Showing papers on "Sickle cell anemia published in 2004"

The Endothelial Biology of Sickle Cell Disease: Inflammation and a Chronic Vasculopathy

Abstract: A single amino acid substitution in hemoglobin comprises the molecular basis for sickle cell anemia, but evolution of the corresponding clinical disease is extraordinarily complicated and likely involves multiple pathogenic factors. Sickle disease is fundamentally an inflammatory state, with activation of the endothelium, probably through proximate effects of reperfusion injury physiology and chronic molestation by adherent red cells and white cells. The disease also involves enhanced angiogenic propensity, activation of coagulation, disordered vasoregulation, and a component of chronic vasculopathy. Sickle cell anemia is truly an endothelial disease, and it is likely that genetic differences in endothelial function help govern its astonishing phenotypic diversity.

Sickle cell disease; a general overview.

Abstract: Sickle cell disease (SCD) is a heterogeneous disorder, with clinical manifestations including chronic haemolysis, an increased susceptibility to infections and vaso-occlusive complications often requiring medical care. Patients with SCD can develop specific and sometimes life-threatening complications, as well as extensive organ damage reducing both their quality of life and their life expectancy. Proven effective treatment options for sickle cell patients are limited to hydroxyurea, blood transfusions and bone marrow transplantation. With the increasing prevalence of SCD in the Netherlands, a fundamental understanding of its pathophysiology and clinical syndromes is of importance for local medical practitioners.

Sickle cell disease and anesthesia.

Abstract: IN October 1902, a “peculiar anomaly in human red blood corpuscles. . .came to notice in the histologic laboratory of the Ohio State University,” Columbus, Ohio. “Examination disclosed the fact that the colored corpuscles in the sample recently drawn by (a) student from his own finger that were elliptical and not circular.” Similar erythrocyte abnormalities were reported in North African Arab subjects shortly afterwards. In November 1910 James B Herrick, M.D. (Professor Of Medicine, Rush Medical College, Chicago, Illinois; 1861–1954) published a detailed case report. This described a patient with jaundice, shortness of breath, lymphadenopathy, dark urine, leg ulcers, epigastria pain, and anemia associated with these same types of “peculiar elongated and sickle-shaped red blood corpuscles.” This classic report was the first unequivocal clinical description in Western scientific literature of sickle cell disease (SCD), a set of closely related hemoglobinopathies that have in common the inheritance of mutant hemoglobin S (fig. 1). Clinically, SCD is characterized by chronic hemolytic anemia, recurrent episodes of intermittent vasoocclusion and severe pain, progressive organ damage, and a striking variation of expression. In 1927, Hahn and Gillespie noted that the eponymous deformation or sickling of the erythrocytes was induced by deoxygenation and reversed with reoxygenation. The clinical segue was a hypothesis that vasoocclusion was triggered by delayed passage of erythrocytes through the microcirculation, leading to a “vicious cycle” of increased sickling, mechanical obstruction to flow, further sickling, vasoocclusion, and infarction. In 1955, the first major review of the anesthetic implications of SCD acknowledged the high incidence of serious and potentially fatal exacerbations of the disease after surgical procedures. The avoidance of factors said to increase erythrocyte sickling and precipitate the vicious cycle has been the traditional foundation of anesthetic management of SCD. The century after the discovery of the peculiar anomaly has seen an immense expansion in the understanding of the complex relationship between these peculiar erythrocytes and the clinical expression of the disease. This article briefly summarizes advances made in understanding of the disease pathophysiology, describes salient clinical features relevant to the anesthesiologist, and reviews data from the perioperative period, emphasizing a new anesthetic approach to this old problem.

Cytokine profile of sickle cell disease in Oman.

Abstract: The aim of our study was to assess the cytokine profile of sickle cell disease (SCD) patients in steady state and in vaso-occlusive crisis (VOC). VOC has a complex nature, involving interactions between sickle red blood cells (RBC), the endothelium, and leucocytes. Endothelial damage due to recurrent adhesion of sickle RBCs may disrupt endothelial function, leading to altered cytokine release. It is therefore pertinent to study the cytokine profile of SCD patients in steady state and in crisis prior to exploring its contribution to vaso-occlusive manifestations, since it is believed that an altered balance of proinflammatory and anti-inflammatory cytokines plays an important role in painful crisis. Cytokines including IL-1beta, IL-2, IL-4, IL-6, IL-8, TNF-alpha, and IFN-gamma were measured by commercially available ELISA kits in SCD patients (n = 60); in steady state (n = 26) and in painful crisis (n = 34) and compared with nonanemic age- and sex-matched normal Omani controls (n = 20). SCD patients in crisis showed elevated levels of TNF-alpha (P < 0.092) and IL-6 (P < 0.024) when compared with steady state. It was also observed that SCD patients in steady state showed a significant elevation in IL-1beta (P < 0.04), IL-6 (P < 0.0001), and IFN-gamma (P < 0.02) as compared to normal subjects. It is thus evident that both type I and type II cytokines are significantly altered in SCD patients. In steady state, type II proinflammatory cytokines are elevated, whereas in crisis, an additional augmentation of type I cytokines occurs, with persistent elevation of type II cytokines, emphasizing the role of perturbed endothelium and activated monocytes in the pathophysiology of vaso-occlusion in sickle cell crisis.

Sickle Red Cell Microrheology and Sickle Blood Rheology

Abstract: The hallmark of the phenotypic expression of sickle cell disease is the remarkable degree of heterogeneity in the clinical manifestations. They vary latitudinally among patients and longitudinally in the same patient. The pathogenesis of sickle cell anemia centers on the sequence of events that occur between polymerization of deoxy hemoglobin S and increased red cell destruction, vasoocclusion, and end organ damage. Cellular dehydration, changes in sickle red blood cell rheology, adhesion of sickle red cells to vascular endothelium, inflammatory response, and tissue injury are some of the factors that contribute to hemolytic anemia, vasoocclusion, and eventual multiorgan damage. The focus of this review is on the rheology of sickle blood and microrheology of sickle RBC. Determinants of sickle RBC rheology and the factors that modulate its severity are discussed.

Pulmonary Hypertension in Sickle Cell Disease

Abstract: Sickle cell disease was first described in 1910 by Herrick and Irons. The irregularly shaped blood cells observed by Irons were those of Walter Clement Noel, a dental student with symptoms that included joint pain and shortness of breath. After graduation, Dr. Noel returned to his native Grenada, where he died suddenly at 32 years of age. Although the cause of death was recorded as pneumonia, his death was most likely the result of sudden, undetected pulmonary hypertension. Today, we know that pulmonary hypertension and chronic lung disease are two of the most common causes of death among patients with . . .

In vivo studies of sickle red blood cells.

Abstract: The defining clinical feature of sickle cell anemia is periodic occurrence of painful vasoocclusive crisis. Factors that promote trapping and sickling of red cells in the microcirculation are likely to trigger vasoocclusion. The marked red cell heterogeneity in sickle blood and abnormal adhesion of sickle red cells to vascular endothelium would be major disruptive influences. Using ex vivo and in vivo models, the authors show how to dissect the relative contribution of heterogeneous sickle red cell classes to adhesive and obstructive events. These studies revealed that (1) both rheological abnormalities and adhesion of sickle red cells contribute to their abnormal hemodynamic behavior, (2) venules are the sites of sickle cell adhesion, and (3) sickle red cell deformability plays an important role in adhesive and obstructive events. Preferential adhesion of deformable sickle red cells in postcapillary venules followed by selective trapping of dense sickle red cells could result in vasoocclusion. An updated version of this 2-step model is presented. The multifactorial nature of sickle red cell adhesion needs to be considered in designing antiadhesive therapy in vivo.

Hydroxyurea in the treatment of major beta-thalassemia and importance of genetic screening.

Abstract: Efforts have been undertaken to find an alternative approach to packed red cell transfusion (PRCT) in major beta-thalassemia. Augmentation of fetal hemoglobin (HbF) by hydroxyurea (HU) has been reported to be less effective in this condition as compared to sickle cell anemia due to molecular heterogeneity of the former disease. HU efficacy and its relation to Xmn1 polymorphism and IVSII-1 mutation was evaluated in major beta-thalassemics. Forty-five patients, M/F ratio 0.8, aged 6-33 years, received oral HU, 20 mg/kg per day, 4 days per week and daily1 mg folic acid. Thirty-six patients were PRCT dependent (group A) and nine independent (group B). The aim was to stabilize or increase pre-PRCT Hb over 10.0+/-0.5 g/dl and to reduce the need or cease the PRCT in group A and to increase Hb level and curb the ineffective erythropoesis, e.g., splenomegaly, facial bone deformity, in group B. HU was administered for at least 6 months (mean: 9 months) and discontinued in case of response failure. Screening for Xmn1 polymorphism and IVSII-1 mutation was carried out in most patients. In group A, 25 patients have become PRCT independent for a period of 2.5-7.3 years (mean: 4 years). The mean Hb, pre-HU 10.0 and post-HU 10.7 g/dl (range: 8.8-13.7 g/dl), mean serum ferritin pre- and post-HU was1877 and 525 ng/ml. The PRCT requirement was reduced in one patient, and ten patients did not respond. In group B HU has been given over 3.3 years (range: 2.8-4.8 years), Hb increased from 9.3 to 10.4/dl, and there was no tangible progression of ineffective erythropoesis. Responders in both groups expressed more comfort with this regimen. Xmn1 and IVSII-1 (homo- and/or heterozygosis) are relevant markers in most responding patients. Molecular determination of genetic markers in early childhood will help to identify candidates for pharmacological HbF switching by HU.

Association of T-786C eNOS gene polymorphism with increased susceptibility to acute chest syndrome in females with sickle cell disease.

Abstract: Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). A retrospective study was performed to evaluate the role of endothelial nitric oxide synthase (eNOS) gene polymorphisms (E298D and T-786C) in African-American SCD patients. The D298 allele showed no association; the C-786 allele showed a statistically significant association (P = 0.0061) in female ACS cases. Multiple logistic regression analysis showed that relative risk of ACS was 8.695 (P = 0.0076, 95% confidence interval 1.761-42.920) for female carriers of C-786. eNOS T-786C is a gender-specific genetic modifier that is associated with increased susceptibility to ACS in female SCD patients.

Are there clinical phenotypes of homozygous sickle cell disease

Abstract: The distribution of clinical features was examined in subjects with homozygous sickle cell (SS) disease in the Jamaican Cohort Study to determine whether there is evidence of distinct clustering of symptoms or clinical phenotypes. A twofold model yielded groups that could be interpreted as painful crisis or leg ulcer phenotypes and 78% of patients were classified with 95% confidence into one of these. The painful crisis phenotype also manifested higher frequencies of dactylitis, meningitis/septicaemia, acute chest syndrome and stroke. Attempts to define a three-group model were less convincing although 43% of patients could be allocated with 95% confidence. The three-group model essentially divided subjects with the leg ulcer phenotype into subgroups with higher and lower frequencies of painful crisis, dactylitis, meningitis/septicaemia and acute chest syndrome. In the three-group model, the painful crisis phenotype had lower total haemoglobin, fetal haemoglobin, mean cell volume and higher reticulocytes but there was no apparent influence of alpha thalassaemia or beta globin haplotype. Both environmental and genetic factors are likely to contribute to most manifestations of SS disease and the evidence for different clinical phenotypes suggests that a search for associated genetic polymorphisms may provide insights into the mechanisms of clinical variability in SS disease.

Established and experimental treatments for sickle cell disease.

Abstract: Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin (HbS), which has the unique property of polymerizing when deoxygenated. The sickling process is markedly accelerated when intracellular concentration of HbS is increased. Due to the unique dependence of HbS polymerization on its cell concentration, a slight reduction in HbS concentration is likely to have a beneficial effect on the kinetic of polymerization and on the generation of dense, dehydrated red cells. The pathophysiology of acute and chronic clinical manifestations of SCD is strictly related to the hemoglobin cyclic polymerization, to the generation of dense, dehydrated red cells and to the interaction between sickle red cells and abnormal activated vascular endothelial cells. In the present paper we have reviewed the principal therapeutic strategies and we have explored the future treatment options for sickle cell disease. Therapy of sickle cell disease is based on two major goals. The first one is the decrease in intracellular HbS concentration obtained with agents activating fetal hemoglobin synthesis, such as hydroxyurea (HU) or with erythrocyte-active agents blocking different red cell membrane ion pathways and preventing sickle cell dehydration. The second one is based on therapeutic strategies, which may reduce sickle cell-endothelial adhesive events.

Myocardial ischaemia in children with sickle cell disease.

Abstract: Background: The heart may be involved in children affected with sickle cell disease (SCD) via several mechanisms. Principally, chronic anaemia increases cardiac output and may cause left ventricular enlargement and cardiac insufficiency. Aims: To investigate whether the heart also suffers from ischaemia in SCD, as has already been shown for other organs (bone, brain, etc), and to look for risk factors predisposing to this complication. Methods: Twenty two children with SCD, and chest pain or ECG or echocardiographic signs (left ventricle dilation or hypokinesis) suggesting myocardial ischaemia were subjected to thallium-201 (201Tl) single photon emission computed tomography (SPECT). Results: Eight children had a normal SPECT, 14 an abnormal one. Myocardial perfusion defects were reversible in nine, fixed in five. Patients with perfusion defects tended to be older and have more severe disease. Five had had cardiac symptoms (episodes of cardiac failure in three, ventricular fibrillation in one, angina in one). Myocardial perfusion was reassessed after six months of hydroxyurea treatment in three patients, and was found to be improved. Conclusions: Myocardial perfusion defects are present in children with SCD and may be demonstrated using SPECT. Hydroxyurea improved perfusion in three patients.

Blood transfusion is associated with donor leukocyte microchimerism in trauma patients.

Abstract: Introduction: Blood transfusion can result in survival of donor leukocyte subpopulations in the recipient. Persistence of donor leukocytes in the transfusion recipient is termed microchimerism. Microchimerism likely reflects engraftment of the recipient with donor hematopoietic stem cells and is very uncommon with transfusion for elective surgery, sickle cell anemia, thalassemia, and HIV. We have found, however, that microchimerism may be more common in trauma patients. Objective: To determine how frequently transfusion after trauma is associated with microchimerism. Methods: We prospectively enrolled 45 trauma patients who were transfused ≥2 units of PRBCs. We sampled blood before hospital discharge and determined microchimerism by polymerase chain reaction (PCR) analysis of specimens using quantitative allele-specific HLA DR assays to detect non-recipient alleles. Data are expressed as median with interquartile range. Results: Patients had a median age of 38 (interquartile range 25, 58) years, ISS of 19 (13, 29), and mortality of 7%. Seventy-eight percent were men, and 84% had blunt trauma. Patients received a median of 6 (4, 16) (range 2, 87) units of PRBCs. Of the 45 patients, 24 (53%) had evidence of microchimerism. Compared with patients without evidence of microchimerism, these patients had no difference in mean age, gender, ISS, units of PRBCs transfused, time from transfusion to blood sampling, or proportion that underwent splenectomy. Twenty-one of the 24 patients with microchimerism had only 1 or 2 non-recipient DR alleles identified by PCR. Conclusions: Transfusion after trauma is associated with over half of recipients having evidence of microchimerism. Age, sex, ISS, and splenectomy of the recipient and the number of transfused units did not correlate with microchimerism. Because the median time from trans' fusion to sampling for PCR analysis was not longer in the group without microchimerism, it is unlikely microchimerism is due merely to failure of the recipient to clear transfused donor leukocytes.

Day case management of sickle pain: 3 years experience in a UK sickle cell unit

Abstract: A day centre was established to determine whether an alternative approach to the management of uncomplicated sickle pain would improve the quality of care and reduce hospital admissions in patients with sickle cell disease. Since the centre opened there has been a 43% decrease in hospital admissions and 49% decrease in occupied bed days. In the third year, 84% of patients treated for severe sickle pain were managed without the need for hospital admission. A centre offering day case management of painful crisis reduced unnecessary hospital admissions for uncomplicated pain. This approach is safe and cost-effective.

Effect of red cell exchange transfusion on plasma levels of inflammatory mediators in sickle cell patients with acute chest syndrome.

Abstract: Red cell exchange transfusion is the recommended therapy for patients with sickle cell disease (SCD) who have severe, progressive acute chest syndrome (ACS). A double-volume red cell exchange transfusion decreases the percentage of hemoglobin S (Hgb S) containing red blood cells to less than 20%, improving vascular perfusion. We speculated that reduction of pro-inflammatory mediators might also contribute to the therapeutic effect of an exchange transfusion. We measured white blood cell count (WBC), absolute neutrophil count (ANC), platelet concentration as well as plasma levels of interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in 8 sickle cell patients with 9 episodes of ACS who received a manual, double-volume exchange transfusion. Six patients with SCD seen during a routine clinic visit were used as controls. The mean number of hospitalization days was 6, with an average of 2 days in the intensive care unit. All patients recovered without complication. Sickle cell patients with ACS had a higher WBC and ANC at baseline but lower sVCAM-1 levels compared to controls. TNF-alpha, IL-1alpha, IL-1beta, and IL-8 levels were not significantly different from controls. WBC, ANC, platelet, and sVCAM-1 measurements were significantly decreased immediately post-exchange in patients with ACS; however, this effect was not persistent as levels trended towards pre-exchange values by 24 hr post-exchange. Due to wide inter-individual variability, a consistent pattern was not seen for TNF-alpha, IL-1alpha, IL-1beta, or IL-8. We conclude that in sickle cell patients with ACS, a manual, double-volume exchange transfusion lowers WBC, ANC, platelets, and sVCAM-1 levels, but the effect is short-lived.

Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome.

Abstract: Acute chest syndrome (ACS) is the most common cause of death in patients with sickle cell anemia. Its management is primarily palliative. We performed a Phase I evaluation of purified poloxamer 188...

Cerebral oximetry in patients with sickle cell disease

Abstract: Background There is limited information concerning the brain's oxygen supply and demand in patients with sickle cell disease. Design We measured near-infrared spectroscopy of brain oxygenation in 27 patients with sickle cell disease regardless of vaso-occlusive crisis, 14 normal healthy controls, and five anaemic patients without sickle cell disease. We also measured pre- and post-transfusion cerebral oximetry in 14 additional sickle cell disease patients who were on transfusion programmes. Results The mean cerebral oxygen saturation in the combined steady-state and vaso-occlusive crisis population was found to be significantly lower than that in the controls and in anaemic patients without sickle cell disease (47·7% vs. 61·3%, 59·8%, P 0·5). However, cerebral oxygen saturation increased from 40·4% to 49·6% (P = 0·01) and correlated significantly with the haemoglobin level (r = 0·553, P = 0·003) in 14 subjects studied before and after transfusions. In seven subjects who received simple transfusions, cerebral oxygen saturation correlated strongly and positively with the haemoglobin level (r = 0·811, P = 0·001) and with percent normal haemoglobin (r = 0·786, P = 0·002), and negatively with abnormal sickle haemoglobin (r = −0·775, P = 0·003). None of these correlations was found to be statistically significant in the seven subjects given exchange transfusions. Cerebral oxygen saturation measured in the sickle cell disease subjects after transfusions was still significantly lower than in the anaemic subjects without sickle cell disease and in the normal controls (49·6% vs. 59·8% and 61·3%, P = 0·001). Conclusions We found that patients with sickle cell disease have subnormal values of cerebral oxygen saturation. Red cell transfusions significantly increased the brain oxygenation in these patients. Cerebral oximetry may be a useful, noninvasive method for assessing the effect of circulating normal red cells in sickle cell patients after transfusions.

Types of anaemic crises in paediatric patients with sickle cell anaemia seen in Enugu, Nigeria

Abstract: Background: Anaemic crises in paediatric patients with sickle cell anaemia are major causes of morbidity and mortality. Some children admitted to hospitals' emergency rooms or paediatric wards of the hospitals with severe anaemia die before blood transfusion. Aims and Methods: A total of 108 episodes of anaemic crises were prospectively evaluated in 108 patients with sickle cell anaemia attending the paediatric sickle cell clinic of the University of Nigeria Teaching Hospital, Enugu, Nigeria. Results: Hyper-haemolytic crises were the commonest types of anaemic crises in the patients studied. The mean haemoglobin concentration of 44.66 (SD 6.42) g/l in crises was significantly lower than the mean steady state level of 78.69 (SD 8.50) g/l. Reticulocytes, unconjugated serum bilirubin concentrations, and the presence of nucleated red blood cells were also increased. About 4.6% of patients were not jaundiced at presentation even though they were profoundly anaemic. Their haematological indices gradually returned to normal without marked changes in their serum bilirubin concentrations. These patients were probably in the early recovery phase of aplastic crises. The classical presentation of acute splenic sequestration crisis with a rapidly enlarging spleen and hypotension was not observed. This was probably because of its precipitate nature and accompanying circulatory collapse, which carried a high mortality rate. Minor forms of sequestration crises may have occurred in the liver and spleen. Conclusions: Malaria appeared to have played a role in precipitating some of the hyper-haemolytic episodes. Further studies to elucidate this role are required so that appropriate recommendations regarding malaria prophylaxis can be made in patients with sickle cell anaemia.

Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease.

Abstract: The lack of healthy HLA-identical sibs limits the use of allogeneic hematopoietic cell transplantation in children with high-risk sickle cell disease (SCD). We evaluated unrelated placental blood cell transplantation (UPBCT) after a preparative regimen of busulfan, cyclophosphamide and antithymocyte globulin in three children with SCD who had cerebrovascular accidents (CVAs) and did not have HLA-matched sib donors. The placental blood cell units were matched with the recipients at four of six HLA-A, HLA-B and HLA-DRB1 antigens. Neutrophil levels above 0.5 x 10(9)/l occurred at 23, 38 and 42 days after UPBCT, and platelet levels above 50 x 10(9)/l without transfusions occurred at 62, 81 and 121 days after UPBCT. All patients developed acute graft-versus-host disease (GVHD; two grade II, one grade III), and one developed extensive chronic GVHD. One patient had graft failure and autologous hematopoietic recovery. Two patients have complete donor hematopoietic chimerism without detectable hemoglobin S or symptoms of SCD at 40 and 61 months, respectively, after UPBCT. These observations demonstrate the feasibility of UPBCT in children with SCD. Further studies of UPBCT for SCD are needed but, because of risks of procedure-related morbidity and graft rejection, should be restricted to pediatric patients with high-risk manifestations of SCD.

Elevated plasma sVCAM-1 levels in children with sickle cell disease: impact of chronic transfusion therapy.

Abstract: Vascular cell adhesion molecule-1 (VCAM-1) has been implicated as being important in the pathophysiology of acute pain episodes (APE) and acute chest syndrome (ACS) of sickle cell disease (SCD). The frequency of these episodes is reduced by chronic transfusion therapy. The impact of chronic transfusion therapy on VCAM-1 expression is unknown. Soluble VCAM-1 (sVCAM-1) levels were measured in plasma using an ELISA assay (R&D Systems) in 61 patients with SCD (age range 1.5-20 years) and 12 normal controls (2.5-14 years). SCD patients included 20 with ACS, 14 with APE, 12 at well-child visits, and 15 receiving chronic transfusion therapy. Asymptomatic SCD patients had higher sVCAM-1 levels compared to normal subjects (P < 0.001). Levels of sVCAM-1 were further elevated during ACS (P < 0.001) and APE (P = 0.072) and returned to the asymptomatic range on resolution. Levels were significantly lower in transfused patients (P = 0.003) compared to asymptomatic SCD patients. Our findings of increased VCAM-1 expression during ACS and perhaps APE offer a rationale for therapeutic use of cytokine and other VCAM-1 modulators. The reduction of sVCAM-1 levels observed in our transfused SCD patients offers insight into the mechanism of the protective effect of transfusion against ACS and APE and possibly stroke.

Sickle cell disease: primary stroke prevention.

Abstract: Stroke is an important and common complication of sickle cell disease (SCD), affecting children as well as adults. Clinically evident stroke, usually brain infarction, is usually associated with stenosis or occlusion of the intracranial arteries of the Circle of Willis, sometimes with formation of moyamoya (a Japanese word for "hazy" or "like a puff of smoke" that describes the appearance of a abnormal microvasculature on angiography believed secondary to internal carotid artery stenosis or occlusion and the resultant extensive collateralization). Several types of intracranial hemorrhage are observed but usually in older children and adults. Cerebrovascular diseases restricted to small vessels may go unrecognized but is associated with cognitive and learning problems. Prevention of recurrent stroke has been accomplished with chronic blood transfusion. A primary prevention strategy for clinical stroke, based on the Stroke Prevention in Sickle Cell Anemia Trial, has been tested in a randomized clinical trial. Over 2,000 young children with SCD were screened with transcranial Doppler ultrasound (TCD) to detect elevated blood flow velocity indicative of vessel disease and high risk of future stroke. Those randomized to standard care (no transfusion) had a 10%/year risk of stroke, which was reduced >90% with chronic transfusion. This approach is the only primary stroke prevention strategy so far tested in SCD in a randomized controlled trial. Silent lesions on magnetic resonance imaging are associated with an approximately 1.5%/year risk of clinical stroke and a trial is now starting in children with these lesions who do not meet Stroke Prevention in Sickle Cell Anemia Trial criteria for transfusion based on TCD. A controlled trial, based on intervention for nocturnal hypoxemia, is also underway. Hydroxyurea, bone marrow transplantation, antiplatelet, and antithrombotic agents may work but have not been tested in primary prevention in a systematic way. If early and repeated, TCD screening of children, as recommended by National Heart Lung and Blood Institute and the American Stroke Association, were implemented broadly the incidence of new strokes could be greatly reduced in these children.