Background Information on life expectancy and risk factors forearly death among patients with sickle cell disease (sicklecell anemia, sickle cell-hemoglobin C disease, and the sicklecell--thalassemias) is needed to counsel patients, target therapy,and design clinical trials.
Methods We followed 3764 patients who ranged from birth to 66years of age at enrollment to determine the life expectancyand calculate the median age at death. In addition, we investigatedthe circumstances of death for all 209 adult patients who diedduring the study, and used proportional-hazards regression analysisto identify risk factors for early death among 964 adults withsickle cell anemia who were followed for at least two years.
Results Among children and adults with sickle cell anemia (homozygousfor sickle hemoglobin), the median age at death was 42 yearsfor males and 48 years for females. Among those with sicklecell-hemoglobin C disease, the median age at death was 60 yearsfor males and 68 years for females. Among adults with sicklecell disease, 18 percent of the deaths occurred in patientswith overt organ failure, predominantly renal. Thirty-threepercent were clinically free of organ failure but died duringan acute sickle crisis (78 percent had pain, the chest syndrome,or both; 22 percent had stroke). Modeling revealed that in patientswith sickle cell anemia, the acute chest syndrome, renal failure,seizures, a base-line white-cell count above 15,000 cells percubic millimeter, and a low level of fetal hemoglobin were associatedwith an increased risk of early death.
Conclusions Fifty percent of patients with sickle cell anemiasurvived beyond the fifth decade. A large proportion of thosewho died had no overt chronic organ failure but died duringan acute episode of pain, chest syndrome, or stroke. Early mortalitywas highest among patients whose disease was symptomatic. Ahigh level of fetal hemoglobin predicted improved survival andis probably a reliable childhood forecaster of adult life expectancy.
The life expectancy of patients with sickle cell disease hasimproved considerably since 1960, when Sir John Dacie describedsickle cell disease as "essentially a disease of childhood.""Indeed," he wrote, "the mortality is high and relatively fewpatients reach adult life, even when the standard of medicalcare is high"1. In his 1973 review based on autopsies, Diggsestimated a median survival of 14.3 years, with 20 percent ofthe deaths occurring in the first 2 years of life, one thirdoccurring before the fifth year of life, half between 5 and30 years of age, and one sixth after the age of 302. In contrast,in the recent Cooperative Study of Sickle Cell Disease (CSSCD),approximately 85 percent of children and adolescents with sicklecell anemia (homozygous for sickle hemoglobin) and 95 percentof patients with sickle cell-hemoglobin C disease (heterozygousfor hemoglobin S and C) survived to 20 years of age3. Amongthe patients less than 20 years of age in that series, mortalitypeaked between 1 and 3 years of age; the primary cause of deathwas infection -- predominantly Streptococcus pneumoniae sepsis.A low level of fetal hemoglobin, a low level of total hemoglobin,and an elevated base-line white-cell count were associated withan increased risk of death.
In most studies of mortality among adult patients, the age atdeath has been determined either from autopsy data or from clinicalrecords. The clinical events leading to death have been recordedonly sporadically. In the Jamaican studies by Thomas et al.,the acute chest syndrome was the principal cause of death after10 years of age,4 with chronic organ damage such as renal orcardiac failure, cerebrovascular accident, and complicationsof pregnancy noted as concomitant causes of death. Powars andcolleagues5 described similar findings in a cohort of patientsfollowed in Los Angeles for 25 years, noting that survival estimatesbased on this group may have been influenced by changes in clinicalpractice over time. For example, they suggest that the highmortality they observed among women with sickle cell anemiareflected the high mortality among pregnant women before 1975.Accurate knowledge is needed about the contemporary mortalityrate, the events that occur shortly before death, and the clinicalconditions that are associated with an increased risk of death.Such information is of great importance in counseling patients,in anticipating dangerous clinical situations, and in designingtargeted therapy and clinical trials. We undertook a prospectiveanalysis of deaths among patients in the CSSCD, with emphasison the risk factors for death in patients over 20 years of age.
Methods
The design of the CSSCD is described elsewhere6. The CSSCD isa prospective study of the clinical course of sickle cell diseasein which more than 3764 patients were enrolled from birth to66 years of age, at 23 clinical centers throughout the continentalUnited States (Table 1). Patients were enrolled at these centersbetween September 1978 and 1988 and were seen at regular intervalsfor laboratory evaluation and physical examination. At enrollment,the genotype was confirmed by review of the hematologic dataand by quantitative hemoglobin electrophoresis performed atthe Centers for Disease Control and Prevention7. Starting latein 1984, -globin gene mapping was performed in patients withsickle cell anemia by Dr. Stephen H. Embury at the Universityof California, San Francisco8,9. Consent was obtained from allpatients, their parents, or their legal guardians.
Table 1. Characteristics of Patients in the Cooperative Study of Sickle Cell Disease.
The laboratory results analyzed in this report were obtainedat routine visits, not during acute illness. All acute and chroniccomplications were documented at the centers. Deaths were reportedon a form that was completed by the center investigator, regardlessof whether deaths occurred at the study center or elsewhere;this form included narrative information about the relevantclinical findings and laboratory data, as well as the deathcertificate. When available, autopsy reports were also provided.
For all patients with sickle cell anemia or sickle cell-hemoglobinC disease we used proportional-hazards regression and the 2Lprogram of BMDP to model age at death rather than the lengthof time from enrollment to death10,11. The Cnaan and Ryan approach10is appropriate for analyses of data in studies, like this one,in which patients enter and leave the study cohort and observationbegins after the onset of the disease. According to this method,a particular patient contributes to the population at risk fora given death only if that patient is enrolled in the studyat the age at which that death occurred.
The probability of survival 10 years after enrollment was estimatedas P2/P1, with P1 denoting the proportion of the study populationalive at the beginning of the decade and P2 the proportion aliveat the end. The proportions were estimated from Kaplan-Meierplots (discussed below).
Because the causes of and risk factors for early death in thechildren and adolescents in this study had already been reported,3we concentrated on the risk factors for early death among thepatients over 20 years of age. We investigated the circumstancesof death in the 209 patients with sickle cell disease (all genotypes)who were 20 years of age or older when they died. For each patient,we reviewed the complete roster of forms recording acute andchronic complications and scheduled visits to the medical center,the death form, and when available, the final hospital dischargesummary and autopsy report. On the basis of this review, patientswere classified as either having or not having clinically diagnosedchronic organ failure before they died. This classificationwas based on either the CSSCD working definition of renal failure(a 20 percent increase in the base-line creatinine concentrationand a creatinine clearance rate below 100 ml per minute) orthe clinical diagnosis of chronic congestive heart failure orchronic debilitating stroke by the local investigator. The CSSCDdid not have a specific working definition of chronic pulmonaryfailure. Acute terminal organ failure and evidence at autopsyof organ damage that was not recognized during life were notcriteria for chronic organ failure. Patients without chronicorgan failure were classified according to their terminal event.Commonly, a death form describing other acute events (e.g.,an episode of pain or the acute chest syndrome) was the onlyevent form submitted, particularly for patients who died outsidethe center hospital where they were enrolled.
We examined the steady-state laboratory values (the averageof yearly routine measurements) and clinical events. Data collectedduring the last year of life or follow-up were excluded so asto avoid biasing the results with changes related to the ultimatecause of death. We excluded patients without at least one yearof observation before the excluded (premortem) year (70 patients)and those for whom data were incomplete (94 patients). The modelsare based on the data on 964 patients with sickle cell anemia,85 of whom died. Each potential risk factor was examined ina separate regression analysis. Each statistically significantlaboratory variable was then categorized in a variety of ways(e.g., by quartiles or quintiles) to identify the values thatcontributed to the significant effect.
Likelihood ratios were used for all statistical tests. All theP values presented are two-tailed.
Results
Survival
Kaplan-Meier survival curves for children and adults with sicklecell anemia (1313 females and 1229 males) or sickle cell-hemoglobinC disease (427 females and 417 males) are shown in Figure 1.Among patients with each phenotype, females survived longerthan males (P = 0.004 by Cox regression), and patients withsickle cell-hemoglobin C disease survived longer than thosewith sickle cell anemia (P<0.001 by Cox regression). Themedian age at death among patients with sickle cell anemia was42 years for males and 48 years for females. Among patientswith sickle cell-hemoglobin C disease, the corresponding ageswere 60 and 68 years; the data on age at death among patientswith sickle cell-hemoglobin C disease should be interpretedwith some caution, however, since the number of deaths was relativelylow in this group. The corresponding survival curves for blacksin the general population12 are included for comparison andshow that life expectancy among patients with sickle cell anemiawas decreased by 25 to 30 years. The improved survival of patientswith sickle cell anemia who had fetal hemoglobin levels abovethe 75th percentile (>8.6 percent) is illustrated in Figure 1C.
Figure 1. Survival of Patients in the Cooperative Study of Sickle Cell Disease.
Panel A shows male and female patients with sickle cell anemia (SS), as compared with black males and females in the general population (data are from the National Center for Health Statistics12). Panel B shows male and female patients with sickle cell-hemoglobin C disease (SC), and Panel C patients with sickle cell anemia more than five years of age who had fetal hemoglobin (Hb F) levels at or below the 75th percentile (8.6 percent).
To investigate the relation between age and the risk of deathin sickle cell disease, we analyzed the data according to decadeof age and calculated the probability of surviving each decade(Figure 2). The probability of surviving for 10 years droppeddramatically with age, particularly after the age of 20 years,when compared with similar data for blacks in the general population.
Figure 2. Probability of Surviving for the Next 10 Years, According to Age, among Males and Females with Sickle Cell Anemia (SS), as Compared with Black Males and Females in the General Population.
Data are from the National Center for Health Statistics12.
Circumstances of Death
Because of the difficulty of ascertaining the exact cause ofdeath in most cases, we focused on the general clinical statusof the patients and the circumstances in which they died. Theresult of the classification is shown in Table 2. Thirty-sevenpercent of the patients underwent autopsies, and approximately60 percent died outside the study center. For 38 of the patientswho died without clinical evidence of chronic organ failure,there was insufficient information to classify their immediatecircumstances of death. A small proportion of patients diedof causes not related to sickle cell disease, including traumaand cancer. In these cases it was impossible to determine theextent to which the underlying hemoglobinopathy contributedto the death.
Table 2. Circumstances of Death in 209 Patients with Sickle Cell Disease Who Were 20 Years of Age or Older at the Time of Death.
Relatively few patients died with clinical evidence of chronicorgan failure (renal failure, congestive heart failure, or chronicdebilitating cerebrovascular accident). In some instances, theorgan failure was attributable to causes other than sickle celldisease, but undoubtedly complicated by it. Because arterial-bloodgas measurements and pulmonary-function studies were not requiredfor all patients, there was no working definition of chronicpulmonary failure in this study.
A large number of patients had no overt chronic organ-systemfailure and died relatively suddenly and unexpectedly, presumablyas a complication of a sickle cell crisis. Death occurred inthe course of a painful episode in 45 patients, 20 of whom hadsimultaneous acute chest syndrome. Nine patients had acute chestsyndrome alone. Acute stroke occurred before death in 15 patients,with documented hemorrhage in 11. Although 13 of the patientswithout chronic organ failure died of infection, the infectionswere varied (Escherichia coli, Staphylococcus aureus, humanimmunodeficiency virus, tuberculosis, malaria, pneumococcus,and hepatitis), in contrast to the almost universal occurrenceof pneumococcal sepsis in children under five years of age whodied of infections.
Risk Factors for Early Death
Although males were at greater risk for early death than females,when sex was factored into the analysis of each of the otherrisk factors, no significant interaction was found (data notshown). Thus, there was no evidence that the risk factors forearly death differed according to sex.
The patients with more symptomatic disease were at higher riskof early death. Mortality varied with the following acute andchronic conditions: renal insufficiency, acute painful episodes,acute anemic episodes, seizures, and the acute chest syndrome(Table 3).
Table 3. Acute and Chronic Conditions as Risk Factors for Early Death in Patients with Sickle Cell Anemia Who Were 20 Years of Age or Older.
The risk of early death was inversely associated with levelof fetal hemoglobin (Table 4). This association was dramaticallyillustrated by the enhanced survival of patients with sicklecell anemia who had fetal hemoglobin levels above the 75th percentile(Figure 1). Differences within the group with values above the75th percentile could not be determined because of the smallnumber of deaths.
Table 4. Laboratory Values as Risk Factors for Early Death in Patients with Sickle Cell Anemia Who Were 20 Years of Age or Older.
Two other laboratory values were found to be associated withmortality (Table 4). In each case, the increase in mortalitywas associated only with values at the end of the distribution;there was no smooth trend of mortality increasing with the laboratoryvalue. Patients with sickle cell anemia who had hemoglobin valuesbelow the 10th percentile ( 7.1 g per deciliter) had a slightlyhigher risk of death than all other patients (2.8 vs. 1.1 deathsper 100 person-years). Similarly, patients with sickle cellanemia who had an elevated white-cell count (15,100 per cubicmillimeter) had a slightly higher risk of death (2.2 vs. 1.2per 100 person-years). In each case, if the 10 percent of patientsin each of these groups was excluded from analysis, no significantassociations were found between mortality and the hemoglobinlevel or the white-cell count.
There was no demonstrable relation between mortality and thepresence or absence of -thalassemia. A binary indicator for-thalassemia did not make a statistically significant contributionto the proportional-hazards model. The delay in collecting dataon -thalassemia interfered with our ability to perform a morerigorous analysis of this variable.
Multiple Regression Analysis
Since the incidence of clinical conditions may vary with laboratoryprofile, and since two or more conditions can occur in the samepatient, there may be redundancy in the results of the risk-factormodeling by single regression analysis. Therefore, the laboratoryvalues and clinical events associated with significant variationin the risk of death were combined in a multivariate model,and backward elimination was used to reduce the model to thesubset of factors that made statistically significant contributionsto the variation in mortality (Table 5). This model showed thatthe fetal hemoglobin level, renal insufficiency, acute chestsyndrome, seizures, and white-cell count were significant riskfactors.
Table 5. Risk Factors for Early Death in Patients with Sickle Cell Anemia Who Were 20 Years of Age or Older.
Discussion
This report presents a snapshot of the life expectancy of patientswith sickle cell disease in the United States during the 1980s.In contrast to the widely held assumption that patients withsickle cell anemia rarely survive to adulthood, the median ageat death among such patients was 42 years for males and 48 yearsfor females. This represents a decrease of roughly 25 to 30years in life expectancy, as compared with that of the blackAmerican population in general. Among patients with sickle cell-hemoglobinC disease, the median age at death was 60 years for males and68 years for females. The longer survival of females with bothtypes of hemoglobinopathy is typical of the findings in blackAmerican and other normal populations.
The pattern of mortality varies with age. We have already reportedthat the peak incidence of death among children with sicklecell anemia occurred between 1 and 3 years of age and that deathsamong patients less than 20 years of age were predominantlycaused by pneumococcal sepsis3. We anticipate that the recentacceptance of universal screening of newborns and the earlyadministration of prophylactic penicillin to infants with sicklecell anemia will mean that more than 85 percent of such childrenwill survive to 20 years of age and that overall survival willbe even greater than we report here. Unfortunately, the riskof death among those over 20 years of age is not easily assignedto a single preventable cause.
In this study, adults with sickle cell anemia had a high mortalityrate, with few surviving into their 60s. The circumstances oftheir deaths were quite varied. Eighteen percent of the deathsoccurred in chronically ill patients with clinically obviousorgan-system failure (renal failure, congestive heart failure,or chronic debilitating cerebrovascular accident). Althougha minority of these patients had other specific factors thatcontributed to organ failure (such as systemic lupus erythematosus,renal tuberculosis, and congenital valvular heart disease),sickling was undoubtedly an important accelerator of organ destruction.Thirty-three percent of deaths occurred in relatively healthypatients who did not have overt chronic organ failure but diedduring a classic sickle crisis. Seventy-eight percent of thesepatients died during an acute painful episode or an episodeof acute chest syndrome. These patients had surely experiencedand survived such episodes when they were younger, but theywere not able to tolerate them in later years.
The precise causes of death under these circumstances remainelusive, probably involving bone marrow and fat embolization,13,14,15,16excessive narcotization,17 the pain event itself,18 or a combinationof these factors. Adults, even those who appear relatively fit,are susceptible to cardiovascular collapse and acute multiorgan-systemfailure and may die suddenly during episodes of acute pain,the chest syndrome, or both. This finding illustrates the needfor more thorough study of acutely ill patients; perhaps somesuch unexpected deaths can be prevented. The other 22 percentof these "healthy" patients with sickle cell anemia died ofacute stroke; all the strokes for which a type was specifiedwere acute hemorrhages.
The clinically well patients were not all as well as they seemed.As Powars and colleagues have described, vascular damage causedby sickling insidiously accumulates in varying degrees5. Ourability to prevent early deaths hinges on the ability to identifypatients at high risk so they can be treated before fatal, oftensilent, vascular lesions develop. We examined clinical and laboratorydata to determine whether we could identify adults at high riskfor early death. We studied steady-state laboratory values usingonly those obtained at the time of routine visits rather thanduring acute illness. We studied steady-state clinical statusby excluding events that occurred during the last year of life;we hoped thus to avoid biasing the results with changes associateddirectly with the cause of death. Our previous reports on thispopulation described a wide range of degrees of clinical severity19.In this analysis, we found that the adult patients who had moresymptoms of the disease were at increased risk of early death.
The important laboratory risk factors were a high white-cellcount and a low fetal hemoglobin level. Patients with a white-cellcount over 15,000 per cubic millimeter were at increased risk.This interesting finding is also well documented in the normalpopulation and is independent of factors, such as smoking, thatare known to raise the base-line white-cell count20. In thisstudy we may simply have "rediscovered" this normal enigmaticobservation, or may have identified a feature peculiar to sicklecell anemia, such as the relation between inflammatory cytokinesand the endothelium, adhesive interactions between white cellsand endothelium, or even interactions between white cells andsickle red cells. It is tempting to speculate that loweringvery high white-cell counts may be therapeutic in sickle celldisease and that the beneficial effects of hydroxyurea and othercytotoxic chemotherapeutic agents that raise the fetal hemoglobinlevel may relate to their tendency to lower the white-cell count.
The most straightforward laboratory risk factor was the fetalhemoglobin level. Patients with high levels had an improvedlife expectancy. Although this result is no surprise, its documentationis of utmost importance. Of all the risk factors we identifiedin this study, the fetal hemoglobin level is the one known tobe relatively stable throughout life21. Adults who had low levelsof fetal hemoglobin as children are likely to die earlier thanthose who had high levels. The fetal hemoglobin level shouldbe considered an important factor in selecting children forhigh-risk interventions such as bone marrow transplantationand long-term treatment with agents that stimulate the productionof fetal hemoglobin.
Supported by the Cooperative Study of Sickle Cell Disease, aprogram of the Sickle Cell Disease Branch of the National Heart,Lung, and Blood Institute.
Source Information
From the Department of Medicine, Children's Hospital, the Dana-Farber Cancer Institute, and Harvard Medical School -- all in Boston (O.S.P.); New England Research Institute, Watertown, Mass. (D.J.B.); the Department of Medicine, Duke University School of Medicine, Durham, N.C. (W.F.R.); the Department of Medicine, Medical College of Georgia, Augusta (P.F.M.); the Department of Medicine, Center for Sickle Cell Disease, Howard University, Washington, D.C. (O.C.); the Hematology-Oncology Section, Jackson Veterans Affairs Medical Center, and the Department of Medicine, University of Mississippi School of Medicine -- both in Jackson (M.H.S.); and the Hematology Division, Texas Tech University Health Science Center, Amarillo (P.P.K.). The investigators who participated in this study are listed in the Appendix.
Address reprint requests to Dr. Platt at the Department of Laboratory Medicine, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
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Appendix
The following investigators participated in the CooperativeStudy of Sickle Cell Disease: R. Johnson, Alta Bates Hospital,Oakland, Calif.; L. McMahon, Boston City Hospital, Boston; O.Platt, Children's Hospital, Boston; F. Gill and K. Ohene Frempong,Children's Hospital, Philadelphia; G. Bray, J.F. Kelleher, andS. Leikin, Children's Hospital National Medical Center, Washington,D.C.; E. Vichinsky and B. Lubin, Children's Hospital, Oakland,Calif.; A. Bank and S. Piomelli, Columbia Presbyterian Hospital,New York; W. Rosse, J. Falletta, and T.R. Kinney, Duke University,Durham, N.C.; L. Lessin, George Washington University, Washington,D.C.; J. Smith and Y. Khakoo, Harlem Hospital, New York; R.B.Scott, O. Castro, and C. Reindorf, Howard University, Washington,D.C.; H. Dosik, S. Diamond, and R. Bellevue, Interfaith MedicalCenter, Brooklyn, N.Y.; W. Wang and J. Wilimas, LeBonheur Children'sHospital, Memphis, Tenn.; P. Milner, Medical College of Georgia,Augusta; A. Brown, S. Miller, R. Rieder, and P. Gillette, StateUniversity of New York Downstate Medical Center, Brooklyn; W.Lande, S. Embury, and W. Mentzer, San Francisco General Hospital,San Francisco; D. Wethers and R. Grover, St. Luke's-RooseveltMedical Center, New York; M. Koshy and N. Talishy, Universityof Illinois, Chicago; C. Pegelow and P. Klug, University ofMiami, Miami; M. Steinberg, University of Mississippi, Jackson;A. Kraus, University of Tennessee, Memphis; H. Zarkowsky, WashingtonUniversity, St. Louis; C. Dampier, Wyler Children's Hospital,Chicago; H. Pearson and A.K. Ritchey, Yale University, New Haven,Conn.; S. McKinlay, D. Gallagher, and D. Brambilla, New EnglandResearch Institute, Watertown, Mass.; and M. Gaston and C. Reid,National Heart, Lung, and Blood Institute, Bethesda, Md.
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(2008). Sickle cell disease-related organ damage occurs irrespective of pain rate: implications for clinical practice. haematol
93: 757-760
[Abstract][Full Text]
VanderJagt, D. J., Trujillo, M. R., Jalo, I., Bode-Thomas, F., Glew, R. H., Agaba, P.
(2008). Pulmonary Function Correlates with Body Composition in Nigerian Children and Young Adults with Sickle Cell Disease. J Trop Pediatr
54: 87-93
[Abstract][Full Text]
Platt, O. S.
(2008). Hydroxyurea for the Treatment of Sickle Cell Anemia. NEJM
358: 1362-1369
[Full Text]
Mekontso Dessap, A., Leon, R., Habibi, A., Nzouakou, R., Roudot-Thoraval, F., Adnot, S., Godeau, B., Galacteros, F., Brun-Buisson, C., Brochard, L., Maitre, B.
(2008). Pulmonary Hypertension and Cor Pulmonale during Severe Acute Chest Syndrome in Sickle Cell Disease. Am. J. Respir. Crit. Care Med.
177: 646-653
[Abstract][Full Text]
Tercyak, K. P., Britto, M. T., Hanna, K. M., Hollen, P. J., Hudson, M. M.
(2008). Prevention of Tobacco Use Among Medically At-risk Children and Adolescents: Clinical and Research Opportunities in the Interest of Public Health. J Pediatr Psychol
33: 119-132
[Abstract][Full Text]
van Beers, E. J., van Eck-Smit, B. L. F., Mac Gillavry, M. R., van Tuijn, C. F. J., van Esser, J. W. J., Brandjes, D. P. M., Kappers-Klunne, M. C., Duits, A. J., Biemond, B. J., Schnog, J.-J. B., on Behalf of the CURAMA Study Group,
(2008). Large and Medium-Sized Pulmonary Artery Obstruction Does Not Play a Role of Primary Importance in the Etiology of Sickle-Cell Disease-Associated Pulmonary Hypertension. Chest
133: 646-652
[Abstract][Full Text]
Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M. G., Sestu, N., Lai, S., Dei, M., Mulas, A., Crisponi, L., Naitza, S., Asunis, I., Deiana, M., Nagaraja, R., Perseu, L., Satta, S., Cipollina, M. D., Sollaino, C., Moi, P., Hirschhorn, J. N., Orkin, S. H., Abecasis, G. R., Schlessinger, D., Cao, A.
(2008). Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of {beta}-thalassemia. Proc. Natl. Acad. Sci. USA
105: 1620-1625
[Abstract][Full Text]
Levenson, J. L., McClish, D. K., Dahman, B. A., Bovbjerg, V. E., de A. Citero, V., Penberthy, L. T., Aisiku, I. P., Roberts, J. D., Roseff, S. D., Smith, W. R.
(2008). Depression and Anxiety in Adults With Sickle Cell Disease: The PiSCES Project. Psychosom. Med.
70: 192-196
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Deane, C. R, Goss, D., O'Driscoll, S., Mellor, S., Pohl, K. R E, Dick, M. C, Height, S. E, Rees, D. C
(2008). Transcranial Doppler scanning and the assessment of stroke risk in children with haemoglobin sickle cell disease. Arch. Dis. Child.
93: 138-141
[Abstract][Full Text]
Smith, W. R., Penberthy, L. T., Bovbjerg, V. E., McClish, D. K., Roberts, J. D., Dahman, B., Aisiku, I. P., Levenson, J. L., Roseff, S. D.
(2008). Daily Assessment of Pain in Adults with Sickle Cell Disease. ANN INTERN MED
148: 94-101
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Quinn, C. T., Lee, N. J., Shull, E. P., Ahmad, N., Rogers, Z. R., Buchanan, G. R.
(2008). Prediction of adverse outcomes in children with sickle cell anemia: a study of the Dallas Newborn Cohort. Blood
111: 544-548
[Abstract][Full Text]
Setty, B. N. Y., Betal, S. G.
(2008). Microvascular endothelial cells express a phosphatidylserine receptor: a functionally active receptor for phosphatidylserine-positive erythrocytes. Blood
111: 905-914
[Abstract][Full Text]
Benjamin, L.
(2008). Pain Management in Sickle Cell Disease: Palliative Care Begins at Birth?. ASH Education Book
2008: 466-474
[Abstract][Full Text]
Mazumdar, M., Heeney, M. M., Sox, C. M., Lieu, T. A.
(2007). Preventing Stroke Among Children With Sickle Cell Anemia: An Analysis of Strategies That Involve Transcranial Doppler Testing and Chronic Transfusion. Pediatrics
120: e1107-e1116
[Abstract][Full Text]
Sebastiani, P., Nolan, V. G., Baldwin, C. T., Abad-Grau, M. M., Wang, L., Adewoye, A. H., McMahon, L. C., Farrer, L. A., Taylor, J. G. IV, Kato, G. J., Gladwin, M. T., Steinberg, M. H.
(2007). A network model to predict the risk of death in sickle cell disease. Blood
110: 2727-2735
[Abstract][Full Text]
Bernaudin, F., Socie, G., Kuentz, M., Chevret, S., Duval, M., Bertrand, Y., Vannier, J.-P., Yakouben, K., Thuret, I., Bordigoni, P., Fischer, A., Lutz, P., Stephan, J.-L., Dhedin, N., Plouvier, E., Margueritte, G., Bories, D., Verlhac, S., Esperou, H., Coic, L., Vernant, J.-P., Gluckman, E., for the Societe Francaise de Greffe de Moelle et d,
(2007). Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood
110: 2749-2756
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Ntagiopoulos, P G, Moutzouris, D-A, Manetas, S
(2007). The "fish-vertebra" sign. Emerg. Med. J.
24: 674-675
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Rivera, A.
(2007). Reduced sickle erythrocyte dehydration in vivo by endothelin-1 receptor antagonists. Am. J. Physiol. Cell Physiol.
293: C960-C966
[Abstract][Full Text]
Boyd, J. H., Macklin, E. A., Strunk, R. C., DeBaun, M. R.
(2007). Asthma is associated with Increased mortality in individuals with sickle cell anemia. haematol
92: 1115-1118
[Abstract][Full Text]
Thein, S. L., Menzel, S., Peng, X., Best, S., Jiang, J., Close, J., Silver, N., Gerovasilli, A., Ping, C., Yamaguchi, M., Wahlberg, K., Ulug, P., Spector, T. D., Garner, C., Matsuda, F., Farrall, M., Lathrop, M.
(2007). Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc. Natl. Acad. Sci. USA
104: 11346-11351
[Abstract][Full Text]
Telfer, P., Coen, P., Chakravorty, S., Wilkey, O., Evans, J., Newell, H., Smalling, B., Amos, R., Stephens, A., Rogers, D., Kirkham, F.
(2007). Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. haematol
92: 905-912
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Thompson, J., Reid, M., Hambleton, I., Serjeant, G. R.
(2007). Albuminuria and Renal Function in Homozygous Sickle Cell Disease: Observations From a Cohort Study. Arch Intern Med
167: 701-708
[Abstract][Full Text]
McClain, B. C., Kain, Z. N.
(2007). Pediatric Palliative Care: A Novel Approach to Children With Sickle Cell Disease. Pediatrics
119: 612-614
[Full Text]
Serjeant, G. R., Higgs, D. R., Hambleton, I. R.
(2007). Elderly Survivors with Homozygous Sickle Cell Disease. NEJM
356: 642-643
[Full Text]
Sachdev, V., Machado, R. F., Shizukuda, Y., Rao, Y. N., Sidenko, S., Ernst, I., St. Peter, M., Coles, W. A., Rosing, D. R., Blackwelder, W. C., Castro, O., Kato, G. J., Gladwin, M. T.
(2007). Diastolic Dysfunction Is an Independent Risk Factor for Death in Patients With Sickle Cell Disease. J Am Coll Cardiol
49: 472-479
[Abstract][Full Text]
DeBaun, M. R., Field, J. J.
(2007). Limitations of Clinical Trials in Sickle Cell Disease: A Case Study of the Multi-center Study of Hydroxyurea (MSH) Trial and the Stroke Prevention (STOP) Trial. ASH Education Book
2007: 482-488
[Abstract][Full Text]
Buchanan, G. R., Kahn, M. J.
(2007). Hemolytic anemias. ASH-SAP
2007: 102-142
[Full Text]
Quinn, C. T., Shull, E. P., Ahmad, N., Lee, N. J., Rogers, Z. R., Buchanan, G. R.
(2007). Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia. Blood
109: 40-45
[Abstract][Full Text]
Boyd, J. H., Macklin, E. A., Strunk, R. C., DeBaun, M. R.
(2006). Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Blood
108: 2923-2927
[Abstract][Full Text]
Okumura, M. J., Campbell, A. D., Nasr, S. Z., Davis, M. M.
(2006). Inpatient Health Care Use Among Adult Survivors of Chronic Childhood Illnesses in the United States.. Arch Pediatr Adolesc Med
160: 1054-1060
[Abstract][Full Text]
de Franceschi, L., Malpeli, G., Scarpa, A., Janin, A., Muchitsch, E. M., Roncada, P., Leboeuf, C., Corrocher, R., Beuzard, Y., Brugnara, C.
(2006). Protective effects of S-nitrosoalbumin on lung injury induced by hypoxia-reoxygenation in mouse model of sickle cell disease. Am. J. Physiol. Lung Cell. Mol. Physiol.
291: L457-L465
[Abstract][Full Text]
Valadi, N., Silva, G. S., Bowman, L. S., Ramsingh, D., Vicari, P., Filho, A. C., Massaro, A. R., Kutlar, A., Nichols, F. T., Adams, R. J.
(2006). Transcranial Doppler ultrasonography in adults with sickle cell disease.. Neurology
67: 572-574
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Tyc, V. L., Throckmorton-Belzer, L.
(2006). Smoking Rates and the State of Smoking Interventions for Children and Adolescents With Chronic Illness. Pediatrics
118: e471-e487
[Abstract][Full Text]
Machado, R. F., Anthi, A., Steinberg, M. H., Bonds, D., Sachdev, V., Kato, G. J., Taveira-DaSilva, A. M., Ballas, S. K., Blackwelder, W., Xu, X., Hunter, L., Barton, B., Waclawiw, M., Castro, O., Gladwin, M. T., for the MSH Investigators,
(2006). N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease.. JAMA
296: 310-318
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Lee, S. P., Ataga, K. I., Orringer, E. P., Phillips, D. R., Parise, L. V.
(2006). Biologically Active CD40 Ligand Is Elevated in Sickle Cell Anemia: Potential Role for Platelet-Mediated Inflammation. Arterioscler. Thromb. Vasc. Bio.
26: 1626-1631
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Strouse, J. J., Cox, C. S., Melhem, E. R., Lu, H., Kraut, M. A., Razumovsky, A., Yohay, K., van Zijl, P. C., Casella, J. F.
(2006). Inverse correlation between cerebral blood flow measured by continuous arterial spin-labeling (CASL) MRI and neurocognitive function in children with sickle cell anemia (SCA). Blood
108: 379-381
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Klings, E. S., Wyszynski, D. F., Nolan, V. G., Steinberg, M. H.
(2006). Abnormal Pulmonary Function in Adults with Sickle Cell Anemia. Am. J. Respir. Crit. Care Med.
173: 1264-1269
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Smith, L. A., Oyeku, S. O., Homer, C., Zuckerman, B.
(2006). Sickle Cell Disease: A Question of Equity and Quality. Pediatrics
117: 1763-1770
[Abstract][Full Text]
Fathallah, H., Atweh, G. F.
(2006). Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease. ASH Education Book
2006: 58-62
[Abstract][Full Text]
Nolan, V. G., Wyszynski, D. F., Farrer, L. A., Steinberg, M. H.
(2005). Hemolysis-associated priapism in sickle cell disease. Blood
106: 3264-3267
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Hankins, J. S., Ware, R. E., Rogers, Z. R., Wynn, L. W., Lane, P. A., Scott, J. P., Wang, W. C.
(2005). Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study. Blood
106: 2269-2275
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Mahaney, M. C., Brugnara, C., Lease, L. R., Platt, O. S.
(2005). Genetic influences on peripheral blood cell counts: a study in baboons. Blood
106: 1210-1214
[Abstract][Full Text]
Jacob, E., Miaskowski, C., Savedra, M., Beyer, J. E., Treadwell, M., Styles, L.
(2005). Trends in Complete Blood Count Values During Acute Painful Episodes in Children With Sickle Cell Disease. Journal of Pediatric Oncology Nursing
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[Abstract]
Yan, J.-H., Ataga, K., Kaul, S., Olson, J. S., Grasela, D. M., Gothelf, S., Kutlar, A., Orringer, E.
(2005). The Influence of Renal Function on Hydroxyurea Pharmacokinetics in Adults With Sickle Cell Disease. J Clin Pharmacol
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Coller, B. S.
(2005). Leukocytosis and Ischemic Vascular Disease Morbidity and Mortality: Is It Time to Intervene?. Arterioscler. Thromb. Vasc. Bio.
25: 658-670
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Serjeant, G. R
(2005). Mortality from sickle cell disease in Africa. BMJ
330: 432-433
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Bakanay, S. M., Dainer, E., Clair, B., Adekile, A., Daitch, L., Wells, L., Holley, L., Smith, D., Kutlar, A.
(2005). Mortality in sickle cell patients on hydroxyurea therapy. Blood
105: 545-547
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Pelton, S. I., Hammerschlag, M. R.
(2005). Overcoming Current Obstacles in the Management of Bacterial Community-Acquired Pneumonia in Ambulatory Children. CLIN PEDIATR
44: 1-17
Gladwin, M. T., Kato, G. J.
(2005). Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia. ASH Education Book
2005: 51-57
[Abstract][Full Text]
Farber, H. W., Loscalzo, J.
(2004). Pulmonary Arterial Hypertension. NEJM
351: 1655-1665
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Jison, M. L., Munson, P. J., Barb, J. J., Suffredini, A. F., Talwar, S., Logun, C., Raghavachari, N., Beigel, J. H., Shelhamer, J. H., Danner, R. L., Gladwin, M. T.
(2004). Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease. Blood
104: 270-280
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Levasseur, D. N., Ryan, T. M., Reilly, M. P., McCune, S. L., Asakura, T., Townes, T. M.
(2004). A Recombinant Human Hemoglobin with Anti-sickling Properties Greater than Fetal Hemoglobin. J. Biol. Chem.
279: 27518-27524
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Quinn, C. T., Rogers, Z. R., Buchanan, G. R.
(2004). Survival of children with sickle cell disease. Blood
103: 4023-4027
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Haynes, J. Jr, Baliga, B. S., Obiako, B., Ofori-Acquah, S., Pace, B.
(2004). Zileuton induces hemoglobin F synthesis in erythroid progenitors: role of the L-arginine-nitric oxide signaling pathway. Blood
103: 3945-3950
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Peters, L. L., Swearingen, R. A., Andersen, S. G., Gwynn, B., Lambert, A. J., Li, R., Lux, S. E., Churchill, G. A.
(2004). Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency. Blood
103: 3233-3240
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Greenough, A.
(2004). Sickle Cell Disease--Pulmonary Complications and a Proinflammatory State?. Am. J. Respir. Crit. Care Med.
169: 663-665
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Holtzclaw, J. D., Jack, D., Aguayo, S. M., Eckman, J. R., Roman, J., Hsu, L. L.
(2004). Enhanced Pulmonary and Systemic Response to Endotoxin in Transgenic Sickle Mice. Am. J. Respir. Crit. Care Med.
169: 687-695
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Zimmerman, S. A., Schultz, W. H., Davis, J. S., Pickens, C. V., Mortier, N. A., Howard, T. A., Ware, R. E.
(2004). Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood
103: 2039-2045
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Gladwin, M. T., Sachdev, V., Jison, M. L., Shizukuda, Y., Plehn, J. F., Minter, K., Brown, B., Coles, W. A., Nichols, J. S., Ernst, I., Hunter, L. A., Blackwelder, W. C., Schechter, A. N., Rodgers, G. P., Castro, O., Ognibene, F. P.
(2004). Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease. NEJM
350: 886-895
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Tong, P. C., Lee, K.-F., So, W.-Y., Ng, M. H., Chan, W.-B., Lo, M. K., Chan, N. N., Chan, J. C.
(2004). White Blood Cell Count Is Associated With Macro- and Microvascular Complications in Chinese Patients With Type 2 Diabetes. Diabetes Care
27: 216-222
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Sylvester, K P, Patey, R A, Milligan, P, Dick, M, Rafferty, G F, Rees, D, Thein, S L, Greenough, A
(2004). Pulmonary function abnormalities in children with sickle cell disease. Thorax
59: 67-70
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West, D. C., Romano, P. S., Azari, R., Rudominer, A., Holman, M., Sandhu, S.
(2003). Impact of Environmental Tobacco Smoke on Children With Sickle Cell Disease. Arch Pediatr Adolesc Med
157: 1197-1201
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Lechapt, E., Habibi, A., Bachir, D., Galacteros, F., Schaeffer, A., Desvaux, D., Brochard, L., Housset, B., Godeau, B., Maitre, B.
(2003). Induced Sputum versus Bronchoalveolar Lavage during Acute Chest Syndrome in Sickle Cell Disease. Am. J. Respir. Crit. Care Med.
168: 1373-1377
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Dempsey, N. J., Ojalvo, L. S., Wu, D. W., Little, J. A.
(2003). Induction of an embryonic globin gene promoter by short-chain fatty acids. Blood
102: 4214-4222
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Varghese, A., Weir, E. K.
(2003). T-Type Calcium Current in Sickle Cell Disease: A Channel to Therapy?. Circ. Res.
93: 274-276
[Full Text]
Perelman, N., Selvaraj, S. K., Batra, S., Luck, L. R., Erdreich-Epstein, A., Coates, T. D., Kalra, V. K., Malik, P.
(2003). Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood
102: 1506-1514
[Abstract][Full Text]
Selvaraj, S. K., Giri, R. K., Perelman, N., Johnson, C., Malik, P., Kalra, V. K.
(2003). Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. Blood
102: 1515-1524
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Zuzak, K. J., Gladwin, M. T., Cannon, R. O. III, Levin, I. W.
(2003). Imaging hemoglobin oxygen saturation in sickle cell disease patients using noninvasive visible reflectance hyperspectral techniques: effects of nitric oxide. Am. J. Physiol. Heart Circ. Physiol.
285: H1183-H1189
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Mak, V, Davies, S C
(2003). The pulmonary physician in critical care * Illustrative case 6: Acute chest syndrome of sickle cell anaemia. Thorax
58: 726-728
[Full Text]
Morris, C. R., Morris, S. M. Jr., Hagar, W., van Warmerdam, J., Claster, S., Kepka-Lenhart, D., Machado, L., Kuypers, F. A., Vichinsky, E. P.
(2003). Arginine Therapy: A New Treatment for Pulmonary Hypertension in Sickle Cell Disease?. Am. J. Respir. Crit. Care Med.
168: 63-69
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Steen, R. G., Hankins, G. M., Xiong, X., Wang, W. C., Beil, K., Langston, J. W., Helton, K. J.
(2003). Prospective Brain Imaging Evaluation of Children with Sickle Cell Trait: Initial Observations. Radiology
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Siddiqui, A K, Ahmed, S
(2003). Pulmonary manifestations of sickle cell disease. Postgrad. Med. J.
79: 384-390
[Abstract][Full Text]
-thalassemias) is needed to counsel patients, target therapy, and design clinical trials. 
-globin gene mapping was performed in patients with sickle cell anemia by Dr. Stephen H. Embury at the University of California, San Francisco8,9. Consent was obtained from all patients, their parents, or their legal guardians. 
7.1 g per deciliter) had a slightly higher risk of death than all other patients (2.8 vs. 1.1 deaths per 100 person-years). Similarly, patients with sickle cell anemia who had an elevated white-cell count (15,100 per cubic millimeter) had a slightly higher risk of death (2.2 vs. 1.2 per 100 person-years). In each case, if the 10 percent of patients in each of these groups was excluded from analysis, no significant associations were found between mortality and the hemoglobin level or the white-cell count. 
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