Adult Sickle Cell Disease Patients Research Articles

A Comprehensive Echocardiographic Portrait of Adult Sickle Cell Disease Patients in the Modern Era

Background Cardiovascular complications, especially pulmonary hypertension, are a known cause of mortality in patients with sickle cell disease (SCD). With advances in medicine and the introduction of various disease-modifying medications, the incidence and prevalence of cardiovascular complications are poorly documented. Aim To determine rates of cardiovascular complications in patients with SCD in the modern era of disease-modifying medications in a single center. Method We performed a retrospective observational single-center study of patients with SCD: all genotyped and ≥16 years old who had a recent echocardiogram performed during the study period of 2019-2023. Demographics, echocardiogram results, and laboratory findings were collected and analyzed. Descriptive statistics are presented in percentages, medians, and interquartile ranges. An unpaired Student's t-test and Fisher's exact test were used to determine, where appropriate, the level of significant differences among continuous and categorical variables, respectively, with p value <0.05 considered statistically significant. Data was analyzed using GraphPad Prism version 9.0.2. Results As of June 2023, 80 patients (38 male and 42 female, median age 30 years) had undergone a routine transthoracic echocardiogram. Sixty-five patients had the HbSS genotype, 8 HbSC, and 7 HbSB null. Sixty-one patients had received at least one treatment, and 19 (24%) were on concurrent therapy. Hydroxyurea was the common SCD-modifying therapy that the patients received (51 patients), followed by L-glutamine and voxelotor (11 each) and crizanlizumab (9 patients). In total, 56 (70%) patients had at least one cardiac abnormality. The most common cardiac abnormality was left atrial dilatation (41%), followed by left ventricular hypertrophy (33%), right atrial dilation (24%), and left ventricular dilatation (23%). Pulmonary hypertension was present in 30 (38%) patients with tricuspid regurgitation velocity (TRV) ≥2.5 msec (Table 1). The cohort of patients with pulmonary hypertension tended to be older (median age 31 years, p=0.0357), have a higher creatinine level (median 0.8, p=0.0414), and have coexisting echocardiographic abnormalities such as left atrial dilatation (70% vs. 24%, p<0.0001) or right atrial dilatation (40% vs. 14%, p=0.0136) than SCD patients without pulmonary hypertension (Table 2). Conclusion We present a comprehensive echocardiographic assessment of patients with SCD. Despite advances in the treatment of SCD, there remains a high prevalence of cardiac involvement in SCD patients. We found out that 70% of the patients we reviewed had at least one cardiac abnormality on echocardiography. Left atrial dilatation and left ventricular hypertrophy were the most common cardiac abnormalities noted. Pulmonary hypertension was observed in 37.5% of patients with co-existing right and left atrial enlargement. Larger studies are needed to corroborate these findings.

Roxyscan: A Novel Method to Assess Red Blood Cell Resilience to Oxidative Stress in Sickle Cell Disease

Background: Red blood cells (RBCs) are biconcave-shaped cells with viscoelastic membranes that are optimally adapted for oxygen delivery and gas exchange during their normal lifespan of 120 days. Reactive oxygen species (ROS) continuously challenge the viability of RBCs. Despite an arsenal of compounds to protect the RBC, including Glutathione (GSH), Vitamin E, superoxide dismutase (SOD) and Catalase, damage can easily be inflicted that will disrupt cellular deformability, structure, and membrane properties. The susceptibility to oxidative stress in individuals with Sickle Cell Disease (SCD) is believed to be linked to multiple factors. These include the release of heme and iron during hemolysis, inflammation processes, and a reduction in antioxidant defenses. Methods:Susceptibility of RBCs to oxidative stress was assessed with the RoxyScan. This novel application of the Lorrca MaxSis (RR Mechatronics) measures rheological behavior of RBCs in response to cumene hydroperoxide (CuHP, 100 µM) exposure during continuous shear (30 Pa). For this we used the Lorrca's peristaltic pump and suction needle, directing the blood and CuHP to the instrument's cup and mixing them for 30 seconds (s) before starting the run. Deformability of RBCs (EI, elongation index) was measured over time. PoX is defined as the time where a 10% decrease in EI is reached. EI start: EI t=0. EI final: EI t=1600s, ΔEI (EIstart-EIfinal). RoxyScan measurements were performed on blood samples from 16 adult SCD patients (HbSS, HbS/β0 or HbS/β+) and 19 healthy controls (HC). Outcome measurement PoX (calculated from curve fitted data) was correlated to laboratory parameters from complete blood count (Cell Dyn Sapphire, Abbott), RBC sickling tendency (Point of Sickling, PoS, as assessed by oxygen gradient ektacytometry on the Lorrca MaxSis), and levels of HbF/HbS (Tosoh G8). Results:RBCs from untreated HC show a stable EI over time (Fig 1A). Upon exposure to CuHP a similar decrease in EI is seen in 19 HC (Fig 1A), mean decrease 0.055, range (0.017 to 0.10). The mean and median calculated PoX in HC is 1723s and 1702s respectively. In contrast, SCD RBC showed an earlier and more pronounced decrease in EI in response to CuHP exposure (representative example, Fig 1A). Comparing the PoX between HC and SCD revealed significant differences: mean PoX HC: 1723s (SD 329s), SCD: 725s (SD 472s), ***p<0.0001, indicating that SCD RBCs are more susceptible to oxidative stress. Correlating PoX to routine laboratory parameters identified a correlation with Hb levels (***p=0.002), inverse correlation with reticulocyte count (***p=0.0014) and hemoglobin distribution width (HDW, ***p<0.001) (Fig 1B). Similarly strong inverse correlations were found for EI start and EI end (***p<0.001) (Fig 1B). PoX also showed an inverse correlation with red cell distribution width (RDW, ns p=0.07) and mean corpuscular volume (MCV, ns p=0.77). Interestingly, PoX showed a significant inverse correlation with PoS (***p=0.004), indicating that SCD RBCs which are more susceptible to oxidative stress tend to sickle at a higher oxygen tension. PoX showed no significant correlations with HbS/HbF levels (Fig 1B). Conclusion: In this study we demonstrate the applicability of the RoxyScan as a novel method to assess RBC resilience to oxidative stress. When applied to SCD, RBCs show an earlier and more pronounced response to oxidative stress than RBCs from HC. The inverse correlation of PoX, the major outcome parameter of this technique, with reticulocyte count could indicate a generally increased susceptibility to oxidative stress due to a higher level of hemolysis. The correlation with Hb levels affirms this. PoX showed other strong and significant correlations with routine laboratory parameters, such as HDW, implying that the greater variability in hemoglobin content is associated with higher susceptibility to oxidative stress. On a functional level, it is interesting to find strong correlations of PoX with PoS, showing a direct link between RBC sickling tendency and ability to withstand oxidative stress. On the other hand, HbS and HbF levels did not correlate significantly to PoX. Overall, our study highlights the potential use of the RoxyScan and its associated biomarkers in the analysis of the RBC's response to oxidative stress. Further research is in progress to investigate the clinical applicability of this new technique.

Haploidentical Aß T Cell Depleted HSCT Represents an Alternative Treatment Option in Pediatric and Adult Patients with Sickle Cell Disease (SCD)

Background: Sickle cell disease (SCD) is the most prevalent inherited hemoglobinopathy worldwide, which is associated with considerable morbidity and early mortality. Although HSCT with a MD offers a curative treatment option with an excellent 2-y OS of 95%, availability of MDs is limited and therefore haploidentical HSCT is increasingly explored. Here we update our in vitro T-depleted haploidentical HSCT approach, which is currently explored in a multicenter international trial (NCT04201210). Methods: 29 pts with SCD or SCD-ß Thal (median age: 18 years; range: 2-32) received either a CD3 +/CD19 + (n=9) or aß/CD19 + (n=20) T-haplo-HSCT and were compared with 20 SCD-pts receiving a BM graft from a MSD (median age: 23 years; range: 9-39) at our center. Indication for T-haplo HSCT pts included severe or moderate SCD related complications such as recurrent pain crisis (>5/year), acute chest syndrome, neurological events, osteonecrosis or nephropathy, transfusion-refractory allo-immunization. After exchange transfusion, almost identical conditioning regimens consisting of treosulfan, thiotepa, fludarabine (FTT) and ATG-Grafalon were applied in almost all pts, with the only difference in the timing of ATG (upfront in T-haplo-HSCT, prior to day 0 in MSD-HSCT). Immunosuppression (IST) was maintained for a minimum of 180 days consisting of calcineurin inhibitors (mainly tacrolimus) and MMF. Results: The OS and DFS for MSD and T-haplo-HSCT was 95% and 83%, respectively (Table 1). The median follow-up was 49 months for MSD (range 5-118) and 67 months for T-haplo-HSCT (range 0.5-135). Neutrophil engraftment was achieved after a median of 29 days for MSD pts and 17 days for T-haplo-HSCT with a median of 2.8 x 10 8 TNC/kg (range: 0.65-4.11) and 12 x 10 6 CD3 +/CD19 + or ab/CD19 + depleted CD34 + cells/kg (range: 4.8-49.2), respectively. One pt received two T-haplo HSCT due to primary graft failure after HHV6 infection with effective engraftment after the second transplantation. One pt required a stem cell boost of the same donor with slow subsequent engraftment and one pt died of infectious complications after the fourth T-haplo HSCT. A mixed chimerism <80% was observed in 1/20 MSD-HSCT (median 94.9%; range 40.5-100%) and in 2/29 T-haplo-HSCT pts (median 97.8%; range: 35.7 -100%). No severe cases of >°III aGVD was observed in both populations. MSD pts reached T cell counts >200/µl on day +62 (median; range: 24-293) and T-haplo-HSCT pts on day +136 (median; range: 25-758). Viral reactivation occurred both in T-haplo HSCT (20/29) and in MSD-BMT (9/20). However, one pt in the T-haplo group developed kidney failure after prolonged BKV infection and four of the T-haplo pts died of complications associated with severe CMV or HHV6 infections that were accompanied by hyperinflammation, macrophage activation and acute respiratory distress despite antiviral and anti-inflammatory treatment. One pt of the MSD group died of late treatment related toxicity in combination with preexisting SCD comorbidity. The last fatality occurred in 2020 with now 16 additional pts being transplanted safely, not least also because of a consistent letermovir prophylaxis. Overall, the treosulfan-based conditioning regimen was well tolerated with only one VOD/SOS and one CNS infarction being observed in this high-risk population. 4/20 pts in the MSD group and none in the T-haplo group developed PRES early after conditioning. Conclusions: The safety and efficacy data of this pilot series of T-haplo-HSCT in SCD reveal that T-haplo-HSCT in advanced stage pediatric and adult SCD patients lacking a MSD is feasible. However, diligent viral monitoring and early treatment of viral reactivation, in particular HHV6 is mandatory as otherwise fatal infections may develop.

Antinuclear and Specific Autoantibodies Predict Autoimmune Disease in Sickle Cell Patients: A Longitudinal Cohort Study

Introduction: Sickle cell disease (SCD), the most frequent genetic disorder, can be associated with systemic autoimmune diseases (ADs). High levels of antinuclear antibodies (ANA) are commonly described in SCD, as alloimmunization after blood transfusion. However, the specificity and the prognostic value of ANA have not been fully determined. We aimed to evaluate the association of ANA with AD development during long-term follow-up in SCD patients. Our secondary goal was to assess mortality and serious SCD-related events in this population. Patients and methods: We conducted a single-center longitudinal cohort study on 66 adult SCD patients with ANA titers ≥1/320 at baseline followed over a 13 year-period. Patients known to have an AD (n=9) were excluded from the risk analysis. Results: During follow-up, 13 out of 57 patients (23%) developed AD. Patients with ANA titers ≥1/1280 had a 3-fold increased risk of developing AD (RR 3.4[1.4;8.6]) and a 9-fold increased risk in the presence of specific autoantibodies (anti-DNA, anti-ENA, RF or ACPA) (RR 9.0[3.7;23]) with a positive (PPV) and negative predictive value (NPV) of 90%. When these two immunological features were associated, specificity and PPV reached 100%, with a NPV of 84%. There was no significant difference in the occurrence of serious SCD-related events or mortality rate according to AD. Conclusions: Sickle cell patients with high level of antinuclear antibodies and specific autoantibodies are at high risk of developing AD. The occurrence of AD does not seem to have a significant impact on the course and severity of SCD.

Iron Overload and Treatment Outcome in an Adult Sickle Cell Disease Cohort

Objective. Blood transfusion plays a prominent role in the management of patients with sickle cell disease (SCD) and has a compounded effect on iron overload, especially when simple top-off transfusions are given. Adults with sickle cell anemia (SCA: HbSS or HbSβ 0-thalassemia), often require episodic blood transfusions on a chronic basis and, hence, are at risk of developing transfusional iron overload. We monitored 83 adult SCD patients with a diagnosis of iron overload during routine treatment and follow up at our clinical center. The aim of this study was to observe and describe treatment outcomes for individuals with iron overload seen at the University of Illinois adult sickle cell center between 2010 and 2023. Method. Patients eligible for the study were aged 18 years or above at the time of their initial visit. Patients were identified from our institutional clinical and translational research informatics data warehouse using computable phenotype algorithms as well as SCD outpatient encounter information to improve accuracy of abstracted data. Results of our queries were abstracted in the form of identified patient data and subsequently reviewed in Epic electronic health record (Epic, Verona, WI). We retrospectively studied adult subjects with SCD seen during routine clinical care between 2010 and 2023. Selected subjects had a diagnosis of iron overload, determined by 2 consecutive ferritin levels >1000ng/ml in steady state plus a significant transfusion history. We extracted data on clinical laboratory markers, abdominal imaging, use of iron chelation at baseline and in the final year of follow up, whether patients were receiving chronic erythrapheresis treatment at baseline and at end of follow up, and if alive at the end of the follow up period. Subjects have variable start date and follow up period, beginning at the start of diagnosis of iron overload and ending in June 2023 or last identifiable follow up visit, or mortality. Result. Baseline characteristics of 83 adult patients included in our study are summarized in table 1. Seventy percent of the patients were female and just about everyone had HbSS disease. The females had older median age (39.5year; IQR 32-50 years) than males. The mean ferritin value was significantly higher than the initial measure after a median follows up period of 5.3 years. During the follow up period, 40% of male patients discontinued iron chelation therapy whereas only 5.6% of females did the same. Multivariable analyses were performed for association between change in ferritin measure (between follow up period) with demographic data and other covariates presented in Table 1. Covariates were eliminated by backward selection. Predictors retained in the final model include follow-up period, initial ferritin value, gender, ALT, AST, and albumin. Females had a higher drop in their follow up ferritin, but this was not significant. Neither use of iron chelation therapy at baseline nor erythrapheresis at baseline predicted a change in ferritin value, however we did not collect information on compliance or duration of therapy. Patients followed up for longer duration, or who have higher ALT, had subsequent higher measure for follow up ferritin. Higher albumin predicted a lower ferritin at follow up. The effects of liver markers on ferritin are likely correlative only. After a median follow up period of 5.3years, about 22% of the patients were confirmed to be deceased. Some patients lost to follow up have an indeterminate alive status. Predictors of mortality in multivariate analysis include follow up ferritin value, albumin, and HCV status. Positive HCV status had a strong association with cirrhosis (p=0.001) as 71% of HCV positive individuals had cirrhosis. In turn 53% of the cirrhotic patients died in the follow up period. Conclusion. Here we present an overview of the clinical outcomes of adult patients with SCD and iron overload during a median follow up period of 5.3 years. Despite limitations of a typical retrospective study, our study illustrates the difficulty associated with the management of transfusional iron overload during routine treatment follow up, especially in patients continuing to undergo episodic transfusion treatment. We also continue to underline the low adherence with chelation therapy in adult populations with SCD and iron overload, and the high mortality associated with the condition.

Fucosyltransferase VII (FUT7) Activity in Patients with Sickle Cell Disease and Healthy Controls

Background:Sickle cell disease (SCD) is a severe monogenic disorder with a majority of the affected individuals living in Africa. Vaso-occlusion is a significant cause of morbidity and mortality in SCD, and selectin mediated intercellular adhesion is recognized as an important target for therapy. As such Anti-P-selectin agents are in clinical use to reduce the frequency of vaso-occlusive crises (VOCs) in SCD patients. Sialyl lewis x is a crucial ligand common to all members of the selectin family and the final step in the biosynthesis of sialyl lewis X antigen (fucosylation), is catalysed by Fucosyltransferase VII (FUT7). This enzyme is most expressed in leukocytes and endothelial cells. We hypothesized that FUT7 enzyme activity is abnormal in SCD patients and differs by VOC severity. We sought to measure plasma levels of FUT7 in SCD patients and healthy controls, and investigate their association with clinical and laboratory features, such as the frequency of VOCs. Methods:This wasa single centre cross-sectional analytical study at the University of Nigeria Teaching Hospital, Enugu. 38 steady state adult SCD patients and 40 HbAA age- and sex-matched healthy control subjects were enrolled. SCD patients were stratified by clinical severity into: Group A- 19 subjects with mild disease (0-1 crises and no disease complication such as stroke, chronic leg ulcers, nephropathy, or avascular necrosis in the previous year), and Group B- 19 patients with moderate to severe disease (2 or more crises in the previous year, with or without complications). We excluded patients with red cell transfusion within 4 months, on hydroxyurea, or other agents that may affect vaso-occlusive crisis frequency, and co-existing chronic disorders unrelated to SCD, such as asthma and diabetes mellitus. We performed a CBC and plasma FUT7 enzyme concentration measurements (ELISA kit, MyBiosource Inc, USA). Statistical analysis was performed with SPSS version 22.0 for Windows. A 2-tailed P value of <0.05 was used. Results:Our subjects were predominantly female (SCD 52.5%, HbAA 55%), with median age 28 years (range 19-46 and 19-45 for SCD and HbAA, respectively). Median frequency of VOCs in patients was 1 (range 0-5). Avascular necrosis (32.5%) was the most common complication, while stroke, acute chest syndrome, and eye disease were the least common. As expected, SCD patients had lower haemoglobin levels than HbAA (7.9±1.3g/dL vs. 12.6±1.4g/dL, P<0.001). Significantly higher WBC, ANC, and platelet counts were observed in SCD patients compared with HbAA controls (P<0.001). No significant correlations were found between FUT7 and haematocrit (r =0.06), WBC count (r = -0.08), neutrophil count (r = -0.12), and platelet count (r =0.1), with P values of 0.7, 0.6, 0.5, and 0.6, respectively. We found no difference between the median and IQR values of plasma FUT7 of SCD (2.1; 1.8-2.5) and controls (2.2; 1.8-2.8), P = 0.7. FUT7 activity was higher in SCD subjects in Group A (2.2; 1.9-2.9) than in Group B (2.0; 1.2- 2.4), with a trend towards significance P = 0.1. Discussion:In this study, FUT7 activity did not differ between SCD patients and controls. We also did not find correlations between FUT7 and blood cell counts, suggesting that plasma FUT7 activity is not increased at baseline in SCD and that the degrees of anemia or leukocytosis are not associated with changes in FUT7. Nonetheless, a mild decrease in FUT7 levels was found in more severe SCD patients and should be confirmed in a larger study. Our study did not evaluate patients in crises or who received hydroxyurea and/or other SCD-modifying therapies. Since FUT7 catalyses selectin expression, variation in its activity may be more relevant in subgroups of SCD patients on anti-selectin therapies. Future studies should be carried out in such patients to explore FUT7 activity as a marker of acute vaso-occlusion and as a modifier of response to therapy.

Machine Learning Predicts Acute Kidney Injury in Hospitalized Patients with Sickle Cell Disease

Introduction: Acute kidney injury (AKI) is common among hospitalized patients with sickle cell disease (SCD) and contributes to increased morbidity and mortality. Early identification and management of AKI is essential to preventing poor outcomes. We aimed to predict AKI earlier in patients with SCD using a machine-learning model that utilized continuous minute-by-minute physiological data. Methods: A total of6,278 adult SCD patient encounters were admitted to inpatient units across five regional hospitals in Memphis, TN, over 3 years, from July 2017 to December 2020. From these, 1,178 patients were selected after filtering for data availability. AKI was identified in 82 (7%) patient encounters, using the 2012 Kidney Disease Improving Global Outcomes (KDIGO) criteria. The remaining 1,096 encounters served as controls. Features derived from five physiological data streams, heart rate, respiratory rate, and blood pressure (systolic, diastolic, and mean), captured every minute from bedside monitors were used. An XGBoost classifier was used for classification. Results: Our model accurately predicted AKI up to 12 h before onset with an area under the receiver operator curve (AUROC) of 0.91 (95% CI [0.89–0.93]) and up to 48 h before AKI with an AUROC of 0.82 (95% CI [0.80–0.83]). Patients with AKI were more likely to be female (64.6%) and have history of hypertension, pulmonary hypertension, chronic kidney disease, and pneumonia than the control group. Conclusion: XGBoost accurately predicted AKI as early as 12 h before onset in hospitalized SCD patients and may enable the development of innovative prevention strategies.

Cerebral hemodynamics and oxygenation in adult patients with sickle cell disease after stem cell transplantation.

Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity-matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased (p < .01), while GM and WM CVR increased (p < .01) compared with the baseline measures. OEF and CMRO2 also increased towards levels in healthy controls (p < .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis (p < .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow-up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.

Impact of Genetic Variations on Thromboembolic Risk in Saudis with Sickle Cell Disease.

Sickle cell disease (SCD) is a Mendelian disease characterized by multigenic phenotypes. Previous reports indicated a higher rate of thromboembolic events (TEEs) in SCD patients. A number of candidate polymorphisms in certain genes (e.g., FVL, PRT, and MTHFR) were previously reported as risk factors for TEEs in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlie TEEs in SCD patients. A multi-center genome-wide association study (GWAS) involving Saudi SCD adult patients with a history of TEEs (n = 65) and control patients without TEE history (n = 285) was performed. Genotyping used the 10× Affymetrix Axiom array, which includes 683,030 markers. Fisher's exact test was used to generate p-values of TEE associations with each single-nucleotide polymorphism (SNP). The haplotype analysis software tool version 1.05, designed by the University of Göttingen, Germany, was used to identify the common inherited haplotypes. No association was identified between the targeted single-nucleotide polymorphism rs1801133 in MTHFR and TEEs in SCD (p = 0.79). The allele frequency of rs6025 in FVL and rs1799963 in PRT in our cohort was extremely low (<0.01); thus, both variants were excluded from the analysis as no meaningful comparison was possible. In contrast, the GWAS analysis showed novel genome-wide associations (p < 5 × 10-8) with seven signals; five of them were located on Chr 11 (rs35390334, rs331532, rs317777, rs147062602, and rs372091), one SNP on Chr 20 (rs139341092), and another on Chr 9 (rs76076035). The other 34 SNPs located on known genes were also detected at a signal threshold of p < 5 × 10-6. Seven of the identified variants are located in olfactory receptor family 51 genes (OR51B5, OR51V1, OR51A1P, and OR51E2), and five variants were related to family 52 genes (OR52A5, OR52K1, OR52K2, and OR52T1P). The previously reported association between rs5006884-A in OR51B5 and fetal hemoglobin (HbF) levels was confirmed in our study, which showed significantly lower levels of HbF (p = 0.002) and less allele frequency (p = 0.003) in the TEE cases than in the controls. The assessment of the haplotype inheritance pattern involved the top ten significant markers with no LD (rs353988334, rs317777, rs14788626882, rs49188823, rs139349992, rs76076035, rs73395847, rs1368823, rs8888834548, and rs1455957). A haplotype analysis revealed significant associations between two haplotypes (a risk, TT-AA-del-AA-ins-CT-TT-CC-CC-AA, and a reverse protective, CC-GG-ins-GG-del-TT-CC-TT-GG-GG) and TEEs in SCD (p = 0.024, OR = 6.16, CI = 1.34-28.24, and p = 0.019, OR = 0.33, CI = 0.13-0.85, respectively). Seven markers showed novel genome-wide associations; two of them were exonic variants (rs317777 in OLFM5P and rs147062602 in OR51B5), and less significant associations (p < 5 × 10-6) were identified for 34 other variants in known genes with TEEs in SCD. Moreover, two 10-SNP common haplotypes were determined with contradictory effects. Further replication of these findings is needed.

HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease.

Red blood cell (RBC) transfusion remains a critical component in caring for the acute and chronic complications of sickle cell disease (SCD). Patient alloimmunisation is the main limitation of transfusion, which can worsen anaemia and lead to delayed haemolytic transfusion reaction or transfusion deadlock. Although biological risk factors have been identified for immunisation, patient alloimmunisation remains difficult to predict. We aimed to characterise genetic alloimmunisation factors to optimise the management of blood products compatible with extended antigen matching to ensure the self-sufficiency of labile blood products. Considering alloimmunisation in other clinical settings, like pregnancy and transplantation, many studies have shown that HLA Ib molecules (HLA-G, -E, and -F) are involved in tolerance mechanism; these molecules are ligands of immune effector cell receptors (LILRB1, LILRB2, and KIR3DS1). Genetic polymorphisms of these ligands and receptors have been linked to their expression levels and their influence on inflammatory and immune response modulation. Our hypothesis was that polymorphisms of HLA Ib genes and of their receptors are associated with alloimmunisation susceptibility in SCD patients. The alloimmunisation profile of thirty-seven adult SCD patients was analysed according to these genetic polymorphisms and transfusion history. Our results suggest that the alloimmunisation of SCD patients is linked to both HLA-F and LILRB1 genetic polymorphisms located in their regulatory region and associated with their protein expression level.

Hydroxyurea treatment for adult sickle cell anemia patients in Kinshasa.

Background: Despite a high incidence of sickle cell anemia, hydroxyurea (HU) treatment is rarely used in the DR Congo. This study aims to assess the efficacy of HU, the incidence of side effects that may limit its use in adults and to determine the dose needed for clinical improvement in patients. Methods: In a prospective study, patients received an initial dose of 15mg/kg/day which was increased by 5mg/kg every 6 months, up to a maximum of 30mg/kg/day. The response and side effects to HU were evaluated biologically and clinically every 3 months during a 2-year period. Results: Seventy adult patients with a moderate or severe clinical phenotype initiated treatment. Only minor side effects were reported. At the end of the 2-year treatment phase, 45 (64.3%) had dropped out, of whom 33 were without a clear reason. Clinical and biological improvement was more marked during the first year. There was a reduction in severe vaso-occlusive crises (p<0.001), need for transfusion (p<0.001), and hospitalization days (p=0.038). Fetal hemoglobin (HbF) levels increased on average 2.9 times after 12 months (p<0.001). The increase in mean corpuscular volume was greater in the first year (p<0.001) than in the second year (p=0.041). The decrease in leukocytes (p<0.001) was significant during the first year. In 70% of patients, the 20mg/kg/day dose was needed to reach the 20% HbF threshold. Conclusion: HU is effective and well tolerated. The magnitude of the response varies from one patient to another. Improvement of clinical manifestations is achieved in most patients with a relatively low dose. Effective implementation of HU treatment will require improved adherence to treatment.

Effect of a Physical Exercise Program on the Inflammatory Response, Cardiac Functions, Functional Capacity, and Quality of Life in Patients with Sickle Cell Disease.

The beneficial effects of physical exercise on functional capacity and inflammatory response are well-known in cardiovascular diseases; however, studies on sickle cell disease (SCD) are limited. It was hypothesized that physical exercise may exert a favorable effect on the inflammatory response of SCD patients, contributing to an improved quality of life. This study aimed to evaluate the effect of a regular physical exercise program on the anti-inflammatory responses in SCD patients. A non-randomized clinical trial was conducted in adult SCD patients. The patients were divided into two groups: 1-Exercise Group, which received a physical exercise program three times a week for 8 weeks, and; 2-Control Group, with routine physical activities. All patients underwent the following procedures initially and after eight weeks of protocol: clinical evaluation, physical evaluation, laboratory evaluation, quality of life evaluation, and echocardiographic evaluation. Comparisons between groups were made using Student's t-test, Mann-Whitney test, chi-square test, or Fisher's exact test. Spearman's correlation coefficient was calculated. The significance level was set at p < 0.05. There was no significant difference in inflammatory response between the Control and Exercise Groups. The Exercise Group showed an improvement in peak VO2 values (p < 0.001), an increase in the distance walked (p < 0.001), an improvement in the limitation domain due to the physical aspects of the 36-Item Short Form Health Survey (SF-36) quality of life questionnaire (p = 0.022), and an increase in physical activity related to leisure (p < 0.001) and walking (p = 0.024) in the International Physical Activity Questionnaire (IPAQ). There was a negative correlation between IL-6 values and distance walked on the treadmill (correlation coefficient -0.444, p = 0.020) and the estimated peak VO2 values (correlation coefficient -0.480; p = 0.013) in SCD patients in both groups. The aerobic exercise program did not change the inflammatory response profile of SCD patients, nor did it show unfavorable effects on the parameters evaluated, and patients with lower functional capacity were those with the highest levels of IL-6.

Malignancy in patients with sickle cell disease: A single center experience.

e22551 Background: The development of malignancy in patients with sickle cell disease has been documented in multiple case reports and case series. The incidence of malignancy in patients with sickle cell disease is unknown. Large national databases like the National Cancer Database, North American Association of Central Cancer Registries, and SEER do not collect data on the presence of sickle cell disease. This has made it difficult to calculate the incidence of malignancy in this patient population. In our study, we aim to calculate the prevalence of malignancy in sickle cell patients following our institution. Methods: After IRB approval, a retrospective analysis was conducted of adult sickle cell disease patients being followed at our Hematology outpatient clinic. We included patients aged &gt; / = 18 years with sickle cell disease (HBSS, HBSC, HBS-beta thalassemia) as per hemoglobin electrophoresis, who were followed at the clinic from 1/1/2017 to 10/1/2022. We excluded prisoners. We did an extensive chart review to identify patients with a diagnosis of malignancy by pathology. Variables of age, sex, race, type of sickle cell disease, type of malignancy, age at the diagnosis of malignancy, and treatment were collected. Continuous descriptive data were summarized as means. Categorical data were summarized with a sample percentage. The prevalence of malignancy was calculated. SAS for windows 9.4 was used for analysis. Results: 438 patients with sickle cell disease were identified from 2017 to 2022. All the patients were African American. Their ages ranged from 16 to 84 with a mean of 35 years. Of these patients 53 % were females and 47 % were male. 62% had HBSS disease, 25 % had HBSC and 13% had HBS beta thalassemia genotype. 4 patients were diagnosed with malignancy. All 4 patients were female. The prevalence of malignancy was calculated as 0.91%. Conclusions: We found four patients with malignancy in the patient population with sickle cell disease at our hematology clinic. This data is based on limited sample size. The incidence of malignancy in sickle cell patients should be calculated in a larger population base. Further studies can be done to determine if a single type of sickle cell genotype increases the risk of malignancy. All the centers where sickle cell patients are followed should monitor the patients prospectively for the development of malignancy.[Table: see text]

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

Self-management for sickle cell disease among patients and parents: A qualitative study.

This study aimed to explore self-management practices among patients and parents of children with sickle cell disease (SCD). The qualitative descriptive design was employed. The study involved 19 participants comprising adult SCD patients ≥16 years, and nine parents of SCD children ≤ 15 years. Purposive sampling was conducted to select participants from a teaching hospital and SCD association. Data was collected using one-on-one interviews, transcribed verbatim, and analysed using qualitative content analysis. Self-management was reported through four categories including preventive health, self-monitoring, self-diagnosis, and self-treatment. Hydration, nutrition, activity limitation, avoidance of cold temperatures, and supportive medications were the most common preventive health actions. Regarding self-monitoring and self-diagnosis, the parents emphasized objective indicators such as changes in urine and eye colour compared to the adults who utilize subjective indicators such as feeling unwell and easy fatigue. Pharmacological and non-pharmacological measures were reported by both groups for treating painful episodes, fever, leg ulcers, priapism, and unspecified symptoms. The participants in this study practice several self-management actions with some differences in application between adults and children. Tailored self-management services may be helpful for adults and children when developing services for SCD patients.

5606726 IMPACT OF ALLOGENEIC STEM CELL TRANSPLANTATION ON PHYSICAL, MENTAL, AND SOCIAL HEALTH OF ADULT SICKLE CELL DISEASE PATIENTS: A MIXED-METHODS STUDY

Background: Sickle cell disease (SCD) is characterized by chronic hemolytic anemia and recurrent painful vaso-occlusive crises, resulting in considerable physical and psychosocial disease burden and early mortality. In recent years, the application of allogeneic hematopoietic stem cell transplantation (HSCT) as a curative treatment for adult SCD patients has increased. As a result, a deeper understanding of the complex relationship between physical, mental, and social health before and after curation is needed. Aim: To explore the experiences and perspectives of adult SCD patients on the impact of HSCT on their physical, mental, and social health. Methods: A mixed methods study design, consisting of a semi-structured interview and completion of 9 Patient Reported Outcomes Measurement Information System (PROMIS®) item banks per participant was used. Adult SCD patients who underwent HSCT ≥ 1 year ago at the Amsterdam University Medical Center were eligible to take part in this study. Interviews were recorded, transcribed verbatim, and thematically analyzed using MAXQDA® software. Standardized T-scores of PROMIS® measures were evaluated and compared to reference scores of the Dutch general population. Results: Ten SCD patients with a median age of 29,5 years (range 19-49) were included in the study and interviewed between October 2021 and May 2022. Median time since HSCT was 2.7 years (range 1 - 3.5). All patients had successful engraftment. Relevant themes were (1) pain/living pain free, (2) physical wellbeing, (3) mental wellbeing, (4) perspective/outlook, (5) education and work, (6) family and friends and (7) activities and participation. Living pain free and the emergence of a future perspective were major improvements for most participants which resonated strongly in their daily lives. Nevertheless, emotional struggles with processing the impact of having had SCD on the one hand, while adjusting to the novel circumstances on the other hand, were common among participants. Before and after HSCT, participants experienced a lack of psychological help. Two patients with ongoing pain from avascular bone necrosis had mixed feelings about the success of the transplant. These two patients scored within the mild, moderate, or severe symptom category on ≥ 7 of 9 PROMIS® item banks. While mean PROMIS® T-scores of all participants fell within the reference values of the general population (Figure 1), a large variation between patients was observed which matched with our findings from the qualitative data. Conclusions: Adult SCD patients experience significant improvements in many aspects of their physical, mental, and social health after cure by HSCT. Yet, they are confronted with a new and often unfamiliar reality, which carries different challenges. Pain as a result of irreversible complications of SCD continues to have a negative impact on quality of life after HSCT. Clinicians should acknowledge these challenges and aim at creating realistic expectations in future transplant candidates. Moreover, patients expressed a need for tailored psychological care, which should be offered before and after HSCT.

5610614 ASSESSING PHYSICAL, SOCIAL AND EMOTIONAL IMPACT OF SICKLE CELL DISEASE IN PORTUGUESE PATIENTS: AN OBSERVATIONAL, MULTICENTER STUDY (ASCEND)

Background: Sickle cell disease (SCD) is a chronic, multisystem autosomal recessive blood disorder that is characterized by painful episodes caused by vaso-occlusion. SCD patients can face social, economic and academic challenges, as well as barriers to accessing quality heath care. Evidence about the impact of SCD and related treatments on the lives of patients is lacking, with a broad definition of health as a combination of physical, mental and social well-being. The purpose of this observational study is to characterize the physical, social and emotional impact of SCD on adult patients with confirmed diagnosis and to characterize patient pathway in the healthcare system. Objectives: The primary objective of ASCEND is to characterize the physical impact of SCD on patients, through collection of PROs that will assess the impact of pain and disease complications in patients’ QoL. As secondary objectives the study aims to characterize SCD patients’ demographics and clinical history, as well as to describe the social and emotional impact of SCD on patients; to describe SCD patient pathway in the healthcare system. In this abstract the authors intend to describe the results obtained for QoL assessment through PRO questionnaires Methods: ASCEND is non-interventional cross-sectional study of 2 cohorts of SCD adult patients with SCD. The study sample is 200 (recruited by hospital sites) + 50 patients (recruited by patient association). PRO questionnaires include both EQ-5D-5L and ASCQ-Me (Pain Episodes Frequency and Severity). Portuguese patients and Social Studies investigators participated in the validation process. Results: Study recruitment is terminating in the current week as 194 have been included already. We expect to have QoL results evaluated through EQ-5D-5L and ASQC-Me for 200 patients by mid September 2022, in due time to be presented in ASCAT. Conclusions: Conclusions will be elaborated upon data analyses

Acute chest syndrome in adult patients with sickle cell disease: The relationship with the time to onset after hospital admission.

Data on acute chest syndrome (ACS) in adult sickle cell disease patients are scarce. In this study, we describe 105 consecutive ACS episodes in 81 adult patients during a 32-month period and compare the characteristics as a function of the time to onset after hospital admission for a vaso-occlusive crisis (VOC), that is early-onset episodes (time to onset ≤24 h, 42%) versus secondary episodes (>24 h, 58%; median [interquartile range] time to onset: 2 [2-3] days). The median age was 27 [22-34] years, 89% of the patients had an S/S or S/β0 -thalassaemia genotype; 81% of the patients had a history of ACS (median: 3 [2-5] per patient), only 61% were taking a disease-modifying treatment at the time of the ACS. Fever and chest pain were noted in respectively 54% and 73% of the episodes. Crackles (64%) and bronchial breathing (32%) were the main abnormal auscultatory findings. A positive microbiological test was found for 20% of episodes. Fifty percent of the episodes required a blood transfusion; ICU transfer and mortality rates were respectively 29% and 1%. Secondary and early-onset forms of ACS did not differ significantly. Disease-modifying treatments should be revaluated after each ACS episode because the recurrence rate is high.

Impact of Vitamin D in the improvement of respiratory function in sickle cell disease adult patients

Abstract The study aimed to discover the role of vitamin D in improving the respiratory function in sickle cell disease patients. In this prospective study, 188 adults were enrolled, drawn from the out-patients unit of Thalassemia Cente The collected data were categorized into three groups: group 1 included the data of 100 healthy individuals of age range of 18-50 years as control; group 2 included the data of 88 (40 males and 48 females) sickle cell disease patients in steady state before supplementation of vitamin D; group 3 represented the data of the same 88 sickle cell disease patients as measured and recorded after 6 weeks of vitamin D supplementation. Laboratory measurements including pulmonary function tests and hematological parameters, while vitamin D levels were estimated for all groups to compare the data before and after supplementation of vitamin We found significant differences in the pulmonary function tests when comparing groups. Mean value of FEV1 revealed significant differences between group 1 and 2 (p &gt;0.05), while vitamin D supplement created a significant difference between group 2 and 3 (p &gt;0.05). The improvement in FEV1 did not reach to that of healthy (group 1), as referred by the significant variation between group 1 and group 3 (p&gt;0.05). The same findings were indicative within most pulmonary function tests, and the percentages of combined cases (restrictive and obstructive) were also deceased in group 3. Conclusion: supplement of vitamin D in SCD patients could result in relative improvement in lung function.

Near-Infrared Spectroscopy Demonstrates the Benefit of Erythracytapheresis in Sickle Cell Disease Adult Patients with Cerebral Vasculopathy.

Cerebral vasculopathy can induce chronic cerebral hypoperfusion leading to stroke in patients with sickle cell disease (SCD) and is treated by blood exchange transfusion (BET). However, no prospective clinical study has demonstrated the benefit of BET in adults with SCD and cerebral vasculopathy. Near Infrared Spectroscopy (NIRS) is a recent non-invasive method complementary to Magnetic Resonance Imaging (MRI). We evaluated cerebral perfusion using NIRS during erythracytapheresis in patients with SCD with and without steno-occlusive arterial disease. We conducted a monocentric, prospective study in 16 adults with SCD undergoing erythracytapheresis in 2014. Among them, 10 had cerebral steno-occlusive arterial disease. NIRS measured the relative amounts of oxyhemoglobin (OxyHb), deoxyhemoglobin (DeoxyHb) and total hemoglobin (Total Hb) in brain tissue and in muscle. In cerebral hemispheres associated with steno-occlusive arterial disease, we observed a significant increase of OxyHb and Total Hb during BET, without modification of DeoxyHb. Using NIRS during BET showed that BET improves cerebral perfusion in adult patients with SCD with cerebral vasculopathy.