Impact of a paediatric-adult care transition programme on the health status of patients with sickle cell disease: study protocol for a randomised controlled trial (the DREPADO trial).

BACKGROUND: Thanks to advancements in medical care, a majority of patients with sickle cell disease (SCD) worldwide live beyond 18 years of age, and therefore, patients initially followed in paediatric departments are then transferred to adult departments. This paediatric-adult care transition is a period with an increased risk of discontinuity of care and subsequent morbidity and mortality. During this period, the patient will have to manage new interlocutors and places of care, and personal issues related to the period of adolescence. To take into consideration all these aspects, an interesting approach is to use the whole system approach to the patient, as presented in the biopsychosocial approach. The aim of this trial is to evaluate the impact of the proposed biopsychosocial paediatric-adult transition programme. METHODS: The DREPADO study is a multicentre randomised control trial comparing a control group (Arm A) to an interventional group with a paediatric-adult transition programme based on a biopsychosocial approach (Arm B). To be included, patients should have the SS, SC, or Sß form of sickle cell disease and be aged between 16 and 17 years. The randomisation in a 1:1 ratio assigns to Arm A or B. The primary outcome is the number of hospital admissions and emergencies for complications in the index hospital, in the 2 years after the first consultation in the adult department of care. Secondary outcomes consider the quality of life, but also include coping skills such as sense of self-efficacy and disease knowledge. To provide patient and parent knowledge and coping skills, the transition programme is composed of three axes: educational, psychological, and social, conducted individually and in groups. DISCUSSION: By providing self-care knowledge and coping skills related to SCD and therapeutics, helping empower patientsin relation to pain management and emotions, and facilitating the relationship to oneself, others, and care in Arm B of the DREPADO study, we believe that the morbidity and mortality of patients with SCD may be reduced after the proposed paediatric-adult transition programme. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03786549; registered on 17 December 2018; https://clinicaltrials.gov/.

Triglyceride/HDL-cholesterol ratio and plasminogen activator inhibitor-1 independently predict high pulse pressure in sickle cell trait and disease.

We hypothesised that TG/HDL-C ratio and PAI-1 would be associated with high pulse pressure (PP) in young adults with sickle cell trait (SCT) and sickle cell disease (SCD). We compared the clinical, biochemical, and cardiometabolic parameters among individuals with normal genotype (HbAA; n = 60), SCT (HbAS; n = 60), and SCD (HbSS; n = 60), all in steady state. Using multivariate linear regression analysis, high PP was positively related to TG/HDL-C ratio in SCT (ß = 0.307; p = .014) and PAI-1 (ß = 0.499; p = .001) in SCD. The curve of receiver operating characteristic also showed that TG/HDL-C ratio and PAI-1 are efficient predictors of high PP in SCT carriers and SCD patients, respectively. This study suggests that increased levels of TG/HDL-C ratio and PAI-1 may be salient risk factors that would promote the development of arterial stiffness and other CVD in SCT carriers and SCD patients.

Polymorphisms in genes that affect the variation of lipid levels in a Brazilian pediatric population with sickle cell disease: rs662799 APOA5 and rs964184 ZPR1.

This cross-sectional study investigated associations between SNPs in metabolizing lipid genes, alpha-thalassemia and laboratory parameters in two forms of sickle cell disease (SCD), sickle cell anemia (SCA) and hemoglobin SC disease (HbSC) in a pediatric population. Among the groups SCA and HbSC was found a higher proportion of increased triglycerides (TG) in SCA. High levels of TG were significantly associated with lower hemoglobin (p = 0.006) and HDL-C (p = 0.037), higher white blood cell count (p = 0.027), LDH (p = 0.004) and bilirubins (p < 0.05) in SCD. Patients with HDL-C ≤40 mg/dL had higher markers hemolytic levels. Therapy of HU significantly influenced several hematological and biochemical parameters but not lipid fractions. Genotypes of the APOA5 rs662799 were not associated with lipid levels. The G-risk allele rs964184/ZPRI ZNF259/ZPR1 gene (GC + GG genotypes) was associated with increased levels of TG in children ≥10 years old (p = 0.045) and the atherogenic ratio TG/HDL-C (p = 0.032) in SCD. The use of HU improves levels of hemolysis and inflammation markers in SCD with high TG and, while not interfering with lipid levels, seems to overlap the effect of the G-risk allele in on them. This study reported for the first time that rs964184 SNP could be a genetic modifier of TG in SCD.

Total Serum Magnesium Levels and Calcium-To-Magnesium Ratio in Sickle Cell Disease.

Background and objectives: Imbalance of calcium/magnesium ratio could lead to clinical complications in sickle cell disease (SCD). Low levels of magnesium have been associated with sickling, increased polymerization and vaso-occlusion (VOC) in sickle cell due to cell dehydration. The K-Cl cotransport plays a very important role in sickle cell dehydration and is inhibited by significantly increasing levels of magnesium. The study evaluated total serum magnesium levels and computed calcium/magnesium ratio in SCD patients and "healthy" controls. Materials and methods: The study was a case-control cross-sectional one, involving 120 SCD patients (79 Haemoglobin SS (HbSS)and 41 Haemoglobin SC (HbSC)) at the steady state and 48 "healthy" controls. Sera were prepared from whole blood samples (n = 168) and total magnesium and calcium measured using a Flame Atomic Absorption Spectrometer (Variant 240FS manufactured by VARIAN Australia Pty Ltd., Melbourne, VIC, Australia). Calcium/magnesium ratios were calculated in patients and the controls. Results: The prevalence of hypomagnesemia and hypocalcaemia among the SCD patients was observed to be 39.17% and 52.50% respectively, higher than the controls (4.17% and 22.92%, for hypomagnesemia and hypocalcaemia, respectively). Level of magnesium was significantly lower in the SCD patients compared to their healthy counterparts (p = 0.002). The magnesium level was further reduced in the HbSS patients but not significantly different from the HbSC patients (p = 0.584). calcium/magnesium ratio was significantly higher in the SCD patients (p = 0.031). Although calcium/magnesium ratio was higher in the HbSC patients compared to those with the HbSS genotype, the difference was not significant (p = 0.101). Conclusion: The study shows that magnesium homeostasis are altered in SCD patients, and their levels are lower in HbSS patients. Although calcium/magnesium ratio is significantly higher in SCD patients compared with controls, there is no significant difference between patients with HbSS and HbSC genotypes. Magnesium supplementation may be required in sickle cell patients.

Assessment of iron status and interplay between lipid peroxidation and antioxidant capacity in common hemoglobin variants in Osun State, southwestern Nigeria.

Hemoglobin (Hb) and iron are prooxidants in nature and sources of free radicals in the biological system of all Hb phenotypes. Recent evidence linked abnormal hemoglobin S and C (HbSC) in sickle cell disease (SCD) to various complications in multiple oxidative processes. However, similar studies in relation to abnormal Hb traits are sparse. Besides, reports on activities of antioxidant enzymes and iron status in SCDs are still contradictory. This study assessed the interplay between lipid peroxidation and antioxidant defense capacity in various Hb variants. We enrolled 193 participants with different Hb phenotypes. They were consecutive patients with sickle cell anemia (HbSS, n = 32) and hemoglobin SC (HbSC) disease (n = 28) regularly followed up in a steady state. Other participants were subjects with abnormal Hb traits (HbAS, n = 50; HbAC, n = 33) and normal controls (HbAA, n = 50). The hematocrit (Hct) level, hemoglobin (Hb) concentration, iron status, and biochemical parameters including malondialdehyde (MDA), total antioxidant status (TAS), superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzymes were investigated simultaneously. The MDA and SOD levels were significantly higher (P < 0.05) in Hb variants in order of HbSS>HbSC>HbAC>HbAS when compared with controls. Conversely, GPx and TAS levels showed significant reductions (P < 0.05). Similarly, Hct, Hb, and iron concentrations showed significant reductions (P < 0.05) sequentially following HbAC > HbAS > HbSC > HbSS compared with controls. The results suggest that both SCDs and the carriers were relatively more vulnerable to systemic oxidative stress against normal phenotype, and may be owing to ineffective antioxidant mechanisms needed for keeping spontaneous generations of free radicals in control without necessarily iron-mediated.

Clinical and hematological profile in a newborn cohort with hemoglobin SC / Perfil clínico e hematológico em uma coorte neonatal com hemoglobina SC

Abstract Objectives: Hemoglobin SC is the second most common variant of sickle-cell disease worldwide, after hemoglobin SS. The objectives of the study were to describe the clinical and laboratory characteristics of hemoglobin SC disease in children from a newborn screening program and treated at a blood center. Methodology: This study assessed a cohort of 461 infants born between 01/01/1999 and 12/31/2012 and followed-up until 12/31/2014. Clinical events were expressed as rates for 100 patient-years, with 95% confidence intervals. Kaplan-Meier survival curves were created. Results: The median age of patients was 9.2 years; 47.5% were female. Mean values of blood tests were: hemoglobin, 10.5 g/dL; reticulocytes, 3.4%; white blood cells, 11.24 × 109/L; platelets, 337.1 × 109/L; and fetal hemoglobin, 6.3%. Clinical events: acute splenic sequestration in 14.8%, blood transfusion 23.4%, overt stroke in 0.2%. The incidence of painful vaso-occlusive episodes was 51 (48.9-53.4) per 100 patient-years and that of infections, 62.2 episodes (59.8-64.8) per 100 patient-years. Transcranial Doppler ultrasonography (n = 71) was normal given the current reference values for SS patients. Hydroxyurea was given to ten children, all of whom improvement of painful crises. Retinopathy was observed in 20.3% of 59 children who underwent ophthalmoscopy. Avascular necrosis was detected in seven of 12 patients evaluated, predominantly in the left femur. Echocardiogram compatible with pulmonary hypertension was recorded in 4.6% of 130 children, with an estimated average systolic pulmonary artery pressure of 33.5 mmHg. The mortality rate from all causes was 4.3%. Conclusions: Clinical severity is variable in SC hemoglobinopathy. Several children have severe manifestations similar to those with SS disease.

Resumo Objetivos: A hemoglobinopatia SC é a segunda variante mais comum da doença falciforme no mundo, após a hemoglobinopatia SS. Os objetivos do estudo foram descrever as características clínicas e laboratoriais da hemoglobinopatia SC em recém-nascidos diagnosticados por programa de triagem neonatal e encaminhados para acompanhamento em hemocentro. Metodologia: Coorte de 461 recém-nascidos SC nascidos entre 01/01/1999 e 31/12/2012 e seguidos até 31/12/2014. A incidência de eventos clínicos foi expressa por taxas relativas a 100 pacientes-ano, com limites de confiança a 95%. Curvas de sobrevida foram construídas segundo Kaplan-Meier. Resultados: Mediana de idade, 9,2 anos; 47,5%, feminino. Médias dos valores hematológicos: hemoglobina 10,5 g/dL; reticulócitos 3,4%; leucometria 11,24 x 109/L; plaquetometria 337,1x109/L; hemoglobina fetal 6,3%. Eventos clínicos: sequestro esplênico agudo em 14,8%, hemotransfusão 23,4%, AVC isquêmico 0,2%. A incidência de episódios vaso-oclusivos dolorosos foi de 51 (48,9-53,4) por 100 pacientes-ano; a de infecções, 62,2 episódios (59,8-64,8) por 100 pacientes-ano. Doppler transcraniano (n = 71) foi normal, se usados os valores de referência de crianças SS. Dez pacientes usaram hidroxiureia, todos com melhoria das crises dolorosas. Retinopatia foi observada em 20,3% das 59 crianças que fizeram fundoscopia. Necrose avascular foi detectada em 7 de 12 pacientes avaliados, com predomínio no fêmur esquerdo. Ecocardiograma compatível com hipertensão pulmonar foi registrado em 4,6% de 130 crianças, com média estimada de 33,5 mm Hg de pressão arterial pulmonar. A taxa de mortalidade por todas as causas foi de 4,3%. Conclusões: A hemoglobinopatia SC tem gravidade variável; várias crianças apresentam manifestações clínicas intensas, semelhantes às da hemoglobinopatia SS.

Predicting changes in hemoglobin S after simple transfusion using complete blood counts.

BACKGROUND: Hemoglobin S percentages are used in the management of patients who have sickle cell disease. However, hemoglobin S measurements often are not routinely or rapidly performed. Rapid and accurate methods to estimate hemoglobin S levels after simple transfusion may improve the care of patients with sickle cell disease. STUDY DESIGN AND METHODS: A comprehensive review of the electronic medical record identified 24 stable patients with sickle cell disease who received simple red blood cell transfusions and had hemoglobin S measurements before and after the transfusion that were less than 72 hours apart. Examination of these patients identified 62 separate transfusions that met our criteria. Three simple equations that utilized complete blood count values and readily available information from the medical record were used to predict the post-transfusion hemoglobin S level after transfusion (Equation 1: predicted post-transfusion hemoglobin = pre-transfusion hemoglobin S × [pre-transfusion hemoglobin/post-transfusion hemoglobin]; Equation 2: predicted post-transfusion hemoglobin S = pre-transfusion hemoglobin S × [pre-transfusion hematocrit/post-transfusion hematocrit]; and Equation 3: predicted post-transfusion hemoglobin S = pre-transfusion hemoglobin S × total pre-transfusion hemoglobin/[total pre-transfusion hemoglobin + (red blood cell volume × 20)]). RESULTS: The predicted hemoglobin S values for all three equations showed a highly significant correlation with the measured post-hemoglobin S value. The coefficient of determination (R2 ) for Equations 1, 2, and 3 was 0.95, 0.92, and 0.97, respectively. Predicting the post-transfusion hemoglobin S value using estimates of the patient's total hemoglobin and the transfused hemoglobin (Equation 3) was the most precise. CONCLUSION: Reductions in hemoglobin S values in patients with sickle cell disease who receive simple red blood cell transfusions can be reliably predicted using complete blood cell measurements and simple arithmetic equations.

Clinical and hematological profile in a newborn cohort with hemoglobin SC.

OBJECTIVES: Hemoglobin SC is the second most common variant of sickle-cell disease worldwide, after hemoglobin SS. The objectives of the study were to describe the clinical and laboratory characteristics of hemoglobin SC disease in children from a newborn screening program and treated at a blood center. METHODOLOGY: This study assessed a cohort of 461 infants born between 01/01/1999 and 12/31/2012 and followed-up until 12/31/2014. Clinical events were expressed as rates for 100 patient-years, with 95% confidence intervals. Kaplan-Meier survival curves were created. RESULTS: The median age of patients was 9.2 years; 47.5% were female. Mean values of blood tests were: hemoglobin, 10.5g/dL; reticulocytes, 3.4%; white blood cells, 11.24×109/L; platelets, 337.1×109/L; and fetal hemoglobin, 6.3%. Clinical events: acute splenic sequestration in 14.8%, blood transfusion 23.4%, overt stroke in 0.2%. The incidence of painful vaso-occlusive episodes was 51 (48.9-53.4) per 100 patient-years and that of infections, 62.2 episodes (59.8-64.8) per 100 patient-years. Transcranial Doppler ultrasonography (n=71) was normal given the current reference values for SS patients. Hydroxyurea was given to ten children, all of whom improvement of painful crises. Retinopathy was observed in 20.3% of 59 children who underwent ophthalmoscopy. Avascular necrosis was detected in seven of 12 patients evaluated, predominantly in the left femur. Echocardiogram compatible with pulmonary hypertension was recorded in 4.6% of 130 children, with an estimated average systolic pulmonary artery pressure of 33.5mmHg. The mortality rate from all causes was 4.3%. CONCLUSIONS: Clinical severity is variable in SC hemoglobinopathy. Several children have severe manifestations similar to those with SS disease.

Differences of microparticle patterns between sickle cell anemia and hemoglobin SC patients.

Sickle cell anemia (SCA) and hemoglobin SC (HbSC) disease are the two most common forms of sickle cell disease (SCD), a frequent hemoglobinopathy which exhibits a highly variable clinical course. Although high levels of microparticles (MPs) have been consistently reported in SCA and evidence of their harmful impact on the SCA complication occurrences have been provided, no data on MP pattern in HbSC patients has been reported so far. In this study, we determined and compared the MP patterns of 84 HbSC and 96 SCA children, all at steady-state, using flow cytometry. Most of circulating MPs were derived from platelets (PLTs) and red blood cells (RBCs) in the two SCD syndromes. Moreover, we showed that HbSC patients exhibited lower blood concentration of total MPs compared to SCA patients, resulting mainly from a decrease of MP levels originated from RBCs and to a lesser extent from PLTs. We did not detect any association between blood MP concentrations and the occurrence of painful vaso-occlusive crises, acute chest syndrome and pulmonary hypertension in both patient groups. We also demonstrated for the first time, that whatever the considered genotype, RBC-derived MPs exhibited higher externalized phosphatidylserine level and were larger than PLT-derived MPs.

Hydroxyurea (hydroxycarbamide) for sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising fetal haemoglobin. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the effects of hydroxyurea therapy in people with SCD (all genotypes), of any age, regardless of setting. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries.Date of the most recent search: 16 January 2017. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials, of one month or longer, comparing hydroxyurea with placebo, standard therapy or other interventions for people with SCD. DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias. MAIN RESULTS: Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sߺthalassaemia (HbSߺthal) genotypes). Studies lasted from six to 30 months.Four studies (577 adults and children with HbSS or HbSߺthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent statistically significant differences in terms of quality of life and adverse events (including serious or life-threatening events). Seven deaths occurred during the studies, but the rates by treatment group were not statistically significantly different.Two studies (254 children with HbSS or HbSߺthal also with risk of primary or secondary stroke) compared hydroxyurea and phlebotomy to transfusion and chelation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts, but more occurrences of acute chest syndrome and infections in the hydroxyurea and phlebotomy group. There were no consistent statistically significant differences in terms of pain alteration and adverse events (including serious or life-threatening events). Two deaths occurred during the studies (one in a the hydroxyurea treatment arm and one in the control arm), but the rates by treatment group were not statistically significantly different. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early.The quality of the evidence for the above two comparisons was judged as moderate to low as the studies contributing to these comparisons were mostly large and well designed (and at low risk of bias); however evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events and results are applicable only to individuals with HbSS and HbSߺthal genotypes.Of the remaining two studies, one (22 children with HbSS or HbSߺthal also at risk of stoke) compared hydroxyurea to observation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts but no statistically significant differences in terms of adverse events (including serious or life-threatening events).The final study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea - there was statistically significant improvement in terms of measures of fetal haemoglobin, but no statistically significant differences in terms of adverse events (including serious or life-threatening events). No participants died in either of these studies and other outcomes relevant to the review were not reported.The quality of the evidence for the above two comparisons was judged to be very low due to the limited number of participants, the lack of statistical power (as both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. AUTHORS' CONCLUSIONS: There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSߺthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly in preventing chronic complications of SCD, recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with HbSC genotype. Future studies should be designed to address such uncertainties.

Thromboelastographic characterization of the activated clotting system in children with sickle cell trait or sickle cell disease.

BACKGROUND: Recent epidemiological evidence suggests sickle cell disease (SCD) and sickle cell trait (SCT) is a risk factor for venous thromboembolism. The increased in-vivo markers of thrombin generation support the notion that such patients are in a chronic hypercoagulable state. In an attempt to better understand the underlying mechanism, global hemostatic assays including thrombin generation assay (TGA) and thromboelastography (TEG) have been utilized by several groups, but thus far, have shown inconsistent results either due to small sample size or technical differences. OBJECTIVES: Global hemostatic characterization of children with SCD or SCT by using TGA and modified TEG methods. MATERIALS AND METHODS: In this pilot study, we obtained TGA, TEG and other hemostatic data on specimens from 13 patients with SCD, 14 with SCT and 12 race-matched healthy controls (NC). RESULTS: R time and K time with modified TEG methods were significantly shorter in SCD when compared to SCT and NC. Alpha and MA did not show any significant differences between the groups. There was no difference seen between SCT and NC. TGA profiles did not show any difference between the three groups. As expected the in-vivo markers of thrombin generation and activation of fibrinolysis including D dimer and thrombin-antithrombin complexes were significantly higher in SCD subjects as compared to SCT and NC. CONCLUSION: The modified TEG methods are able to detect the activated coagulation system for the SCD population but a larger and more homogenous SCT cohort needs to be studied for more conclusive results.

Velocidade de fluxo sanguíneo cerebral em crianças em crianças e adolescentes com doença falciforme em Salvador, Bahia / Cerebral blood flow velocity in children and adolescents with sickle cell disease in Salvador, Bahia

INTRODUÇÃO: A doença falciforme (DF) é caracterizada por complicações agudas e crônicas. Entre as agudas podemos citar: episódios álgicos, síndrome torácica aguda (STA), priapismo, crise hemolítica, infecções agudas e acidente vascular cerebral (AVC), sendo este útimo responsavel por complicações a longo prazo na infância. A velocidade do fluxo sanguíneo cerebral (VFSC) elevada é o fator de risco mais importante para o desenvolvimento do AVC em crianças com anemia falciforme. A identificação de pacientes de risco associados a velocidades de fluxo sanguíneos cerebrais anormais é realizada pelo Doppler transcraniano (DTC), exame fundamental à prevenção primária do AVC. OBJETIVOS: Avaliar as velocidades de fluxo sanguíneo cerebral em crianças e adolescentes com DF em Salvador-Bahia, para identificar aqueles com risco alto de AVC, além de correlacionar as velocidades de fluxo cerebral com os perfis clínico e hematológico dos pacientes. PACIENTES E MÉTODOS: O DTC por insonação, utilizando uma sonda de 2 MHZ...

BACKGROUND: Sickle cell disease (SCD) is characterized by acute episodes of illnesses (crises) such as bone pain crisis, acute chest syndrome (ACS), priapism, hemolytic crisis, acute infections; and acute and long term complications such as cerebrovascular accident (CVA). Abnormally high cerebral blood flow velocity is the most important risk factor for development of stroke in pediatric patients with sickle cell anemia, and its detection by transcranial Doppler (TCD) is fundamental in primary stroke prevention. Other clinical, hematologic and genetic risk factors of stroke have also been identified. OBJECTIVES: The study aimed at evaluating the cerebral blood flow velocities of children and adolescents with SCD in Salvador, Brazil, detect those at high risk of stroke and correlate the flow velocities with clinical and hematological profiles of the patients. PATIENTS AND METHODS: Transcranial Doppler was performed on subjects aged 2 to 16 years who fulfilled the inclusion criteria, using a 2 MHz...

Kidney Disease among Patients with Sickle Cell Disease, Hemoglobin SS and SC.

BACKGROUND AND OBJECTIVES: Sickle cell disease (SCD) is an inherited anemia that afflicts millions worldwide. Kidney disease is a major contributor to its morbidity and mortality. We examined contemporary and historical SCD populations to understand how renal disease behaved in hemoglobin SS (HbSS) compared with HbSC. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kidney function was examined in the multicentered Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) Trial (HbSS=463; HbSC=127; years 2007-2009) and historical comparator populations from the Cooperative Study of Sickle Cell Disease (CSSCD; HbSS=708) and the Multicenter Study of Hydroxyurea in Sickle Cell Disease (MSH; HbSS=299). RESULTS: In adults with SCD, eGFR was lower among older individuals: -1.78 ml/min per 1.73 m(2) per year of age (95% confidence interval [95% CI], -2.06 to -1.50; Walk-PHaSST Trial), -1.75 ml/min per 1.73 m(2) per year of age (95% CI, -2.05 to -1.44; MSH), and -1.69 ml/min per 1.73 m(2) per year of age (95% CI, -2.00 to -1.38; CSSCD) in HbSS compared with -1.09 ml/min per 1.73 m(2) per year of age (95% CI, -1.39 to -0.75) in HbSC (Walk-PHaSST Trial). Macroalbuminuria was seen in 20% of participants with SCD (HbSS or HbSC; P=0.45; Walk-PHaSST Trial), but microalbuminuria was more prevalent in HbSS (44% versus 23% in HbSC; P<0.002). In the Walk-PHaSST Trial, albuminuria was associated with hemolysis (higher lactate dehydrogenase, P<0.001; higher absolute reticulocyte count, P<0.02; and lower Hb, P=0.07) and elevated systolic BP (P<0.001) in HbSS. One half of all participants with HbSS (20 of 39) versus one fifth without (41 of 228) elevated tricuspid regurgitant jet velocity (≥3 m/s; adverse prognostic indicator in SCD) had macroalbuminuria (P<0.001). In the CSSCD, overt proteinuria, detected (less sensitively) by urine dipstick, associated with higher 3-year mortality (odds ratio, 2.48; 95% CI, 1.07 to 5.77). Serum bicarbonate was lower in HbSS (23.8 versus 24.8 mEq/dl in HbSC; P<0.05) and associated with reticulocytopenic anemia and decreased renal function. CONCLUSIONS: In SCD, albuminuria or proteinuria was highly prevalent, in HbSS more than in HbSC. Proteinuria associated with mortality in HbSS. Older individuals had a lower than expected eGFR, and this was more prominent in HbSS. Current management does not routinely address renal complications in SCD, which could plausibly reduce morbidity and mortality.

Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality.

Haemoglobin (Hb) SC disease is the second most common subtype of sickle cell disease and is potentially fatal. This study aimed to determine the clinical characteristics, outcome and predictors of mortality in HbSC disease patients, and to compare these findings with patients followed-up in different centres. Clinical, laboratory and outcome data were collected from a cohort of adult patients with HbSC disease followed between 1991 and 2103. Cox regression multivariate analysis was used to determine predictors of mortality. One hundred and fifty-five patients were followed-up over 20 years: 9% died and 70·8% had at least one complication. The most common complications were: painful crises (38·3%), retinopathy (33·8%), cholelithiasis (30·3%), osteonecrosis (24·8%) and sensorineural hearing disorders (9·7%). Frequency of chronic complications was similar in most studies. In multivariate analysis, hearing disorders remained an independent predictor of mortality (Odds Ratio 9·26, 95% confidence interval 1·1-74·8; P = 0·03). It was concluded that patients with HbSC disease receive a late diagnosis and there is remarkable similarity between the studies conducted in different centres around the world. Sensorineural hearing disorders were an independent predictor of mortality, suggesting that it may be useful to implement routine diagnostic screening.

Elevated hypercoagulability markers in hemoglobin SC disease.

Hemoglobin SC disease is a very prevalent hemoglobinopathy; however, very little is known about this condition specifically. There appears to be an increased risk of thromboembolic events in hemoglobin SC disease, but studies evaluating the hemostatic alterations are lacking. We describe the findings of a cross-sectional observational study evaluating coagulation activation markers in adult patients with hemoglobin SC, comparing them with those in sickle cell anemia patients and healthy controls. A total of 56 hemoglobin SC and 39 sickle cell anemia patients were included in the study, all in steady state, and 27 healthy controls. None of the patients was taking hydroxyurea. Hemoglobin SC patients had a significantly up-regulated relative expression of tissue factor, as well as elevations in thrombin-antithrombin complex and D-dimer, in comparison to controls (P<0.01). Hemoglobin SC patients had lower tissue factor expression, and thrombin-antithrombin complex and D-dimer levels when compared to sickle cell anemia patients (P<0.05). Markers of endothelial activation (soluble thrombomodulin and soluble vascular cell adhesion molecule-1) and inflammation (tumor necrosis factor-alpha) were both significantly elevated in hemoglobin SC patients when compared to controls, being as high as the levels seen in patients with sickle cell anemia. Overall, in hemoglobin SC patients, higher hemolytic activity and inflammation were associated with a more intense activation of coagulation, and hemostatic activation was associated with two very prevalent chronic complications seen in hemoglobin SC disease: retinopathy and osteonecrosis. In summary, our results demonstrate that hemoglobin SC patients have a hypercoagulable state, although this manifestation was not as intense as that seen in sickle cell anemia.

Blood typing profile of a school-aged population of a North Togo township.

The aim of this study was the determination of hemoglobin (Hb) variants and ABO blood groups in a school population aged 6 to 9 years in the township of Agbandé-Yaka in North Togo. A cross-sectional study was carried out on 570 children of four primary schools at Agbande-Yaka, between March and July 2010. Hemoglobin characterization was done by alkaline buffer electrophoresis and the blood types ABO-Rhesus (Rh) D by immuno-hematological methods. A Hb variant was detected in 37.0% of the schoolchildren. Among them, the AS trait accounted for 11.9% and the AC trait for 20.2%. Homozygous Hb S (HBB: c.20A>T) was not found but Hb C (HBB: c.19G>A) appeared at a frequency of 3.3%, while compound heterozygotes carrying Hb SC were seen at a frequency of 1.6%. The O, B and A blood groups accounted for 49.0, 26.8 and 21.9%, respectively. The Hb anomalies reached a high prevalence in this school population. These results are remarkable by the absence of homozygous Hb S individuals compared to homozygous Hb C individuals, which were as numerous as expected. The frequencies of the ABO blood groups are similar to what has been found in other West African populations.

Effects of oxidative stress on red blood cell rheology in sickle cell patients.

Sickle cell anaemia (SS) and sickle cell-haemoglobin C disease (SC) patients exhibit severe red blood cell (RBC) rheological alterations involved in the development of several complications. The contribution of oxidative stress in these haemorheological abnormalities is still unknown. We compared RBC reactive oxygen species (ROS) and glutathione (GSH) content, and the haemorheological profile of SS (n = 11), SC (n = 11) and healthy subjects (n = 12) at baseline and after in-vitro treatment with t-butyl hydroperoxide (TBHP). We showed: (i) higher RBC ROS content in SS and SC patients, with the highest level observed in SS patients; (ii) lower RBC GSH content in sickle syndrome patients, especially in SS patients; (iii) TBHP increased RBC ROS production and decreased RBC GSH content in all groups; (iv) TBHP decreased RBC aggregation and increased the strength of RBC aggregates in all groups but the increase in RBC aggregates strength was greater in sickle cell patients; (v) TBHP decreased RBC deformability in the three groups but with a higher magnitude in sickle cell patients. These data suggest that RBCs from sickle cell patients have an exaggerated response to oxidative stress, which is accompanied by a profound abnormal haemorheological profile, with greater alterations in SS than in SC patients.