has a critical role in the management of sickle cell disease (SCD). Patients may suffer from several pain syndromes, which may be or not may be associated with other clinical complications, such as anemia, organ failures, and infections. Design. Data for review were identified by using PubMed to search MEDLINE, limiting the search to abstract/articles in English, Italian, French, and Dutch. The key words pain, sickle cell disease, anemia, hemoglobin, hemoglobinopathy, analgesics, opioids, morphine, acetaminophen, paracetamol, nonsteroidal anti-inflammatory drugs, hematology, and quality of life were variously combined in the title, abstract, and key word search list. The abstract database of most hematological congresses and the bibliographies of most relevant articles were also considered. Results. There are two major types of SCD pain: acute and chronic. Sometimes, mixed and neuropathic pain can be also observed. Acute pain is mostly related to vaso-occlusion. Chronic pain may be due to some SCD complications, such as leg ulcers and avascular necrosis. Conclusions. Pain management in the SCD setting needs multidisciplinary approaches, given the several syndromes and the pathogenic mechanisms that are likely involved. Pain management is not standardized and often difficult, so that many patients with SCD are still poorly treated. Further efforts to develop care plans and treatment protocols as well as management guidelines are required.

Hepatic iron overload in children with sickle cell anemia on chronic transfusion therapy.

Abstract: Hepatic iron overload is a serious complication of chronic transfusion therapy in patients with sickle cell disease (SCD). No firm consensus has been reached with regard to correlation between hepatic iron content (HIC) and variables including age, number of transfusions, and serum iron makers. Also, the role of HIC in determining hepatic injury is not well established. There is scarcity of data on chronically transfused children with SCD and no other confounding liver pathology. We aimed to further explore relationships between these variables in a cohort of children with SCD on chronic transfusion therapy naive to chelation. Liver biopsies obtained before starting chelation therapy from 27 children with sickle cell anemia receiving chronic transfusion therapy were evaluated for histologic scoring and determination of HIC. Average serum ferritin and iron saturation values were determined for 6 months before biopsy. Duration and total volume of transfusion were obtained from the medical records. All children were negative for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infections. Mean age at biopsy was 10.95+/-3.34 years. Mean duration and total volume of transfusions were 50.0+/-26.6 months and 17.4+/-9.6 L, respectively. Pearson product-moment bivariate correlation coefficients indicated significant correlations between HIC and histologic iron score, serum ferritin, iron saturation, age, and transfusion volume. After adjusting for transfusion volume, a significant correlation was only seen between HIC and transfusion volume. Mean HIC was 21.8+/-10.4 mg/g dry weight, with fibrosis observed in 10 patients and lobular inflammation in 9. HIC was higher in biopsies with fibrosis (28.2+/-3.8 mg/g) than biopsies without fibrosis (17.6+/-18.3 mg/g; P=0.012). HIC did not differ between biopsies with lobular inflammation (25.5+/-4.0 mg/g) and biopsies without inflammation (19.9+/-2.5 mg/g; P=0.22). These findings show that transfusion volume provides more insight on hepatic iron overload than serum iron markers.

Sickle cell disease in children: differentiating osteomyelitis from vaso-occlusive crisis.

Abstract: Objective To identify clinical and laboratory features predictive of osteomyelitis in children with sickle cell disease and bony pain. Design Patients in the case group and participants in the control group were randomized in a 1:3 ratio. Setting The Hospital for Sick Children, Toronto, Ontario, Canada. Participants Patients with sickle cell disease and osteomyelitis (case patients) and patients with sickle cell disease and bony, vaso-occlusive crisis (control patients), 18 years or younger. Main Outcome Measures Five characteristics (number of painful sites, white blood cell count, swelling of the affected limb[s], and duration of pain and fever before presentation) at the time of presentation to hospital. Results Data were analyzed for 31 cases and 93 controls. Compared with controls, cases had more days of pain (5 vs 2 days; odds ratio [OR], 1.2; 95% confidence interval [CI], 1.1-1.4 days) and fever (1 vs 0 day; 1.7; 1.2-2.4 days) before presentation. Cases were also more likely to have swelling of the affected limb(s) (71% vs 17%; OR, 11.8; 95% CI, 4.6%-30.0%) and fewer painful sites (1 vs 2; 0.7; 0.5-1.0). On laboratory evaluation, cases had higher white blood cell counts (18.6 vs 15.6/μL; OR, 1.1; 95% CI, 1.0-1.1/μL). Multivariate logistic regression showed that the significant predictors of osteomyelitis were duration of fever (OR, 1.8; 95% CI, 1.2-2.6) and pain (1.2; 1.0-1.4) before presentation and swelling of the affected limb (8.4; 3.5-20.0). The risk of osteomyelitis was decreased if more than 1 painful site was present (OR, 0.7; 95% CI, 0.5-1.0). Conclusion In the clinical scenario of a child with sickle cell disease presenting with bony pain and swelling affecting a single site, with prolonged fever and pain, the physician should consider closer monitoring and investigations to exclude a diagnosis of osteomyelitis.

Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients

Abstract: A lowering of the haemoglobin oxygen saturation as determined by pulse oximetry is common in patients with sickle cell disease at steady state despite the lack of overt evidence of pulmonary dysfunction or intrinsic lung disease (Rackoff et al, 1993; Homi et al, 1997; Setty et al, 2003; Quinn & Ahmad, 2005). Decreased affinity of haemoglobin S for oxygen (Seakins et al, 1973; Ueda et al, 1979) and increased erythrocyte 2,3-bisphosphoglycerate (Milner, 1974) may partially, but probably not fully, explain decreased oxygen saturation in sickle cell disease given the wide range of saturations in patients. Several groups have reported the association of low with elevated serum lactate dehydrogenase, severity of anaemia and/or reticulocytosis, suggesting a possible aetiological relationship of haemolysis with hypoxemia (Rackoff et al, 1993; Homi et al, 1997; Setty et al, 2003; Quinn & Ahmad, 2005; Kato et al, 2006). It has been proposed that this association might involve haemolysis-associated ventilation-perfusion mismatch (Kato et al, 2007a). A developing paradigm of sickle cell disease manifestations proposes two overlapping but distinctively characteristic subphenotypes (Kato et al, 2007a). In the vasculopathy subphenotype, complications such as stroke, pulmonary hypertension, priapism and leg ulcers predominate and are linked to the degree of haemolysis and associated vascular dysfunction. In the vaso-occlusive subphenotype, markers of increased blood viscosity predict risk for infarctive complications, such as frequent pain crises, acute chest syndrome and avascular necrosis of bone. Steady state haemoglobin oxygen desaturation is a risk factor for overt stroke (Quinn & Sargent, 2008) and for pulmonary hypertension (Pashankar et al, 2008; Liem et al, 2009; Minniti et al, 2009) in sickle cell disease, two of the prominent manifestations of the haemolytic subphenotype. Nocturnal oxygen desaturation is also a risk factor for stroke, silent infarct or seizure (Kirkham et al, 2001). On the other hand, reported associations of lower haemoglobin oxygen saturation with increased episodes of pain (Hargrave et al, 2003) and acute chest syndrome (Rackoff et al, 1993), manifestations of the vaso-occlusive subphenotype, have not been confirmed in other studies (Quinn & Ahmad, 2005; Uong et al, 2006). We recently reported the initial results of an ongoing prospective, multicenter study of the prevalence and risk factors for developing pulmonary hypertension in children with sickle cell disease (PUSH Study) (Minniti et al, 2009). Both haemolysis and oxygen desaturation were independently associated with elevated tricuspid regurgitation velocity in this study. Pulmonary function testing and a six-minute walk were performed as a part of this study and pulse oximetry measurements were made before and after the walk. We hypothesized that lower oxygen saturations at steady state and oxygen desaturation during the six-minute walk may reflect pulmonary ventilation/perfusion mismatch related to the vascular effects of accelerated haemolysis. We investigated the relationship of oxygen saturation with medical history, echocardiographic measurements, pulmonary function testing and laboratory test results in this cohort.

Utilization of TCD screening for primary stroke prevention in children with sickle cell disease

Abstract: Background: In 1998, the Stroke Prevention Trial in Sickle Cell Anemia showed a >90% reduction in stroke rates after blood transfusion therapy in children with sickle cell disease (SCD) identified as high risk with transcranial Doppler ultrasonography (TCD) screening. Methods: We studied the utilization of TCD screening in a retrospective cohort of all children with SCD within a large managed care plan from January 1993 to December 2005. Rates of first TCD screening were estimated using life table methods; predictors of TCD were evaluated using Cox proportional hazards regression. Stroke incidence rates were estimated in person-time before (pre-TCD) and after (post-TCD) first TCD. Results: The average annual rate of TCD screening in 157 children with SCD was 1.8 per 100 person-years pre-1998, 5.0 from January 1, 1998, to December 31, 1999, and 11.4 after 1999. The only independent predictor of TCD screening was proximity to the vascular laboratory. The annualized stroke rate pre-TCD was 0.44 per 100 person-years, compared to 0.19 post-TCD. Conclusions: Since the Stroke Prevention Trial in Sickle Cell Anemia, the rate of transcranial Doppler ultrasonography (TCD) screening in sickle cell disease (SCD) has increased sixfold within a large health care plan. Children living farther from a vascular laboratory are less likely to be screened. Increased availability of TCD screening could improve the utilization of this effective primary stroke prevention strategy.

Haemoglobin oxygen saturation is a determinant of cerebral artery blood flow velocity in children with sickle cell anaemia.

Abstract: Steady-state haemoglobin (Hb) desaturation is a common finding in sickle cell anaemia (Hb SS) that could predispose to stroke by limiting oxygen delivery to the brain. To determine its association with the risk of overt stroke, we examined the relationship between daytime Hb saturation measured by pulse oximetry (SpO(2)) and cerebral artery blood flow velocity measured by transcranial Doppler ultrasonography (TCD), an established risk factor for overt stroke in Hb SS. We studied 181 children using multivariate models to control for known determinants of TCD velocity, including age, haematocrit, and a measure of stenosis. We found that SpO(2) correlated significantly and inversely with TCD velocity in both the right and left middle cerebral arteries. Hb desaturation was associated with increased cerebral artery blood flow velocities and increased odds of abnormal TCD velocities, hence increased risk of stroke. About 5% of the variation in TCD velocity could be ascribed to Hb saturation while controlling for other determinants of TCD velocity. In conclusion, Hb saturation is a determinant of TCD velocity and a risk factor for stroke in children with Hb SS.

Senicapoc (ICA-17043): A potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia

Abstract: Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hem...

An observational study of children with sickle cell disease in Kilifi, Kenya

Abstract: Globally, sickle cell disease (SCD) has its highest prevalence and worst prognosis in sub-Saharan Africa. Nevertheless, relatively few studies describe the clinical characteristics of children with SCD in this region. We conducted a prospective observational study of children with SCD attending a specialist out-patient clinic in Kilifi, Kenya. A total of 124 children (median age 6·3 years) were included in the study. Splenomegaly was present in 41 (33%) subjects and hepatomegaly in 25 (20%), both being common in all age groups. A positive malaria slide was found at 6% of clinic visits. The mean haemoglobin concentration was 73 g/l, compared to 107 g/l in non-SCD controls (P < 0·001). Liver function tests were elevated; plasma bilirubin concentrations were 46 μmol/l and aspartate aminotransferase was 124 iu/l. Forty-eight (39%) children were admitted to hospital and two died. Children with SCD in Kilifi have a similar degree of anaemia and liver function derangement to patients living in developed countries, but splenomegaly persists into later childhood. The prevalence of malaria was lower than expected given the prevalence in the local community. This study provides valuable data regarding the clinical characteristics of children living with SCD in a rural setting in East Africa.

Doppler-defined pulmonary hypertension and the risk of death in children with sickle cell disease followed for a mean of three years

Abstract: Pulmonary hypertension (PH) is associated with increased mortality in adults with sickle cell disease (SCD), but its prognostic significance in children is unknown. Eighty-eight children with SCD were followed after echocardiographic screening for PH. After a mean follow-up of 3 years, all 18 subjects with PH were alive. In our children, as in adults with SCD, PH was associated with increased haemolysis. In contrast, our subjects with PH did not have overt systemic disease observed in adults. PH may be a manifestation of progressive organ damage from chronic haemolysis and systemic vasculopathy that ultimately leads to early death in adulthood.

Auto-adjusting positive airway pressure in children with sickle cell anemia: results of a phase I randomized controlled trial

Abstract: Low nocturnal oxygen saturation (SpO2) is implicated in complications of Sickle Cell Anemia (SCA). Twenty-four children with SCA were randomized to receive overnight auto-adjusting continuous positive airway pressure (auto-CPAP) with supplemental oxygen, if required, to maintain SpO2 ≥94% or as controls. We assessed adherence, safety, sleep parameters, cognition and pain. Twelve participants randomized to auto-CPAP (3 with oxygen) showed improvement in Apnea/Hypopnea Index (p 3%/hour (p=0.02), mean nocturnal SpO2 (p=0.02) and cognition. Primary efficacy endpoint (Processing Speed Index) showed no group differences (p=0.67), but a second measure of processing speed and attention (Cancellation) improved in those receiving treatment (p=0.01). No bone marrow suppression, rebound pain or serious adverse event resulting from auto-CPAP use was observed. Six weeks of auto-CPAP therapy is feasible and safe in children with SCA, significantly improving sleep-related breathing disorders and at least one aspect of cognition.

Growth patterns in children with sickle cell anemia during puberty

Abstract: group screened and recruited for the study at the Clinical Center at Vanderbilt University Medical Center (CRC) included 19 males and 14 females, 10‐13 years old. Additionally, 31 African-American children from Nashville, who did not carry the sickle cell (HbS) gene or any other hemoglobinopathy were matched for sex, Tanner stage, and approximate height, weight, and fat mass to serve as a control for the study. The presence or absence of homozygous sickle cell disease (SCA) was confirmed through Hgb electrophoresis in all participants [11]. Patients with vaso-occlusive or pain crisis in the two months before screening, receiving chronic transfusion, on hydroxyurea therapy at baseline, or having apparent metabolic, skeletal, hepatic, or renal dysfunction, as well as pregnant females, were excluded from enrollment in the study. There were no subjects with disease characterized by stroke, multiple episodes of acute chest syndrome, or greater than three hospitalizations per year for pain due to the exclusion criteria of hydroxyurea or chronic transfusion. Self-reported complications occurring between the study visits were recorded. All children in the study were prescribed folic acid 1 mg orally per day by their primary hematologist. Children and their parents or guardians received Background. Previous studies of children with homozygous sickle cell anemia (SCA) show impaired growth and maturation. The correlation of this suboptimal growth with metabolic and hematological factors during puberty is poorly understood. Procedure. We studied a group of pre-adolescent children with SCA (19 males, 14 females) and healthy controls (16 males, 15 females) matched for race, sex, body size, and pubertal development. Height, weight, body mass index (BMI), and body composition changes were longitudinally assessed over a 2-year period and compared between the groups and with Z scores based on US growth charts. These changes were correlated with hemoglobin (Hgb) concentration and with energy expenditure (EE) measured using indirect whole-room calorimetry. Results. Children with SCA progressed through puberty slower than control children. While, after 2 years, pubertal males with SCA were shorter, their annual increases in weight were not different from controls. The mean fat free mass (FFM) increments were significantly less in males and females with SCA than in control children. In males with SCA, growth in height declined over time and was significantly slower than in matched controls (P < 0.05). Conclusion. Growth delays were present during puberty in children with SCA. Decreased growth velocity in children with SCA was independently associated with decreased Hgb concentration and increased total EE. Pediatr Blood Cancer. Pediatr Blood Cancer 2009;53: 635‐641. 2009 Wiley-Liss, Inc.

Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease.

Abstract: Carbon monoxide (CO) has anti-inflammatory properties. We previously reported that acute treatments with inhaled CO inhibit vascular inflammation and hypoxia-induced vasoocclusion in sickle cell disease mouse models. Therefore, we hypothesized that chronic CO inhalation would decrease vascular inflammation and organ pathology in a sickle cell disease mouse model. The treatment of sickle cell disease mice with 25 or 250 parts/million inhaled CO for 1 h/day, 3 days/wk for 8–10 wk significantly decreased the total mean white blood cell, neutrophil, and lymphocyte counts in peripheral blood. Eight weeks of 250 parts/million CO treatments reduced staining for myeloid and lymphoid markers in the bone marrow of sickle mice. Bone marrow from treated sickle mice exhibited a significant decrease in colony-forming unit granulocyte-macrophage during colony-forming cell assays. Anti-inflammatory signaling pathways phospho-Akt and phospho-p38 MAPK were markedly increased in CO-treated sickle livers. Importantly, CO-treated sickle mice had a significant reduction in liver parenchymal necrosis, reflecting the anti-inflammatory benefits of CO. We conclude that inhaled CO may be a beneficial anti-inflammatory therapy for sickle cell disease.