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Pathology of sickle cell disease
Abstract
Sickle cell disease (SCD) is a hereditary chronic hemolytic anemia with numerous clinical consequences. Intravascular sickling of red blood cells leads to multiorgan dysfunction. Although the pathophysiology of SCD has been well studied, there remains a lack of effective treatment. Refinements in overall care have improved quality of life; however, premature death is still not uncommon. SCD usually presents in childhood and is common in areas where malaria is (or was) common. The association with malaria is apparently of benefit to the individual because these individuals tend to contract a milder form of the disease. This review highlights the spectrum of pathology seen in people with SCD, with an emphasis on the pathogenesis of sudden death.
... A anemia falciforme (AF) é uma hemoglobinopatia de caráter hereditário, causada por uma mutação de ponto no gene da beta globina, gerando a hemoglobina S. Esta possui modificações físicas e químicas que conferem ao eritrócito uma maior rigidez e menor poder de deformabilidade na microcirculação e, quando em ambientes pobres em oxigênio, polimeriza-se, formando hemácias em foice. Os pacientes com essa patologia podem apresentar uma anemia hemolítica severa e contínua, em decorrência dadestruição dos eritrócitos pelo baço, sendo observado no seu hemograma um baixo nível de hemoglobina (MALOWANY, 2012;YAWN, 2014;YAZDANBAKHSH, 2012). ...
... A crise vasoclusiva geralmente é desencadeada por infecções agudas, em especial viroses e processos inflamatórios. A variação na sintomatologia da AF desencadeia nos pacientes desde a necessidade de transfusões de emergência, devido à anemia severa, ou nenhuma transfusão (MALOWANY, 2012;YAWN, 2014;YAZDANBAKHSH, 2012). ...
p> Objetivos: A aloimunização eritrocitária é um problema grave em pacientes que recebem transfusões, principalmente no tratamento das hemoglobinopatias, como a anemia falciforme. Os objetivos desse trabalho são estabelecer a frequência da aloimunização eritrocitária em pacientes com anemia falciforme e apontar os fatores envolvidos na aloimunização. Métodos: Estudo descritivo transversal retrospectivo de prevalência, sendo levantadas informações sobre aloimunização e fatores associados, em pacientes com anemia falciforme atendidos pelo Hemocentro de Caruaru, entre janeiro de 1987 a dezembro de 2012. As informações foram obtidas a partir da consulta a dados no sistema de prontuários médicos do Hemocentro, tabuladas em planilhas do programa Excel 2007 (Microsoft Office®) e analisadas estatisticamente através do software R, utilizando o Teste Exato de Fisher e OddsRatio. Resultados: A produção de anticorpos irregulares foi identificada em 11 pacientes, representando uma taxa de aloimunização de 34%. Os anticorpos encontrados foram: 05 anti-C (25%), 05 anti-E (25%), 03 anti-K (15%), 01 anti-D (5%), 01 anti-C<sup>w</sup> (5%), 01 anti-Fy<sup>a</sup> (5%), 01 anti-Jk<sup>a</sup> (5%), 01 anti-S (5%), 01 anti-Le<sup>a</sup> (5%) e 01 anti-Le<sup>b</sup> (5%). Observou-se que indivíduos com idade acima de 30 anos e pacientes que receberam acima de 10 concentrados de hemácias tiveram maior risco em desenvolver aloanticorpos. Conclusão: Transfusões de hemácias continuam sendo essenciais para o tratamento de complicações da anemia falciforme. A realização da fenotipagem eritrocitária poderá contribuir para reduzir a alosensibilização e consequentemente o número de reações transfusionais hemolíticas, aumentando a segurança transfusional e influenciando na qualidade de vida destes pacientes.</p
... 1 A hallmark of the disease is repeated bouts of ischemia secondary to polymerizing sickle red blood cells. 2 This leads to vaso-occlusion and microvessel injury, 3,4 as well as large vessel injury. [5][6][7] Consequently, the vast array of vascular complications in SCD, including strokes, retinopathy, sudden cardiac death, recalcitrant leg ulcers, kidney failure and other organ dysfunction, is likely multifactorial and complex. ...
... [5][6][7] Consequently, the vast array of vascular complications in SCD, including strokes, retinopathy, sudden cardiac death, recalcitrant leg ulcers, kidney failure and other organ dysfunction, is likely multifactorial and complex. 2,8,9 A normal physiological response to vascular injury is the development of collateral vessels to preserve end-organ function. That these patients experience multiple vascular complications may suggest impairment in collateral vessel formation after ischemic injury. ...
Objective:
The adaptive response to vascular injury is the formation of functional collateral vessels to maintain organ integrity. Many of the clinical complications associated with sickle cell disease can be attributed to repeated bouts of vascular insufficiency, yet the detailed mechanisms of collateral vessel formation after injury are largely unknown in sickle cell disease. Here, we characterize postischemic neovascularization in sickle cell disease and the role of neutrophils in the production of reactive oxygen species.
Approach and results:
We induced hindlimb ischemia by ligation of the femoral artery in Townes SS (sickle cell) mice compared with AA (wild type) mice. Perfusion recovery, ascertained using LASER Doppler perfusion imaging, showed significant diminution in collateral vessel formation in SS mice after hindlimb ischemia (76±13% AA versus 34±10% in SS by day 28;P<0.001; n=8 per group). The incidence of amputation (25% versus 5%) and foot necrosis (80% versus 15%) after hindlimb ischemia was significantly increased in the SS mice. Motor function recovery evaluation by the running wheel assay was also impaired in SS mice (36% versus 97% at 28 days post-hindlimb ischemia;P<0.001). This phenotype was associated with persistent and excessive production of reactive oxygen species by neutrophils. Importantly, neutrophil depletion or treatment with the antioxidant N-acetylcysteine reduced oxidative stress and improved functional collateral formation in the SS mice.
Conclusions:
Our data suggest dysfunctional collateral vessel formation in SS mice after vascular injury and provide a mechanistic basis for the multiple vascular complications of sickle cell disease.
... SCD is an autosomal recessive genetic blood disorder characterized by red cells which transform into abnormal, rigid, sickle shaped red RBCs, when they are in a hypoxic environment. SCD may lead to various acute complications with a high mortality rate such as splenic sequestration crisis, aplastic crisis and hemolytic crisis [1]. Blood transfusion with normal hemoglobin A RBCs is thought to increase oxygen saturation, and reduce red blood cell sickling. ...
... Comparison between TUBE and molecular genotyping in 9 SCD patients.1. identical/total = number of SCD patients with identical results from TUBE and molecular genotyping/number of total SCD patients; 2. discrepancy/total = number of SCD patients with discrepancy between TUBE result and molecular genotyping result/number of total SCD patients. ...
Objectives: Accurately identifying the Antigens (Ags) on recipient red blood cells (RBCs) is critical in prevention of RBC alloimmunization in chronically transfused patients. The goal of this study was to compare RBC molecular genotyping to serological phenotyping in those patients. Methods: Serological phenotyping and molecular genotyping methods were used to study blood samples from 18 healthy blood donors and 16 transfused patients. Reticulocyte harvesting or hypotonic cell separation was added to recheck RBC phenotypes of the patients with discrepancies between phenotyping and genotyping. Results: No discrepancies were found between the two genotyping methods in all the donors and patients. 1 of 9 sickle-cell disease (SCD) patients and all 3 thalasse-mia patients demonstrated discrepancies in multiple blood groups between phenotyping and ge-notyping, which were not corrected by reticulocyte harvesting or hypotonic cell separation. Conclusions: These findings suggest that RBC molecular genotyping is superior to serological pheno-typing in chronically transfused SCD or thalassemia patients.
... These changes lead to various acute and chronic complications. 5 Clinical presentations vary among sickle cell patients. Some include leg ulcers, priapism, fatigue, dizziness, osteonecrosis, bacteraemia, and dactylitis. ...
Sickle cell disease is caused by an abnormality of the β-globin gene and is characterised by sickling of the red blood cells. Globally, sub-Saharan African countries share the highest burden of the disease. This study aimed at critically reviewing studies focusing on challenges of sickle cell anaemia in sub-Saharan Africa. A literature search was carried out in five major databases. Articles that met the inclusion criteria were included in the bibliometric review and critical analysis. A majority of the studies were undertaken in the West African region (85.5%), followed by Central Africa (9.1%). Very few studies had been undertaken in East Africa (3.6%), whilst the Southern African region had the fewest studies (1.8%). Distribution in relation to country revealed that three quarters of the studies were carried out in Nigeria (74.5%), followed by the Democratic Republic of the Congo (9.1%). According to healthcare settings, a strong majority of the studies were undertaken in tertiary health care facilities (92.7%). Major themes that emerged from the review include interventions, cost of treatment, and knowledge about sickle cell disease. Public health awareness and promotion as well as improving the quality of sickle cell centers for prompt management of patients with sickle cell disorder was identified as a critical strategy towards reducing the burden of the disease in sub-Saharan Africa. To achieve this, governments in countries located in this region need to adopt a proactive strategy in addressing gaps that have been identified in this study, as well as instituting other relevant measures, such as continuous media engagement and public health interventions relating to genetic counselling. Reforms in other areas that can help reduce the disease burden, include training of practitioners and equipping sickle cell disease treatment centers according to World Health Organization specifications.
... The common manifestations of SCD include extreme anemia, hemolysis, Vaso-occlusive crisis and multi-organ damage due to ischemia/reperfusion injury, organ injury, splenic sequestration, jaundice, bone dactylitis, acute chest syndrome. SCD patients also suffer from several other bone related disorder such as osteomyelitis, dactylitis and avascular necrosis of femoral head making them refrain walking (3,4). ...
Introduction: Sickle cell disease (SCD) is one of the hereditary blood disorders that affects the red blood cells. Several lines of evidence indicated that the vitamin D deficiency (VDD) is quite common in children with SCD and vitamin D supplementation enhanced health-related quality of life in these patients. The present study is aimed to assess the exact prevalence of VDD in SCD patients using meta-analysis. Materials and Methods: A systematic search was conducted in PubMed and Google Scholar to extract the papers that contain prevalence data and numbers of patients with VDD in SCD patients and healthy people. Pooled prevalence was estimated using MAJOR module of Jamovi library. The overall risk ratio of having VDD in patients with SCD was calculated using the Review Manager (RevMan 5.4.1) program. Results: A total of 26 prevalence estimates from 25 papers were included in the meta-analysis. The pooled prevalence of VDD among SCD patients is 60% (95% CIs: 50%-70%). Further, VDD is not significantly different in both SCD patients and healthy controls (risk ratio of 1.28 and 95% CI of 0.81-2.04). Conclusion: Results of this meta-analysis indicate prevalence of VDD in SCD patients. Further, a well-designed, placebo-controlled RCTs have to be conducted to determine the effects and the safety of vitamin D supplementation in children and adults with SCD.
... This mutation results in the sickle shape of the affected hemoglobin molecule, which changes to that shape when deoxygenated in certain situations like infections. 7 This process can cause several acute complications like acute vaso-occlusive pain, acute chest syndrome, stroke, and priapism. 8,9 Sickle cell disease can result in some chronic complications as well, for example, it can cause chronic anemia, chronic bone pain, and avascular necrosis. ...
The presented case will shed some light on one of the rarest complications of HBSE disease, which is acute chest syndrome, and will highlight the management of that complication. The presented case will shed some light on one of the rarest complications of HBSE disease, which is acute chest syndrome, and will highlight the management of that complication.
... 1 Red cell deformation into rigid, sickle shapes under hypoxic stress conditions leads to ischaemia-reperfusion injury, haemolysis and endotheliopathy, resulting in organ damage and premature mortality. 2,3 While pregnancy in women with SCD is currently viewed more favourably, 4 maternal-fetal morbidity and mortality persist. [5][6][7][8][9] Sickle cell disease predominantly affects Black women. ...
We aimed to identify risk factors for adverse outcomes in pregnancies of women with sickle cell disease (SCD) and develop risk prediction models. Models were derived from a retrospective cohort of pregnant women with SCD and constructed using generalised estimating equation logistic regression, with clustering by woman. Maternal event(s) consisted of acute anaemia; cardiac, pulmonary, hepatobiliary, musculoskeletal, skin, splenic, neurological or renal complications, multi-organ failure, venous thromboembolism, admission-requiring vaso-occlusive events (VOE), red cell transfusion, mortality or hypertensive disorder of pregnancy. Fetal events included preterm birth, small-for-gestational-age or perinatal mortality. Of 199 pregnancies, 71% and 45% resulted in adverse maternal and fetal outcomes respectively. Low first-trimester haemoglobin, admission-requiring VOE in the year before pregnancy, multiple transfusions before pregnancy, SCD genotype and previous cardiac complications predicted maternal risk. Younger age and SCD genotype allowed early prediction of fetal risk (model-F1). Adding maternal event(s) and high lactate dehydrogenase enabled re-assessment of fetal risk with advancing gestation (model-F2). Models were well calibrated and moderately discriminative for maternal outcome (c-statistic 0·81, cross-validated value 0·79) and fetal outcome (model-F1 c-statistic 0·68, cross-validated value 0·65; model-F2 c-statistic 0·72, cross-validated value 0·68). The models will allow early identification of women with SCD at high risk of adverse events, permitting early targeted interventions and ongoing fetal risk re-assessment enabling intensification of surveillance and optimisation of delivery timing.
... We successfully engrafted SCD HSPCs in huHepMISTRGFah mice and detected circulating, sickling huRBCs in the mouse PB. In addition, we observed pathological changes in the lung, spleen, liver, and kidney that were comparable to changes in patients (30)(31)(32)(33) and established SCD mouse models (27,29). ...
A red-letter day for RBC research
The study of primary human red blood cell (huRBC) disorders such as sickle cell disease (SCD) and infectious diseases such as malaria has been hampered by a lack of in vivo models of human erythropoiesis. Song et al. transferred human fetal liver cells into MISTRG mice, which are immunodeficient and are genetically engineered with several human genes involved in hematopoiesis. This approach was unsuccessful because mature huRBCs are rapidly destroyed in the mouse liver. They then used CRISPR-Cas9 to mutate these mice into a fumarylacetoacetate hydrolase–deficient strain, allowing them to replace the mouse liver with engrafted human hepatocytes. These mice exhibited enhanced human erythropoiesis and circulating huRBC survival and could recapitulate SCD pathology when reconstituted with SCD-derived HSCs.
Science , this issue p. 1019
... For instance, variations associated with a certain disease in one population may appear harmless or are irrelevant in other populations. One famous example is malaria resistance in people carrying certain variations in hemoglobin, which on the one hand results in sickle-cell anemia, but on the other hand is a selection advantage, at least for heterozygous carriers, in geographic regions where malaria is prevalent [1,2]. As with other genetic variations, functional variations in TPC2 may also impact health and survival under certain environmental conditions and in certain geographical areas, while in others they might not. ...
The endo-lysosomal two-pore channel (TPC2) has been established as an intracellular cation channel of significant physiological and pathophysiological relevance in recent years. For example, TPC2 -/- mice show defects in cholesterol degradation, leading to hypercholesterinemia; TPC2 absence also results in mature-onset obesity, and a role in glucagon secretion and diabetes has been proposed. Infections with bacterial toxins or viruses e.g., cholera toxin or Ebola virus result in reduced infectivity rates in the absence of TPC2 or after pharmacological blockage, and TPC2 -/- cancer cells lose their ability to migrate and metastasize efficiently. Finally, melanin production is affected by changes in hTPC2 activity, resulting in pigmentation defects and hair color variation. Here, we analyzed several publicly available genome variation data sets and identified multiple variations in the TPC2 protein in distinct human populations. Surprisingly, one variation, L564P, was found to be the predominant TPC2 isoform on a global scale. By applying endo-lysosomal patch-clamp electrophysiology, we found that L564P is a prerequisite for the previously described M484L gain-of-function effect that is associated with blond hair. Additionally, other gain-of-function variants with distinct geographical and ethnic distribution were discovered and functionally characterized. A meta-analysis of genome-wide association studies was performed, finding the polymorphisms to be associated with both distinct and overlapping traits. In sum, we present the first systematic analysis of variations in TPC2. We functionally characterized the most common variations and assessed their association with various disease traits. With TPC2 emerging as a novel drug target for the treatment of various diseases, this study provides valuable insights into ethnic and geographical distribution of TPC2 polymorphisms and their effects on channel activity.
... In India, it is prevalent in the states of Chhattisgarh, Odisha, Maharashtra, Telangana, Gujarat, etc. (Deshmukh et al., 2006). It is a monogenetic, autosomal recessive haemoglobin disorder caused by a point mutation (A→T) that leads to replacement of glutamic acid with valine at sixth position in β-globin chain of haemoglobin (Malowany & Butany, 2012). In heterozygous state (AS), the person remains asymptomatic and is referred as sickle cell trait or carrier. ...
Sickle cell disease (SCD) is a haemoglobin disorder prevalent in Sub-Saharan Africa, Middle East and India. SCD is a major cause of morbidity and low quality of life in Chhattisgarh and other central Indian states. Currently, there is no estimate available for the number of SCD patients and carriers in Chhattisgarh. The Government of Chhattisgarh conducted a screening project for measuring prevalence of SCD among school-age children in the state in October 2007–December 2017 in six districts of the state. Using these screening data, an estimate of prevalence of SCD was made for school-age children in different geographical regions and social categories in Chhattisgarh. The numbers of SCD patients and carriers among school-age children in Chhattisgarh were estimated as 27,101 and 714,483, respectively. Furthermore, 79.64 per cent patients among school-age children, that is, 21,583 patients were estimated to reside in rural areas. The estimates may be of use in designing policies and developing strategies with better coordination and outreach for care of SCD patients. It is call of the time to develop dedicated infrastructure having medical, training, counselling and research facilities in a hierarchical manner comprising dedicated tertiary to primary care facilities in remote rural areas.
... Sickle cell anemia: Is due to a point mutation in the β globin gene, resulting in the creation of abnormal hemoglobin molecules with a hydrophobic motif that is exposed in its deoxygenated state (Malowany and Butany, 2012). ...
The present study was aimed to investigate the association between Vitamin B12 and iron levels in patients suffering from Helicobacter pylori infection in Gaza Strip. This study used descriptive, case-control design to find the association between study variables. The population consisted of 150 patients with positive H. pylori infection (cases) and equal number healthy individuals (control). H. pylori stool antigen was detected by strips, iron levels were measured using spectrophotometer, vitamin B12 levels were measured using immulite and CBC using Cell-dyne1800. The results of the study showed that B12, iron, Hb, RBCs, WBCs, HCT and MCHC levels between cases and control before treatment were significantly decreased (P ≤ 0.05). RDW levels between cases and control before treatment were significantly increased (P ≤ 0.05). B12 and iron levels between cases and control after treatment with Omeprazole, Amoxicillin and clarithromycin were significantly improved. In addition, there were significant differences in the levels of B12 and iron among cases before and after treatment, mean difference was 179.813, 49.743 and (P ≤ 0.05) respectively. The study concluded that H. pylori induced gastritis, gastric and duodenal ulcer appears to cause decrease in vitamin B12, iron levels and red blood cell index. Treatment of H. pylori with Omeprazole, Amoxicillin and clarithromycin improve most of parameters. H. pylori is associated with B12 and iron deficiency anemia in patients with gastritis.
Keywords: Vitamin B12, Iron, Gastric epithelial cells, Helicobacter pylori, Gaza strip
... Further, both chronic and acute clinical states of vaso-occlusion, ischemia and hypoxia are of potentially remarkable multiple sequels are evident. Several other complications, including stroke, splenic infarction, infection, priapism, acute chest syndrome, kidney failure, pulmonary hypertension, necrosis of bone, pain crisis and retinopathy are also prevalent in SCD [9][10][11]. The microcirculation occlusions (both clinical and subclinical), hemolysis and infections are of crucial events (inflammatory and non-inflammatory) that are involved in promoting of the cytokines and acute-phase proteins production and further secretion. ...
Abstract The word of hemoglobinopathy is described for an array of disorders that affecting hemoglobin (Hb) functions. Hb is a molecule with 68 kDa molecular weight, serving as oxygen carrying metalloprotein. Hemoglobinopathy includes a wide range of Hb structural deficits varying from thalassemia to sickle cell disease. Cyto-chemokine network members are pivotally involved in the pathogenesis of hemoglobinopathies, however, the exact role of these mediators in the development of these disorders yet to be well addressed. Cytokines and chemokines are generated by inflamed endothelial cells that promote the expression of their respected receptors and further activate NF-κβ, recruit red blood cells (RBCs) and white blood cells (WBCs) toward the inflamed endothelium. Therefore, due to critical roles played by the cyto-chemokine network in several aspects of hemoglobinopathies pathophysiology including apoptosis of endothelial cells, RBC, WBC and etc.…, in the present review, we focused on the critical parts played by this network in the pathogenesis of hemoglobinopathies.
... 2 Maternal complications include worsening anemia and a higher susceptibility to pain crises, acute chest syndrome, and infections. 1,11 SCD also doubles the risk of preeclampsia (PE) and increases the risk of eclampsia in homozygous patients by five times. 8 Fetal complications include higher risk of growth restriction, fetal demise, low birth weight, and prematurity. ...
Impact statement:
Environmentally induced changes in placental morphological and molecular phenotypes may provide relevant insight towards pathophysiology of diseases. The rare opportunity to evaluate the same patient, with sickle cell anemia (SCA), in two different pregnancies, of opposite outcomes (one early onset severe preeclampsia (PE) and the other mostly non-complicated) can prove such concept. In addition, the comparison to other conditions of known placental and vascular/inflammatory involvement strengthens such findings. Our results suggest that the clinical association between SCA and PE can be supported by common pathophysiological mechanisms, but that pathways involving response to copper and triglyceride metabolism may be important drivers of the pathophysiology of PE. Future studies using in a larger number of samples should confirm these findings and explore pathways involved in the pathophysiology of PE and its relationship with SCA.
... Sickle cell disease (SCD) is one of the most common inherited monogenic diseases and results from a homozygous single base substitution i.e., A > T in the β-globin (HBB) gene, leading to a glutamic acid (polar amino acid) to a valine (non-polar amino acid) change in codon 6 of HBB. This shift leads to a defective form of adult hemoglobin (Malowany and Butany, 2012). The use of gene therapy to correct the disease phenotype has had limited efficacy and furthermore, hydroxyurea remains the only disease-altering and clinically approved drug for SCD, to date (Agrawal et al., 2014). ...
Induced pluripotent stem cells (iPSCs) were first described over a decade ago and are currently used in various basic biology and clinical research fields. Recent advances in the field of human iPSCs have opened the way to a better understanding of the biology of human diseases.
Disease-specific iPSCs provide an unparalleled opportunity to establish novel human cell-based disease models, with the potential to enhance our understanding of the molecular mechanisms underlying human malignancies, and to accelerate the identification of effective new drugs. When combined with genome editing technologies, iPSCs represent a new approach to study single or multiple disease-causing mutations and model specific diseases in vitro. In addition, genetically corrected patient-specific iPSCs could potentially be used for stem cell based therapy. Furthermore, the reprogrammed cells share patient-specific genetic background, offering a new platform to develop personalized therapy/medicine for patients.
In this review we discuss the recent advances in iPSC research technology and their potential applications in hematological diseases. Somatic cell reprogramming has presented new routes for generating patient-derived iPSCs, which can be differentiated to hematopoietic stem cells and the various downstream hematopoietic lineages. iPSC technology shows promise in the modeling of both inherited and acquired hematological disorders. A direct reprogramming and differentiation strategy is able to recapitulate hematological disorder progression and capture the earliest molecular alterations that underlie the initiation of hematological malignancies.
... Other more sinister affecting 60% to 70% of people with SCD. [1,2] scenarios include; cholestasis, hepatic Approximately 24% of Nigerians are carriers of impairment and hepatitis. The chronic the sickle cell trait while another 150,000 complications tend to occur more frequently children are born annually with SCA. ...
... These individuals moved on a track that likely started in West Africa and continued to the Caribbean before reaching the United States (Hobart et al. 1998). It is tempting to speculate that the C6-deficient genotype in these individuals may have been selectively maintained in the face of malaria infection as has been suggested for sickle cell disease and systemic lupus erythematosus (Wurzner 2003;Malowany and Butany 2012;Waisberg et al. 2011). The protective effect of terminal pathway protein deficiency for malaria or CM remains to be established in humans; however, the studies with C5 −/− mice and treatment with anti-C9 antibodies provide a compelling basis for additional studies. ...
Studies demonstrate that complement is activated in malaria infections, including cerebral malaria (CM), the most severe form of the disease. Complement-mediated host defense offers little protection against malaria infection. What role then does complement play in malaria infection, particularly CM? Studies demonstrate that C5-deficient mice are highly resistant to experimental CM, the animal model for CM. Using complement-deficient mice, our laboratory surveyed the complement system to address which complement activation pathway(s) and components contribute to ECM development. Surprisingly, C4- and factor B-deficient mice were susceptible to disease, indicating that activation of the classical or alternative pathways is not required for ECM. C3-deficient mice are susceptible to ECM suggesting that the canonical C5 convertases are not required for ECM development and progression. Mice deficient in the receptors for C3a and C5a are fully susceptible to ECM. These results implicated C5b and the membrane attack complex (MAC) as the drivers of ECM pathogenesis. Indeed, treatment with anti-C9 antibody reduced mortality in ECM. The detection of C5a in the serum of C3-deficient mice suggested cleavage of C5 possibly by the extrinsic protease pathway. Overall, these data indicate that complement-mediated pathogenesis in ECM is terminal pathway dependent.
... Sickle cell disease (SCD) is an autosomal recessive disease that results from a point mutation on the beta-globin molecule leading to erythrocyte rigidity and increased episodes of vaso-occlusive crisis [1]. Under precipitating conditions, red blood cell sequestration and hemolysis give rise to the clinical presentation of the disease mainly marked by anemia, pain and multi-organ ischemic damage [2]. Recurrence of vaso-occlusive episodes has been associated to cerebro-vascular ischemic events, renal damage, pulmonary ischemia and alteration of some endocrine functions in SCD [3,4]. ...
Rheological modifications observed in sickle cell anemia are associated with ischemic complications that can cause target organ functional impairment. The objective was to investigate adrenal function of adult patients with sickle cell disease. In this cross-sectional study conducted in a tertiary referral hospital of the capital city of Cameroon, we enrolled ten crisis-free adult patients with sickle cell disease (SCD) and ten age- and sex-matched healthy individuals. We assessed adrenal function by testing basal cortisol levels and 60 min after tetracosactide (Synacthen®) injection using immuno-chemiluminescence method. Post-stimulatory cortisol was defined as primary endpoint and secondary endpoints include basal cortisol levels, post-stimulatory cortisol increments and the fold increase of cortisol one hour after stimulation. Sickle cell patients had an impairment of adrenal function despite no significant difference between patients’ and controls’ for basal or post-stimulatory cortisol levels. In fact, one patient in two failed to achieve a two-fold increase in cortisol levels after stimulation (5/10) as opposed to 1 in 10 in the control population (1/10), P = 0.070. The percent increment of cortisol after stimulation was lower in patients versus controls (133 vs 207, P = 0.047). Relative adrenal insufficiency is frequent in sub-Saharan adult patients with sickle cell disease despite normal basal cortisol levels. Our results suggest that adrenal function require further investigation during SCD crises as these represent an important stress and may worsen the prognosis.
... The condition is inherited as an autosomal recessive condition and is prevalent in the tropics where malaria is endemic. 1 SCD is due to a point mutation in the β-globin gene, resulting in the creation of abnormal haemoglobin (Hb) molecules with a hydrophobic motif that is exposed in its deoxygenated state. 2 The prevalence of healthy carriers of the sickle cell gene (sickle cell trait) ranges between 1% and 40% across Africa. 3 Nigeria has an estimated carrier prevalence of 6% to 24%. 4 An estimated 150,000 children are born with SCD in Nigeria annually 5 due to lack of premarital genotype test. ...
Background and Objectives: Bacterial infection in sickle cell anaemic patients is a major cause of mortality and requires proper treatment with appropriate antibiotics. However, continue defiant of these infections causing pathogens to many antibiotics and inadequate screening methods in overburden health care facilities such as ours in Kano, Nigeria necessitates the conduct of this study. A research was therefore conducted to isolate, characterize and test for antimicrobial susceptibility of bacteraemia-causing pathogens from febrile children with and without sickle cell disease in Kano, Nigeria. Method: A total of 225 venous blood samples from suspected sickle cell anaemic children attending three selected hospitals within Kano metropolis were collected and screened for sickle cell disease, followed by blood culture using automated blood culture system. The bacteria isolated from confirmed febrile SCD and non-SCD children were characterized using microscopic, biochemical and serological techniques. Their susceptibility to commonly used antibiotics was tested using disc diffusion method. Results: Of the 225 blood specimens screened, 68 (30.22%) were SCD positive, with the highest percentage (16%) among subjects within 1-2 years of age. A total of 11 genera of bacteria were isolated from both SCD and non SCD positive bloods, with Salmonella typhi having highest occurring rate in SCD positive children 27 (39.71%), followed by Streptococcus pneumoniae 10(14.71%), Salmonella Group B 9(13.24%), Staphylococcus aureus 4 (5.88%), and Escherichia coli 3 (4.41%). Majority of the isolates from SCD children 59 (86.76%) were highly susceptible to ciprofloxacin followed by cefuroxime 45 (66.18%), gentamicin 38 (55.88%), ceftriaxone 30 (44.12%), augmentin 39 (57.35%), ampicillin 25 (36.77%) and co-trimoxazole (22.06%). Conclusion: Bacteraemia in SCD confirmed children in the three hospitals are caused by a combination of 11 genera of bacteria. The lesser rate of bacteraemia was found in non-SCD children. Resistance to commonly used antibiotics is on increase, but treatment with ciprofloxacin and some 3 rd generation cephalosporin are still promising.
... The condition is inherited as an autosomal recessive condition and is prevalent in the tropics where malaria is endemic. 1 SCD is due to a point mutation in the β-globin gene, resulting in the creation of abnormal haemoglobin (Hb) molecules with a hydrophobic motif that is exposed in its deoxygenated state. 2 The prevalence of healthy carriers of the sickle cell gene (sickle cell trait) ranges between 1% and 40% across Africa. 3 Nigeria has an estimated carrier prevalence of 6% to 24%. 4 An estimated 150,000 children are born with SCD in Nigeria annually 5 due to lack of premarital genotype test. ...
Background and Objectives: Bacterial infection in sickle cell anaemic patients is a major cause of mortality and require proper treatment with appropriate antibiotics. However, continue defiant of these infections causing pathogens to many antibiotics and inadequate screening methods in overburden health care facilities such as our in Kano, Nigeria necessitates the conduct of this study. A research was therefore conducted on the characterizations and antimicrobial susceptibility of septicaemia-causing pathogens isolated from febrile children with sickle cell disease in Kano, Nigeria.
Method: A total of 225 venous blood samples from suspected sickle cell anaemicchildren attending three selected hospitals within Kano metropolis were collected and screened for sickle cell disease, followed by blood culture using automated blood culture system (BD BACTEC) respectively. The bacteria isolated from confirmed SCD patients were characterized using microscopic, biochemical and serological techniques. Results: Results showed that of the 225 specimens collected,68 (30.22%) were SCD positive, with the highest percentage (16%) among subjects within 1-2 years of age. A total of 11 genera of bacteria were isolated from the SCD confirmed bloods, with Salmonella typhi having highest occurring rate 27 (39.71%), followed by Streptococcus pneumoniae10 (14.71%), Salmonella Group B 9(13.24%), Staphylococcus aureus 4 (5.88%),and Escherichia coli 3 (4.41%).Majority of the isolates 59 (86.76%) were highly susceptible to ciprofloxacin followed by cefuroxime 45 (66.18%), gentamicin 38 (55.88%), ceftriaxone 30 (44.12%), augmentin 39 (57.35%), ampicillin 25 (36.77%) and co-trimoxazole (22.06%).
Conclusion: Septicaemia in SCD confirmed children in the three hospitals are caused by a combination of 11 genera of bacteria. Resistance to commonly used antibiotics are on increase, but treatment with ciprofloxacin is still promising.
... Leucocytes, particularly neutrophils, also share by expressing adhesive molecules. 1,7,8 ...
Sickle cell disease is an autosomal recessive disease characterized by recurrent vaso-occlusive events. Despite the genetic basis of its pathophysiology, recent researchers stated that it is an inflammatory immune-mediated disease where inflammation plays a crucial role in the initiation of adherence between sickle cells and vascular endothelial cells. Allergic, as well as infectious, inflammation is proposed to contribute to the initiation of vaso-occlusive events. Although several researchers reported an association between sickle cell disease and atopic conditions such as bronchial asthma and allergic rhino-conjunctivitis, few cases have reported an association between sickle cell disease and atopic dermatitis. Atopy was reported to be considerably linked to sickle cell disease for several reasons. Firstly, patients with sickle cell disease have higher IgE levels than the general population. Secondly, the mechanism of activation of molecular adhesion between endothelial and blood cells are similar between both sickle cell disease and atopic disease. Thirdly, the cytokines produced from platelet activation are the same cytokines that stimulate allergic inflammation in atopic diseases and promote adherence of sickle cells and endothelium in sickle cell disease. Lastly, sickle cell disease was reported to be associated with other atopic diseases.
... Sickle cells in human blood: both normal red blood cells and sickle-shaped cells are present. Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate (Malowany and Butany et al., 2012). ...
A great percentage of sickle cell anaemic patients in this University are in steady
state because of increased level of fetal haemoglobin (HbF) in most of them but
very few have minimal level of HbF which easily undergo crisis.Most of the
patients were detected in the course of medical examination. Because of the
delicate nature of these patients, the researchers of this study saw the necessity to
carry out the study. 20 confirmed sickle cell patients were used as the patients aged
4-34 year, 14 males and 6 females and 40 subjects with haemoglobin genotypes
AA were used as the controls. The study showed significant increase in WBC,
Neutrophil and Lymphocytes (P<0.05), significant decrease in PCV (P<0.05) and
no significant change in monocyte (P>0.05) when the mean values of the SCA
patients were compared relative to HbAA subjects.SCA patients should be
monitored closely and prevented from triggering factors to crisis.
... Under normal physiological conditions antioxidant defense system, balance the ROS and prevents or limits oxidative damage. Intracellular metabolism is the generator of ROS such as superoxide (.O 2-), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical (.OH), oxidative stress occur due to imbalance between oxidants and antioxidants because of increased pro- oxidants and/or decreased antioxidants trigger a cascade of oxidative reactions (Malowany et al., 2011). 50 Oxidative stress is a major cause of anemia and have role in complicating anemia with other infectious diseases (Wellems et al., 2009). ...
We present in this study a theoretical review of Sickle Cell Disease (SCD), highlighting on the pathophysiology and targeted pathways of antisickling products. Sickle cell disease (SCD) is one of the most common genetic disorders worldwide. It is caused by a point mutation that changes glutamic acid (Glu6) to valine (Val6) in the β chain of hemoglobin. This change has many damages: polymerization of abnormal haemoglobin HbS when oxygen tension decreases; red blood cell membrane deformability and cell-to-cell adherence, adhesion of sickle red blood cells to the endothelium, high production of reactive oxygen species (ROS), decreasing lactate dehydrogenase activity and Fe 2+ /Fe 3+ ratio of HbS. Understanding polymerization and pathophysiological of SCD constitute a therapeutic strategy base in the pharmacology research of this molecular disease.
... The bonding interaction between heme, iron and oxygen in oxygenated haemoglobin is association with an electron transfer. In response, there is an integrated network of the antioxidant system consisting of both enzymes and low molecular weight compounds which help to mitigate oxidative stress and injury to the red cell and tissues in general (Malowany and Butany, 2012). Congenital haemoglobin mutations may alter this balance and create a pro-oxidant and micronutrient reactive milieu (Kumar et al., 2009). ...
Sickle cell disease (SCD) is an inherited disorder of haemoglobin caused by a single nucleotide substitution of thymidine for adenine (GAG-GTG) of the β-chain that results in the amino acid valine instead of glutamic acid. This congenital haemoglobin mutation alters this balance and creates a pro-oxidant and micronutrient reactive milieu. This study investigated some micronutrients status of sickle cell patients. A total of one hundred (100) participants were recruited for this study which consists of fifty (50) sickle cell subjects and fifty (50) apparently healthy age-matched individuals were monitored as control. Blood samples were collected by venepuncture and some micronutrients (Iron, Zinc, Manganese, cobalt, Calcium and Magnesium) were analyzed using Atomic Absorption Spectrophotometer. All parameters were significantly decreased in sickle cell patients when compared with apparently controls (p<0.05). Considering the results obtained in this study, it could be inferred that sickle cell subjects are predisposed to nutritional deficiencies. We therefore advocate routine assessment of micronutrients in sickle cell patients. It may be necessary to routinely provide nutritional supplements for sickle cell disease patients in Nigeria.
... Sickle cell anaemia may lead to various acute and chronic complications with high mortality rate [11]. The main symptoms of this disorder includes increased susceptibility to infection, anaemia, pains and crises due to the polymerization of HbS molecules and irreversible sickling of red blood cells leading to vaso-occlusion [12]. ...
This is a case-controlled study designed to evaluate iron status of adult sickle cell anaemia patients and to compare findings with vaso-occlusive crises in sickle cell anaemia. One hundred and one (101) subjects aged 18-46 years participated in this study and these participants were divided into thirty five (35) sickle cell anaemia subjects in stable state (SS), thirty five (35) sickle cell anaemia subjects with history of vaso-occlusive crises (VOC) in the last preceding three months and thirty one (31) apparently healthy subjects (Hb AA) as control subjects (C) were recruited into the study using simple random sampling. Approximately 4 ml of venous blood samples was collected from each subject into a plain tube, allowed to clot and serum sample separated from it was analysed for serum iron, ferritin, total iron binding capacity (TIBC) and percentage transferrin saturation. The haemoglobin electrophoresis was determined using the alkaline cellulose acetate electrophoresis method Serum iron was analysed using atomic absorption spectrophotometer (AAS). Serum ferritin was determined using Ferritin Enzyme Immunoassay (Genway). TIBC was done using Ferene method and percentage transferrin saturation (%TFS) was derived from serum iron and TIBC. The mean values of serum iron and ferritin were significantly lower (P=0.00, P=0.00) respectively in SCA subjects compared with control. However, there was no significance difference in the mean values of TIBC and %TFS between SCA subject and control (P=0.56, P=0.14) respectively. There was significant difference in the mean values of serum iron and ferritin between SCA in stable state and control subjects (P=0.00, P=0.00) respectively. Also, there was significant difference in the mean values of serum iron and ferritin between SCA subjects with vaso-occlusive crises and control subjects (P=0.00, P=0.00) respectively. However, the comparison of the mean values of TIBC and %TFS between SCA in stable state and control subjects did not show any significance difference (P=0.56, P=0.33) respectively. Also, the mean values of TIBC and %TFS between SCA with vaso-occlusive crises and control subjects did not show any significant difference (P=0.88, P=0.37) respectively. The mean values of serum iron, ferritin, TIBC and %TFS between SS and VOC did not show any significant difference (P=1.00, P=0.99, P=0.79, P=0.97) respectively. The outcome of this work show reduced serum iron and ferritin levels in SCA subjects. Periodic assessment of iron status is therefore suggested in the monitoring and management of sickle cell anaemia.
... Sickle cells in human blood: both normal red blood cells and sickle-shaped cells are present. Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate (Malowany and Butany, 2012). Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis. ...
Three quarters of sickle-cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10 and 40% across equatorial Africa, decreasing to 12% on the North African coast and <1% in South Africa. Our aim was to determine the haemorrheologic and fibrinolytic activities of HbSS, HbAS and HbAA subjects in a view to provide information on the status of the activities for proper management. One hundred and seventy (170) subjects were used for this study; 50 were sickle cell (HbSS) patients, 60 were hemoglobin S carriers (HbAS) and the remaining 60 were normal haemoglobin (HbAA) individuals (control group) seen within a six-month period in Abuja, Nigeria had their blood samples analyzed. Haemoglobin electrophoresis, euglobulin lysis time, fibrinogen level, plasma viscosity, haemoglobin and platelet count were determined using standard methods. The mean age (years) of subjects studied were 8.23±1.24, 12.7±1.07 and 13.50±1.46 for HbSS, HbAS and HbAA, respectively. RPV, PLT and FIB concentration of HbSS were significantly raised while Hb level were reduced when compared with HbAA and AS subjects (p<0.05). However, the mean values for HbAS and AA subjects fell within the reference value. There was no significant difference (p>0.05) in the mean values of ELT for HbAA, AS and SS subjects in this study as they all fall within the reference range. The result shows that there were no significant changes in all the parameters studied based on gender. There was a significantly high RPV and fibrinogen in HbSS patients and reduced level of Hb concentration and platelet count when compared to HbAS and HbAA subjects. Therefore it is recommended that regular check-up and that fibrinogen assay and relative blood viscosity should be included as routine tests in the management of sickle cell anaemia patients. © 2016, Asian Network for Scientific Information. All rights reserved.
... Sickle cells in human blood: both normal red blood cells and sickle-shaped cells are present. Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate (Malowany and Butany et al., 2012). ...
... Sickle cell disease (SCD) is characterized by deformation of red blood cells (RBCs) into rigid, sickle shapes under conditions of hypoxic stress, leading to ischemia-reperfusion injury, hemolysis-mediated endotheliopathy, and multiorgan damage. 1 Recent estimates in 2010 identified SCD to be responsible for ;28 600 deaths annually worldwide. 2 Disease course depends in part on SCD genotype, with greater severity encountered in HbSS and HbS/b 0 thalassemia and a more benign course in HbSC and HbS/b 1 thalassemia, although adverse events have been observed in all subtypes. ...
Pregnancy in women with sickle cell disease is associated with adverse maternal and neonatal outcomes. Studies assessing the effects of prophylactic red blood cell transfusions on these outcomes have drawn inconsistent conclusions. The objective of this systematic review was to assess the effect of prophylactic compared to on-demand red blood cell transfusions on maternal and neonatal outcomes in women with sickle cell disease. A systematic search of MEDLINE, EMBASE, EBM Reviews and CINAHL was conducted. Twelve studies involving 1291 participants met inclusion criteria. The studies had moderate to high risk of bias. Meta-analysis demonstrated that prophylactic transfusion was associated with a reduction in maternal mortality (7 studies, 955 participants, OR 0.23; 95% CI 0.06-0.91), vaso-occlusive pain episodes (11 studies, 1219 participants, OR 0.26, 95% CI 0.09-0.76), pulmonary complications (9 studies, 1019 participants, OR 0.25; 95% CI 0.09-0.72), pulmonary embolism (3 studies, 237 participants, OR 0.07; 95% CI 0.01-0.41), pyelonephritis (6 studies, 455 participants, OR 0.19, 95% CI 0.07-0.51), perinatal mortality (8 studies, 1140 participants, OR 0.43; 95% CI 0.19-0.99), neonatal death (5 studies, 374 participants, 0.26; 95% CI 0.07-0.93), and preterm birth (9 studies, 1123 participants, OR 0.59; 95% CI 0.37-0.96). Event rates for most of the results were low. Prophylactic transfusions may positively impact several adverse maternal and neonatal outcomes in women with sickle cell disease; however, the evidence stems from relatively small number of studies with methodological limitations. A prospective, multi-center, randomized trial is needed to determine whether the potential benefits balance the risks of prophylactic transfusions.
Copyright © 2015 American Society of Hematology.
... The disease is also discovered to be very rampant among tropical and sub-tropical sub-Saharan regions where there used to be malaria (Wellems et al, 2003). SCA may lead to various acute and chronic complications, several of which have a high mortality rate (Malowany et al, 2012). People with sickle cell disease may also develop anemia including some jaundice and body pains. ...
A fuzzy logic-based system has been applied to a number of cases in medicine especially in the area of the development of diagnostic systems and has been discovered to produce accurate results. In this paper, a fuzzy logic-based system is presented which is used to simulate a prediction model for determining the likelihood of Sickle Cell Anemia (SCA) in individuals given a 3-tuple record containing the level of fetal haemoglobin, genotype and the degree of Anemia. Knowledge was elicited from an expert at Federal Medical Centre, Owo, Ondo State, Nigeria and was used in developing the rule-base and simulated the prediction model using the MATLAB software. The results of the fuzzification and defuzzification of variables, inference engine definition and model testing was also presented and showed that the fuzzy logic based model will be very useful in the prediction of the likelihood of Sickle Cell Anemia (SCA) among Nigerian patients.
... Sickle cell disease (SCD) is a sickling syndrome that results from homozygote or double heterozygote inheritance of mutant βs globin gene. This results in abnormal haemoglobin (Hgb) molecules with hydrophobic motif that is exposed in deoxygenated state [1]. The abnormal Hgb cascades processes of abnormal cellular adhesion, inflammation, coagulation and vasoconstriction in SCD. ...
... Common sites of infarction include the spleen, bone and bone marrow, the medulla of the kidney, mesenteric vessels, and pulmonary vessels [6]. Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate [7]. Many patients with SCA are in reasonably good health most of the time and achieving a steady state level of fitness. ...
Abstract: Sickle cell anemia (SCA) is a major cause of morbidity and mortality and affect hematological profile, a
case control study conducted at national health laboratory in Khartoum state in period between 14 December 2011 to
20 November 2012, 80 patients with Sickle cell anemia (SCA) were enrolled, blood samples were collected in
EDTA containers from each individual, Automated Cell Counter; Sysmex 21 was used to determine complete blood
counts including blood cell indices, hemoglobin electrophoresis apparatus was used to estimate sickle cell genotypes
using cellulose acetate alkaline electrophoresis technique. The frequency distribution of sickle cell phenotypes of
study group on basis of hemoglobin electrophoresis were SS 29(36.2%), AS 49(61.2%), SC 1(1.3%), SF 1(1.3%).
The mean hemoglobin concentration, mean packed cell volume, mean cell volume (MCV), mean cell hemoglobin
(MCH) and mean cell hemoglobin concentration (MCHC) were 9.2 ± 3.2 gm/dl, 30.2 ± 9.2%, 76.6 ± 7.9/fl, 23.2 ±
3.0/pg, 30.1 ± 2.3gm/dl. Significant lower hemoglobin (p value <0.05), The mean TWBC, RBC and platelet counts
were 11.1 x 109/L ± 8.6, 3.9 x 1012/L ± 1.3, 450 x 109/L ± 15.8, significant higher TWBC and lower RBC counts
of p value <0.05 for both. the findings indicates for moderate to severe anemia.
... Sickle cell disease (SCD) is characterized by periodic vaso-occlusive crises, chronic hemolysis, and frequent infections that are accompanied by pain and organ damage [1,2]. Vaso-occlusive crises have been generally attributed to the abnormal shape and poor deformability of sickle erythrocytes [3]. Recent studies have pointed out that sickle red blood cells (SS RBCs) have the ability to bind vascular endothelial cells [4,5] and ultimately cause hypoxia and infarction. ...
Objective: The aim of this study was to investigate the relation between tumor necrosis factor-superfamily 15 (TNFSF15) gene expression and clinical findings in children with sickle cell disease (SCD).
Materials and Methods: Forty-nine patients with SCD and 38 healthy controls were included in this study. TNFSF15 gene expression and plasma levels were analyzed. TNFSF15 gene expression was compared in subgroups considering the frequency of painful crises and acute chest syndrome (ACS).
Results: It was found that TNFSF15 gene expression was significantly higher in patients with SCD than the controls (p=0.001), whereas there was no significant difference between the patients with SCD and the control groups considering plasma levels of TNFSF15. TNFSF15 gene expression was also significantly higher in SCD patients with ACS (p=0.008).
Conclusion: These findings suggest that TNFSF15 may have a role in the pathogenesis of SCD presenting with ACS. Further studies on larger groups are needed to determine the function of TNFSF15 in SCD patients with ACS and pulmonary hypertension. Analysis of TNFSF15 expression may also serve as a promising approach in ACS therapy.
... The highest frequencies of homozygous sickle cell disease in the world occur in sub-Saharan Africa where 3.0 to 4.0% of populations are affected (1). The sickle cell genes commonly occur in areas of the world with endemic malaria as in the Democratic Republic of Congo (DRC) (2,3). The first cases of sickle cell disease in this country were described in the 1950s and every year, approximately 50,000 children are born with this disease (4,5). ...
Abstract In the Democratic Republic of Congo (DRC), sickle cell disease is not yet really regarded as a health care priority. The patterns of sickle cell disease in patients living in Kinshasa, DRC are discussed and the difficulties encountered in their management are highlighted. The cross-sectional survey is of sickle cell patients and their families attending the Centre de Médecine Mixte et d'Anémie SS de Yolo (CMMASS), Kinshasa, DRC, between January and April 2009. Completed questionnaires were received from 168 respondents (111 girls; 57 boys). Seventy-one percent of the subjects were diagnosed before the age of 2 years but none in the neonatal period. Sickle cell disease was diagnosed in 54.8% of the patients after they had suffered pain crises. Of the 168 subjects, 74.0% had previously received blood transfusions. Seventy-five (45.0%) had more than three severe pain crises per year. A minority of 35.0% reported that they regularly took an antibioprophylaxis. Seventy-five (45.0%) subjects were eligible for hydroxyurea (HU) therapy but in all cases this drug was taken irregularly. Eighty-two percent of drugs were purchased by the parents. One hundred and sixty-three children (97.0%) were vaccinated according to the Expanded Programme on Immunization (EPI), 61.0% against Streptococcus pneumoniae and 16.0% against the Hepatitis B virus (HBV). No case of immunization against Hemophilus influenzae and Salmonella sp was reported. Neonatal screening programs, early educational detection programs for families, use of current method treatments and an implementation of a health insurance system for sickle cell disease will improve detection and management for these and future patients in our population.
... The ACS is characterized by fever, leucocytosis, and respiratory symptoms leading to chronic lung damages [7][8][9]. These clinical manifestations are involved in two main processes in sickle cell disease: hemolysis and vascular occlusion [10]. Hemolysis leads to cardiovascular, pulmonary, gastrointestinal and renal manifestations [11]. ...
... Sickle cell disease (SCD) is due to a point mutation in the β globin gene, resulting in the creation of abnormal hemoglobin molecules with a hydrophobic motif that is exposed in its deoxygenated state [1]. In sickle cell anaemia (SCA), an individual inherits the homozygous form of sickle cell gene (S). ...
Aims: To determine the pattern and associated risk factors for musculoskeletal complications among sickle cell anaemia patients in South-east Nigeria. Methodology: A retrospective review of prospectively collected data. The study was conducted at the Sickle Cell Clinic of the University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu, Nigeria between December 31 st 2004 and January 1 st 2013. We included 163 eligible sickle cell anaemia patients (105 males and 58 females; age range 6-53 years). Clinical, haematological (haemoglobin, white cell count, platelet) and radiological evaluation of these patients were done. Data analysis was by SPSS version 19. Chi-square and Fisher's exact tests were used to test for significant association of the categorical variables while Mann Whitney U test was used to compare the mean ranks of the continuous variables and the dependent outcome. Results: The three most common musculoskeletal complications seen among our patients population were leg ulcer (29.4%), avascular necrosis (17.8%) and osteomyelitis (12.9%). Complications were significantly more in older patients (P=0.04) and those with higher platelet counts (P=0.04). Haemoglobin level and platelet count were significantly higher in patients with avascular necrosis (P=0.01) and osteomyelitis respectively (P=0.01). Conclusion: Musculoskeletal complications of SCA are not uncommon among our patients. Age and higher steady state haemoglobin were risk factors for developing complications. Further controlled studies are required to evaluate the steady state hematological parameters and risk of complications among SCA patients.
... This substitution results in the production of abnormal hemoglobin (HbS). Deoxygenated HbS polymerizes, resulting in intravascular hemolysis of the red blood cell and release of hemoglobin and other compounds into the plasma [2]. Repeating cycles of polymerization and hemolysis lead to vaso-occlusion and ischemia-reperfusion injury. ...
Previous studies have shown that the sickle environment is highly enriched for reactive oxygen species (ROS). We examined the oxidative effects of sickle cell disease on hematopoietic stem cell function in a sickle mouse model. In vitro colony-forming assays showed a significant decrease in progenitor colony formation derived from sickle compared to control bone marrow (BM). Sickle BM possessed a significant decrease in the KSL (c-kit(+), Sca-(1+), Lineage(-)) progenitor population, and cell cycle analysis showed that there were fewer KSL cells in the G(0) phase of the cell cycle compared to controls. We found a significant increase in both lipid peroxidation and ROS in sickle-derived KSL cells. In vivo analysis demonstrated that normal bone marrow cells engraft with increased frequency into sickle mice compared to control mice. Hematopoietic progenitor cells derived from sickle mice, however, demonstrated significant impairment in engraftment potential. We observed partial restoration of engraftment by n-acetyl cysteine (NAC) treatment of KSL cells prior to transplantation. Increased intracellular ROS and lipid peroxidation combined with improvement in engraftment following NAC treatment suggests that an altered redox environment in sickle mice affects hematopoietic progenitor and stem cell function.
... Individuals deficient in terminal pathway components are susceptible to meningococcal infections (37,40), a genotype with no apparent selective advantage. However, selective pressure in the face of malaria infection frequently maintains genetic mutations that can be life threatening (sickle cell anemia (41)) or are associated with autoimmune disease (systemic lupus erythematosus (42)) but provide a survival advantage in malaria-endemic regions. We are currently pursuing studies to address this possibility for C6 deficiency in malaria and cerebral malaria. ...
Cerebral malaria (CM) is the most severe manifestation of clinical malaria syndromes and has a high fatality rate especially in the developing world. Recent studies demonstrated that C5−/− mice are resistant to experimental CM (ECM) and that protection was due to the inability to form the membrane attack complex. Unexpectedly, we observed that C4−/− and factor B−/− mice were fully susceptible to disease, indicating that activation of the classical or alternative pathways is not required for ECM. C3−/− mice were also susceptible to ECM, indicating that the canonical C5 convertases are not required for ECM development and progression. Abrogation of ECM by treatment with anti-C9 antibody and detection of C5a in serum of C3−/− mice confirmed that C5 activation occurs in ECM independent of C5 convertases. Our data indicate that activation of C5 in ECM likely occurs via coagulation enzymes of the extrinsic protease pathway.
Background: The terminal complement pathway contributes to cerebral malaria (CM) pathogenesis.
Results: The terminal pathway is activated in CM through a unique mechanism independent of the C5 convertases.
Conclusion: We propose that enzymes of the coagulation system activate C5 in CM.
Significance: Inhibition of complement at the level of C5 represents a unique therapeutic target in CM.
The presentation of kidney diseases can vary widely between children and adults as can age-related differential diagnoses and the consequences of treatment. This comprehensive and practical guide to pediatric nephropathology covers a range of conditions and diseases, including abnormal kidney development, glomerular diseases, vascular diseases and transplant pathology. Special emphasis is placed on integrating mechanisms of disease to pathology and therapeutic options. The book also includes ancillary testing such as genetics, as these are fast becoming the gold standard for a number of paediatric kidney diseases. Over a hundred high-quality colour images are included, fully annotated to display the key features of the diseases discussed. Summaries of key points and knowledge gaps condense vital information for an accessible read by busy clinicians and trainees. An online version of the book with expandable figures can be accessed on Cambridge Core, via the code printed on the inside of the cover.
Helicobacter pylori infection has been recognized as a public health problem worldwide with raising prevalence in developing than the developed countries. More than 50% of the world's population infected, and 80% of infected have no symptoms. Megaloblastic anemia can occur due to impaired DNA synthesis resulting from deficiencies of vitamin B 12 and folate. The development of autoantibodies to thyroid peroxidase (anti-TPO), thyroglobulin (anti-Tg), and thyroid-stimulating hormone receptor (TSH-R) is the main characteristic of autoimmune thyroid disease. H. pylori may decrease absorption of oral thyroxine by decreasing gastric acid secretion in the stomach. H. pylori has important role of in the development of autoimmune thyroid diseases, vitamin B 12 deficiency and malfunctions of human. The primary goal of this chapter is to observe association between H. pylori infection in the gastric mucosa and of autoimmune thyroid diseases vitamin B 12 deficiency because eradication of H. pylori can prevent the development of complications.
ImRisikoEinführung Kap. 2 werdenGefahrEinführungverschiedeneGefährdungEinführung Risiken und Gefährdungen in Form von Beispielen und Zahlenangaben vorgestellt. Dabei werden länger andauernde Prozesse und kurzfristige Ereignisse gemischt. Teilweise überschneiden sich die Zuordnungen.
The objective of this study was to examine prior studies on maternal and neonatal outcomes with prophylactic compared with emergent blood transfusion in pregnant women with sickle cell disease. A review of the literature was performed. Twenty-one articles were identified and included in the analysis. A generalized linear mixed-effects model was used to analyze the outcomes. Pregnancy outcomes assessed were preeclampsia, pneumonia, pyelonephritis, pain crises, intrauterine growth restriction, neonatal death, perinatal death, and maternal mortality. Women who underwent emergent transfusion were more likely than women who underwent prophylactic transfusion to have the following adverse perinatal outcomes: preterm delivery (adjusted odds ratio [aOR 2.04], 95% confidence interval [CI] 1.14-3.63), pneumonia (aOR 2.98, 95% CI 1.44-6.15), pain crises (aOR 1.67, 95% CI 1.18-2.38), and perinatal death (aOR 1.84, 95% CI 1.06-3.07). Prophylactic transfusion should be reexamined as a potentially beneficial approach to the management of sickle cell disease in pregnancy.
Environmental and multiple genetic factors influence many pathophysiological aspects of SCD that contribute to a highly variable clinical expression in patients. Fetal hemoglobin (HbF) has emerged as a central disease modifier; genetic variants at three principal loci, BCL11A, HBS1L–MYB and HBB cluster, account for 10–20% of HbF variation among SCD patients in USA, Brazil and the UK [17,18] (Table 1); these findings have been replicated in SCD patients living in Tanzania and Cameroon [19–22]. Interestingly, the expression of these modifiers is amenable to therapeutic manipulation, leading to new hope for treatment routes for SCD [23–25]. Moreover, cardiovascular phenotypes of SCD represent a major cause of morbidity and mortality in patients. The vast clinical heterogeneity observed in stroke, kidney disease or hypertension development in SCD, indicates that genetic factors may play a role as substantiated by a few studies [26]. The co-inheritance of α-thalassemia and specific variants in the HbF promoting loci have been proven to delay the clinical progression of kidney disease and stroke in SCD [27–32] (Table 1). In addition, genetic variants in both APOL1 and HMOX1 have been associated with SCD nephropathy among African–American adults and children [33–36] (Table 1). Lastly, there are consistent studies that have shown associations among variants in UGT1A1 and serum bilirubin, and cholelithiasis [37–39]. Nevertheless, there is the lack of validation of multiple studies on suggestive genetic modifiers associated with the development of various subphenotypes of SCD such as stroke, painful episodes, acute chest syndrome, bacteremia/infection, osteonecrosis, priapism, leg ulcers, sickle vasculophathies and hemolysis [40].
Background. An exponential increase in the number of sickle cell disease (SCD) patients in paediatric services in Cape Town, South Africa, has been reported. The trend in adult/adolescent services has not been investigated.
Objectives. To evaluate epidemiological trends of SCD and the profile of patients affected by SCD attending the Haematology Clinic at Groote Schuur Hospital (GSH), Cape Town.
Methods. (i) A retrospective review of the number of SCD patients over the past 20 years; (ii) a cross-sectional analysis of clinical and haematological characteristics of SCD patients; and (iii) molecular analysis of the haemoglobin S mutation, the haplotype in the β-globin-like genes cluster, the 3.7 kb α-thalassaemia gene deletion and 19 selected single-nucleotide polymorphisms (SNPs) associated with fetal haemoglobin (HbF) levels.
Results. From 1995 to 2016, 81 adolescent/adult patients with SCD were registered, mostly originating from other African countries (n=61, 75.3%). There was an increase of over 200% in new cases (n=47) during the last quarter of the two decades investigated. Data from 34 of 58 regular attendees (58.6%) were analysed. The mean age of the patients was 26.1 years (standard deviation (SD) 9.8), and 70.6% were male. With the exception of four patients with sickle/β-thalassaemia, all the patients had SCD (haemoglobin SS). The co-inheritance of a single 3.7 kb α-globin deletion was found in 42.3% of cases (n=11). The Bantu haplotype was the most observed (65.4% of chromosomes). Most HbF-promoting SNPs were not associated with variable levels of haematological indices.
Conclusions. There is an increasing burden of adult SCD patients at GSH. National health and academic institutions need to adapt policies and healthcare professional training accordingly.
Background: Susceptibility of sickle cell disease subjects to various infectious agents is on the increase, but information relating SCD to allergic condition is scarce. Hence, assessment of immunoglobulin status in SCD children may provide useful information to improve management of SCD children.
Objectives: To determine the levels of immunoglobulin classes (IgG, IgA, IgM, and IgE) in Nigerian HbSS children below 5 years of age compared with sex- and age-matched HbAA children.
Materials and Methods: Blood samples were collected from a total of 45 children less than 5 years of age who were recruited into the study as follows: 26 HbSS and 19 HbAA subjects for the estimation of serum immunoglobulin levels using enzyme-linked immunosorbent assay (ELISA) techniques and determination of genotype using electrophoresis technique.
Results: IgG concentration was nonsignificantly higher (P = 0.997) in HbSS children (1022.56 ± 148.97 ng/ml) compared to HbAA children (933.68 ± 106.10 ng/ml). IgA (P = 0.906) and IgM (P = 0.986) concentrations were nonsignificantly lower in HbSS children (255.07 ± 133.71 ng/ml) compared to HbAA children. IgE was significantly higher (P = 0.000***) in HbSS (108.67 ± 69.22 IU/ml) compared to HbAA (24.51 ± 17.58 IU/ml) children.
Conclusion: SCD children in steady state have adequate levels of Ig classes. Non-specific elevation of IgE levels may be a factor of inflammatory response in SCD children, and this may be proposed for reduced allergic reaction among SCD children.
Aims: To compare the mean levels of plasma total Homocysteine (tHct), Methylmalonic acid (MMA), vitamin B12, folate and haematological parameters(PCV, WBC, Platelet counts, MCV, MCH, MCHC) among adult SCA patients in steady state (SS), SCA in (VOC) and age and sex matched controls in order to determine significant differences.
Study Design: Case-control study.
Place and Duration of Study: Department of Haematology and Department of Chemical Pathology, University College Hospital, Ibadan, Nigeria between March 2012 and July 2012.
Methodology: We included 60 SCA patients (30 in VOC, 30 in Steady State; and 30 age and sex matched controls. Plasma tHct, MMA, folate and vitamin B12 were assessed using HPLC and haematological parameters were determined using haematological autoanalyzer (Syxmex Kx21).
Results: The mean plasma tHct, MMA, vitamin B12 of SCA patients (VOC and SS) were significantly lower (p=0.000) compared to control population but the mean folate levels were comparable (p=0.085). The SCA (in VOC) had significantly lower (p=0.000) MMA and folate levels compared to SS group but the SS group had significantly lower (p=0.001) tHct level compared to VOC group. While the PCV, Hgb, MCV, and MCH were significantly lower; the WBC, platelet count and the MCH were significantly elevated in SCA patients compared to controls.
Conclusion: A larger, better controlled, multicenter study is required to confirm lower tHct and MMA found in SCA groups compared to control group and higher tHct in SCA (VOC) but higher MMA level in SCA (SS) when VOC and SS groups were compared. The haematological parameters in SCA groups were not in keeping with macrocytic anaemia but were indicative of chronic haemolytic and inflammatory process.
South Africa has a low incidence of sickle cell disease (SCD). However, its demographics are changing because of immigration from sub-Saharan African countries where SCD is prevalent.
We aimed to determine the frequency of SCD presenting to the Haematology/Oncology Service at Red Cross War Memorial Children's Hospital in Cape Town and to measure the associated disease burden.
This was a retrospective cross-sectional study of patients first attending the Haematology Service between January 2001 and June 2010.
A total of 58 SCD patients were identified, with an annual frequency that increased over the study period by 300 - 400%. Up to 93.1% (n=54) were originally from other African countries, mainly the Democratic Republic of Congo (62.1%, n=36). One patient had sickle D-Punjab genotype, and all the other patients had the homozygous sickle cell anaemia genotype (Hb SS). Their haematological parameters demonstrated a normocytic anaemia with high white cell counts. The mean number of clinic visits per patient per year was 22.2 (range 0 - 64), and the mean number of hospital admissions per patient per year was 1.2 (range 0 - 5). All the patients were on antibiotic prophylaxis. The majority had at least one blood transfusion (65.5%, n=38), and a significant proportion required intravenous analgesia on admission (29.3%, n=17) and hydroxyurea treatment (36.2%, n=21).
Over the past 10 years the frequency of SCD has increased considerably, imposing a significant burden and new challenges to the health services in Cape Town.
The total protein, albumin, globulin, and immunoglobulin levels of sera from 96 children with homozygous sickle cell disease were studied. A comparison of the results with the levels found in a control group of normal children of the same age shows that the sicklers have higher total protein, globulin, and IgM levels. The amounts of albumin and IgA seen were almost the same in both groups. The IgG levels differed considerably, the sicklers having only about half the quantity seen in normal children.
A study of fibrinolytic activity in sickle-cell patients during asymptomatic periods has shown a normal fibrinolytic response to exercise and local heat to the arm. During vasoocclusive crises there was no significant decrease in fibrinolytic activity. These results contrast with earlier reports of decreased fibrinolysis during crisis and a suggestion that fibrinolytic activators might be of value in preventing vasoocclusive episodes. Patients in painful crisis showed a significant rise in fibrinogen concentration and fall in platelet count. The former may contribute to localized vascular sludging by increasing whole-blood viscosity, while the latter probably results from local trapping of platelets in areas of sickling or from subsequent splenic sequestration of damaged platelets. There was no evidence of disseminated, as opposed to localized, intravascular coagulation during crisis.
The blood biochemistry of 84 young homozygous sickle cell patients aged 1 to 11 years was analysed for evidence of liver disease. A comparison of the values found in their blood with those seen in normal children from an identical age group, assessed at the same time, shows no convincing evidence of liver cell damage except in 12% of cases. The normal transaminase observed in many of the patients assessed, together with the high alkaline phosphatase activity which seemed to be out of proportion to plasma bilirubin, is a picture compatible with localised obstructive lesions of the liver or bone lesions, both of which are common in sickle cell disease. This biochemical pattern suggests that the conjugated bilirubin, which dominates the picture in 40% of patients who have 'haemolytic jaundice', is due largely, not to liver cell damage, but to a combination of two factors, namely, intrahepatic cholestasis and the presence of actively functioning liver cells. Adequate albumin synthesis found in these patients, together with normal thymol reactions, provides further evidence of the absence of severe liver cell damage.
Background. Silent infarcts have been reported in 17% of young patients with sickle cell disease and are associated with impaired performance on standardized psychometric tests. Risk factors for the development of these lesions have not been identified. Methods. Investigators in the Cooperative Study of Sickle Cell Disease performed a brain magnetic resonance imaging scan on sickle cell anemia patients age 5.9 years and older who had been followed according to the protocols of the Cooperative Study since birth. Individuals with a known history of cerebrovascular accident were excluded from this analysis. Patients with and without silent infarctions were compared with regard to clinical and laboratory parameters. Results. The study sample included 42 patients (18.3%) with silent infarcts. Patients who had silent infarcts were significantly more likely to have a clinical history of seizure and a lower painful event rate. Lower hemoglobin level, increased leukocyte count, elevated pocked red blood cell count, and SEN beta(s) globin gene haplotype were associated also with the presence of silent infarcts. There was no relationship between silent infarcts and platelet count, fetal hemoglobin level, reticulocyte percentage, serum aspartate aminotransferase level, total bilirubin concentration, blood pressure, growth parameters, or presence of cu-thalassemia. A multivariate model for silent infarction identified the following as risk factors: low pain event rate, history of seizure, leukocyte count greater than or equal to 11.8 x 10(9)/L, and the SEN beta(s) globin gene haplotype. Conclusions. Patients with risk factors for silent infarcts should be evaluated for cerebrovascular disease. If evidence of infarction is found, consideration must be given to therapeutic intervention. At present, the appropriate treatment has not been determined.
Premature death and cardiac abnormalities are described in individuals with sickle cell disease (SCD), but the mechanisms are not well characterized. We tested the hypothesis that cardiac abnormalities in children with SCD are related to sleep-disordered breathing. We enrolled 44 children with SCD (mean age, 10.1 years; range, 4-18 years) in an observational study. Standard and tissue Doppler echocardiography, waking oxygen saturation averaged over 5 minutes, and overnight polysomnography were obtained in participants, each within 7 days. Eccentric left ventricular (LV) hypertrophy was present in 46% of our cohort. After multivariable adjustment, LV mass index was inversely related to average asleep and waking oxygen saturation. For every 1% drop in the average asleep oxygen saturation, there was a 2.1 g/m(2.7) increase in LV mass index. LV diastolic dysfunction, as measured by the E/E' ratio, was present in our subjects and was also associated with low oxygen saturation (sleep or waking). Elevated tricuspid regurgitant velocity (> or = 2.5 m/sec), a measure of pulmonary hypertension, was not predicted by either oxygen saturation or sleep variables with multivariable logistic regression analysis. These data provide evidence that low asleep and waking oxygen saturations are associated with LV abnormalities in children with SCD.
Sickle cell disease (SCD) is the most common genetic disease worldwide. The increase in life expectancy of SCD patients in recent years has led to the emergence of more complications of the disease, e.g. ocular, which in the past were uncommon. This review describes current knowledge of the ocular manifestations of patients with SCD. SCD can affect virtually every vascular bed in the eye and can cause blindness in the advanced stages. The most significant ocular changes are those which occur in the fundus, which can be grouped into proliferative sickle retinopathy, and non-proliferative retinal changes based on the presence of vascular proliferation. This distinction is important because the formation of new vessels is the single most important precursor of potentially blinding complications. Although various systemic complications of SCD are known to be more common in patients with the Hb SS genotype, visual impairment secondary to proliferative sickle retinopathy is more common in patients with the Hb SC genotype. There is also an increase with age in the incidence and prevalence rates of all ocular complications of SCD. It is therefore recommended that all patients with SCD undergo periodic ophthalmological screening from the age of 10 years.
The objective of this study was to obtain representative echocardiographic measurements of cardiac size and function in stable patients with sickle cell disease. This prospective, multicenter study utilized central reading of echocardiograms by an investigator blinded to other patient data. Stable outpatients from a balance of inner city and rural settings with SS phenotype and a broad age range were selected, because conflicting results from earlier studies were believed to be due to these patient selection criteria. Right and left ventricular dimensions and wall thickness, left atrial and aortic root dimensions, and systolic time intervals were measured. Body surface area indexed chamber dimensions and septal thickness were significantly increased from normal. Except for the right ventricle, chamber dimensions and wall thickness were inversely correlated with hemoglobin. The relationship between left ventricular dimension and hemoglobin was significantly dependent on age. Systolic time interval ratios were normal though left ventricular ejection time was prolonged. Shortening fraction was normal but velocity of circumferential fiber shortening was abnormally low. Stable patients with sickle cell disease have dilated chambers, septal hypertrophy, and normal contractility. Though left ventricular dilatation was inversely related to hemoglobin, age (duration of illness) was an important factor in that relationship. No specific cardiomyopathy was associated with sickle cell anemia.
Gross and microscopic findings consistent with acute (three patients) and healed (four patients) myocardial infarction were found in seven (9.7%) of 72 consecutive hearts from patients with sickle cell disease studied after autopsy between 1950 and 1982. Gross obstructive and atherosclerotic lesions were absent in all seven patients, while microthrombi were present in the arterioles of infarcted tissue in two patients. Pathophysiological mechanisms responsible for the infarction are unclear, but anemia, platelet thrombi, coronary vasospasm, and abnormal rheology related to sickle cells may all be important. Chest pain occurred clinically in six of the seven patients and ECG findings typical of infarction were found in two patients. One patient died suddenly. These findings suggest that ischemic heart disease may be present in a significant number of patients with sickle cell disease and should be considered in all patients who complain of chest pain, whether or not the patient is in crisis.
To examine the histopathologic and morphometric features of neovascular lesions in human proliferative sickle cell retinopathy.
Postmortem ocular tissue was obtained from three subjects (aged 20, 28, and 40 years) with SS hemoglobinopathy and prepared for adenosine diphosphatase flat-embedding. Morphometric analysis was performed before serial sectioning.
Numerous active and autoinfarcted lesions were found that represented virtually all stages in the life cycle of preretinal neovascularization. These formations ranged from single small loops extending from arteries and veins along the retinal surface to the typical complex, elevated sea fan formations. Sea fans developed at hairpin loops and at arteriovenous crossings. There was an average of 5.6 connections between sea fans and retinal vessels; of these, 45% were arteriolar, 52.5% were venular, and 2.6% were at the capillary level. Six of eight sea fans were located at arteriovenous crossings. Autoinfarction appeared to occur initially within the sea fan capillaries. The average height of sea fans was 123 microns above the retinal surface.
Preretinal neovascularization in sickle cell retinopathy can arise from both the arterial and venous sides of the retinal vasculature and can assume a variety of morphologic configurations. Multiple feeding arterioles and draining venules are common, and autoinfarction appears to occur initially at the preretinal capillary level rather than at feeding arterioles. Arteriovenous crossings may be a preferential site for sea fan development.
Cerebrovascular accident (CVA) is a major complication of sickle cell disease. The incidence and mortality of and risk factors for CVA in sickle cell disease patients in the United States have been reported only in small patient samples. The Cooperative Study of Sickle Cell Disease collected clinical data on 4,082 sickle cell disease patients enrolled from 1978 to 1988. Patients were followed for an average of 5.2 +/- 2.0 years. Age-specific prevalence and incidence rates of CVA in patients with the common genotypes of sickle cell disease were determined, and the effects of hematologic and clinical events on the risk of CVA were analyzed. The highest rates of prevalence of CVA (4.01%) and incidence (0.61 per 100 patient-years) were in sickle cell anemia (SS) patients, but CVA occurred in all common genotypes. The incidence of infarctive CVA was lowest in SS patients 20 to 29 years of age and higher in children and older patients. Conversely, the incidence of hemorrhagic stroke in SS patients was highest among patients aged 20 to 29 years. Across all ages the mortality rate was 26% in the 2 weeks after hemorrhagic stroke. No deaths occurred after infarctive stroke. Risk factors for infarctive stroke included prior transient ischemic attack, low steady-state hemoglobin concentration and rate of and recent episode of acute chest syndrome, and elevated systolic blood pressure. Hemorrhagic stroke was associated with low steady-state hemoglobin and high leukocyte count.
Silent infarcts have been reported in 17% of young patients with sickle cell disease and are associated with impaired performance on standardized psychometric tests. Risk factors for the development of these lesions have not been identified.
Investigators in the Cooperative Study of Sickle Cell Disease performed a brain magnetic resonance imaging scan on sickle cell anemia patients age 5.9 years and older who had been followed according to the protocols of the Cooperative Study since birth. Individuals with a known history of cerebrovascular accident were excluded from this analysis. Patients with and without silent infarctions were compared with regard to clinical and laboratory parameters.
The study sample included 42 patients (18.3%) with silent infarcts. Patients who had silent infarcts were significantly more likely to have a clinical history of seizure and a lower painful event rate. Lower hemoglobin level, increased leukocyte count, elevated pocked red blood cell count, and SEN betaS globin gene haplotype were associated also with the presence of silent infarcts. There was no relationship between silent infarcts and platelet count, fetal hemoglobin level, reticulocyte percentage, serum aspartate aminotransferase level, total bilirubin concentration, blood pressure, growth parameters, or presence of alpha-thalassemia. A multivariate model for silent infarction identified the following as risk factors: low pain event rate, history of seizure, leukocyte count >/=11.8 x 10(9)/L, and the SEN betaS globin gene haplotype.
Patients with risk factors for silent infarcts should be evaluated for cerebrovascular disease. If evidence of infarction is found, consideration must be given to therapeutic intervention. At present, the appropriate treatment has not been determined.
The acute chest syndrome is the leading cause of death among patients with sickle cell disease. Since its cause is largely unknown, therapy is supportive. Pilot studies with improved diagnostic techniques suggest that infection and fat embolism are underdiagnosed in patients with the syndrome.
In a 30-center study, we analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. We evaluated a treatment protocol that included matched transfusions, bronchodilators, and bronchoscopy. Samples of blood and respiratory tract secretions were sent to central laboratories for antibody testing, culture, DNA testing, and histopathological analyses.
Nearly half the patients were initially admitted for another reason, mainly pain. When the acute chest syndrome was diagnosed, patients had hypoxia, decreasing hemoglobin values, and progressive multilobar pneumonia. The mean length of hospitalization was 10.5 days. Thirteen percent of patients required mechanical ventilation, and 3 percent died. Patients who were 20 or more years of age had a more severe course than those who were younger. Neurologic events occurred in 11 percent of patients, among whom 46 percent had respiratory failure. Treatment with phenotypically matched transfusions improved oxygenation, with a 1 percent rate of alloimmunization. One fifth of the patients who were treated with bronchodilators had clinical improvement. Eighty-one percent of patients who required mechanical ventilation recovered. A specific cause of the acute chest syndrome was identified in 38 percent of all episodes and 70 percent of episodes with complete data. Among the specific causes were pulmonary fat embolism and 27 different infectious pathogens. Eighteen patients died, and the most common causes of death were pulmonary emboli and infectious bronchopneumonia. Infection was a contributing factor in 56 percent of the deaths.
Among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progresses to respiratory failure. Treatment with transfusions and bronchodilators improves oxygenation, and with aggressive treatment, most patients who have respiratory failure recover.
Children with sickle cell anemia (HbSS) are at high risk for neurologically overt cerebral infarcts associated with stroke and neurologically silent cerebral infarcts correlated with neuropsychometric deficit. We used complete magnetic resonance imaging (MRI) histories from 266 HbSS children, aged 6 through 19 years, who were enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) to examine silent infarct prevalence, localization, recurrence, and progression. We report a baseline prevalence of 21.8%, marginally higher than previously reported due to improved imaging technologies. Although we observed no overall sex difference in prevalence, most lesions in girls occurred before age 6, whereas boys remained at risk until age 10. Silent infarcts were significantly smaller and less likely to be found in the frontal or parietal cortex than were infarcts associated with stroke. Children with silent infarct had an increased incidence of new stroke (1.03/100 patient-years) and new or more extensive silent infarct (7.06/100 patient-years) relative to stroke incidence among all children in our cohort (0.54/100 patient-years). Both events were substantially less frequent than the risk of stroke recurrence among children not provided chronic transfusion therapy. Although chronic transfusion is known to decrease occurrence of new silent infarcts and strokes in children with elevated cerebral arterial blood flow velocity, further study is required to determine its risk-benefit ratio in children with silent infarct and normal velocities. Until safe and effective preventive strategies against infarct recurrence are discovered, MRI studies are best reserved for children with neurologic symptoms, neuropsychometric deficits, or elevated cerebral artery velocities.
Pulmonary hypertension is one of the major causes of morbidity and mortality of patients with sickle cell hemoglobinopathy (SCH). Although a clinically recognized complication of sickle cell disease (SCD), there are few published pathologic studies of pulmonary findings in these patients. The aim of this study was to define the pulmonary pathologic changes and to investigate correlation between the pathologic changes, the antemortem diagnosis of pulmonary hypertension, and the severity of SCH. Cases of SCH were identified from the autopsy database using Snomed codes. Clinical and echocardiograph data were collected for correlation with the pathologic data. A total of 20 adult patients (12 males and 8 females) were identified. Hemoglobin electrophoresis results were available for 16 patients, with hemoglobin S fraction percentages ranging from 23% to 97.8%. Eleven patients had SCD, 5 patients had sickle cell trait (SCT), and the remaining 4 patients without hemoglobin electrophoresis were included in the SCT group. The mean age of the SCT group was higher than that of the SCD group (P = 0.03). Histologically, all 20 patients demonstrated changes in pulmonary vasculature considered diagnostic of pulmonary hypertension grade I to grade IV, associated with plexiform lesions in 60% of patients. Medial hypertrophy and intimal hyperplasia/fibrosis, considered potentially reversible lesions, were seen in all patients. A weak association was found between SCD and plexiform lesions. Fibroelastic degeneration of small arteries, arterioles, and venules was identified in almost all (95%) cases. Clinically, tricuspid regurgitation was detected by echocardiogram in 10 of 20 (50%) patients; 6 of these 10 had significant regurgitation to allow estimation of systolic pressure. Sudden death occurred in 8 patients, with males having a significantly higher incidence. Cardiomegaly was present in 95% of patients, however, autosplenectomy and hepatic cirrhosis/hemochromatosis were observed almost exclusively in patients with SCD. Cirrhosis was found to have a strong positive association with SCD. This study demonstrates pulmonary hypertensive changes in all 20 autopsied patients who had SCH but died from various causes. We conclude that a high prevalence of pulmonary hypertension is associated with SCH with consequent high mortality. Therefore, patients with SCH would benefit from a regular periodic assessment for pulmonary hypertension regardless of age, sex, and severity of hemoglobinopathy.
Objective. Brain magnetic resonance imaging (MRI) and neuropsychological evaluations were conducted to determine whether neuroradiographic evidence of infarct in children with sickle cell disease between ages 6 and 12 years would result in impairment in cognitive and academic functioning.
Method and Design. Children enrolled in the Cooperative Study of Sickle Cell Disease were evaluated with brain MRI and neuropsychological evaluation. Completed studies were obtained for 194 children, 135 with HbSS. MRIs were categorized according to the presence of T2-weighted, high-intensity images suggestive of infarct and were further categorized on the basis of a clinical history of cerebrovascular accident (CVA). An abnormal MRI but no clinical history of CVA was classified as a silent infarct. Neuropsychological evaluations included assessment of both global intellectual functioning and specific academic and neuropsychological functions.
Results. Central nervous system (CNS) abnormalities were identified on MRI in 17.9% of the children (22.2% of children homozygous for HbS), and a clinical history of CVA (N = 9, 4.6%) was identified in only children with HbSS disease. Subsequent analyses examined only children with HbSS. Children with a history of CVA performed significantly poorer than children with silent infarcts or no MRI abnormality on most neuropsychological evaluation measures. Children with silent infarcts on MRI performed significantly poorer than children with no MRI abnormality on tests of arithmetic, vocabulary, and visual motor speed and coordination.
Conclusions. These results substantiate the importance of careful evaluation, educational planning, and medical intervention for CNS-related complications in children with sickle cell disease.
Eleven patients, aged 20 to 38 with Sickle S Disease and one with Sickle C Disease had pulmonary function evaluation including mechanics and shunt studies. All had a history of Sickle Cell Crises. Two subjects had a diffuse reticular pattern on chest x ray, and one had a pulmonary edema pattern. Mean total lung capacity percent (TLC%) predicted was 72 ± 6%. Mean dynamic compliance (Cdyn) was 0.106 ± .037 liter/cm H 2O. Mean coefficient of retraction was 7.018 ± 3.061. Mean elastic recoil pressure at maximal inspiration (Pst, TLC) was 26.55 ± 7.53 cm H 2O. Pst, TLC, and CR correlated significantly with Cdyn (P<0.05). Shunt studies performed in six subjects with 100% oxygen demonstrated a mean venous to arterial shunt of 19.7 ± 8.7%. Sickle Cell Disease of the lung is a restrictive process characterized by decreased dynamic compliance, high normal elastic recoil pressure, decreased diffusing capacity, and increased coefficient of retraction. Hypoxemia is due mainly to venous to arterial shunting. The etiology of Sickle Cell Disease of the lung is related to recurrent in situ pulmonary infarctions and pulmonary arteriolar obliteration.
In the absence of evidence for pneumonia or pulmonary embolus, primary pulmonary infarction has been assumed to be the cause of the syndrome of chest pain, fever, and pulmonary infiltrate on chest X-ray that commonly complicates sickle cell anaemia. To find out whether the syndrome might be due to rib infarction, 99m Tc-diphosphonate bone scans were done. In the eleven episodes thus investigated (10 patients) the scans showed segmental areas of increased radionuclide uptake in ribs, indicative of bone infarction. A possible sequence of events is that the rib infarcts are primary and cause bone pain, followed by soft tissue reaction, pleuritis, and splinting. The resultant hypoventilation leads to atelectasis and subsequent development of the radiographic changes of the acute chest syndrome. Prevention of hypoventilation and treatment of bone pain are important therapeutic goals.
Over a 12-month period, there were 51 admissions for sickle cell pain crisis. Of these, the course of four patients (two with hemoglobin SS, one with hemoglobin SC, and one with hemoglobin S-Thal) was complicated by the development of pulmonary edema. Pulmonary edema complicating the management of sickle cell pain crisis has not previously been described. Vigorous fluid replacement with hypotonic saline and parenteral narcotic analgesics are conventional modalities of therapy, but may contribute to the development of pulmonary edema. Narcotic analgesics causing increased permeability are well established. In pulmonary vascular beds predisposed to injury, hypotonic saline administration causing an increased hydrostatic pressure and decreased oncotic pressure may further compound pulmonary edema development. On the basis of the experience in this study, a conservative approach to the use of fluid administration and narcotic analgesics is advised.
Acute splenic sequestration crises (ASSC) is a potentially life-threatening com plication in young children with sickle cell anemia. The clinical picture includes huge splenomegaly accompanied by signs and symptoms of acute circulatory insufficiency caused by profound anemia. The authors describe 20 such episodes in 14 children aged six to 55 months. Rapid transfusion of packed erythrocytes produced rapid and dramatic improvement. The spleens became nonpalpable in seven to ten days following transfusion. Four children died, four had one or more recurrences, four have splenic involution, and two were splenectomized. The recurrences were within four months of the previous ASSC. "Our current recommendation is to consider splenectomy only after at least two ASSCs."
Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ in the body, including the bones, lungs, liver, kidneys, brain, eyes, and joints. Dactylitis (pain and/or swelling of the hands or feet) in infants and young children is often the earliest manifestation of sickle cell disease. In children the spleen can become engorged with blood cells in a “splenic sequestration crisis.” The spleen is also particularly subject to infarction and the majority of individuals with SCD are functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation. Individuals with the highest rates of hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg ulcers but are relatively protected from vaso-occlusive pain.
The term “sickle cell disease” encompasses a group of symptomatic disorders associated with mutations in HBB and defined by the presence of hemoglobin S (Hb S). Normal human hemoglobin is a heterotetramer composed of two α-hemoglobin chains and two β-hemoglobin chains. Hemoglobin S results from a point mutation in HBB, changing the sixth amino acid in the β-hemoglobin chain from glutamic acid to valine (Glu6Val). Sickle cell anemia (homozygous Hb SS) accounts for 60%-70% of sickle cell disease in the US. Other forms of sickle cell disease result from coinheritance of Hb S with other abnormal β-globin chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle β-thalassemia (Hb Sβ+-thalassemia and Hb Sβ°-thalassemia); rarer forms result from coinheritance of other Hb variants such as D-Punjab and O-Arab. The diagnosis of sickle cell disease is established by demonstrating the presence of significant quantities of Hb S by isoelectric focusing (IEF), cellulose acetate electrophoresis, high-performance liquid chromatography (HPLC), or (less commonly) DNA analysis. Targeted mutation analysis is used to identify the common mutations of HBB associated with hemoglobin S, hemoglobin C, and additional rarer mutations. HBB sequence analysis may be used to detect mutations associated with β-thalassemia hemoglobin variants. Gel electrophoresis or HPLC can differentiate these disorders from heterozygous carriers of the Hb S mutation (Hb AS). In the US, mandatory newborn screening establishes the diagnosis of sickle cell disease in neonates with the goal of assuring referral to specialty care prior to the onset of symptoms.
Treatment of manifestations: The mainstay of therapy for pain episodes is supportive: hydration (e.g., intravenous fluids), anti-inflammatory agents, and pain medication (e.g., nonsteroidal anti-inflammatory drugs and narcotic analgesia). Pain episodes are additionally managed with a multi-model approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). Aggressive pulmonary toilet and prompt evaluation and treatment of underlying infections are essential. Life-threatening or severe complications (e.g., acute chest syndrome and stroke) are often treated with transfusion to reduce the percentage of Hb S while increasing oxygen carrying capacity. Other treatments may include joint replacement, hemodialysis, kidney transplantation, splenectomy for splenic sequestration crisis, and/or cholecystectomy for cholelithiasis. Acute treatment of stroke includes red blood cell exchange transfusion and aggressive management of increased intracranial pressure and seizures. Severe priapism may require aspiration and irrigation. Management of pulmonary hypertension can include routine treatments and specific therapies such as phosphodiesterase inhibitors or nitric oxide. Prevention of primary manifestations: The mainstay is good hydration and avoidance of climate extremes, extreme fatigue, and activities leading to inflammation. Hydroxyurea can decrease the frequency and severity of vaso-occlusive processes, reduce transfusion needs, and increase life span. Chronic red blood cell transfusion is indicated in children with either a history of or risk factors for stroke and other specific complications, such as pulmonary hypertension and chronic renal failure. Prevention of secondary complications: Aggressive education on the management of fevers; prophylactic antibiotics, including penicillin in children; up-to-date immunizations; and iron chelation therapy for those with iron overload. Surveillance: Yearly: CBC and reticulocyte count, assessment of iron status, liver and renal function tests, and urinalysis. Yearly starting at age two to three years for all individuals with Hb SS and Hb Sβ°-thalassemia: transcranial Doppler studies of arterial blood flow velocity. Yearly starting at age seven years: chest x-ray, pulmonary function tests, abdominal ultrasound examination, eye examination, and vision screening. Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, and extremely high altitude. Evaluation of relatives at risk: Early diagnosis of at-risk family members allows education and intervention before symptoms or end-organ damage are present.
Sickle cell disease is inherited in an autosomal recessive manner. If one parent is a carrier of the HBB Hb S mutation and the other is a carrier of an HBB mutation (e.g., Hb S, Hb C, β-thalassemia), each child has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for common forms of sickle cell disease is most commonly accomplished by HPLC. Prenatal diagnosis for pregnancies at increased risk for sickle cell disease is possible by molecular genetic testing if the HBB mutations have been identified in the parents.
Myocardial infarction in young adults is, in practice, a diagnosis of exclusion. Given the fact that most of the patients with sickle cell disease are young and have predisposition to painful crisis, they are often overlooked for myocardial infarction. These patients often have few or no traditional risk factors for coronary artery disease, and risk stratification tools such as the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) models place these patients at low risk. Nonspecific changes on electrocardiogram are of little diagnostic value. Myocardial infarction is very often a missed diagnosis in patients with sickle cell disease. Diagnostic criteria, potential mechanisms, and management for acute myocardial infarction in patients with sickle cell disease are discussed.
Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease.
The inherited hemoglobin disorders sickle cell disease and thalassemia are the most common monogenetic disorders worldwide. Pulmonary hypertension is one of the leading causes of morbidity and mortality in adult patients with sickle cell disease and thalassemia, and hemolytic disorders are potentially among the most common causes of pulmonary hypertension. The pathogenesis of pulmonary hypertension in hemolytic disorders is likely multifactorial, including hemolysis, impaired nitric oxide (NO) bioavailability, chronic hypoxemia, chronic thromboembolic disease, chronic liver disease, and asplenia. In contrast to patients with traditional forms of pulmonary arterial hypertension, patients with hemolytic disorders have a mild-to-moderate degree of elevation in mean pulmonary pressures, with mild elevations in pulmonary vascular resistance. The hemodynamic etiology of pulmonary hypertension in these patients is multifactorial and includes pulmonary arterial hypertension, pulmonary venous hypertension, and pulmonary hypertension secondary to a hyperdynamic state. Currently, there are limited data on the effects of any specific treatment modality for pulmonary hypertension in patients with hemolytic disorders. It is likely that maximization of treatment of the primary hemoglobinopathy in all patients and treatment with selective pulmonary vasodilators and antiproliferative agents in patients with pulmonary arterial hypertension would be beneficial. However, there is still a major need for large multinational trials of novel therapies for this patient population.
Sickle cell disease (SCD) is associated with early mortality. We sought to determine the incidence, cause, and risk factors for death in an adult population of patients with SCD. All patients aged >/=18 years seen at the Adult Sickle Cell Center at Duke University Medical Center between January 2000 and April 2005 were enrolled. Forty-three patients (21 males and 22 females) died during the study period. The median age of survival was 39 years for females (95% CI: 34-56), 40 years for males (95% CI: 34-48), and 40 years overall (95% CI: 35-48). Cardiac causes of death accounted for 25.6% (11/43 patients); pulmonary, 14.0% (six patients); other SCD related, 32.6% (14 patients); unknown, 14.0% (six patients); and others, 14.0% (six patients). Pulseless electrical activity arrest, pulmonary emboli, multiorgan failure, and stroke were the most frequent causes of death. Among the deceased patients, the most common premorbid conditions were cardiopulmonary: acute chest syndrome/pneumonia (58.1%), Pulmonary hypertension (pHTN; 41.9%), systemic HTN (25.6%), congestive heart failure (25.6%), myocardial infarction (20.9%), and arrhythmias (14.0%). Tricuspid regurgitant jet velocity was significantly higher (3.1 m/sec vs. 2.6 m/sec, P < 0.001) and hemoglobin significantly lower (8.3 g/dL vs. 9.2 g/dL, P < 0.05) in deceased patients when compared with patients who lived, respectively. With improved preventive and therapeutic advances, including hydroxyurea therapy, acute complications such as infection are no longer the leading cause of death; instead, causes of death and premorbid conditions are shifting to chronic cardiopulmonary complications. Further, arrhythmia leading to premature death is under-recognized in SCD and warrants further investigation.
Sickle cell disease (SCD) is a pleiotropic genetic disorder of hemoglobin that has profound multiorgan effects. The low prevalence of SCD ( approximately 100,000/US) has limited progress in clinical, basic, and translational research. Lack of a large, readily accessible population for clinical studies has contributed to the absence of standard definitions and diagnostic criteria for the numerous complications of SCD and inadequate understanding of SCD pathophysiology. In 2005, the Comprehensive Sickle Cell Centers initiated a project to establish consensus definitions of the most frequently occurring complications. A group of clinicians and scientists with extensive expertise in research and treatment of SCD gathered to identify and categorize the most common complications. From this group, a formal writing team was formed that further reviewed the literature, sought specialist input, and produced definitions in a standard format. This article provides an overview of the process and describes 12 body system categories and the most prevalent or severe complications within these categories. A detailed Appendix provides standardized definitions for all complications identified within each system. This report proposes use of these definitions for studies of SCD complications, so future studies can be comparably robust and treatment efficacy measured. Use of these definitions will support greater accuracy in genotype-phenotype studies, thereby achieving a better understanding of SCD pathophysiology. This should nevertheless be viewed as a dynamic rather than final document; phenotype descriptions should be reevaluated and revised periodically to provide the most current standard definitions as etiologic factors are better understood, and new diagnostic options are developed.
Twenty-four percent of sickle cell disease (SCD) patients have a stroke by the age of 45 years. Blood transfusions decrease stroke risk in patients deemed high risk by transcranial Doppler. However, transcranial Doppler has poor specificity, and transfusions are limited by alloimmunization and iron overload. Transfusion withdrawal may be associated with an increased rebound stroke risk. Extended blood typing decreases alloimmunization in SCD but is not universally adopted. Transfusions for thalassemia begun in early childhood are associated with lower rates of alloimmunization than are seen in SCD, suggesting immune tolerance. Optimal oxygen transport efficiency occurs at a relatively low hematocrit for SCD patients because of hyperviscosity. Consequently, exchange rather than simple transfusions are more effective in improving oxygen transport efficiency, but the former are technically more demanding and require more blood units. Although viscosity is of importance in the noncerebral manifestations of SCD, inflammation may play a larger role than viscosity in the development of large-vessel stroke. The future of SCD stroke management lies in the avoidance of transfusion. Hydroxyurea and anti-inflammatory measures may reduce the need for transfusion. Recent genome-wide association studies may provide methods for modulating fetal hemoglobin production enough to attenuate stroke risk and other complications of SCD.
Silent infarcts have been reported most commonly in school-aged children with homozygous sickle cell disease (SCD-SS) and are associated with neurocognitive deficits. However, the prevalence of silent infarcts in younger children with SCD-SS is not well defined. In this retrospective study, brain magnetic resonance imaging and angiography (MRI/A) studies performed before 6 years of age in a cohort of children with SCD-SS were analysed and the prevalence of abnormalities was calculated. Clinical and laboratory parameters were compared between the groups with and without silent infarcts. Sixty-eight of 96 children in the cohort had brain MRI/A performed prior to age 6 years. Of the 65 who were neurologically asymptomatic, 18 (27.7%, 95% CI 17.3-40.2%) had silent infarcts (mean age 3.7 +/- 1.1 years, range 1.3-5.9 years). Factors associated with silent infarcts included cerebral vessel stensosis by magnetic resonance angiography, lower rates of vaso-occlusive pain and acute chest syndrome and lower haemoglobin levels. The prevalence of silent infarcts in young children with SCD-SS is similar to that of older children and anaemia and severe vasculopathy may be risk factors.
The renal features of sickle cell disease (SCD) include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Painless hematuria is usually benign--unless massive--and can be treated with hydration alone if renal medullary carcinoma has been ruled out. Tubular functional defects, which tend to reduce urinary concentrating capacity, generally require no specific treatment. Proteinuria might indicate the development of chronic sickle cell nephropathy, which can be treated effectively. Measurement of glomerular filtration rate in SCD is problematic, which makes identification and monitoring of chronic kidney disease difficult in patients with SCD. Although managing and predicting the outcomes of chronic kidney disease in the SCD setting is challenging, affected individuals do benefit from transplantation. This Review summarizes the presentation, processes, pathology, modifiers, diagnosis and treatment of the renal effects of SCD.
Sickle cell disease patients are more likely than the general population to undergo surgery and usually do so at a younger age. Female sickle cell disease patients also have special gynecological and obstetric issues related to their disease.
We collected data through standardized clinical report forms, patient interviews, and medical records from 509 adult sickle cell disease patients. Logistic regression was used to estimate the association between multiple variables and each of the surgery types. We also determined the prevalence and outcomes of pregnancy in 284 women with sickle cell disease in this population.
Almost 50% of patients aged 18-27 years had had a cholecystectomy. Mean corpuscular hemoglobin, total bilirubin, and lactate dehydrogenase were significantly higher in the postcholecystectomy group; 9.5% of 504 individuals had undergone splenectomy. Hematocrit, body mass index, and red blood cell count were significantly higher in the postsplenectomy group. Hip replacement had been performed in 9.2% of individuals, with the prevalence increasing as early as the fourth decade and continuing to increase through the sixth decade of life. A history of pregnancy was present in 190 women (67%). Of 410 pregnancies, only 53.9% resulted in live births, 16.6% were voluntarily terminated, and 29.5% were complicated by miscarriage, still birth, or ectopic implantation.
Sickle cell disease continues to have a strong effect on the mean age for common surgeries and impacts pregnancy outcomes. We conclude that this population has a unique surgical and obstetric history that should be further studied to provide insight into potentially more effective preventive approaches to end-organ damage.
To determine the role of hematological and genetic factors in the development of orbital infarction in sickle cell disease.
Retrospective, noncomparative case series.
Fourteen sickle cell disease patients were diagnosed with orbital infarction during a vaso-occlusive crisis. Clinical and radiological findings were reviewed retrospectively. Sickle cell disease patients without orbital infarction were recruited as controls after matching for disease severity. Sickle haplotypes were determined for all patients. Differences between groups were evaluated statistically.
Patients with orbital infarction in sickle cell disease presented with acute periorbital pain and swelling with or without proptosis, ophthalmoplegia, and visual impairment during a vaso-occlusive crisis. Radiological findings included orbital soft tissue swelling (100%), hematoma (orbital, 36%; intracranial, 21%), and abnormal bone marrow intensities. Severity of orbital involvement was unrelated to that of the systemic disease (Pearson correlation coefficient, -0.1567). Affected patients predominantly had the Benin haplotype (P < .00782).
Orbital infarction is a potential threat to vision in sickle cell disease patients. Magnetic resonance imaging is more specific than computed tomography or nuclear scintigraphy in the evaluation of orbital changes. The degree of severity of the orbital manifestations appears unrelated to the severity of sickle cell disease. Patients with the Benin haplotype are more likely to develop orbital infarction during vaso-occlusive crises.
Intracranial aneurysms are an unusual complication of sickle-cell anemia; only 15 patients have been described in the world literature. An additional 15 patients with sickle-cell anemia and subarachnoid hemorrhage (SAH) from ruptured intracranial aneurysms are presented. There was a high incidence of multiple aneurysms (60%); some of which were in unusual locations. The clinical and pathological features of this series of patients have provided a paradigm for acquired aneurysm formation that may be applicable to other intracranial aneurysms. Thirteen patients underwent craniotomy and clip ligation; the perioperative management of these patients is discussed. Of these 13, eight had a good recovery, three were left with moderate disability, one patient died of surgical complications, and one died of complications related to sickle-cell anemia. Two of the 15 patients died of SAH. The authors propose that endothelial injury from the abnormal adherence of sickle erythrocytes to the endothelium is the initiating event in arterial wall injury. Subsequently, there is fragmentation of the internal elastic lamina and degeneration of the smooth-muscle layer. Hemodynamic stress at these loci of arterial wall damage results in aneurysm formation. This hypothesis also explains other cerebrovascular manifestations of sickle-cell anemia, namely vaso-occlusive disease and hemorrhage without aneurysm formation. Pathological material from this series and data from the literature are presented to support this hypothesis.
The neurological complications of sickle-cell disease include cerebral intracerebral hemorrhage; subarachnoid hemorrhage (SAH) has been infrequently reported. Among 325 patients with sickle-cell disease followed at the University of Illinois between 1975 and 1989, 11 cases of SAH were identified. Aneurysms were found in 10 of these patients, three of whom had multiple aneurysms. All of the patients had some degree of anemia and nine underwent craniotomy without hematological or neurological complications. From this review it appears that SAH is not uncommon in sickle-cell disease patients and tends to occur at a younger age and with smaller aneurysm size than in the general population. With proper perioperative management, including exchange transfusions to reduce the proportion of hemoglobin S to less than 30%, these patients can undergo angiography and craniotomy without an increased incidence of complications. The techniques used in managing sickle-cell disease patients with SAH are discussed.
We report the natural course of the hip in fifty-two patients (ninety-five hips) who had sickle-cell disease and had had avascular necrosis in childhood. There were twenty-one African, twenty-one West Indian, and ten Mediterranean patients. At the most recent follow-up examination (at an average duration of nineteen years after the onset of the disease), 80 per cent of the hips that had been affected by avascular necrosis during childhood were painful and had permanent damage with regard to decreased mobility, limb-length discrepancy, and an abnormal gait. When the patients were evaluated, at an average age of thirty-one years, fifteen hips (16 per cent) had had an operation for progressive disability and sixty (63 per cent) had major problems because of pain. Of the twenty hips (21 per cent) that were not painful, five were in patients who had an abnormal gait, with decreased agility. The mean Iowa hip-rating score at the most recent follow-up examination was 73 points (range, 30 to 100 points). Correlations were found between the hip score and the patient's age at the onset of the disease and at the latest follow-up, between the hip score and degenerative changes in the hip, and between degenerative changes and radiographic evidence of deformity of the hip.
Over a 12-month period, there were 51 admissions for sickle cell pain crisis. Of these, the course of four patients (two with hemoglobin SS, one with hemoglobin SC, and one with hemoglobin S-Thal) was complicated by the development of pulmonary edema. Pulmonary edema complicating the management of sickle cell pain crisis has not previously been described. Vigorous fluid replacement with hypotonic saline and parenteral narcotic analgesics are conventional modalities of therapy, but may contribute to the development of pulmonary edema. Narcotic analgesics causing increased permeability are well established. In pulmonary vascular beds predisposed to injury, hypotonic saline administration causing an increased hydrostatic pressure and decreased oncotic pressure may further compound pulmonary edema development. On the basis of the experience in this study, a conservative approach to the use of fluid administration and narcotic analgesics is advised.
Liver biopsy results and clinical records from 13 patients with sickle cell anemia were reviewed to assess the relative importance of local ischemia or of factors unrelated to sickling as a cause of their liver disease. Two of the biopsy specimens were normal and one showed cirrhosis. Nine patients had received multiple blood transfusions and nine had cholelithiasis, of whom two also had choledocholithiasis. Seven had both risk factors. Five had lobular cholestasis and four had acute or chronic hepatitis. One biopsy specimen showed changes of the Budd-Chiari syndrome. Another showed clear portal tract ch