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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ESickle cell disease can lead to stroke, which affects about 40% of those with the disease by mid-adolescence. The cognitive damage can lessen IQ and diminish quality of life. Research is leading to helpful strategies, and has also revealed details of the arterial accumulation of the affected red blood cells.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Esilent stroke\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Echildren\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eadolescents\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ebiology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ephysiology\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ESilent Strokes\u003C\/h2\u003E\n         \u003Cp id=\u0022p-2\u0022\u003EMichael R. DeBaun, MD, MPH, Vanderbilt University Medical Center, Nashville, Tennessee, USA, discussed silent strokes in children and adolescents with sickle cell disease (SCD).\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EFrom 1990 to 1999, the incidence of SCD in the United States was 1 in every 2474 live births overall [Kanter J, Kruse-Jarres R. \u003Cem\u003EBlood Rev\u003C\/em\u003E. 2013], which exceeds that of primary congenital hypothyroidism (1:3044) and cystic fibrosis (1:3000). The incidence for African Americans was markedly higher (1:400 live births). The implementation of newborn screening at the state level in 1988 was key; a study at that time by Vichinksy and colleagues showed that the mortality attributed to SCD decreased from 8% to 1.8% with newborn screening. \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E illustrates the relative increase in survival [Quinn CT et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Improved Survival of Sickle Cell DiseaseAdapted from Quinn CT et al. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115:3447-3452. With permission of American Society of Hematology.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-105202915\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Improved Survival of Sickle Cell DiseaseAdapted from Quinn CT et al. Improved survival of children and adolescents with sickle cell disease. \u0026amp;lt;em\u0026amp;gt;Blood.\u0026amp;lt;\/em\u0026amp;gt; 2010;115:3447-3452. With permission of American Society of Hematology.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11641\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-4\u0022 class=\u0022first-child\u0022\u003EImproved Survival of Sickle Cell Disease\u003C\/p\u003E\n               \u003Cp id=\u0022p-5\u0022\u003EAdapted from Quinn CT et al. Improved survival of children and adolescents with sickle cell disease. \u003Cem\u003EBlood.\u003C\/em\u003E 2010;115:3447-3452. With permission of American Society of Hematology.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe link between so-called silent strokes, which occur without any awareness in the person who is affected, has become recognized since only the 1990s. The cerebral damage inflicted by silent strokes can blunt academic performance and quality of life. The cerebral insult occurs early in life: by age 6 years, nearly one-third of those with SCD will have suffered at least 1 stroke, with deleterious effects apparent even before age 2 years.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe damage caused by a silent stroke includes diminished cognitive function, evident as decreased full-scale IQ [King AA et al. \u003Cem\u003EAm J Hematol.\u003C\/em\u003E 2014]. Cognitive function may further diminish, given the progressive nature of silent strokes with time [Miller ST et al. \u003Cem\u003EJ Pediatr.\u003C\/em\u003E 2001]. Blood transfusions are valuable in reducing the risk of progression of silent cerebral infarcts [DeBaun MR et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2014; King AA et al. \u003Cem\u003EPediatr Blood Cancer.\u003C\/em\u003E 2008]. Socioenvironmental factors, including level of parental education and household income, can influence cognitive improvement [King AA et al. \u003Cem\u003EAm J Hematol.\u003C\/em\u003E 2014]. With the life span of those with SCD now extended to adulthood, the consequences of the disease in the decades following childhood have become important to understand.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EDr DeBaun\u2019s interests in SCD have included Nigeria, the country with the largest burden of the disease, with 150\u2009000 newborn cases annually, compared to 1400 in the United States. Among Nigerian children and adolescents, the prevalence of strokes and silent strokes is estimated to be 15\u2009000 and 45\u2009000 per birth cohort year, respectively. The ongoing SPIN study [Galadanci NA et al. \u003Cem\u003EPediatr Blood Cancer.\u003C\/em\u003E 2014], funded by the US National Institute of Neurological Disorders and Stroke, is assessing the feasibility of low-dose hydroxyurea (the only approved drug for SCD) in children with elevated transcranial Doppler-determined blood velocity in lowering this velocity and so lessening the risk of stroke. This strategy could enable effective treatment in countries where blood transfusions are not economically feasible.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EBiological and Physiologic Aspects of SCD\u003C\/h2\u003E\n         \u003Cp id=\u0022p-9\u0022\u003ERobert Hebbel, MD, University of Minnesota, Minneapolis, Minnesota, USA, addressed biological and physiologic issues of SCD. The root of SCD is hemoglobin, the protein responsible for ferrying oxygen from the lungs throughout the body. SCD is caused by a single-point mutation on the \u03b2-globin subunit of hemoglobin, resulting in a mutant form of hemoglobin known as sickle hemoglobin (HbS). The sickle mutation confers an abnormal property on the HbS that causes it to polymerize when switched from the oxygenated to deoxygenated conformation, which causes the characteristic sickling of the red blood cells (RBCs). This is a reversible mutation; should the HbS become reoxygenated, the sickled RBC returns to its normal shape. As demonstrated by Dr Hebbel and colleagues in decades of research, the RBCs of a patient with SCD become sticky and accumulate in blood vessel of limbs and organs. The result is pain, organ damage, anemia, and increased risk of infection.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EResearch into the altered nature of RBCs in SCD that drives their vascular accumulation began with the serendipitous observation, first described in 1978 by Dr Hebbel and colleagues, of the tendency of the cells to aggregate and become less capable of flow when compared with normal RBCs (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Demonstration of the Altered Behavior of Red Blood Cells in Sickle Cell DiseaseReproduced with permission from R Hebbel, MD.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-105202915\u0022 data-figure-caption=\u0022Demonstration of the Altered Behavior of Red Blood Cells in Sickle Cell DiseaseReproduced with permission from R Hebbel, MD.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11642\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EDemonstration of the Altered Behavior of Red Blood Cells in Sickle Cell Disease\u003C\/p\u003E\n               \u003Cp id=\u0022p-12\u0022\u003EReproduced with permission from R Hebbel, MD.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-13\u0022\u003ESubsequent in vitro studies by Dr Hebbel and others in the 1980s revealed the tendency of the abnormal red erythrocytes to form rosettes with endothelial cells and the correlation of the degree of cell adhesion with the severity of vascular occlusion. The association between sickle RBCs and endothelial cells is driven by an associative force that is stronger than that exhibited by normal RBCs, which produces more erythrocyte\u2013endothelial cell contacts. The consequence is accumulation of the RBCs along the walls of the microvasculature immediately following the capillaries, which leads to vaso-occlusion.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003ENormally, RBCs flow uniformly through the vessels; however, studies with a mouse strain that produces HbS have shown that the more pronounced surface attraction of the sickle erythrocytes produces more of a rolling motion along the vessel walls, which can lead to adherence and piling up of more erythrocytes. The result is a vicious cycle in which vascular occlusion drives ischemia reperfusion and systemic inflammation that in turn fuels occlusion and an overall vicious cycle in which systemic inflammation promotes endothelial dysfunction, which in turn encourages endothelial adhesion of both red and white blood cells (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The Vicious Cycles of Sickle Cell DiseaseHb, hemoglobin; HbS, hemoglobin S; pO2, partial pressure of oxygen; RBC, red blood cell; WBC, white blood cell.Reproduced with permission from R Hebbel, MD.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-105202915\u0022 data-figure-caption=\u0022The Vicious Cycles of Sickle Cell DiseaseHb, hemoglobin; HbS, hemoglobin S; pO2, partial pressure of oxygen; RBC, red blood cell; WBC, white blood cell.Reproduced with permission from R Hebbel, MD.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F3.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/2\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11643\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \n               \u003Cp id=\u0022p-15\u0022 class=\u0022first-child\u0022\u003EThe Vicious Cycles of Sickle Cell Disease\u003C\/p\u003E\n               \u003Cp id=\u0022p-16\u0022\u003EHb, hemoglobin; HbS, hemoglobin S; pO2, partial pressure of oxygen; RBC, red blood cell; WBC, white blood cell.\u003C\/p\u003E\n               \u003Cp id=\u0022p-17\u0022\u003EReproduced with permission from R Hebbel, MD.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-18\u0022\u003ESickle cell adhesion is also influenced by platelets, increased expression of von Willebrand factor by activated endothelial cells, endothelial inflammation, and perhaps even endothelial damage caused by exposure to tobacco smoke.\u003C\/p\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EAntiadhesive therapeutic studies have revealed that the inhibition of P-selectin on the endothelial cell surface improves blood flow, while inhibition of E-selectin (another adhesion molecule, which is expressed on the surface of cytokine-activated endothelial cells) does not. The findings support the view that increased expression of P-selectin in SCD mediates the adhesion of sickle erythrocytes to the endothelium. Other antiadhesive strategies are focusing on disrupting cell signals that mediate the association between sickle erythrocytes and adhesion molecules.\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003EWhether the vascular accumulation of sickle erythrocytes involves capillaries is unclear. If this does occur\u2014and whether it involves different mechanisms and so could require a different therapeutic approach\u2014is also unknown.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/55\/2.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzo942\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo942\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}