Frequency Of Painful Crises Research Articles

Sickle Cell Disease in Children

Early identification of infants with sickle cell disease (SCD) by newborn screening, now universal in all 50 states in the US, has improved survival, mainly by preventing overwhelming sepsis with the early use of prophylactic penicillin. Routine transcranial Doppler screening with the institution of chronic transfusion decreases the risk of stroke from 10% to 1% in paediatric SCD patients. Hydroxyurea decreases the number and frequency of painful crises, acute chest syndromes and number of blood transfusions in children with SCD. Genetic research continues to be driven toward the prevention and ultimate cure of SCD before adulthood. This review focuses on clinical manifestations and therapeutic strategies for paediatric SCD as well as the evolving topic of gene-focused prevention and therapy.

Limitations of Hb F as a Phenotypic Modifier in Sickle Cell Disease: Study of Kuwaiti Arab Patients

Sickle cell disease is characterized by phenotypic heterogeneity and many genetic modifiers have been identified with elevated Hb F being the most recognized ameliorating factor. Kuwaiti sickle cell disease patients carry the India/Arab chromosomal haplotype, which is associated with elevated Hb F (on average ∼22%) on account of the Xmn1 site in the Gγ-globin gene promoter. Most patients had either Hb SS or Hb S-β0-thalassemia (β0-thal) and there are a few Hb SD compound heterozygotes. We have carried out longitudinal clinical studies of these patients to document the pattern of morbidity, spleen function, brain and hip magnetic resonance imaging (MRI) for prevalence of silent brain infarcts and avascular necrosis of the femoral head (AVNFH), respectively. In addition, pulmonary function, SPECT (single photon emission computerized tomography) brain cerebral blood flow and response of selected patients to hydroxyurea (HU) treatment were also studied. The Hb SS and Hb S-β-thal patients have a generally mild phenotype compared to sickle cell disease in other populations and most patients do not have their first pain crisis until about the age of 4 years. Spleen function is retained till late childhood; pneumococcemia and other severe bacterial infections are rare. Overt stroke and silent brain infarcts are uncommon in childhood (∼3% prevalence) although SPECT reveals cerebral blood flow deficits in ∼30%. Avascular necrosis of the femoral head is, however, common with a prevalence of ∼26% in children and 50% in adults. There is brisk response to HU in patients with frequent pain crises, with marked increases in Hb F levels. Patients who are compound heterozygotes for Hbs S and D-Los Angeles, have the most severe phenotype despite Hb F levels of >20% and Hb S <30%. In conclusion, although the patients have a uniformly elevated Hb F level, there are still considerable phenotypic heterogeneity and other modulating genetic factors that require further studies.

Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis. Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions. Results showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age. Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.

Epidemiology and Risk Factors for Pain In Children and Adolescent with Sickle Cell Anemia.

AbstractAbstract 1651 Background:Pain crises are the most common symptom experienced by individuals with sickle cell anemia (SCA). Frequency of pain crises varies significantly and high rate is a risk factor for higher mortality in adults with SCA. The risk factors for pain crises in children and adolescents with SCA are not completely understood. To determine factors associated with frequent severe pain crises, we analyzed the cohort of children and adolescents with SCA who were enrolled in the prospective study “The Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)”. All children were evaluated in their steady, non-crisis state. Methods:Family-reported history of number of severe pain crises in the preceding 12 months was recorded prospectively in 365 children and adolescents with SCA. Severe pain crises were defined as painful vaso-occlusive episodes requiring evaluation in Emergency Department (ED) or in-patient hospitalization. Lifetime history of red cell transfusions, echocardiography, and laboratory studies were obtained. Clinical and laboratory characteristics of study subjects who had ≥3 severe pain crises in the preceding year were compared to subjects with < 3 severe pain crises. Results:Study subject ranged in age from 3–20 years and 175 (48%) were female. Seventy two children (20 %) had ≥3 severe pain crises in the preceding year (frequent pain crisis group); 293 (80%) children had < 3 severe pain crises (infrequent pain crisis group), including 224 (61%) subjects who had no admissions/ ED visits for pain. Associated factors for frequent pain crisis included older age (odds ratio 1.2; 95% confidence interval 1.12–1.35; P <0.001) and α-thalassemia trait (odds ratio 3.22; 95% confidence interval 1.55–6.69; P =0.002) while higher steady state serum lactate dehydrogenase (LDH) was associated with infrequent pain crisis (odds ratio 0.35; 95% confidence interval 0.13–0.98; P =0.045). In a group of patients without α-thalassemia trait, older age and low LDH were linked to frequent pain crisis. Subjects in the frequent pain crisis group had higher median hemoglobin (9.0 vs. 8.5 gm/dL; p=0.003) and higher ferritin (median 455 vs. 191 ng/mL; p=0.008). Higher ferritin in the frequent pain crisis group was mirrored by the higher percentage who reported >10 lifetime transfusions (42% vs. 22%; p=0.001). Median tricuspid regurgitation jet velocity (TRV) was higher in the frequent pain crisis group (2.41 vs. 2.31; p= 0.001) but the proportion of children with TRV>2.5 was not different (19.4% vs.11.5% in infrequent crises group; p=0.09). Hydroxyurea use was not different between the groups (51% vs. 40%; p=0.08) nor was fetal hemoglobin (10% vs. 12%; p=0.2). Conclusions:The occurrence of severe pain crisis varies among children and adolescents with SCA with a large number of children experiencing no severe painful episodes. Consistent with the Cooperative Study of Sickle Cell Disease report, the risk of severe pain crisis increases with age. Individuals with α-thalassemia trait are likely to experience more frequent pain crises possibly related to higher hemoglobin concentration and viscosity. However, even after controlling for α-thalassemia trait, children and adolescents who reported more frequent severe pain crises showed evidence of less hemolysis, consistent with a hypothetical model associating the hemolytic subphenotype of SCA with less frequent vasoocclusive pain crises. Further studies are indicated to identify the molecular mechanisms of pain in sickle cell anemia. Disclosures:No relevant conflicts of interest to declare.

Addition of Hydroxyurea to Transfusion Programme to Treat Progressive Cerebral Vasculopathy

AbstractAbstract 4813Cerebro-vascular accidents (CVA) amongst paediatric patients with sickle cell disease (SCD) cause significant morbidity and mortality. Regular blood transfusions are used to prevent progressive cerebral vasculopathy. In primary stroke prevention, transcranial Doppler (TCD) studies are used to identify children at high risk of developing CVA and maintaining regular transfusion to keep HaemoglobinS (HbS) below 30% has shown to reduce this risk by 90%. However, about 10% children maintained on regular blood transfusions continue to have progressive vasculopathy despite maintaining HbS% below 30. There are few established options to try and prevent progressive vasculopathy despite adequate transfusion; possible approaches include intensifying the transfusion regime to maintain an even lower HbS%, revascularization surgery and correction of other thrombogenic risk factors. Hydroxyurea (HU) has been used in SCD to reduce the frequency of painful crises and acute chest syndrome. Its primary mode of action is thought to be to increase HbF levels but other mechanisms of action which may be beneficial include the reduction in white cell count, endothelium stabilization, improved expression profile of adhesion molecules, and nitric oxide donation. Herein we present our experience of combining treatment with HU to a transfusion programme in paediatric sickle cell patients with evidence of progressive cerebral vasculopathy whilst optimally transfused.4 paediatric patients with SCD were transfused as secondary stroke prevention, but had progressive cerebrovascular disease on magnetic resonance imaging (MRI/MRA). Following detailed discussions with the parents, HU was started in addition to the transfusion to try and arrest the progression. The dose of HU was gradually increased whilst monitoring counts, assessing tolerability with a view to achieving doses of at least 25mg/kg. All patients had regular clinical review, full blood counts, HbF and HbS percentages monitored baseline pre and post transfusion. All patients had annual TCD to assess cerebral circulation flow velocities and MRI/MRA. Iron chelation was commenced or continued as appropriate to their clinical circumstances for secondary iron overload.In this cohort, there were 2 females and 2 males, all of African descent. The mean age at diagnosis of first CVA was 5years (Range3-5yrs) with a mean steady state Hb of 7g/dl, mean HbF of 2.8% and mean HbS of 82.1%. MRI/MRA showed middle cerebral artery (MCA) cortical infarction in all patients at diagnosis but in addition showed varying degrees of areas of watershed infarction, small vessel disease with deep white matter ischemic change and moya-moya formation with small haemorrhages. The cohort remained on transfusions for a mean period of 55 months (Range 25–108) and received transfusions at a mean of 4 weekly intervals (Range 2–6 weeks). Mean Hb values post transfusion were 10.8g/dl with a mean HbF of 2% and HbS of 24.2%. TCD velocities in non-stenosed vessels showed a mean decrease in MCA by 26cm/sec (-11.8%), and in Internal carotid artery (ICA) by 14cm/sec (-8%). All 4 patients had evidence of clinical symptoms with new neurological deficits, and MRI/MRA scans showed a worsening picture of cerebral vasculopathy with increasing stenosis and new vessel formation. The mean duration of treatment with HU and transfusion was 18 months (Range 12–32months) with a mean Hb value of 11.4g/dl with a mean HbF of 5.8% and HbS of 14.6%. TCD on treatment with HU and transfusion showed a further mean reduction in flow velocity in MCA by 8cm/sec (-4.1%) in the non-stenosed vessels, and in ICA by 4cm/sec (-2.5%). MRI/MRA showed no evidence of progression. One patient had clinical symptoms of TIAs without further infarction and underwent neuro-revascularization.Our study shows that a carefully selected cohort of paediatric patients with advancing cerebral vasculopathy, may benefit from HU in addition to transfusion with modest but clinically significant improvement in HbF% and TCD profile over and above the substantial improvement seen after transfusions. It is possible that this added benefit is by way of HU reducing vascular endothelial damage, mild increases in HbF% and as yet, undefined mechanism. Further, larger studies are needed to assess the value of combining HU and transfusion, although our experience suggests that it is safe, well tolerated and potentially beneficial. Disclosures:No relevant conflicts of interest to declare.

S17 A pilot study of the prevalence of sleep disordered breathing (SDB) and nocturnal hypoxia in symptomatic adults with Sickle Cell Disease (SCD) and its relationship with disease severity

IntroductionThere are few effective therapies available for the long-term management of the cardiac and renal sequelae of SCD. Identifying reversible factors, which exacerbate disease severity, would facilitate development of new...

Pediatric Vasoocclusive Crisis and Weather Conditions

Background Previous studies have demonstrated associations of frequency of vasoocclusive crisis with weather conditions in adults, although relationships have been inconsistent. Objectives Our objective was to determine if there is an association between weather conditions and pediatric emergency department (ED) visits, hospital admissions, and day and severity of pain precipitation for vasoocclusive crisis (VOC). Methods A retrospective observational study was performed at a large tertiary care pediatric center. We reviewed health records of all VOC patients under the age of 18 years with a chief complaint of pain and performed correlations between daily and average weekly and monthly weather conditions and frequency of painful crises. Results A total of 430 visits for VOC to the ED were documented from January 2005 to December 2006. Significant correlations were noted between the daily and weekly number of painful crises and colder temperatures (ρ = −0.11, p = 0.004 for daily data and r = 0.25, p = 0.01 weekly) and wind speed (ρ = 0.13, p < 0.001 and r = 0.25, p = 0.01). The monthly number of painful crises was moderately correlated with temperatures ( r = −0.42, p = 0.04). The average monthly pain score was higher in more humid months ( r = 0.44, p = 0.03). Conclusion We found significant correlations of VOC with weather conditions where colder temperatures and higher wind speed were associated with a higher incidence of VOC in children. Health care providers as well as parents should be aware of these findings and ensure that preventive measures are instituted in patients at risk.

Depression and loneliness in Jamaicans with sickle cell disease

BackgroundSickle cell disease (SCD) is the commonest genetic disorder in Jamaica, and has life-long implications for those afflicted with it. It is well known that depression and loneliness may exist in those with chronic diseases, but the coexistence of depression and loneliness in people with sickle cell disease is not clear. The aim of this study is to determine the prevalence of and factors associated with depression and loneliness in the Jamaica Sickle Cell Cohort Study and its age and sex matched controls.Methods277 patients with SCD and 65 controls were administered a questionnaire that studied demographics, disease severity, depression, and loneliness. Regression analyses were done to examine relationships between outcomes and associated variables.ResultsDepression was found in 21.6% of patients and 9.4% in controls. Loneliness scores were also significantly higher in patients (16.9 ± 5.1) than in controls (14.95 ± 4.69). Depression was significantly associated with unemployment [OR = 2.9, p-value: < 0.001], whereas unemployment (p-value: 0.002), and lower educational attainment were significantly associated with loneliness.In patients with SCD, depression was significantly associated with being unemployed (OR 2.4, 95% CI 1.2,4.6, p-value:0.01), presence of a leg ulcer (OR = 3.8, 95% CI: 1.7, 8.4, p-value: 0.001), frequent visits (OR = 3.3, 95% CI: 1.2, 8.9, p-value: 0.019), and frequent painful crises (OR = 2.5, 95% CI: 1.1, 5.8, p-value: 0.035). Not being employed (Coef.: 2.0; p-value: 0.004) and higher educational attainment (tertiary vs. primary education, Coef.: -5.5; p-value: < 0.001) were significant associations with loneliness after adjusting for genotype.ConclusionsHealth workers need to actively look for and manage these problems to optimize their patients' total biopsychosocial care.

Hydroxyurea in sickle cell disease: What will it take to change practice?

American Journal of HematologyVolume 85, Issue 6 p. 401-402 CommentaryFree Access Hydroxyurea in sickle cell disease: What will it take to change practice?† George F. Atweh, Corresponding Author George F. Atweh [email protected] Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, OhioDivision of Hematology/Oncology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, PO Box 670562, Cincinnati, OH 45267-0562Search for more papers by this author George F. Atweh, Corresponding Author George F. Atweh [email protected] Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, OhioDivision of Hematology/Oncology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, PO Box 670562, Cincinnati, OH 45267-0562Search for more papers by this author First published: 13 April 2010 https://doi.org/10.1002/ajh.21733Citations: 1 † Conflict of interest: Nothing to report. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 D eSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA 1982; 79: 4428– 4431. 2 Ley TJ, DeSimone J, Anagnou NP, et al. 5-Azacytidine selectively increases gamma-globin synthesis in a patient with beta1 thalassemia. N Engl J Med 1982; 307: 1469– 1475. 3 Ley TJ, DeSimone J, Noguchi CT, et al. 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood 1983; 62: 370– 380. 4 Letvin NL, Linch DC, Beardsley GP, et al. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N Engl J Med 1984; 310: 869– 873. 5 Charache S, Dover GJ, Moyer MA, Moore JW. Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia. Blood 1987; 69: 109– 116. 6 Platt OS, Orkin SH, Dover G, et al. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984; 74: 652– 656. 7 Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332: 1317– 1322. 8 Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: Risks and benefits up to 9 years of treatment. JAMA 2003; 289: 1645– 1651. 9 Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of longterm use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol, in press; DOI: 10.1002/ajh.21699. Citing Literature Volume85, Issue6June 2010Pages 401-402 ReferencesRelatedInformation

Prevalence of Nocturnal Hypoxia and Its Association with Disease Severity in Adults with Sickle Cell Disease.

Abstract 261 Introduction:In children with sickle cell disease (SCD), obstructive sleep apnoea (OSA) is common and the degree of overnight hypoxia is closely correlated with disease severity, particularly frequency of painful crises, risk of stroke and presence of pulmonary hypertension. No studies have examined the prevalence or effects of OSA in adults with SCD. Methods:All adults with SCD attending routine sickle cell out-patient clinics were offered screening for OSA using the Epworth Sleepiness Score (ESS) questionnaire. All of those in whom the score was >10 or in whom there was a high clinical suspicion of OSA were offered overnight domiciliary oximetry. Oximetry traces were both analysed by computer and manually. Computerised analysis was used to quantify night time hypoxic load (mean nocturnal SpO2 and sleep time with SpO2 below 90%) and frequency of desaturation (number of times per hour the SpO2 dropped by >4%, or Overnight Desaturation Index, ODI). Manual analysis of each trace was performed by four independent sleep physicians who assigned a diagnosis of normal, OSA, non-OSA nocturnal hypoxia or inadequate based on the pattern of the oxygen saturation and heart rate traces. These parameters were then correlated with measures of disease severity and presence of complications taken from the patient's medical record. Statistical analysis was performed using the t-test and linear regression. Results:93 patients completed the ESS, with 34 patients identified for subsequent oximetry (26 ESS>10, 8 clinical suspicion). 22 patients went on to have subsequent oximetry. 17/22 of recordings (77%) were abnormal of which 11 showed OSA (65%) and 6 showed nocturnal hypoxia without OSA (35%). Nocturnal hypoxic load, measured as mean overnight oxygen saturation, was correlated with glomerular filtration rate (r=0.5; p=0.0008) and pulmonary artery systolic pressure estimated by echocardiography (r=0.71; p=0.0001). Furthermore, urine protein level correlated with ODI (r=0.5 p=0.0007) and mean overnight oxygen saturation (r=0.35; p=0.02). In addition, mean overnight oxygen saturation was 87% in male patients that experienced priapism and 94% in those who did not (p=0.004). Mean ODI was 10/hr in patients with priapism and 4 in those without (p=0.008). There were no correlations demonstrated between either hypoxic load or ODI with the frequency of painful crises, frequency of hospital admissions or avascular necrosis. Lung function test parameters, history of chest syndrome, hydroxyurea therapy and Epworth score did not predict either hypoxic load or ODI. However, daytime SpO2 were highly predictive of nocturnal hypoxic load (r=0.69 p=0.0000007) but not ODI. Conclusion:OSA and non-OSA nocturnal hypoxia are common in adults with sickle cell disease. The degree of nocturnal hypoxia is associated with impaired renal function, proteinuria, priapism and pulmonary hypertension. Daytime SpO2 appears to be a better predictor of night time hypoxic load than daytime somnolence. Further work is needed to investigate the effect of interventions such as nocturnal oxygen therapy or continuous positive airway pressure on the associations reported. Disclosures:No relevant conflicts of interest to declare.

Pain Rate and Social Circumstances Rather Than Cumulative Organ Damage Determine the Quality of Life in Adults with Sickle Cell Disease.

Abstract 4605 BackgroundPrevious studies have demonstrated a significantly reduced quality of life (QoL) in sickle cell patients which appeared to be related to the significant morbidity associated with sickle cell disease such as frequent painful crises. With the longevity of sickle cell patients in the Western world chronic organ damage may also be an important factor to the QoL of sickle cell patients. Furthermore, not directly disease related factors such as socioeconomic circumstances may also be important in the general well being of these patients. Aim of the studyFirst, to determine the contribution of chronic organ damage and cumulative sickle cell related complications to QoL of sickle cell patients in the Netherlands. Second, we analysed the effect of socio-economic circumstances on QoL in our patients. MethodsConsecutive adult sickle cell patients cared for in a teaching hospital were included. QoL was assessed with SF-36 forms and was represented in a physical component scale (PCS) and a mental component scale (MCS). In all patients a systematic evaluation of chronic organ damage was performed including: pulmonary hypertension, renal failure, microalbuminuria, retinopathy and iron overload. In addition, sickle cell related complications including: the frequency of painful crises, chronic leg ulcers, avasculair osteonecrosis, stroke, acute chest syndrome and priapism were assessed in the previous five years by chart review. We studied the QoL scores in relation to presence of chronic organ damage, sickle cell related complications and socioeconomic circumstances (patients occupation and educational level). ResultsA total of 96 patients were included in our study. The presence of chronic organ damage was not related to the QoL of our patients despite the incidence of pulmonary hypertension in 24% of our patients. Of the sickle cell related complications in the previous five years, pain rate was significantly associated with mental component score (MCS) but not with the physical component score (PCS). With respect to the socioeconomic circumstances, 35% of the sickle cell patients were unemployed as compared to 6% of the general population and 16% of immigrants without SCD. Both occupation and the level of education were significantly related to PCS while no relation with MCS or pain rate was found. ConclusionIn sickle cell patients in Amsterdam, the Netherlands, QoL is mainly determined by pain rate and socioeconomic circumstances such as occupation and educational level. Chronic organ damage, although a major factor determining life expectancy in SCD, was not a determinant of QoL. Disclosures:No relevant conflicts of interest to declare.

Definition of the Responder to Hydroxyurea Therapy: Revisited.

Abstract 1513Poster Board I-536 IntroductionTreatment of sickle cell anemia with hydroxyurea (HU) is associated with significant decreases in the frequency of painful crises, acute chest syndrome, morbidity, and mortality. Some patients, however, show no improvement even with prolonged HU therapy. Identifying treatment responders is important for predicting clinical improvements and for assessing the risk/benefit ratio of HU treatment for individual patients. The salutary effects of HU are thought to be the result of increasing the fetal hemoglobin (Hb F) level. NHLBI guidelines for sickle cell treatment define levels of 15%-20% Hb F as therapeutic endpoints. Research and reviews based on pediatric and adult patients have variously argued that levels from about 10% to 20% are beneficial. Patients and MethodsPatients in this study were from the Multicenter Study of Hydroxyurea (MSH) in Sickle Cell Anemia, a randomized double-blind placebo controlled trial of HU. The N=299 adult patients were recruited from 21 sites across the U.S. and Canada, and were evenly distributed between males and females. Following randomization to placebo or HU, patients had biweekly follow-up visits until the trial was terminated early due to a significant reduction in painful crises (the primary study endpoint) in the HU arm. Levels of Hb F in MSH patients were assessed at baseline and again approximately 18-21 months after treatment began, with the level at each time being the average of two measurements. In the previously reported MSH study, patients were divided into quartiles of Hb F change as a measure of response to HU treatment. In this approach the bottom two quartiles showed either no or minimal positive change in Hb F levels, and fully overlapped with placebo group in the extent of change. We redefined HU patients as ‘responders' or ‘nonresponders' based on a 15% Hb F threshold; those with baseline HbF below 15% and follow-up above 15% were labeled ‘responders,' while all others were labeled ‘nonresponders.' The 15% level was chosen due to its frequent identification in previous publications as a level at which meaningful benefits could be expected. For both coding schemes, we compared the following outcomes between subgroups: rate of painful crises, proportion of days at home with pain and with opioid use, and average daily pain. ResultsUsing the 15% rule, responders had significantly better outcomes than nonresponders on all outcome measures: rate of painful crises (p=.011), proportion of at-home days with pain (p=.025), proportion of days with analgesic use (p=.002), and average daily pain (p<.0001). Nonresponders, in turn, did not differ from the placebo group on any of these outcomes. Using the quartiles approach, the highest quartile had significantly fewer painful crises (p<.05) than the bottom two and placebo, but did not differ from the second highest; for the proportion of days with pain, the highest group did not differ from 2 of the other 3 quartiles or from the placebo group. Only for proportion of days with analgesic use and average daily pain did the highest quartile significantly differ from all other quartiles and from placebo patients. Finally, applying the 15% rule to the pl‘cebo group resulted in no placebo patients being mislabeled as treatment responders, suggesting that increases above the 15% cutoff for post-treatment Hb F levels is outside normal variability in sickle cell patients not in HU treatment. ConclusionsThe 15% Hb F rule successfully identified a ‘responder' group that significantly differed from other HU patients and from placebo patients on all outcomes, including painful crises. Despite overlap with responders under the 15% rule, patients in the highest quartile for Hb F change did not consistently differ from all other quartiles or placebo on the primary outcome (painful crises) and on proportion of days with pain. Our data suggest that using the 15% Hb F threshold identifies a subset of patients with the best clinical outcomes. DisclosuresNo relevant conflicts of interest to declare.

Footprints of Response to Hydroxyurea Are in the Hemogram.

Abstract 4619 IntroductionThe salutary effects of hydroxyurea (HU) in sickle dell anemia (SS) include decreased frequency of painful crises, decreased incidence of acute chest syndrome, decreased blood transfusion, and decreased mortality & morbidity. Markers of the response to HU include increased Hb F level, macrocytosis, improved RBC survival & deformability, and decreased WBC count. In this study we report markers of early response to HU by using mixed (random effects) models to determine the relationship between HU usage and the longitudinal trajectories of RBC parameters and the corresponding longitudinal trajectories of reticulocytes parameters. Materials and MethodsRBC and reticulocyte parameters were determined on peripheral blood from selected patients (10 HU subjects and 11 placebo subjects) enrolled in the placebo controlled double blind multicenter study of hydroxyuea (MSH) in SS. Multiple blood samples were obtained during enrollment in the study at a rate of about once every two weeks. The mean weeks of follow-up from enrollment date was 86.6 weeks (range 2-172 weeks). RBC and Reticulocyte indices were measured on a Siemens H*3 RTX (H*3) hematology analyzer. Laser light scattering was used to quantify cell volume, Hb concentration, and the light absorbance of cells stained with oxazine 750 to detect reticulocytes and distinguish them from mature cells. A total of 20,000 cells were counted for each sample. After the volume (V) and Hb concentration (HC) of individual mature RBC and reticulocytes were measured, the Hb content (CH) of individual cells was calculated. Mixed (random effects) models were used to determine the relationship between the longitudinal trajectories of RBC and reticulocyte indices and HU usage. ResultsGoodness-of-fit criteria for the mixed (random effects) models [Akaike Information Criterion (AIC), Akaike Information Criterion, Small Sample Size Corrected Version (AICC) and the Bayesian Information Criterion (BIC)] indicated that the RBC indices modeled more precisely than those of reticulocytes. However, both the RBC indices and reticulocytes provided useful information regarding the relationship between their longitudinal trajectories and HU usage. There was a significant relationship between HU usage and the following longitudinal trajectories: mean cell hemoglobin (CH) (p<.0001), reticulocyte mean cell hemoglobin (CHr) (p<.0001); Cell hemoglobin concentration (CHCM) (p=.0394); Reticulocyte mean cell volume (MCVr) (p=.0019); hemoglobin distribution width (HDW) (p=.0003); and reticulocyte hemoglobin distribution width (HDWr) (p=.0008). HU usage produced higher value trajectories than those generated by placebo usage for the following: CH, CHr; and MCVr. These changes were first detected 10 weeks after starting HU and before the increase in Hb F levels. ConclusionTogether the data suggest that subtle and early markers of response to HU reside in the hemogram. This is a fast, simple and inexpensive methodology provided the lab in question has the capability to determine the indices of both reticulocytes and RBC. Disclosures:No relevant conflicts of interest to declare.

Health Status of Offspring Conceived During Hydroxyurea Therapy for Sickle Cell Disease.

Abstract 1533Poster Board I-556Hydroxyurea (HU) is an S-phase specific cytotoxic agent (pregnancy category D), approved for use in sickle cell disease (SCD) primarily due to its ability to augment production of fetal hemoglobin (HbF), which has been shown to reduce the frequency of pain crises and decrease the need for blood transfusions. In all animal species tested, HU produced an increase in congenital anomalies. Defects of the central nervous system, palate, and skeleton occurred in rats treated with HU in the ninth to twelfth gestational days. Embyonic cytotoxicity may be secondary to formation of reactive free radicals. Because of its teratogenic potential, patients with SCD are instructed to practice contraception while on HU therapy. However, risks associated with maternal or paternal HU exposure at the time of conception is unclear. Our review of the literature has only shown six case reports of HU exposure in pregnancy for the treatment of SCD. Two of these pregnancies were terminated with medical abortion, the remaining four cases described liveborn infants with normal phenotypes at 15 to 21 months of follow up. 236 patients followed at the Medical College of Georgia Sickle Cell Center have been on HU for a period of 6 months to 14 years. Despite precautionary counseling, we have identified seven women and three men with SCD who have conceived while on HU therapy. We analyzed the birth records of ten children conceived during HU therapy. The duration of HU therapy varied from 2 weeks to 3 years at the time pregnancy was diagnosed; gestational age when HU was discontinued ranged from 3 to 10.5 weeks. Some children were born prematurely or preterm, with birth weights ranging from 922 to 3178 grams. APGAR scores ranged from 2 to 9 for the first minute and 8 to 10 for the five minute score. One child who had been born severely premature at 26 weeks with a birth weight of 922 grams and APGAR scores of 2 and 8 at one and five minutes to a father who had been on HU at the time of conception was ultimately withdrawn from life support measures. The remaining nine children were assessed for appropriate development by questionnaires provided to parents as well as pediatric records when available. One child with APGAR scores of 5 and 9 has been diagnosed with mental retardation and attention deficit disorder. Developmentally, the other eight children have achieved appropriate milestones. Women with sickle cell disease are more likely to develop complications such as intrauterine growth retardation and preterm delivery than those without the disease. These findings suggest that children conceived on HU therapy are not significantly different from other infants born to parents with SCD who are not on HU. Our sample size is not large enough to observe the potential effects of in utero HU exposure. The small number of subjects is likely secondary to potential teratogenicity discouraging women to become pregnant as well as paucity of exposed pregnancies due to menstrual disturbances induced by HU. It is therefore important to develop and maintain a national registry to allow longer follow up of exposed children and more careful assessment of fetotoxic effects for those conceived during HU therapy for SCD. DisclosuresNo relevant conflicts of interest to declare.

Stroke in Sickle Cell Anemia After Excellent Response to Hydroxyurea.

Abstract 4622 IntroductionStrokes occur in about 10% of children with sickle cell anemia (SS) less than 10 years old. These strokes are usually ischemic in nature. Stroke due to SS in adults is less common and is usually hemorrhagic in nature. We wish to report an unusual adult patient with SS and excellent response to HU who developed a stroke that was unrelated to SS. Case Report and ResultsA 35-year-old female with sickle cell anemia had mitral valve prolapse and migraine headaches presented 2 days after developing abrupt bilateral blurry vision, left facial numbness and weakness of her left leg. Her SS has been complicated by acute chest syndrome, bilateral hip avascular necrosis and frequent painful crises prior to hydroxyurea (HU) therapy. She was enrolled in the multicenter study of hydroxyurea (MSH) in SS and has been on 2500mg of HU per day for the past 13 years. She had an excellent response to HU with no recurrent acute chest syndrome and decreased need for blood transfusion. After starting HU, the frequency of crises requiring hospital admission decreased from 1 admission every 1 to 2 months to less than 1 admission per year except when hydroxyurea was discontinued for pregnancy. Her fetal hemoglobin increased from 6.1 % before HU to a maximum of 45%. Her MCV increased from 96 fl to a maximum of 132 fl and Hb from 8.0 g/dl to 9.8 g/dl Her exam was remarkable for left lower extremity weakness which was more pronounced proximally. All cranial nerves were intact and there was normal sensation bilaterally. CT scan of the brain showed three foci of hypodensity and MRI of the brain showed increased signal on T2, FLAIR and diffusion weighted images within the frontoparietal deep white matter consistent with infarction in the border zone of the middle cerebral artery (MCA)-anterior cerebral artery (ACA). MR angiography of the intracerebral and extracerebral vessels demonstrated focal narrowing of the right MCA at the trifurcation suggesting an embolic cause. Common causes of stroke were ruled out with routine studies. Her hemoglobin electrophoresis after admission but before blood exchange transfusion showed HbS of 55% and HbF of 45%. She underwent exchange transfusion 2 days after admission and was started on chronic blood exchange transfusions with the assumption that she had ischemic stroke due to SS. Initial transthoracic echocardiogram with contrast injection did not show an atrial shunt. Follow-up transesophageal echocardiogram after discharge showed a secundum atrial septal defect with a defect size of 1.4 cm. Right heart catheterization was performed and the pulmonary flow to systemic flow (Qp/Qs) was 1.7:1. An Amplatzer atrial septal defect (ASD) closure device was deployed with transesophageal echocardiographic guidance and a large thrombus was removed from the right atrium. At the patient's request exchange red cell transfusions were discontinued. The patient has continued treatment with hydroxyurea and aspirin. ConclusionsYoung patients with cryptogenic stroke have a much higher prevalence of atrial shunts and in particular patent foramen ovale than patients with other forms of stroke and therefore a cause-effect association is suggested. Young adults with stroke should be evaluated for common and reversible causes of stroke including paroxysmal emboli. Transesophageal echocardiography is the gold standard for diagnosing atrial shunts. Strokes in patients younger than age 55 are related to paroxysmal emboli and have a risk of recurrence of approximately 30% within one year. High risk features for stroke recurrence with an atrial shunt include hypercoagulable states, large opening and presence of an atrial septal aneurysm. Optimal management of patients with a stroke and an atrial shunt is unknown. Options include surgical closure, percutaneous device closure, anticoagulation and antiplatelet therapy. Patients with sickle cell disease and stroke should receive long term blood transfusions to reduce HbS below 30% if the stroke is felt to be related to sickle cell disease vasculopathy. The patient described with SS had a stroke and had an atrial septal defect that was repaired. The MRI/MRA findings are consistent with paroxysmal emboli. The patient is receiving treatment with hydroxyurea and aspirin having discontinued red cell exchange transfusions and at two years of follow-up has not had a recurrent stroke. Disclosures:No relevant conflicts of interest to declare.

Thrombosis after kidney transplantation

The diagnosis of deep vein thrombosis (DVT) is unusual in patients with sickle cell disease (SCD). Despite the incidence of cerebral thrombosis in SCD patients due to vasooclusion, thrombotic manifestations in peripheral vessels are rare. Patients with homozygous SCD present a variety of renal abnormalities as a result of sickle crisis. In this group of patients, kidney transplantation has been performed in the renal endstage patients; with graft survival rates similar to that of the general transplant population at 1 year. However, patients with SCD experience an augmentation in the frequency of painful crises in the first year after transplantation, which has been attributed to concurrent elevations in hematocrit and plasma viscosity. Despite etiology, renal transplant patients are at increased risk for the development of thromboembolic events such as deep vein thrombosis and renovascular thrombosis after allograft procedure. These events can be due to a prothrombotic state generated by the use of immunosuppressive agents. Although other factors such as acquired or inherited disorders of the clotting system may increase the risk of thrombosis. Here, we report a case of a renal transplant patient with sickle cell disease who presented recurrent episodes of DVT and increase painful sickle episodes after kidney transplantation.

A Patient with a Previous Diagnosis of Hemoglobin S/C Disease with an Unusually Severe Disease Course

A 17-year-old African American male presented to the hematology clinic for treatment of sickle cell disease (SCD).1 He had received the diagnosis of hemoglobin (Hb) S/C disease at an outside hospital at the age of 6 years; the diagnosis was confirmed in house at 11 years of age. His disease course had been severe, with frequent pain crises of increasing intensity and 2 episodes of acute chest syndrome requiring hospitalization and multiple blood transfusions. The patient’s physical examination was unremarkable: blood pressure, 120/64 mmHg; pulse, 83 beats/min; temperature, 36.9 °C. Laboratory results were as follows: white blood cell count, 11.8 × 109/L [reference interval (RI), 3.9–10.3 × 109/L]; Hb, 6.39 mmol/L (RI, 8.68–10.8 mmol/L); packed cell volume, 0.28 (RI, 0.42–0.50); red blood cell count, 3.59 × 1012/L (RI, 4.5–6.0 × 1012/L); platelet count, 417 × 109/L (RI, 135–370 × 109/L); mean corpuscular volume, 78 fL (RI, 83–102 fL); mean corpuscular Hb, 28.7 pg (RI, 27–31 pg); mean corpuscular Hb count, 368 g/L (RI, 320–340 g/L); red cell distribution width, 17.3% (RI, 11.5%–14.5%); and absolute reticulocyte count, 0.115 (RI, 0.02–0.10). A peripheral blood smear showed scattered target and sickle cells, rare nucleated red cells, and mild anisopoikilocytosis. Results for the qualitative sickle cell solubility test were positive. Considering the severe disease course, Hb analysis by HPLC and isoelectric focusing (IEF) was ordered (Fig. 1⇓ ). Figure 1. IEF and HPLC analysis of Hbs in the patient’s sample. (A), The migration pattern of the standard and patient’s sample by IEF. Lane 1 shows the patient’s sample. Lane 2 shows the Hb standard containing Hb C, Hb S, Hb F, and Hb A. (B), Elution chromatographs of standard and patient Hb species by HPLC with the Bio-Rad Variant II System (β-thalassemia …

Correction of Murine Sickle Cell Disease Using γ-Globin Lentiviral Vectors to Mediate High-level Expression of Fetal Hemoglobin

Increased levels of red cell fetal hemogloblin, whether due to hereditary persistence of expression or from induction with hydroxyurea therapy, effectively ameliorate sickle cell disease (SCD). Therefore, we developed erythroid-specific, gamma-globin lentiviral vectors for hematopoietic stem cell (HSC)-targeted gene therapy with the goal of permanently increasing fetal hemoglobin (HbF) production in sickle red cells. We evaluated two different gamma-globin lentiviral vectors for therapeutic efficacy in the BERK sickle cell mouse model. The first vector, V5, contained the gamma-globin gene driven by 3.1 kb of beta-globin regulatory sequences and a 130-bp beta-globin promoter. The second vector, V5m3, was identical except that the gamma-globin 3'-untranslated region (3'-UTR) was replaced with the beta-globin 3'-UTR. Adult erythroid cells have beta-globin mRNA 3'-UTR-binding proteins that enhance beta-globin mRNA stability and we postulated this design might enhance gamma-globin expression. Stem cell gene transfer was efficient and nearly all red cells in transplanted mice expressed human gamma-globin. Both vectors demonstrated efficacy in disease correction, with the V5m3 vector producing a higher level of gamma-globin mRNA which was associated with high-level correction of anemia and secondary organ pathology. These data support the rationale for a gene therapy approach to SCD by permanently enhancing HbF using a gamma-globin lentiviral vector.

Haemoglobin F modulation in childhood sickle cell disease

While supportive care remains the best option for most well children with sickle cell disease (SCD), increasing awareness of early signs of chronic organ damage in childhood has focused attention on therapy which modulates the natural history of the disease. Since cure by stem cell transplantation is only feasible for a minority and gene therapy remains developmental, pharmacological modification by Haemoglobin F (HbF)-inducers, is the most widely used approach in SCD. Currently, the only HbF modulator with a clear place in the management of childhood SCD is hydroxycarbamide for which the main indications are frequent painful crises and recurrent acute chest syndrome. In the majority of SCD children treated with hydroxycarbamide there is clear evidence of clinical benefit and the drug is well tolerated. The main disadvantages are the need for frequent monitoring and uncertainity about long-term risks of carcinogenicity and impaired fertility, although these risks appear to be very low. The role of hydroxycarbamide in sickle-associated central nervous system disease remains to be established. Decitabine and butyrate derivatives show some promise although robust data in children with SCD are lacking. A number of other drugs are currently under investigation for their effects on HbF production including thalidomide and lenolidamide.

Prolonged Administration of Hydroxyurea Reduces Morbidity and Mortality in Adult Patients with Sickle-Cell Syndromes: Long-Term Experience of a Single Center.

Hydroxycarbamide (hydroxyurea; HU) is now considered as the main pharmacological agent capable to prevent the painful crises, to reduce the frequency and length of hospital admissions, and to improve the quality of life of patients with sickle-cell disease (SCD); whether HU can prevent the severe chronic complications or modify the mortality of these patients remains still an interesting unresolved question. The present study aims to evaluate the above effects of HU in a large number of SCD patients who received HU over long period of time and were followed in a single Center. To this effect, we evaluated the records of 330 patients with SCD who have been followed in the Thalassemia Center of Laikon Hospital over the last twenty years (136M/194F; median age: 42 years, range: 20- 76 years); 34 with homozygous HbS (SS) and 296 compound heterozygotes for HbS and beta-thalassemia. Of the latter, 131 patients had HbS/beta0-thal and 165 HbS/beta+-thal (107 with the IVSI-110 and 58 with the IVSI-6 thalassemic mutation). Administration of HU was started as early as 1991; progressively, the total number of patients who received HU reached 131 (“group A”); the remaining 199 were treated conventionally (“group B”). The mean age of the patients in the two groups was similar (mean ±SD: 43.3±9.9 years for group A and 44.1±12.6 years for group B) as well as the levels of HbF. The usual dosage of HU was 20 mg/kg/day, except for some patients, where toxicity or lack of effectiveness imposed modifications of the dosage in the range of 15 to 35 mg/kg/day. The median follow-up period was 8 years (range: 0.1–17 years) for the patients who received HU and 5 years (range: 0.1–18 years) for those who did not receive HU. Apart rare exceptions, patients reported every 4–8 weeks to the Outpatient Clinic, where they had a thorough clinical and laboratory evaluation, including FBC and reticulocytes, LDH, bilirubin, other basic biochemistries and HbF using conventional techniques. The percentage of HbS/HbS, HbS/beta0-thal, and HbS/IVSI-110 patients who were given HU was 70%, 49% and 40% respectively; in contrast, very few HbS/IVSI-6 compound heterozygotes had symptoms justifying use of the drug (3.6%). Patients receiving HU showed a dramatic reduction of the frequency of severe painful crises (from 7.4±6.5 episodes per year pre-HU to 0.2±0.4 episodes post-HU; p<0.001) along with a significant reduction of transfusion requirements (mean number of administered packed red cell units: 1.5±5.9 per year pre-HU diminishing to almost zero during HU treatment; p<0.001). These results led to a significant reduction of hospital admissions from 2.1±2.9 per year pre-HU to 0.06±0.02 per year post-HU (p<0.001). Moreover, we noticed a significant reduction of the frequency of chest syndrome from 6.1% pre-HU to 0.8% during the HU period (p=0.013). In contrast, we failed to observe any significant differences in the frequency of aseptic avascular necrosis (p=0.219) or cerebrovascular episodes among the patients who received and those who did not receive HU (p=0.65). Importantly, the death rate in the group of patients receiving HU was significantly lower than that observed among patients who were conventionally treated (12 deaths in group A vs. 47 in group B; 9.1% vs. 23.6%, respectively; p=0.001). The probability of 10-year survival was 91% for the patients treated with HU, while that of the patients conventionally treated was only 70% (Figure). This difference is further magnified if one considers that prior to starting HU the patients of group A had significantly higher transfusion requirements, frequency of painful crises, yearly number of admissions to hospital and intensity of hemolysis in comparison to the group of patients who were not given HU (p=0.004, <0.001, <0.001, and 0.01, respectively). Factors that predicted for a superior survival in the HU group include the increased level of total hemoglobin, a reduced platelet and leukocyte count, increased HbF levels, low reticulocyte counts and low bilirubin and serum LDH levels at 6 months post-HU administration. Side-effects of HU therapy were minimal, predictable and easily manageable. Our study provides evidence that, in addition to reducing the number of painful crises, the frequency of hospital admissions and the transfusion requirements, the long-term administration of HU in adult patients with sickle cell syndromes can improve survival. These results highlight the beneficial effect of HU in SCD and raise the issue of expanding the use of HU in all patients with these conditions. [Display omitted]