Hallmarks of SCD pathophysiology—anemia, hemolysis, vaso-occlusion, inflammation, and endothelial dysfunction—may
contribute to organ damage.
The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6
Data from a Brazilian study that followed 395 HbSS-genotyped pediatric patients from birth for a mean follow-up period of 9.04 years (range: 1.32-15.74 years). Patients were assessed from birth (January 1999 to December 2008) to June 2015.7
Data shown are from a univariate analysis. Hb was not included in final multivariate analyses.7
Interpretation of the study may be limited due to the use of medical records as a retrospective data source and the definition of outcomes, as children who carry genetic modifiers that could increase stroke risk may be misclassified in the non-stroke group.7
Data are from a study conducted outside the United States, where the management of SCD may differ.
Data from a cohort of 261 HbSS-genotype–unrelated patients with sickle cell anemia who were monitored at a single center in Brazil between August 2010 and November 2011. Medical files, including imaging exams, clinical histories, and DNA samples, were analyzed and used as inclusion criteria. Full blood counts and quantification of fetal Hb were performed on these patients.8
Of those patients studied, mean age to develop stroke was 12.4 years (range: 1-44 years); 67 of these patients presented with a documented primary stroke event on clinical record, and 140 did not. The remaining 54 patients in this cohort presented with a risk of developing a stroke, but without evidence of a stroke event, and were included in a separate stroke-risk category.8
Data shown are from a univariate analysis. Limited information on the univariate and a separate multivariate analysis was reported in the publication.8
Data are from a study conducted outside the United States, where the management of SCD may differ.
Data from a retrospective study of 96 children with HbSS sickle cell disease born between January 1997 and December 2002 at a single center in the United States. Of the 97 children studied, 1 patient was excluded because his parent withdrew consent and 65 patients were neurologically asymptomatic. Mean age at study enrollment was 0.65 ± 1.2 years and age at end of study period was 7.2 ± 1.7 years.9
Data shown are from an exploratory univariate analysis.9
Limitations of this study include its design as an explorative, descriptive trial, potential selection bias, and a limited sample size.9
Data from a subset analysis of a large multicenter trial in the United States that evaluated 814 patients with SCD (HbSS or HbSβ0 thalassemia) between the ages of 5 and 15 years, with data finalized in September 2010.3
Data shown are from a univariate analysis. In a multivariate log regression model with a select set of covariates, lower Hb concentrations (first tertile of Hb in the study, <7.6 g/dL) were associated with an odds ratio for silent cerebral infarct of 2.12.3
Limitations of the study included a lack of standardization of routine blood pressure measurements and exclusion of children with severe disease.3
Hb: hemoglobin; HbSS: homozygous hemoglobin S; HbSβ0: hemoglobin sickle beta zero; SCI: silent cerebral infarct.
Data from a cross-sectional study of 78 patients with steady-state SCD (31 [39.7%] with HbSS [sickle cell anemia], 47 [60.25%] with HbSβ0 thalassemia) who attended a single center in Egypt. Patients’ ages ranged from 2-18 years (mean 8.3 ± 4.2 years). All patients had a Hb level of >7.0 g/dL at the time of TCD evaluation and the last blood transfusion was at least 12 weeks prior to evaluation and blood sampling.10
Limitations of this study include the small sample size of patients with conditional/abnormal TCD velocities.10
Data are from a study conducted outside the United States, where the management of SCD may differ.
ACA: anterior cerebral artery; dICA: distal internal carotid artery; HbSS: homozygous hemoglobin S; HbSβ0: hemoglobin sickle beta zero; MCA: middle cerebral artery; RT: right; TCD: transcranial Doppler.
Data from a retrospective, observational cohort study using US Medicaid databases over a study period from 2009 to 2013. Mean age was 18 years and mean follow-up time was 2.7 years. Approximately 60% were children and 66% were African American. SCD genotype was not reported. Comparisons were made between individuals with SCD who were hospitalized for a VOC, with an event defined as an inpatient stay with a primary or secondary clinical claim of SCD with crisis, and those who were not. Cox regression was used for analysis of the time to first complication after the index date with follow-up VOCs modeled as time-varying variables.11
Because many VOCs do not require inpatient hospitalization, the actual rate of VOCs might be underestimated, diminishing the association between VOCs and complications. Additionally, the study may not be generalizable to other populations.11
Result from a Cox model to examine the relationship between VOCs and the time to stroke. Significant covariates included age, sex, baseline VOCs, follow-up acute chest syndrome, and pulmonary hypertension.11
Data from a retrospective study of 395 HbSS-genotyped pediatric patients who were followed for a mean of 9.04 years, from birth to June 2015, in Brazil. ACI was defined as neurological deficit lasting >24 hours (stroke) and/or a history of a transient ischemic attack, both requiring confirmation by imaging.7
Data shown are from a univariate analysis. In a multivariate regression model, white blood cell (WBC) counts as a covariate had a hazard ratio of 1.24.7
Limitations of the study include the definitions used (eg, misclassification in non-stroke group) and the use of medical records as a retrospective data source generated for clinical follow-up and not for research.7
Data are from a study conducted outside the United States, where the management of SCD may differ.
HbSS: homozygous hemoglobin S.
Data from a retrospective analysis of 322,644 SCD-related hospitalizations in the United States, comparing patients with or without concomitant Moyamoya syndrome using data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. Data were obtained for all discharges between January 2001 and December 2014. Differences in outcomes of SCD patients with or without Moyamoya syndrome was assessed by Students’ T-test and Wilcoxon-Rank Sum test. Multivariable logistic regression was performed on the weighted sample to identify predictors of stroke.12
Limitations of using a Nationwide Inpatient Sample data source included unavailable confounding variables or effect modifiers, lack of context regarding timing of diagnoses or procedures, inability to make inferences regarding epidemiology of disease process, and possibility of selection bias, as dataset is 20% of nationwide nonfederal hospital admissions.12
Data from a retrospective chart review of pediatric patients of all ages with HbSS and HbSβ0 thalassemia at a single center in the United States. Analysis was performed on 4 years of data to identify pediatric patients with microalbuminuria, along with risk factors associated with microalbuminuria, and included 82 patients not receiving therapeutic intervention. Patients were classified as having microalbuminuria if their urine albumin/creatinine ratio was ≥30 mg/g using a Siemens DCA Vantage Analyzer.13
This study is subject to the limitations of observational studies, including the possibility of inadvertent bias by confounding variables that were not accounted for in the study. This study was also conducted at a single center over a defined period and, as such, may not be representative of patients in different regions and other periods of time. In addition, the number of patients included in this study was relatively small. Results should be considered preliminary and not definitive.
Data from a prospective, longitudinal follow-up study of 189 HbSS-genotyped adult patients with SCD at a single center in Guadeloupe. Mean age of patients was 34.8 years. The medical follow-up of the patients included at least 1 routine visit per year during which renal function was assessed. Patients with HIV infection or hepatitis B or C infection were excluded. Patients were classified as having microalbuminuria if their urine albumin concentration ranged from 20 to 200 mg/mL using rate nephelometry and standardized colorimetric procedure with a Roche Diagnostics COBAS INTEGRA 800.14
Data shown are from a univariate analysis. Multivariate analyses were not reported in the publication.14
Hb: hemoglobin; HbSS: homozygous hemoglobin S; HbSβ0: hemoglobin sickle beta zero; HIV: human immunodeficiency virus.
Data from a retrospective chart review of pediatric patients of all ages with HbSS and HbSβ0 thalassemia at a single center in the United States. Analysis was performed on 4 years of data to identify pediatric patients with microalbuminuria, along with risk factors associated with microalbuminuria, and included 82 patients not receiving therapeutic intervention. Patients were classified as having microalbuminuria if their urine albumin/creatinine ratio was ≥30 mg/g using a Siemens DCA Vantage Analyzer.13
This study is subject to the limitations of observational studies, including the possibility of inadvertent bias by confounding variables that were not accounted for in the study. This study was also conducted at a single center over a defined period and, as such, may not be representative of patients in different regions and other periods of time. In addition, the number of patients included in this study was relatively small. Results should be considered preliminary and not definitive.
Data from a prospective, longitudinal follow-up study of 189 HbSS-genotyped adult patients with SCD at a single center in Guadeloupe. Mean age of patients was 34.8 years. The medical follow-up of the patients included at least 1 routine visit per year during which renal function was assessed. Patients with HIV infection or hepatitis B or C infection were excluded. Patients were classified as having microalbuminuria if their urine albumin concentration ranged from 20 to 200 mg/mL using rate nephelometry and standardized colorimetric procedure with a Roche Diagnostics COBAS INTEGRA 800.14
Data shown are from a univariate analysis. Multivariate analyses were not reported in the publication.14
HbSS: homozygous hemoglobin S; HbSβ0: hemoglobin sickle beta zero; HIV: human immunodeficiency virus; LDH: lactate dehydrogenase.
Data from a retrospective chart review of 197 admissions from 97 patients at a single center in the United States for VOCs over a 2-year period from 2014 to 2015. AKI was defined as an increase in serum creatinine by ≥0.3 mg/dL or 50% increase in serum creatinine from baseline. Baseline values were determined by most recent visit within 12 months of admission.15
Limitations included lack of standardized AKI definition, lack of serum creatinine data on every hospital day for each patient, lack of data on total days/doses of oral nonsteroidal anti-inflammatory drugs utilized at home, and lack of tools to adequately assess for hydration status at time of presentation in the emergency room.15
Data from a multicenter observational study using the Research Patient Data Registry that included 254 Black adults with SCD in the United States, collected between 2005 and 2018. Renal function decline was assessed by mean annual change in estimated glomerular filtration rate. Mean age of patients was 32 years and median follow-up was 7.6 years.16
Data from a prospective multicenter study of 310 patients with mild to severe SCD under steady-state conditions. Patients were aged 3-20 years (median age 13 years) and were recruited from 3 medical centers in the United States.17
Data from an analysis of markers prospectively hypothesized to be associated with pulmonary hypertension according to TRV category. Analyses were adjusted for age and study site. Note that in a subsequent logistic regression analysis of the same TRV data set that included 4 variables chosen prospectively, Hb concentration had an odds ratio of 1.1; accordingly, the authors concluded that an Hb increase >1 g/dL was not associated with elevated TRV.17
Data from a prospective study of 195 adult patients with SCD in the United States who were recruited from the community through multimedia advertisements, community outreach, and regional clinics to avoid tertiary care referral bias. Patients were in a steady-state/stable condition with no recent crisis. All SCD genotypes were eligible; the study included 132 patients with HbSS, 35 with HbSC, and 23 with HbSβ0 thalassemia or HbSβ+ thalassemia. Genotype information was missing for 5 patients. TRV was evaluated with Doppler echocardiography.18
Data shown are from a univariate analysis. Multiple logistic-regression analysis of TRV <2.5 m/s and ≥2.5 m/s included variables, such as Hb, considered biologically related. Results for Hb from the multiple logistic-regression analysis were not reported in the publication.18
Hb: hemoglobin; HbSC: hemoglobin sickle C; HbSS: homozygous hemoglobin S; HbSβ0: hemoglobin sickle beta zero; HbSβ+: hemoglobin sickle beta plus; TRV: tricuspid regurgitation velocity.
Data from a prospective multicenter study of 310 patients with mild to severe SCD under steady-state conditions. Patients were aged 3-20 years (median age 13 years) and were recruited from 3 medical centers in the United States.17
Data from an analysis of markers prospectively hypothesized to be associated with pulmonary hypertension according to TRV category. Analyses were adjusted for age and study site. In a subsequent logistic regression analysis of TRV that included 4 variables chosen prospectively, hemolytic index had an odds ratio of 4.5; accordingly, the authors concluded that a hemolytic index increase of 2 standard deviations was associated with elevated TRV. Hemolytic index was derived from a principal component analysis of lactate dehydrogenase, aspartate aminotransferase, and bilirubin concentrations, and reticulocyte count.17
Data from a prospective study of 195 adult patients with SCD in the United States who were recruited from the community through multimedia advertisements, community outreach, and regional clinics to avoid tertiary care referral bias. Patients were in a steady-state/stable condition with no recent crisis. All SCD genotypes were eligible; the study included 132 patients with HbSS, 35 with HbSC, and 23 with HbSβ0 thalassemia or HbSβ+ thalassemia. Genotype information was missing for 5 patients. TRV was evaluated with Doppler echocardiography.18
Data shown are from a univariate analysis. Multiple logistic-regression analysis of TRV <2.5 m/s and ≥2.5 m/s included variables, such as direct bilirubin, considered biologically related. Results for direct bilirubin from the multiple logistic-regression analysis were not reported in the publication.18
HbSC: hemoglobin sickle C; HbSS: homozygous hemoglobin S; HbSβ0: hemoglobin sickle beta zero; HbSβ+: hemoglobin sickle beta plus; TRV: tricuspid regurgitation velocity.
Data from a retrospective, observational cohort study using US Medicaid databases over a study period from 2009 to 2013. Mean age was 18 years and mean follow-up time was 2.7 years. Approximately 60% were children and 66% were African American. SCD genotype was not reported. Comparisons were made between individuals with SCD who were hospitalized for a VOC, with an event defined as an inpatient stay with a primary or secondary clinical claim of SCD with crisis, and those who were not. Cox regression was used for analysis of the time to first complication after the index date with follow-up VOCs modeled as time-varying variables.11
Because many VOCs do not require inpatient hospitalization, the actual rate of VOCs might be underestimated, diminishing the association between VOCs and complications. Additionally, the study may not be generalizable to other populations.11
Result from a Cox model to examine the relationship between VOCs and the time to pulmonary hypertension. Significant covariates included age, baseline use of opioids, follow-up pulmonary embolism, stroke, and acute chest syndrome.11
Data from a cross-sectional observational study of pediatric patients with SCD conducted at multiple care centers in Italy between January 2018 and August 2018. Eighteen patients aged 5-16 years (mean 10.9 years) were included in the study, with HbSS, HbSC, and HbSβ+ genotypes represented.19
Limitations of this study include a small sample size, absence of subjects with genotype HbSC older than 10 years, and lack of follow-up.19
Data are from a study conducted outside the United States, where the management of SCD may differ.
Hb: hemoglobin; HbSC: hemoglobin sickle C; HbSS: homozygous hemoglobin S; HbSβ+: hemoglobin sickle beta plus.
Data from a cross-sectional observational study of pediatric patients with SCD conducted at multiple care centers in Italy between January 2018 and August 2018. Eighteen patients aged 5-16 years (mean 10.9 years) were included in the study, with HbSS, HbSC, and HbSβ+ genotypes represented.19
Limitations of this study include a small sample size, absence of subjects with genotype HbSC older than 10 years, and lack of follow-up.19
Data are from a study conducted outside the United States, where the management of SCD may differ.
HbSC: hemoglobin sickle C; HbSS: homozygous hemoglobin S; HbSβ+: hemoglobin sickle beta plus.
Data from a retrospective chart review of pediatric patients at a single center in the United States from 2000 to 2010 who had a diagnosis related to SCD, including sickle cell anemia and sickle thalassemia. Two hundred fifty-eight pediatric patients who had previously undergone a dilated fundus examination were included in the study, of which 54 had sickle retinopathy. The majority of patients with retinopathy were HbSS (59%) and HbSC (33%). Clinical data, not International Classification of Disease codes, were used to determine the history of events, and information pertaining to pain crisis severity was not reported.20
Limitations include the lack of a standardized eye exam, inclusion of patients with systemic manifestations not identified in medical records, patients matched by birth date and not by age at time of examination, and a sample size limited by age.20
Data shown are from a univariate analysis. Multivariate analyses were not reported in the publication.20
HbSC: hemoglobin sickle C; HbSS: homozygous hemoglobin S.
Organ damage in patients with SCD was explored in a study of autopsies from 306 patients at multiple sites across the United States between 1976 and 1996. All available clinical data, autopsy gross and microscopic findings, photographs, and/or histological slides were studied by a single pathologist to determine in a consistent manner the most precise cause of death.24
Limitations of the study include clinically remarkable or severe cases and the possibility that many cases may not have been examined because autopsies were contingent upon consent of next of kin or judgment of the medical examiners. In addition, some cases were based on dated autopsies and clinical documentation that may no longer apply to current clinical practice.24
Chronic organ damage may be responsible for the morbidity and mortality of most patients with SCD. However, it can often go unrecognized.22-24
Progression of organ damage was monitored prospectively over a period of 7 years in a cohort of adult patients with SCD at a single center in the Netherlands. At baseline in 2006, 104 adult patients were enrolled; all patients were included in this follow-up study and were screened systematically for sickle cell–related manifestations biannually.25
Limitations of this study include a limited sample size and the inclusion of elevated TRV, previously thought to be a reliable marker for pulmonary hypertension, as a form of organ damage. However, a recent study showed that only 25% of the patients with a TRV >2.5 m/s actually suffer from pulmonary hypertension.25
No significant association between the prevalence of SCD complications, with the exceptions of iron overload and acute chest syndrome, and the frequency of hospital admissions for vaso-occlusive crises (VOCs) was observed among patients monitored for organ damage and VOCs for 7 years.25
Data are from a study conducted outside the United States, where the management of SCD may differ.
*Defined as tricuspid regurgitation velocity (TRV) ≥2.5 m/s.
Data from a mortality study examining circumstances of death among 141 adult patients with SCD at a single center in the United States over a 25-year period from 1976 to 2001. Findings (proportion of patients, %) at the time of death were determined by autopsy report and/or clinical assessment. Note that most patients had more than 1 factor contributing to death.27
References: 1. Gladwin MT. Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 2016;387(10037):2565-2574. doi:10.1016/S0140-6736(16)00647-4 2. Bush AM, Borzage MT, Choi S, et al. Determinants of resting cerebral blood flow in sickle cell disease. Am J Hematol. 2016;91(9):912-917. doi:10.1002/ajh.24441 3. DeBaun MR, Armstrong FD, McKinstry RC, Ware RE, Vichinsky E, Kirkham FJ. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood. 2012;119(20):4587-4596. doi:10.1182/blood-2011-02-272682 4. Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006;17(8):2228-2235. doi:10.1681/ASN.2002010084 5. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-1634. doi:10.1681/ASN.2011111078 6. Buchanan G, Vichinsky E, Krishnamurti L, Shenoy S. Severe sickle cell disease—pathophysiology and therapy. Biol Blood Marrow Transplant. 2010;16(1 suppl):S64-S67. doi:10.1016/j.bbmt.2009.10.001 7. Belisário AR, Sales RR, Toledo NE, Muniz MBSR, Velloso-Rodrigues C, Silva CM, et al. Reticulocyte count is the most important predictor of acute cerebral ischemia and high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia. Ann Hematol. 2016;95(11):1869-1880. doi:10.1007/s00277-016-2789-5. 8. Domingos IF, Falcão DA, Hatzlhofer BL, et al. Influence of the βs haplotype and α-thalassemia on stroke development in a Brazilian population with sickle cell anaemia. Ann Hematol. 2014;93(7):1123-1129. doi:10.1007/s00277-014-2016-1 9. Kwiatkowski JL, Zimmerman RA, Pollock AN, et al. Silent infarcts in young children with sickle cell disease. Br J Haematol. 2009;146(3):300-305. doi:10.1111/j.1365-2141.2009.07753.x 10. Salama K, Rady R, Hashem RH, El-Ghamrawy M. Transcranial Doppler velocities among sickle cell disease patients in steady state. Hemoglobin. 2020;44(6):418-422. doi:10.1080/03630269.2020.1843483 11. Shah N, Bhor M, Xie L, et al. Evaluation of vaso-occlusive crises in United States sickle cell disease patients: a retrospective claims-based study. J Health Econ Outcomes Res. 2019;6(3):106-117. Published 2019 May 3. doi:10.36469/9667 12. Rallo MS, Akel O, Kalakoti P, Sun H. Characteristics and outcomes of stroke hospitalizations in patients with sickle cell disease and moyamoya syndrome. J Stroke Cerebrovasc Dis. 2022;31(10):106705. doi:10.1016/j.jstrokecerebrovasdis.2022.106705 13. Lebensburger J, Johnson SM, Askenazi DJ, Rozario NL, Howard TH, Hilliard LM. Protective role of hemoglobin and fetal hemoglobin in early kidney disease for children with sickle cell anemia. Am J Hematol. 2011;86(5):430-432. doi:10.1002/ajh.21994 14. Nebor D, Broquere C, Brudey K, et al. Alpha-thalassemia is associated with a decreased occurrence and a delayed age-at-onset of albuminuria in sickle cell anemia patients. Blood Cells Mol Dis. 2010;45(2):154-158. doi:10.1016/j.bcmd.2010.06.003 15. Baddam S, Aban I, Hilliard L, Howard T, Askenazi D, Lebensburger JD. Acute kidney injury during a pediatric sickle cell vaso-occlusive pain crisis. Pediatr Nephrol. 2017;32(8):1451-1456. doi:10.1007/s00467-017-3623-6 16. Olaniran KO, Allegretti AS, Zhao SH, Nigwekar SU, Kalim S. Acute kidney injury among Black patients with sickle cell trait and sickle cell disease. Clin J Am Soc Nephrol. 2021;16(3):348-355. doi:10.2215/CJN.06960520 17. Minniti CP, Sable C, Campbell A, et al. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica. 2009;94(3):340-347. doi:10.3324/haematol.13812 18. Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350(9):886-895. doi:10.1056/NEJMoa035477 19. Grego L, Pignatto S, Alfier F, et al. Optical coherence tomography (OCT) and OCT angiography allow early identification of sickle cell maculopathy in children and correlate it with systemic risk factors. Graefes Arch Clin Exp Ophthalmol. 2020; 258:2551-2561. doi:10.1007/s00417-020-04764-y 20. Rosenberg JB, Hutcheson KA. Pediatric sickle cell retinopathy: correlation with clinical factors. J AAPOS. 2011;15(1):49-53. doi:10.1016/j.jaapos.2010.11.014 21. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet. 2017;390(10091):311-323. doi:10.1016/S0140-6736(17)30193-9 22. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018‐2031. doi:10.1016/S0140-6736(10)61029-X 23. Vichinsky E. Chronic organ failure in adult sickle cell disease. Hematology Am Soc Hematol Educ Program. 2017;2017(1):435-439. doi:10.1182/asheducation-2017.1.435 24. Manci EA, Culberson DE, Yang YM, et al. Causes of death in sickle cell disease: an autopsy study. Br J Haematol. 2003;123(2):359-365. doi:10.1046/j.1365-2141.2003.04594.x 25. van Tuijn CFJ, Schimmel M, van Beers EJ, Nur E, Biemond BJ. Prospective evaluation of chronic organ damage in adult sickle cell patients: a seven-year follow-up study. Am J Hematol. 2017;92(10):E584-E590. doi:10.1002/ajh.24855 26. Telen MJ, Malik P, Vercellotti GM. Therapeutic strategies for sickle cell disease: towards a multi‐agent approach. Nat Rev Drug Discov. 2019;18(2):139-158. doi:10.1038/s41573-018-0003-2 27. Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O. Circumstances of death in adult sickle cell disease patients. Am J Hematol. 2006;81(11):858-863. doi:10.1002/ajh.20685