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Approximately 2,000 infants with sickle cell disease are born each year in the United States. Sickle cell disease is an inherited disorder of red blood cell hemoglobin. Sickle cells increase adhesion and cause blockage in the small blood vessels, resulting in tissue damage. The cells' production of hemoglobin S results in two major pathophysiologic features of sickle cell disorders: chronic hemolytic anemia and vaso-occlusion. These disorders cause ischemic tissue damage and acute and chronic organ failure. Potential complications for children with sickle cell disease include vaso-occlusive events, splenic sequestration, bacterial septicemia from splenic hypofunction, aplastic crisis, pulmonary compromise including acute chest syndrome, renal tubular dysfunction and renal failure, priapism, aseptic necrosis, gallstones, delayed growth and development, leg ulcers, stroke and premature death. Three major sickle cell complications during the first years of life are dactylitis, splenic hypofunction and splenic sequestration. The risk for pneumococcal meningitis is 36 times greater in children with sickle cell anemia than for black children without the disease, and 314 times greater than for white children.
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PMID:The young child with sickle cell disease. 970 52

Hemoglobin S/O(Arab) (Hb S/O(Arab)) is a rare compound heterozygous hemoglobinopathy characterized by the presence of two variant beta-globin chains: beta6Glu --> Val (Hb S) and beta121Glu --> Lys (Hb O(Arab)). The diagnosis of Hb S/O(Arab) requires electrophoresis on both cellulose acetate and citrate agar, since Hb O(Arab) co-migrates with Hb C at alkaline pH and close to Hb S at acidic pH. To date only case reports and small series of patients with Hb S/O(Arab) have been described. To better characterize the clinical and laboratory aspects of this unusual disorder, we reviewed the Duke University Medical Center experience. We identified 13 African-American children and adults with Hb S/O(Arab) ranging in age from 2.7 to 62.5 years. All patients had hemolytic anemia with a median Hb of 8.7 gm/dL (range 6.1-9.9 gm/dL), and a median reticulocyte count of 5.8% (range 1.2-10.3%). The peripheral blood smear typically showed sickled erythrocytes, target cells, polychromasia, and nucleated red blood cells. All 13 patients have had significant clinical sickling events including acute chest syndrome (11), recurrent vasoocclusive painful events (10), dactylitis (7), gallstones (5), nephropathy (4), aplastic crises (2), avascular necrosis (2), leg ulcers (2), cerebrovascular accident (CVA) (1), osteomyelitis (1), and retinopathy (1). Four patients have died, including two from pneumococcal sepsis/meningitis at ages 5 and 10 years, one of acute chest syndrome at age 14 years, and one of multiorgan failure at age 35 years. We conclude that Hb S/O(Arab) disease is a severe sickling hemoglobinopathy with laboratory and clinical manifestations similar to those of homozygous sickle cell anemia.
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PMID:Hemoglobin S/O(Arab): thirteen new cases and review of the literature. 1020 1

Fifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9. 4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from -0.7 before transplantation to -0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients. (Blood. 2000;95:1918-1924)
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PMID:Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. 1070 55

Sickle cell disease is caused by a variant of the beta-globin gene called sickle hemoglobin (Hb S). Inherited autosomal recessively, either two copies of Hb S or one copy of Hb S plus another beta-globin variant (such as Hb C) are required for disease expression. Hb S carriers are protected from malaria infection, and this protection probably led to the high frequency of Hb S in individuals of African and Mediterranean ancestry. Despite this advantage, individuals with sickle cell disease exhibit significant morbidity and mortality. Symptoms include chronic anemia, acute chest syndrome, stroke, splenic and renal dysfunction, pain crises, and susceptibility to bacterial infections. Pediatric mortality is primarily due to bacterial infection and stroke. In adults, specific causes of mortality are more varied, but individuals with more symptomatic disease may exhibit early mortality. Disease expression is variable and is modified by several factors, the most influential being genotype. Other factors include beta-globin cluster haplotypes, alpha-globin gene number, and fetal hemoglobin expression. In recent years, newborn screening, better medical care, parent education, and penicillin prophylaxis have successfully reduced morbidity and mortality due to Hb S.
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PMID:Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. 1079 57

Clinical, molecular, and genetic advances have revealed new pathophysiologic insights and treatments for the growing number of recognized hematologic and nonhematologic abnormalities in sickle cell disease. Treatment targets of cellular dehydration, sickle hemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation have been validated as potential therapy. New uses for transfusion therapy hold the promise of decreased major symptoms of acute chest syndrome, stroke, and severe pain crises, but at the expense of increased risk for transfusion reactions, infections, and iron overload. Accumulated experience with autologous, chimeric, and stem cell bone marrow transplantation holds promise for a small percentage of patients with disease. Patient selection, suitable donors, and early mortality are still limiting factors. Genetic manipulation, which offers hope for ameliorating the disease in a larger percentage of patients, is progressing slowly. Combination and staged therapies will be developed and matched to the severity and progression of the patient's disease. Strategies for prevention of major organ damage to the brain, heart, lungs, and kidneys will be prospectively evaluated and refined.
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PMID:Major changes in sickle cell disease. 1095 46

A subset of 299 patients with homozygous sickle cell anaemia, enrolled in the cohort of the French Study Group on sickle cell disease (SCD), was investigated in this study. The majority of patients were children (mean age 10.1 +/- 5.8 yr) of first generation immigrants from Western and Central Africa, the others originated from the French West Indies (20.2%). We report the frequency of the main clinical events (mean follow-up 4.2 +/- 2.2 yr). The prevalence of meningitis-septicaemia and osteomyelitis was, respectively, 11.4% and 12% acute chest syndrome was observed in 134 patients (44.8%). Twenty patients (6.7%) developed stroke with peak prevalence at 10-15 yr of age. One hundred and seventy-two patients (58%) suffered from one or more painful sickle cell crises, while the others (42.5%) never suffered from pain. The overall frequency of acute anaemic episodes was 50.5%, (acute aplastic anaemia 46%; acute splenic sequestration 26%). A group of 27 patients were asymptomatic (follow-up > 3 yr). Epistatic mechanisms influencing SCD were studied. Coinherited alpha-thalassemia strongly reduced the risk of stroke (p <0.001) and increased that of painful crises (p < 0.02). There was a low prevalence of Senegal and Bantu (CAR) betas-chromosomes in patients with meningitis (p <0.04) and osteomyelitis (p < 0.03). Prevalence of Senegal betas-chromosomes was lower in the asymptomatic group of 27 patients (p < 0.02). The patients come from a population of unmixed immigrants in whom the beta-globin gene haplotype strongly reflects the geographic origin and identifies subgroups with a homogenous genetic background. Thus the observed effects might result more from differences in as yet unidentified determinants in the genetic background than from the direct linkage with differences in the beta-globin gene locus.
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PMID:Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. 1100 50

While the problem of stroke in the patients with sickle cell disease (SCD) has been known for more than 75 years, adequate preventive and treatment strategies are just now being tested. Recent data on prevalence and incidence have been obtained from the Cooperative Study of Sickle Cell Disease of more than 4000 patients with SCD observed in 23 US clinical centers over a 10-year period.1 The overall age-specific incidence of first stroke in SCD (homozygous sickle cell anemia) is low (0.13%) at ages younger than 24 months, increasing to just over 1% at ages 2 to 5 years, with only a slight decrement to 0.79% at ages 6 to 9 years. The risk of brain infarction declines until a second peak is seen at ages older than 50 years, when the incidence again increases to nearly 1.3%. Although intracranial hemorrhage does occur in young children with SCD, the risk is low compared with older children and adults. The Cooperative Study of Sickle Cell Disease reported risk factors for infarction to be prior transient ischemic attack, low steady-state hemoglobin values, and rate and recency of episodes of acute chest syndrome, as well as elevated systolic blood pressure. Risk factors for intracranial hemorrhage included low steady-state hemoglobin values and a high leukocyte count. The burden of cerebrovascular disease is even higher if subclinical magnetic resonance imaging (MRI) lesions, presumed to be ischemic, are included. The prevalence of such lesions is more than 22% in patients with SCD, and most of these patients have not reported symptoms, although specialized neuropsychological testing shows lower scores in children with silent lesions on MRI scans. Patients with a history of clinical stroke typically have infarcts in the cortex and deep white matter, whereas silent infarcts tend to be more limited to deep white matter. Common infarction patterns are characterized by wedge-shaped lesions of large-vessel territories; border zone infarctions, particularly of the middle and cerebral artery watershed region; and small punctate lesions of the deep white matter. Fat embolism to the brain and venous thromboses are encountered rarely.
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PMID:Stroke prevention and treatment in sickle cell disease. 1129 86

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P =.0002) and days in the hospital (P <.01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support. (Blood. 2001;97:3628-3632)
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PMID:Five years of experience with hydroxyurea in children and young adults with sickle cell disease. 1209 15

The relationship between each of haemoglobin concentration (Hb), red cell count (RCC), white cell count (WBC), platelet count (PLT), mean corpuscular volume (MCV), red cell width difference (RWD), and average number of acute admissions per year (AVEADM), were determined in a cross-sectional study of 128 Afro-Caribbean sickle cell anaemia patients attending the Sickle Cell Disease Clinic of Central Middlesex Hospital in London for a mean of 7.6 patient-years. The diagnosis of sickle cell anaemia was made by both haematological and DNA analyses. The haematological parameters were determined using Coulter S automated counter during the steady state periods while the AVEADM was computed from all admissions for painful crisis, acute anaemia and acute chest syndrome, priapism, and acute stroke. Haemoglobin F level was determined by HPLC. Analysis was done in the paediatric and adult patients separately. There were no significant correlations between any of the parameters and AVEADM in the paediatric group. In adult patients, there was significant positive correlation (P < 0.05) between WBC and AVEADM. WBC has a negative correlation with Hb concentration and HbF level. WBC 10 x 10(9)/L and above is associated with Hb and HbF level below the mean for the group. WBC is lower but not significantly, in patients with single alpha-gene deletion than in those without deletion (P = 0.06). This study suggests that higher WBC count may suggest possible increased hospital admission, lower Hb concentration, and lower HbF level, in adult patients, and that, as a single parameter it can be of value in the assessment of patients with sickle cell anaemia. Possible mechanisms for these findings are also suggested.
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PMID:The predictive value of white cell count in assessing clinical severity of sickle cell anaemia in Afro-Caribbeans patients. 1137 63

Acute and chronic vascular occlusion underlies much of the morbidity and mortality in sickle disease. Abnormal polymerization of deoxygenated hemoglobin S (HbS) resulting in stiff, non-deformable erythrocytes is central to sickle cell pathogenesis. However, a complex interplay of many factors determines the balance between adequate blood flow and vessel obstruction. Serum markers of inflammation have provided evidence for a state of chronic inflammation in sickle cell disease (SCD). Inflammation promotes endothelial adherence to sickle erythrocytes. Studies demonstrating a beneficial effect of steroid therapy for painful episodes and acute chest syndrome provide indirect evidence for the role of inflammation in this disease. Leukocytosis, in the absence of infection, is common in SCD patients and predicts for stroke, acute chest syndrome, and overall mortality. Neutrophils and monocytes have been shown to be activated in these patients. Activated leukocytes further promote vascular inflammation and vessel damage. A reduction in leukocytes, and thus inflammation, may partially explain the beneficial effects of hydroxyurea in this disease. These data provide a strong rationale for clinical studies of therapy directed at inflammation and/or leukocytes in sickle cell disease.
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PMID:The Role of Inflammation and Leukocytes in the Pathogenesis of Sickle Cell Disease; Haemoglobinopathy. 1139 40


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