Cooperative Study Of Sickle Cell Disease Research Articles

Risk factors associated with sickle cell retinopathy: findings from the Cooperative Study of Sickle Cell Disease

BackgroundSickle cell retinopathy (SCR) is one of the most important ocular manifestations of sickle cell disease (SCD). This study aims to assess the prevalence of SCR in SCD, identify risk factors for its development and progression to proliferative sickle cell retinopathy (PSCR), and evaluate the potential implications of these results on clinical practice.MethodsThis research is a secondary analysis of patients diagnosed with SCD from the epidemiological, multicenter Cooperative Study of Sickle Cell Disease (CSSCD). We included all patients who completed a full ophthalmic evaluation. We identified clinical and laboratory SCD characteristics associated with SCR using multivariate logistic regression models. Proliferative sickle cell retinopathy (PSCR) was diagnosed according to the Goldberg classification system.ResultsOf the 1904 study participants with SCD who met the inclusion criteria, 953 (50.1%) had retinopathy; of which 642 (67.3%) had bilateral disease. SCR was associated with older age (p < 0.001), history of smoking (p = 0.001), hematuria (p = 0.050), and a lower hemoglobin F (HbF) level (p < 0.001). PSCR risk increased with smoking (p = 0.005), older age (p < 0.001) higher hemoglobin level (p < 0.001) and higher white blood cell count (p = 0.011). Previous blood transfusion (p = 0.050), higher reticulocyte count (p = 0.019) and higher HbF level (p < 0.001) were protective factors against the development of PSCR. Ocular symptoms were associated with progression to PSCR in patients with SCR (p = 0.021).ConclusionIn this cohort of individuals with SCD, half of the participants had signs of SCR. Smoking and blood hemoglobin level were the two modifiable risk factors associated with increased retinopathy progression. Screening to identify the different stages of retinopathy, actively promoting smoking cessation, and optimizing the hematological profile of patients with SCD should guide treatment protocols designed to prevent the vision-threatening complications of the disease.

Ocular Manifestations of Sickle Cell Disease in Different Genotypes

ABSTRACT Background Sickle cell disease (SCD) is a multisystemic disorder with variable systemic involvement which varies according to genotype. In this study, our aim is to compare ocular complications between HbSS, HbSC, HbS/β+ thalassemia, HbS/β0 thalassemia, SS alpha thalassemia, and S/β0 + alpha thalassemia genotypes. Methods Data of patients included in this study was recruited from the Cooperative Study of Sickle Cell Disease (CSSCD). Patients with major sickle cell hemoglobinopathies (SS, SC, Sβ- thalassemia, SS alpha thalassemia) were eligible for enrollment, after that, a detailed eye exam was performed. We categorized ocular complications into conjunctival sign, iris atrophy, and both proliferative and non-proliferative sickle cell retinopathy. Results A total of 1867 patients were included in this study, with a mean age of 27.7 (± 11.7) years. They were 830 (44.5%) males and 1037 (55.5%) females. The most common genotype was SS with 971 (52%) patients, and the least common form was sickle cell with both alpha and beta thalassemia major with 42 (2.2%) patients. We found a significant difference in the frequency of proliferative sickle cell retinopathy, where SC genotype had the highest frequency and S B0 thalassemia genotype had the lowest frequency. We also found a significant difference in the frequency of conjunctival sign, where SS genotype had the highest frequency and the S B+ thalassemia has the lowest frequency. Conclusion We identified ocular complications for major sickle cell hemoglobinopathies, where we confirmed previous small study’s findings and identified ocular complications of less common hemoglobinopathies.

Ocular Manifestations of Sickle Cell Disease: Signs, Symptoms and Complications

ABSTRACT Background Sickle cell disease is an inherited hematological disorder that can affect any organ in the body including the eyes (1–6). Previous studies on ocular manifestations of sickle cell disease generally included samples of less than 100 patients. In this study, we aim to assess the frequency of different ocular signs, symptoms and complications among sickle cell disease patients. Methods This study was conducted using data from the Cooperative Study of Sickle Cell Disease (CSSCD). Patients with major sickle cell hemoglobinopathies (SS, SC, S β-thal) were eligible for enrollment. Patients from all age groups were included. Patients underwent detailed ophthalmological examination under standardized conditions. Results A total of 1904 patients were included in this study, with a mean age of 27.67 (±11.72) years. 1,802 (96.4%) patients had BCVA of more than 20/40 in the better-seeing eye. On slit lamp examination, the presence of vascular loops and segment, representing a positive conjunctival sign, was the most common reported abnormal finding (54.1%). The most common complication was peripheral retinal artery occlusion detected in225 patients (20.3%) bilaterally and 77 patients (6.9%) unilaterally. Conclusion In this study that included one of the largest samples ever studied to assess ocular complications of sickle cell disease, we identified the frequency and percentages of different ocular signs, symptoms and complications in different age groups.

Unusually High Prevalence of Silent Stroke and Cerebral Vasculopathy in Hemoglobin SC Disease

Introduction Children and adults with sickle cell disease (SCD) suffer from overt stroke, the prevalence of which has been reported to be 11% &lt; 20 years. More commonly, they suffer from silent cerebral Infarction (SCI) that has a reported prevalence of 37.1% in children at 4 years of age1. Unlike homozygous SS disease (HbSS), the reported prevalence of overt and silent stroke in Hemoglobin SC (HbSC) is low (0% and 5.8%, respectively) in Cooperative Study of Sickle Cell Disease (CSSD)2. However, in a recent study, the prevalence of silent stroke in HbSC was found to be 13.5%3. The goal of our study was to determine the prevalence of stroke and neurovascular complications in children and adults with HbSC in the Central Missouri Cohort (MU-SCD). We also examined the demographic and laboratory factors, SCD related complications, and disease modifiers that correlated with stroke in this cohort. Methods We retrospectively analyzed charts of 131 children and adults with (SCD) who sought care at the University of Missouri between 2000 and 2018, between the ages of 1- 65 years. Clinical, laboratory, Transcranial Doppler (TCD) ultrasound, and Magnetic Resonance Imaging/Angiography (MRI/MRA) data for clinically documented overt stroke, SCI and vasculopathy were analyzed. An expert neuroradiologist analyzed all the MRI/MRAs in a blinded manner. Fisher's exact tests for categorical data and two-sided t-tests for continuous data analysis were used. P value &lt;0.05 was considered as statistically significant. Results Of the 131 individuals analyzed, 9 were excluded from the study due to incomplete clinical information. The genotype consisted of HbSS 72 (59.0%), HbSC 39 (32.0%), and HbS/β Thal 11(9.0%) (Table 1). The overall prevalence of cerebrovascular complications were 30%, 17.7% and 22.2% in the HbSS, HbSC and HbS/β Thal (p-0.47), respectively (Table 2). Among HbSC individuals, those with stroke and cerebral vasculopathy had a marginally higher serum creatinine compared to those without complications (p-0.08) (Table 3). Prevalence of proteinuria was higher in individuals with cerebrovascular lesions (p-0.015). Of the SCD related complications, acute chest syndrome (57.7% versus 33.8%; p-0.038), gall bladder stones with cholecystectomy (53% versus 23%; p-0.006) and pulmonary hypertension (46.2% versus 7.8%, p-&lt;0.0001) correlated with stroke (Table 4). Though not statistically significant, Hydroxyurea use was more prevalent in individuals without stroke or vasculopathy whereas, chronic transfusion was more prevalent in SCD individuals with stroke (Table 4). The neuroradiological lesions consisted of lacunae, encephalomalacia, atrophy, leukoencephalopathy and microhemorrhage in individuals with HbSC (data not shown). Conclusion We noted a higher prevalence of neurovascular complications in individuals with HbSC than previously reported by the Cooperative Study of Sickle Cell disease. The prevalence of cerebrovascular complications in comparison group of HbSS was similar to that reported previously in CSSD cohort. This study indicates that both silent stroke and vasculopathy occur in HbSC and appeared to be more prevalent than overt stroke. As TCD screenings are not routinely used in individuals with HbSC, MRI may be warranted to detect SCI and cerebral vasculopathy. Larger prospective studies are required to understand genetic and non-genetic risk factors associated with stroke in children and adults with HbSC for establishment of prevention, early detection, and treatment modalities.

Comprehensive Sickle Cell Disease Management Is Associated with Superior Grade Attainment and High School Graduation Rates

Abstract Background: Sickle cell disease (SCD) in adolescents and young adults has been associated with low high school graduation rates. Complications of the disease may decrease school attendance, academic performance, and grade attainment. The graduation rate for patients with SCD enrolled in the Cooperative Study of Sickle Cell Disease (CSSD) was 71%. Poor educational outcomes might be due to a number of factors including socioeconomic status or days spent in the hospital due to illness. Neurological complications of SCD may also contribute. Stroke and microvascular ischemic events are detrimental to cognitive function and influence academic achievement and grade attainment. Patient and practitioner adherence to best practices, such as those described in the NHLBI 2014 guidelines vary widely, and the association of best practices with graduation rates has not been studied. We compared high school graduation rates of patients at Akron Children's Hospital Sickle Cell Disease Program (ACHSCDP) with national and local rates. Methods: We conducted a retrospective chart review of patients born between 1994 and 2000 who received care for all forms of SCD at ACHSCDP. Patients were identified through an onsite registry. Thirty-two patients were identified for chart review. We defined successful high school attainment as graduation from 12th grade, or having completed 11th grade by July 2018 and enrolled to begin 12th grade in Fall 2018, before or at 19 years of age. We determined successful high school attainment for patients at Akron Children's Hospital and assessed factors associated with success. Results: Patients born from 1994 to 2000 with sickle cell disease (SS, SC, SBeta-0, SBeta-+) were analyzed (n=32). Two patients transferred out of ACHSCDP prior to age 14 and were not included in our analysis. Of 30 patients studied, 14 were male and 16 were female. Twenty-six patients (86.7%) had graduated or were starting senior year as of July 2018. Of the 26 successful students, 12 (46.2%) had either an IEP or 504 (federally defined accommodation plan) in place. None of the 4 unsuccessful students had an IEP, however 1 student had a 504. Of the 26 successful students, 13 had HbSS, 1 had HbS/B o thal, 5 had HbS/B + thal, and 7 had HbSC. All 4 unsuccessful students had HbSS. Of the 26 successful students, clinical data from 4 years before graduation or 3 years before completion of the 11th grade revealed that the students were hospitalized an average of 5.77 days per year and visited the emergency department an average of 1.38 times per year. Of the 4 unsuccessful patients, data collected 4 years before the age of 19 revealed that the patients were hospitalized an average of 5.85 days per year and visited the emergency department an average of 1.37 times per year. Only one patient had a documented stroke, and this child successfully graduated from high school. Of the 26 successful students, 18 (69.2%) were enrolled in college after finishing high school and 3 students were in their senior year of high school. Discussion: In this cohort, a high percentage of patients (86.7%) graduated or were on track to graduate from high school. In the United States, approximately 90% of patients with SCD are African American. All patients analyzed here were African American. With this in mind, ACHSCDP patients' graduation rate compares favorably to estimated graduation rates across the US general population (84%), the U.S. African America population (76%), the U.S. sickle cell patient population (71%), the Ohio general population (84%), and the Ohio African American population (68%). The higher graduation rate among children at the ACHSCDP is associated with a multidisciplinary care model that prioritizes optimal hematologic care adhering to evidence based best practices including stroke risk screening and prevention, and use of hydroxyurea. In addition, team members assess for educations status and disease specific limitations at each encounter. A social worker advocates for educational needs. An outreach nurse makes school visits to educate staff and assist with implementation of federal accommodation plans. A teacher is available during inpatient stays to provide education in coordination with the patients' school. With comprehensive care, SCD is not a barrier to successful grade attainment, and academic distress in SCD patients should prompt re-evaluation of the patient's holistic medical care. Disclosures No relevant conflicts of interest to declare.

Exercise capacity and clinical outcomes in adults followed in the Cooperative Study of Sickle Cell Disease (CSSCD).

To determine the factors associated with exercise capacity in adults with sickle cell disease (SCD) and its relationship to hospitalizations and mortality. A total of 223 participants in the Cooperative Study of Sickle Cell Disease (CSSCD) (64% female, 70% hemoglobin SS/Sβ0 thalassemia, mean age 43.3±7.5years) underwent maximal exercise testing using a treadmill protocol with a mean duration of 11.6±5.2minutes. Female sex (β=-3.34, 95% CI [-1.80, -4.88], P<0.001), older age (β=-0.14, 95% CI [-0.24, -0.04], P=0.005), higher body mass index (β=-0.23, 95% CI [-0.37, -0.10]; P=0.001), and lower hemoglobin (β=0.56, 95% CI [0.08, 1.04], P=0.02) were independently associated with lower fitness, while there was a trend with abnormal pulmonary function testing (β=-1.42, 95% CI [-2.92, 0.07]; P=0.06). Lower percent-predicted forced expiratory volume in 1second (FEV1 ) was independently associated with lower fitness (β=0.08, 95% CI [0.03, 0.13], P=0.001). Genotype and hospitalization rates for pain and acute chest syndrome (ACS) prior to testing were not associated with exercise capacity. Baseline exercise capacity predicted neither future pain or ACS nor survival in our cohort. Adults with SCD tolerated maximal exercise testing. Prospective studies are needed to further evaluate the impact of regular exercise and improved fitness on clinical outcomes and mortality in SCD.

Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease.

Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (−α3.7 deletion) and β-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the −α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the −α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the −α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the −α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and β-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.

Biomarker Signatures of Sickle Cell Disease Severity

▪Introduction. Sickle cell disease (SCD) is characterized by a point mutation in the β-hemoglobin gene. Phenotypically and genetically, SCD is heterogeneous. Genetic variants have been identified that correlate with fetal hemoglobin (HbF) levels and some disease complications. Scores reflecting disease severity have been proposed to stratify patients by risk of complications and typically they include a combination of laboratory data and patient medical history. Except for the relationship of variants in HbF-modulating genes and α thalassemia with some aspects of disease severity, predicting patients at higher risk for complications using only genetic data has been difficult. Between a genetic variant and a physiologic outcome, or genotype and phenotype, are the proteins whose effects can be captured by laboratory measures. We propose a new approach to identify patients with various risks for common complications using hierarchical cluster analysis of standardized blood biomarkers coupled with a new method to identify statistically significant clusters.Methods and Results. We selected 17 uncorrelated blood biomarkers measured in 2,320 SCD patients with the common β-globin genotypes of this disorder from the Cooperative Study of Sickle Cell Disease (CSSCD). The biomarkers were selected based on significant correlation with age and sex and included 4 previously validated markers of hemolytic severity. We used hierarchical clustering to generate 17 clusters characterized by specific patterns of the biomarkers; the Figure shows an example. Eight of the 17 clusters included more than 40 patients, and we tested whether patients stratified in these 8 clusters differed in the distribution of β-globin genotypes, and risk of painful episodes, seizure, stroke, and mortality in longitudinally collected data. Compared with the largest cluster of 675 patients (Cluster 2) that is characterized by all 17 blood biomarkers following the average distribution, we identified a cluster of 437 patients (Cluster 3) with elevated HbF, hemoglobin, reduced bilirubin, LDH and other biomarkers who had reduced risk for stroke (hazard ratio HR=0.17, p=0.018) and mortality (HR=0.27, p=0.00045). Another cluster of 341 patients (Cluster 4) was characterized by elevated HbF, LDH and other markers of hemolysis and had reduced risk for number of seizures (OR=0.2, p=0.02) and pain severity (OR=0.59, p=0.00041). Cluster 3 was characterized by 47% HbSC disease patients and approximately 16% HbS homozygotes who, by their inclusion in this cluster, were likely to have milder disease. Cluster 4 was characterized by 79% HbS homozygotes and 18% HbS homozygotes with α thalassemia. Compared to patients in Cluster 2, patients with a signature represented by Cluster 3 had reduced hemolysis after 1 year and maintained a significantly higher HbF, while patients with a signature of Cluster 1 had increased hemolysis after 1 year and lower HbF.For independent replication, we implemented a Bayesian classification rule to predict the cluster membership of patients enrolled in the PUSH and WalkPHASST studies of SCD using only the blood biomarker data. We had 16 of the 17 biomarkers (missing uric acid) measured at enrollment in the PUSH study and 13 of the 17 biomarkers (missing eosinophils, lymphocytes, monocytes, and uric acid) in the WalkPHASST study. Patients in the 2 studies grouped into clusters with profiles of biomarkers similar to those discovered in the CSSCD. The predicted clusters also had a similar distribution of SCD genotypes as in CSSCD.Discussion and Conclusions. We identified a subset of patients with blood biomarker signatures associated with a better prognosis and hypothesize that the small number of HbS homozygotes with a positive prognosis characterized by reduced morbidity and mortality could carry rare protective variants. Identifying these variants could lead to the discovery of new therapeutic targets. These variants might be discovered in analysis of whole genome sequences available in the PUSH and WalkPHAAST study, and confirmed in CSSCD patients where GWAS data is available. Another advantage of this method is that commonly available laboratory data can be used to stratify patients by risk of complications in time for preventive therapy or for enrollment in clinical trials. [Display omitted] DisclosuresGordeuk:Emmaus Life Sciences: Consultancy.

Cardiopulmonary Fitness and Clinical Outcomes in Adults Followed in the Cooperative Study for Sickle Cell Disease

Introduction: Cardiopulmonary fitness is significantly reduced among individuals with sickle cell disease (SCD). Cardiopulmonary fitness is also an important predictor of morbidity and all-cause mortality in the general population. However, the relationship between fitness and clinical outcomes in SCD has not been well studied. The objectives of this analysis were to: 1) determine the factors associated with fitness in a cohort of adults with SCD, and 2) evaluate the relationship of fitness to hospitalization for pain and acute chest syndrome (ACS) and overall mortality. We hypothesized that clinical factors such as age, sex, hemoglobin, SCD genotype and cardiopulmonary disease significantly affect fitness, and that poor fitness is a predictor of more frequent hospitalizations for pain and ACS and higher mortality in adults with SCD.Methods: A cohort of adults with SCD was constructed from participants enrolled in phase 2 of the Cooperative Study of Sickle Cell Disease (CSSCD) who underwent exercise testing (modified Balke treadmill protocol). Primary measure for fitness was total treadmill duration. Retrospective pain or ACS hospitalization rates were calculated using events in the 3 years prior to exercise testing. Mortality and prospective hospitalization rates for pain and ACS were calculated using events after exercise testing with a minimum 6 month follow-up. Results of pulmonary function testing (PFT), echocardiography, and laboratory testing within 3 years of exercise testing were included in our analysis. Standard descriptive analyses were performed (SPSS V24). Multivariable negative binomial and Cox proportional hazards models were constructed to evaluate the relationship of fitness to ACS and pain hospitalization rates and mortality, respectively. Multivariable linear models were constructed to determine factors associated with fitness.Results: A total of 223 participants had valid exercise testing data (64% female, 70% hemoglobin SS or S/b0 thalassemia, mean age 43.3 ± 7.5 years, mean hemoglobin 9.1 ± 2.2 g/dl, mean follow-up 2.7 ± 0.7 years after exercise testing). Participants completed a mean of 11.6 ± 5.2 min on the treadmill, with 87% completing ≥ 3 stages but only 17% completing all 10 stages. We categorized fitness into tertiles of treadmill duration (5.7 vs. 11.8 vs. 18.1 min, p < 0.001). Age (45.2 vs. 43.1 vs. 41.3 years, p = 0.007), baseline hemoglobin (8.5 vs. 9 vs. 9.8 g/dl, p = 0.003), as well as the proportion of females (77 vs. 71 vs. 40%, p < 0.001) and participants with abnormal PFT (58 vs. 35 vs. 39%, p = 0.008), differed significantly across fitness tertiles. Pain or ACS hospitalization rates during the 3 years prior to exercise testing were not significantly different across fitness tertiles. Using multivariable linear regression, male sex (β = 3.1, p < 0.001), lower age at exercise testing (β = -0.14, p = 0.003), and higher hemoglobin (β = 0.44, p = 0.049) were independently associated with higher fitness, with abnormal PFT trending toward significance (β = -1.28, p = 0.07). In this model, genotype, tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s, and pain and ACS hospitalization rates prior to exercise testing were not significantly associated with fitness. Using a negative binomial regression model, we found that fitness did not predict future pain or ACS episodes after adjustment for age, sex, genotype, hemoglobin and TRJV. Fitness also did not predict survival in our cohort (hazard ratio, 0.97; 95% CI [0.84, 1.13], p = 0.71), in which death was reported in only 9 participants. In our Cox regression model, male sex (HR 7.1; 95% CI [1.3, 38.9]; p = 0.02) and lower hemoglobin (HR 0.56; 95% CI [0.36, 0.88]; p = 0.01) were independent predictors of death, but age at exercise testing, abnormal PFT and TRJV ≥ 2.5 m/s were not.Conclusions: In adults with SCD, lower fitness is significantly associated with female sex, older age, lower hemoglobin and abnormal PFT. Fitness did not predict survival or future pain or ACS events in the CSSCD. Given that cardiopulmonary fitness remains an important predictor of all-cause mortality in the general population, larger scale prospective studies in SCD are needed to evaluate the impact of regular exercise on improving fitness, quality of life, clinical outcomes and mortality in this population. DisclosuresBadawy:Ann & Robert H. Lurie Children’s Hospital of Chicago: Employment; Ann & Robert H. Lurie Children’s Hospital of Chicago: Research Funding; Salveo Health Communications LLC: Consultancy. Payne:National Center on Birth Defects and Developmental Disabilities: Employment. Liem:Ann & Robert H. Lurie Children’s Hospital of Chicago: Employment; Ann & Robert H. Lurie Children’s Hospital of Chicago: Research Funding; National Institute of Health: Research Funding.

Characteristics of Sickle Cell Patients with Frequent ED Visits and Hospitalizations: Demographic, Clinical, Laboratory and Psycho-Social Aspects

Vaso-occlusive episodes (VOE), are considered a hallmark of sickle cell disease (SCD), and account for >90% of health care encounters for this patient population. Although an orphan disease (total number of patients in the US ~110,000), SCD has a huge medical-economic impact, with annual hospitalization costs of nearly $ 0.5 billion by 2004 figures, mostly for VOEs. The Cooperative Study of Sickle Cell Disease (CSSCD) was a large natural history study, carried in 23 Centers in the US, enrolling >3000 patients between 1977-93. An analysis of the frequency of VOEs in CSSCD showed that the majority of patients (80%) experienced 0-3 major pain crises/year; this was similar across all genotypes of the disease (SS, SC, Sβ0 thalassemia, Sβ+ thalassemia). Only a small minority (~5%) experienced ≥6 VOEs/year. Similar findings have been reported in subsequent, smaller studies, with 5-10% of SCD patients with frequent ED visits and hospitalizations. Hydroxyurea (HU), the only disease modifying agent approved for adults with SCD, results in a ~50% reduction in the frequency of VOEs and hospitalizations. Despite this, HU is underutilized in SCD. Recent NIH evidence based guidelines includes strong recommendations for HU therapy in the majority of SCD patients. Although 230 of the 650 adult SCD patients at our Center are prescribed HU, in a recent study we found that ~40% of these patients were non-adherent, based upon their own admission, and/or the lack of anticipated change in several laboratory parameters (Hb F, MCV, Hb, WBC, reticulocyte and platelet count). A minority of SCD patients followed at our Center have frequent ED visits and hospitalizations. We conducted a study analyzing demographic, clinical, laboratory and psycho-social characteristics of 25 patients with ≥6 ED visits and hospitalizations per year (high utilizers), and compared these with 9 patients (controls) who experienced ≤2 ED visits/hospitalizations (low utilizers). Data on gender, age, genotype, number of ED visits and hospitalizations, CBC, chemistry panel, Hb F, HU usage, opioid use (morphine equivalents), education level, employment, annual income and marital status were collected. All subjects were also administered a depression, anxiety and Health Locus of Control Questionnaire, and underwent quantitative sensory testing (QST) with three different modalities: pressure pain sensitivity with a hand held, computerized algometer (AlgoMed, Medoc, Israel), heat and cold sensitivity (Q-Sense, Medoc, Israel) and Von Frey monofilament testing for neuropathic pain.Of the 25 patients (13M, 12F), 19 were SS, 4 SC, 1 SD-Los Angeles and 1 Sdβ-thalassemia. The median age was 28 (range 21-49). In the low utilizer group (6M, 3F) all were SS with a median age of 39 (range 23-46). The average number of hospitalizations in the high utilizer group was 15.6/year (range 6-33), while in the low utilizer group it was 0.44/year. Annual opioid usage as mg morphine equivalents was significantly higher in the high utilizers (12125.7 mg vs 2423.1 mg, p=0.0048). 19/25 (76%) of high utilizers, and 7/9 (78%) of low utilizers were on HU. Laboratory data on both groups are shown in Table 1. High utilizers had significantly higher WBC, ANC, total bilirubin and lower MCV. Hb F was also lower in the high utilizers (11.8% vs 17.5%) although this did not reach significance. QST results showed significantly lower pressure pain threshold at ulna (224.4 KPa vs 338.9 KPa, p=0.04), and higher baseline sensitivity with von Frey monofilament (0.92 vs 0.33, p=0.056) in the high utilizer group. High utilizers also had a higher anxiety score (9.0 vs 4.6, p=0.039) and depression score (10.0 vs 6.0, p=0.051). While the low utilizers had higher education levels with more associate and bachelor degrees (p=0.009), there was no difference in household income. These data show that multiple factors contribute to high health care utilization in SCD; these include biologic (younger age, disease severity as indicated by higher WBC and ANC, bilirubin, opioid induced hyperalgesia, and poor adherence to HU) as well as psycho-social factors (higher anxiety and depression scores, lower educational status). A multi-disciplinary and multi-faceted approach, including a sound patient education and transition program, a concerted effort to increase adherence to HU therapy, and psycho-social as well as pharmacologic approaches to anxiety and depression will be required to address this complex problem. [Display omitted] DisclosuresKutlar:Novartis Pharmaceuticals: Research Funding.

Clinical events in a large prospective cohort of children with sickle cell disease in Nagpur, India: evidence against a milder clinical phenotype in India.

The clinical phenotype of sickle cell disease (SCD) has been reported to be milder in India than in the United States. The objective of this large single-center study was to examine the rate of complications to define the phenotype of SCD in India. The rate of complications per 100 person-years in 833 pediatric SCD patients for 1954 person-years in Nagpur, India including those diagnosed on newborn screen (NBS) and those presenting later in childhood (non-NBS) was compared to those reported in the cooperative study of sickle cell disease (CSSCD). Event rates were also compared between patients belonging to scheduled castes (SCs), scheduled tribes (STs), and other backward classes (OBC). Comparison of CSSCD versus Nagpur NBS versus Nagpur non-NBS for rates of pain (32.4 vs. 85.2 vs. 62.4), severe anemia (7.1 vs. 27 vs. 6.6), stroke (0.7 vs. 0.8 vs. 1.4), splenic sequestration (3.4 vs. 6.7 vs. 1.6), acute chest syndrome (24.5 vs. 23.6 vs. 1.0), and meningitis (0.8 vs. 0 vs. 0.1) revealed more frequent complications in Nagpur compared to CSSCD. Comparison of ST, SC, and OBC for rates of pain (84.6 vs. 71.9 vs. 63.5), acute chest syndrome (3.6 vs. 2.8 vs. 2.2), severe anemia (5.4 vs. 9.5 vs. 11.4), stroke (1.2 vs. 0.4 vs. 0.3), splenic sequestration (0.6 vs. 2.4 vs. 1.9), and meningitis (0.8 vs. 0 vs. 0.1) revealed significantly more frequent complications among ST. SCD-related complications are more frequent in Indian children than that observed in CSSCD. Further study is indicated to define SCD phenotype in India.

Association of FOXO3A Polymorphisms with Hematocrit, LDH and Longevity in Patients with Sickle Cell Anemia from CSSCD, Walk-Phasst, and PUSH Clinical Trials

BackgroundThe FOXO3A genotype is strongly associated with longevity in humans. It encodes a transcription factor that appears to regulate anti-oxidant genes during erythroid differentiation in mice, resulting in a hemolytic anemia. The gene has also been implicated in the regulation of fetal hemoglobin expression in children with sickle cell disease. We performed a gene-wide association study to identify and replicate variants of FOXO3A that might be associated with seven biomarkers in patients with sickle cell anemia.Methods1198 patients from the Cooperative Study of Sickle Cell Disease (CSSCD) study, 308 patients from the Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) study, and 220 patients from the Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease (PUSH) study were analyzed. Biomarkers included hematocrit, reticulocyte count, fetal hemoglobin (HbF), serum levels of lactate dehydrogenase (LDH), aspartate aminotransferase and bilirubin, and the calculated hemolytic component, each appropriately transformed to achieve normality. A total of 189 single nucleotide polymorphisms (SNP) that were either genotyped or imputed (quality r2 > 0.9) were used. Association between each biomarker and SNP was tested using linear regression assuming an additive genetic model, adjusted for age and sex. None of the patients in the CSSCD were treated with hydroxyurea at the time of measurements of the biomarker variables. In the Walk-PHaSST and PUSH, we first examined whether there was a significant association between the biomarker and treatment effect of hydroxyurea; if there was a significant treatment effect, then we looked at potential SNP-by-treatment interaction. For those with significant interactions, only patients without hydroxyurea treatment were included in the analysis. The genetic analysis results from the three studies were then combined to produce meta-analyzed results. Finally, a survival analysis using Cox regression was performed to model age at death in a subset of 54 patients in the CSSCD.ResultsAmong the seven biomarkers, hematocrit showed the most robust enrichment of associations with FOXO3A SNPs. Eight of the 16 published variants had meta-analyzed p-value <0.05. Of those, six had a consistent direction of effects across all three cohorts. Overall, there were 8 loci with 34 SNPs that had meta-analyzed p<0.05 in hematocrit. The most significantly associated SNP (rs6911407; meta-analyzed Beta=-0.0127, meta-analyzed p=0.0013) is one previously associated with human longevity. LDH was most significantly associated with variant rs12206094 (meta-analyzed Beta=0.0256, meta-analyzed p=0.0072), another SNP previously associated with human longevity. Four of the allelic variants associated with LDH were also associated with hematocrit in the appropriate direction. There were also some evidence of enrichment of associations with reticulocyte counts (2 loci with 22 SNPs), HbF (1 locus with 11 SNPs; 10 SNP associations overlapped with reticulocyte count in the appropriate direction), and hemolytic component (2 loci with 8 SNPs); however, the strengths of associations in these biomarkers were marginal (0.01<p<0.05). The survival analysis revealed one locus significantly associated with age at death in the CSSCD patients (rs2802297; p=0.028).ConclusionFOXO3A genetic polymorphisms are associated with hematocrit and serum LDH in this meta-analysis of patients with sickle cell anemia, with less robust associations with fetal hemoglobin level and reticulocyte count. Our genetic findings are biologically consistent with published knockout mouse data indicating that FOXO3A regulates red cell antioxidant capacity and hemolytic severity. Our observation of fetal hemoglobin association with FOXO3A helps to validate previously presented results from Sheehan and colleagues. Parallel to well-documented results in the general population, we find preliminarily that a FOXO3A allelic variant predicts longevity in patients with sickle cell anemia. FOXO3A appears to play a significant role in phenotypic variation in sickle cell anemia. DisclosuresNo relevant conflicts of interest to declare.

Lower Airway Obstruction Is Associated with Increased Vaso-Occlusive Pain Episodes in Adults with Sickle Cell Anemia

Background: Vaso-occlusive pain episodes (VOE) are the most common complication and reason for hospital admission in individuals with Sickle Cell Anemia (SCA). Recently our team demonstrated that in adults with SCA followed prospectively for approximately 5 years, a lower baseline Forced Expiratory Volume in 1 second percent predicted (FEV1%), which is associated with earlier mortality, but evidence of obstructive or restrictive lung function patterns is not (Blood 2015, in press). Based on the evidence that abnormal pulmonary function is associated with earlier mortality, we tested the hypothesis that baseline pulmonary function patterns were associated with SCA-related morbidity, including VOE and acute chest syndrome (ACS) events.Procedure: A prospective cohort of adults with SCA followed in the Cooperative Study for Sickle Cell Disease (CSSCD) was constructed based on a planned secondary analysis. Data from the first PFT record at age 21 and older were used for this study. Percent predicted values were determined for each participant based on their age, gender, height, and race for FEV1 and the ratio of FEV1 to forced vital capacity (FEV1/FVC) using the Global Lung Function 2012 equations (Eur Respir J, 2012; 40(6): 1324-1343). Assessment of lower airway obstruction was based on % predicted FEV1/FVC. Percent predicted total lung capacity (TLC), a measure of restrictive lung disease, was determined using published equations and corrected based on race. All PFT evaluations were checked for quality. Negative binomial regression models were used to determine the association between future VOE, ACS events, and spirometry measurements after adjusting for age, sex, hemoglobin, and fetal hemoglobin levels.Results: A total of 430 adults with SCA were evaluated. Ages of the study participants ranged from 21.7-66.4 years with a median age of 32.6 years at the time of first PFT and median follow-up was 5.5 years. Only FEV1/FVC% predicted as a continuous covariate was a significant predictor of future VOE. Lower FEV1/FVC% predicted was associated with higher future pain event rates with a rate ratio of 1.022 (95% CI 1.002 - 1.042; p=0.028). For every 10% decrease in FEV1/FVC% predicted there is a 23% increase in the rate ratio. TLC% predicted did not predict future VOE (p=0.762). FEV1/FVC% predicted or TLC% predicted did not predict future ACS events (p=0.618 and p=0.430 respectively). When FEV1/FVC% predicted and TLC% predicted < 5th percentile were used in the regression equation instead of continuous values, neither abnormal lung function parameter was associated with an increased incidence of VOE or ACS events.Conclusions: For the first time, we have demonstrated that spirometry evaluation with FEV1/FVC% predicted, as a measure of lower airway obstruction, identifies a group of adults with SCA at increased risk for future vaso-occlusive pain episode.Table 1CovariateRate Ratio (95% CI)PAge at PFT*-.112 (.850, .941).000Male1.032 (.581, 1.836).914Average Fetal Hemoglobin.985 (.894, 1.085).754Average Hemoglobin.954 (.763, 1.193).682Negative FEV1/FVC percent predicted**.022 (1.002, 1.042).028Final Negative Binomial Regression model for vaso-occlusive pain episodes after lung function testing (N= 430)*PFT is Pulmonary Function Test** Negative FEV1/FVC percent is reverse-coded so that lower values are associated with rate ratios above 1. DisclosuresNo relevant conflicts of interest to declare.

Traffic Light: prognosis-based eligibility for clinical trials of hematopoietic SCT in adults with sickle cell anemia.

Estimating prognosis in sickle cell anemia (SCA) assumes greater importance as intensive treatments, such as hematopoietic SCT (HSCT), are being tested. Here we estimate the mortality risk from the walk-PHaSST (Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease) trial of homozygous SCA patients with suspected pulmonary hypertension (19/468 deaths; 10 centers in the US and UK). Parallel investigations were also undertaken in the Cooperative Study of Sickle Cell Disease (CSCCD) and a contemporary urban sickle cell disease population (Case Western Reserve University-University Hospitals (CWRU-UH), Cleveland, OH, USA). One- and two-value positive predictive values for 2-year mortality (from study entry) are calculated using factors that include demographics, laboratory values and clinical evaluations. We define high-, intermediate-, and low-risk SCA as > 15%, 10-15% and < 10% 2-year mortality. In walk-PHaSST, no single factor qualifies as high-risk SCA, although several combinations of two factors (that is, both age > 35 years and history of chronic transfusion) do. Either elevated white blood cell count (> 13.5 × 10(3) cells/mcL, 7/70 deaths) or elevated Tricuspid Regurgitant Jet Velocity (⩾ 3.0 m/s, 8/67 deaths) was individually associated with intermediate-risk disease, as were many two-factor combinations. N-terminal pro-brain natriuretic peptide > 160 ng/L, lactate dehydrogenase > 600 IU/L, history of chronic transfusion, sepsis or age > 35 years are individually associated with low-risk SCA, as are many two-factor combinations. SCA risk was integrated with estimated donor type-associated risk from HSCT to form 'Traffic Light' eligibility criteria for clinical trials of HSCT. This method is adaptable to evolutions in clinical care.

Genes Associated with Alloimmunization to Blood Group Antigens in Sickle Cell Disease

BACKGROUND: Alloimmunization to minor blood group antigens is more common in sickle cell disease (SCD) than in the general population. Causes include the high frequency of transfusion as well as phenotypic differences between the largely African-American SCD population and mostly Caucasian blood donors. Alloimmunization, as well as the risk of alloimmunization, results in higher costs as well as reduced availability of and delays in obtaining antigen-matched blood to meet clinical needs. We used a candidate gene approach to determine if specific genetic signatures were associated with alloimmunization and thus could identify patients at high risk for alloimmunization and therefore requiring prospective antigen matching for transfusion.METHODS: Patient data were previously collected through a multicenter study to identify genetic factors associated with SCD complications (Duke and UNC; DU) and through the Cooperative Study of SCD (CSSCD). All subjects were adults with HbSS genotype (DU mean yrs 34.9 ± 12.1, CSSCD mean yrs 29.1 ± 9.5, p < .0001). The DU data set was 43.7% male while the CSSCD data set was 37.1% male (p = .18). A genome-wide association study (GWAS) was conducted with the Illumina 610 BeadChips for ­­­390 individuals (215 DU, 175 CSSCD). Quality control processing of these data was published previously (Solovieff et al, 2010). Additionally, imputation of the DU data set was conducted using IMPUTE2 (Howie et al, 2009) and a global reference panel from 1000 Genomes in order to have consistent genotypes across both studies. Based on previous literature, we studied 255 SNPs in the HLA locus as well as 684 SNPs in 53 genes previously associated with immune responses, totaling 939 SNPs. Additive logistic regression was performed separately for the DU and CSSCD data sets with PLINK (Purcell et al, 2008), controlling for age at enrollment. Results from the two data sets were combined by meta-analysis, using the invariance weight method in METAL (Willer et al, 2010). False discovery rate (FDR) q-values were generated using PROC MULTTEST in SAS v9.4 (SAS Systems). Contingency tables were produced using SAS and association between candidate SNPs and specific antibodies was tested using PLINK.RESULTS: Alloimmunization rates were different in the DU and CSSCD cohorts (30.7% vs. 18.9%, respectively; p = .0075) but were not associated with age or number of transfusions > 0 in either cohort. The most significant genetic associations with alloimmunization (FDR q = .28) occurred for 46 SNPs in the HLA locus and 10 other genes (Table 1). Two of these SNPs were missense mutations in GZMB (granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)), one of which (rs8192917) has previously been associated with acute kidney transplant rejection and acute GVHD after stem cell transplant. A missense mutation in TRIM31 (E3 ubiquitin-protein ligase) was also associated with alloimmunization (p = .01). TRIM31 regulates Src-induced anchorage-independent cell growth and has been implicated in antiretroviral defense, cancer and ADHD. Within the DU cohort, we conducted a sub-analysis among only antigen-negative individuals, in whom immunization rates were 15.8%, 14%, 4.5%, 10.2%, 11%, and 8.3% to E, C, K, S, Jkb and Fya, respectively. Regression analysis of all 939 SNPs identified nominally significant associations predicting specific antibody alloimmunization. A missense mutation in PRKCQ (rs2236379) was associated with both anti-E and –C alloimmunization. Additional missense mutations were identified as follows: in TGFBR3 and GZMB with anti-C; in CFH, andTLR6 with anti-K, and in TLR10 with anti-Jkb.CONCLUSIONS: We have identified several immune response genes that are also associated with increased risk of alloimmunization in SCD (nominal p ≤ .006, FDR q = .28). Some associations may arise from the prevalence of alloimmunization to specific antigens. For example, PRKCQ was associated with development of alloantibodies to both E and C antigens, which reside on the same nonglycosylated RH protein. Expanded studies may identify those patients who would benefit from intensive or specific antigen-matching transfusion protocols. TableGenes Associated with AlloimmunizationGene or Locus (ordered by descending p value)SNPs with FDR q = 0.28 SNPs with p ≤ .006GZMB3 (2 missense)3TGFBR242TLR311HLA locus262TGFBR332PRKCQ3CD801VAV21TRIM312 (1 missense)RNF391ZNRD11 DisclosuresNo relevant conflicts of interest to declare.

Forced Expiratory Volume in 1 Second Is Associated with Earlier Death in Sickle Cell Anemia

Background: Sickle cell anemia (SCA) is a life threatening monogenic disorder associated with early death. Platt et al. reported median ages of death (42 years males; 48 years females) from the Cooperative Study of Sickle Cell Disease (CSSCD). Forced expiratory volume in one second (FEV1) on pulmonary function testing (PFT), is commonly used to monitor disease severity in individuals with asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease. FEV1 (% predicted) has been shown to predict mortality in the general population, but no PFT result has predicted earlier death in SCA. We tested the hypothesis that abnormal pulmonary function was associated with earlier death.Methods: A prospective cohort study using the CSSCD data was constructed. We evaluated a total of 430 participants from the CSSCD study who had evaluable PFT, using data from the first PFT at age 21 years and older, and reviewed centrally for quality. Predicted values were determined for each subject based on age, gender, height, and race for FEV1, forced vital capacity (FVC), and the FEV1/FVC ratio using the Global Lung Function 2012 equations. Abnormal results for FEV1, FEV1/FVC, and FVC were determined by comparison to their lower limits of normal. Predicted values for total lung capacity (TLC) were obtained utilizing the prediction equations published, and adjusted by 12% to account for the effect of race on these values; a value <80% predicted was considered abnormal. Values of FEV1, FEV1/FVC, FVC, and TLC were used to categorize PFT patterns as normal, obstructive, or restrictive based on American Thoracic Society/European Respiratory Society guidelines according to a modified algorithm based on Pellegrino (2005). Assessment of the association between PFT and mortality was investigated using Kaplan-Meier product limit estimation and Cox proportional hazards regression. The full regression models were adjusted for factors known to be associated with mortality. Multivariable Cox regression models were constructed, and only covariates that were nominally significant predictors (p<0.20) were used for the final model. FEV1% was reverse-coded so that lower values are associated with hazard ratios above 1.Results: Median age was 31.4 years at time of first PFT and median follow-up was 5.5 years. In the cohort, 47% had normal, 29% restrictive, 8% obstructive, 2% mixed, and 14% non-specific pulmonary function patterns. There were no differences in SCA severity between groups (PFT vs no PFT). During follow-up, 63 (15%) participants died. Those who died had significantly higher WBC, lower hemoglobin levels, and lower FEV1% predicted, but not lower FEV1/FVC ratio. Pulmonary function patterns were not associated with earlier death- obstructive (p= 0.97), restrictive (p=0.41), and non-specific (p= 0.609). In the final multi-variable model, lower FEV1% predicted is associated with increased hazard of death [HR per %-predicted 1.02 (95% CI 1.00 – 1.04; p =0.037)], as did older age [HR 1.07 (95% CI 1.04-1.10; p<0.001)], male sex [HR 2.09 (95% CI 1.20-3.65; p=0.010)], higher ACS incidence rate [HR per event/yr 10.4 (95% CI 3.11-34.8; p <0.001)], LDH [HR per mg/dl 1.002 (95% CI 1.00-1.003; p = 0.015)] Table. A threshold of <70 FEV1 % predicted was associated with earlier death (Log rank test (p =0.002) Figure.Conclusion: For the first time, we have demonstrated that spirometry evaluation with FEV1% predicted identifies adults with sickle cell anemia who have increased hazard of death. Routine spirometry testing should become standard care in individuals with SCA, enabling early intervention for those at risk.Table:Final Cox Regression Model for death after lung function testing with reduced set of covariates (N=404)CovariateBHazard Ratio (95% CI)PAge at PFT#0.071.07 (1.04, 1.10)<0.001Male0.742.09 (1.20, 3.65)0.010White blood cell count (109/L)0.081.09 (0.98, 1.20)0.096ACS rate post-PFT (# per year)2.3410.39 (3.11, 34.78)<0.001Pain rate post-PFT (# per year)0.141.15 (0.98, 1.36)0.095Lactic dehydrogenase (mg/dL)0.0021.002 (1.00, 1.003)0.015FEV1 percent predicted**0.0211.02 (1.00, 1.04)0.037# PFT = Pulmonary function test** FEV1% is reverse-coded so that lower values are associated with hazard ratios above 1. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Venous thromboembolism incidence in the Cooperative Study of Sickle Cell Disease

Venous thromboembolism (VTE) has been recently recognized as a complication of sickle cell disease (SCD); however, the incidence of VTE in SCD is unknown. The primary objective of this study was to determine the incidence of first VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), among SCD patients age ≥ 15 years. We also evaluated genotypic differences in VTE risk and determined the relationship between VTE and mortality. In this retrospective cohort study, we used data from the Cooperative Study of Sickle Cell Disease (CSSCD) to calculate incidence rates for first VTE. We used Cox proportional hazard models to estimate hazard ratios (HRs) for time to VTE by genotype and time to death by VTE status. We included 1523 SCD patients aged ≥ 15 years with 8862 years of follow-up in this analysis. The incidence rate for first VTE was 5.2 events/1000 person-years (95% confidence interval [CI] 3.8-6.9) with a cumulative incidence of 11.3% (95% CI 8.3-15.3) by age 40 years. Individuals with the SS/Sβ(0) -thalassemia genotype had the highest rate of VTE (7.6 events/1000 person-years [95% CI 5.3-10.6]). The incidence of PE exceeded that of isolated DVT (3.6 [95% CI 2.5-5.1] events/1000 person-years vs. 1.6 [95% CI 0.9-2.7] events/1000 person-years), although this difference was not statistically significant. SCD patients with VTE had a higher mortality rate (adjusted HR 2.32 [95% CI 1.20-4.46]) than those without VTE. Patients with SCD are at substantial risk for VTE, and individuals with VTE are at higher risk of death than those without VTE.

Impact of long-term erythrocytapheresis on growth and peak height velocity of children with sickle cell disease.

Children with sickle cell disease (SCD) lag in weight and height and have a delayed growth spurt compared to normal children. We studied the effect of long-term erythrocytapheresis (LTE) on the growth of children with SCD and the age at which they attained peak height velocity. A retrospective chart review was performed recording weight, height, and body mass index (BMI) measurements of 36 patients with SCD who received LTE every 3-5 weeks for an average duration of 5 years. The z-scores for weight, height, and BMI of these patients were compared with that of patients with SCD from the Cooperative Study of Sickle Cell Disease (CSSCD) and a sub-set of 64 controls matched for age, sex, and initial growth parameter z-scores at the start of LTE. The z-scores for all parameters improved significantly for our patients on LTE compared to match controls from CSSCD and the entire pediatric CSSCD cohort (P-value: <0.01). Peak height velocity was achieved 2 months earlier for females (P-value: 0.94) and 11 months earlier for males (P-value: 0.02), who started LTE before 14 years of age, compared to matched CSSCD controls. The study subjects who had not been on regular simple transfusions prior to starting LTE had a mean serum ferritin of 681 ng/ml after LTE for an average duration of 63 months. LTE improves the growth of children with SCD without the risk of iron overload.

Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease.

Prior analyses of the Cooperative Study of Sickle Cell Disease (CSSCD) newborn cohort identified elevated white blood cell (WBC) count, low baseline hemoglobin and dactylitis between the ages of 1 and 2 years as markers of severe disease. Reticulocytosis was also associated with severe disease. Here, we further analyzed data collected on enrolled CSSCD infants for the predictive value of those markers for stroke and death later in life. Three hundred fifty-four CSSCD subjects were identified who had absolute reticulocyte counts (ARC) measured during infancy (2 to 6 months of age). Infants with higher ARC had significantly increased risk of stroke or death during childhood; lower hemoglobin levels also increased the risk but to a lesser degree than ARC. WBC levels and dactylitis were not predictive of death or stroke. These data suggest that reticulocytosis among asymptomatic infants with sickle cell anemia is associated with an increased risk of death or stroke during childhood.

Venous Thromboembolism Incidence In The Cooperative Study Of Sickle Cell Disease: The Untold Story

BackgroundAn increased risk of venous thromboembolism (VTE) among individuals with sickle cell disease (SCD) has only recently been recognized. Unlike arterial thrombosis such as stroke which primarily occurs in children with SCD, VTE risk in SCD appears to increase in young adulthood. To date, no studies have described the incidence of VTE in adolescents and adults with SCD. We performed a secondary analysis of the largest prospective cohort of SCD patients, the Cooperative Study of Sickle Cell Disease (CSSCD), to estimate the incidence rate and age-specific cumulative incidence of first VTE among SS/Sβ0 patients aged 15 or older. MethodsWe used available data from Phase 1 of the CSSCD,1 a multi-institution longitudinal prospective study conducted from 1978-1988, to identify cases of first VTE in patients aged 15 or older at enrollment with SS/Sβ0 genotype. Individuals with a history of prior VTE were excluded. VTE was defined as any pulmonary embolism (PE) or deep venous thrombosis (DVT) identified by ICD-9 code except in the case of pregnancy where VTE events were explicitly collected. Because the definition of acute chest syndrome (ACS) in the CSSCD also included PE and because the ICD-9 code for PE was also used for pulmonary infarct in cases of potential ACS, PE cases that were identified during an admission for ACS were included only if a negative chest X-ray was recorded. The date of VTE was recorded as being the date of the annual visit for any interim VTE or as the date of discharge for any VTE that occurred during a hospitalization. 95% Confidence intervals (CI) for incidence rates were calculated using a Poisson distribution assumption. Kaplan-Meier failure curves were generated to estimate age-specific cumulative incidence. ResultsA total of 1,133 individuals with SS/Sβ0 aged ≥ 15 years with 6,608 years of follow-up were included for analysis. During this study period, 43 incident VTE events were identified. The median age at VTE was 26.3 years (range 17-47 years) and 25 (58%) were female. The overall incidence rate for VTE was 6.5 events/1000 person-years (CI 4.7, 8.8). The Kaplan-Meier failure curve for VTE is shown below. The cumulative incidence of first VTE was estimated as 9.0% (CI 6.4-12.7) by age 30 and 14.1% (CI 10.2-19.2) by age 40. [Display omitted] ConclusionsThe incidence rate of first VTE among SS/Sβ0 patients aged ≥ 15 years appears to be high, with an estimated cumulative incidence by age 40 that far exceeds that for Factor V Leiden carriers (estimated 6.2% by age 65).2 This study underscores the thrombophilic state of SCD and emphasizes the need for further research into the risk factors for VTE in the SCD population.1. Gaston M, Rosse WF. The cooperative study of sickle cell disease: review of study design and objectives. Am J Pediatr Hematol Oncol 1982; 4: 197-201.2. Heit JA, Sobell JL, Li H, Sommer S. The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. J Throm Haemost 2004; 3: 305-11.This Abstract was prepared using CSSCD Research Materials obtained from the NHLBI via BioLINCC (https://biolincc.nhlbi.nih.gov/). Disclosures:Naik:NHLBI: Research Funding. Haywood:NHLBI: Research Funding. Lanzkron:GlycoMimetics, Inc.: Research Funding.