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The Epidemiology of Neurological Complications in Adults With Sickle Cell Disease: A Retrospective Cohort Study
Introduction: Risk factors for neurological complications in sickle cell disease differ in the adult and pediatric populations. Here, we focused on neurological complications in adults with sickle cell disease.Methods: Patients were selected using the audit data from the St George's Hospital Red Cell Database. The genotyping, demographics, clinical data, and investigation findings were collected.Results: A total of 303 patients were enrolled in the study: hemoglobin S homozygosity (HbSS) genotype 56%, hemoglobin S and C coinheritance (HbSC) genotype 35%, and hemoglobin S and β-thalassemia coinheritance (HbSβ) thalassemia genotype 9%; the mean age was 38.8 years (±13.5 SD) with 46% males. The most common neurological complication was cerebrovascular disease (n = 37, 12%) including those with ischemic stroke (10%), cerebral vasculopathy (3%), and intracranial hemorrhage (1%). Ischemic stroke was common among the HbSS genotype compared with other genotypes (8 vs. 1.6%, p = 0.001). Comparing the patients with sickle cell disease who had suffered a stroke to those who had not, there was a higher proportion of intracranial vasculopathy (p = 0.001, in particular, Moyamoya) and cognitive dysfunction (p < 0.0001).Conclusion: Our cohort supports previous reports that the most common neurological complication in adult sickle cell patients is cerebrovascular disease. Strategies to prevent cerebral vasculopathy and cognitive impairment should be explored.
Abstract Background: Adult sickle cell patients on chronic transfusion therapy (CTT) garnered special concern during the COVID-19 pandemic, when mass cancellation of blood drives threatened the national blood supply. In response, the American Society of Hematology proposed several strategies to decrease blood utilization, while maintaining adequate disease control for sickle cell patients on CTT. These included targeting a higher end hemoglobin S%, switching patients to simple transfusions when appropriate, and transitioning to alternative disease modifying therapies. There is little evidence to support the safety of altering exchange therapy regimens. Accordingly, at the Johns Hopkins Sickle Cell Center for Adults, a multidisciplinary team of clinicians and transfusion medicine specialists evaluated patients on a case by case basis to determine how their exchanges could be modified to accommodate for anticipated blood supply shortages. We describe our blood conservation efforts during the COVID-19 pandemic and resulting clinical outcomes for adult patients with sickle cell anemia (SCA). Methods: For inclusion in this IRB-approved retrospective study, patients received at least 7 monthly exchange transfusions between March 2019 and February 2020 and continued care through March 2021. Decisions regarding CTT were made prior to data collection. Modifications to chronic exchanges included increasing the fraction of cells remaining (FCR), decreasing the end hematocrit, or switching to a hemodilution method. Additionally, select patients transitioned to monthly simple transfusions if they were clinically stable, had a hemoglobin ≤ 7 g/dL, and had a persistently suppressed hemoglobin S% (≤ 30). We collected basic demographics, pre-exchange laboratory studies, and exchange parameters before and after each transfusion encounter in the year before (March 2019 - February 2020) and during (March 2020 - February 2021) the COVID-19 pandemic. Lastly, we recorded presentations to urgent care and the emergency department; and hospital admissions during each time period. We reported descriptive statistics for the cohort and compared outcomes using the Wilcoxon signed-rank test and Mann Whitney U test. We analyzed data using Stata/SE Version 16.1. Results: We identified 58 patients with SCA who qualified for inclusion (Table 1). Fifty-three patients remained on chronic exchange transfusions during the pandemic, and five were switched to simple transfusions. For patients who remained on chronic exchanges, most received conventional automated red cell exchange (RCE) prior to (85%) and during the pandemic (77%). Use of hemodilution increased (15% to 23% of patients). Forty-three patients experienced an increase in mean FCR (33.6 (SD 11.6) vs 37.7 (4.7), p = .00). Of those, 22 patients saw a concomitant decrease in mean end hematocrit (30.8 (1.7) vs 29.6 (1.1), p = .00). These changes resulted in a decline in the average number of units per procedure (8.6 (1.9) vs 7.3 (1.7), p = .00), which corresponded to 890 units conserved. Mean pre-transfusion hemoglobin values declined (9.4 (1.3) vs 9.2 (1.3), p = 0.01), but hemoglobin S%, reticulocyte count, and ferritin values were unchanged (p > 0.05). Acute care presentations and hospital admissions declined, which were likely spurred by concerns about COVID-19 infection (Table 2, p < 0.05). During the pandemic, three patients died, one of whom had been switched to simple transfusions. This patient experienced a consistent rise in hemoglobin S% until death. Two of the remaining patients on simple transfusions were switched back to automated RCE due to an increase in hemoglobin S% above goal (Figure 1). Conclusions: During the COVID-19 pandemic, we conserved red blood cell units through expanded use of hemodilution, higher FCR values, and switching some patients to simple transfusions. Patients who remained on exchanges maintained hemoglobin S% values near a goal of 30% without increasing iron burden. In contrast, the majority of patients who were switched to simple transfusions were unable to maintain goal hematologic parameters, and one patient died. Our data suggest that in a blood shortage crisis, changing the exchange procedure itself may be the safest means of conserving blood in a population of adult sickle cell patients; however longer follow-up is needed to ensure that these changes are safe. Figure 1 Figure 1. Disclosures Lanzkron: GBT: Research Funding; Shire: Research Funding; Novo Nordisk: Consultancy; CSL Behring: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company; Novartis: Research Funding; Imara: Research Funding; Bluebird Bio: Consultancy.
Abstract Background: Erythrocytapheresis or red cell exchange (RCE) is an invaluable treatment option for patients with complications related sickle cell disease, including acute stroke, stroke prevention, acute chest syndrome, and recurrent pain crisis. The procedure entails the removal of each patient's red blood cells containing the abnormal sickle hemoglobin and replacing them with normal red blood cells carrying non-sickled hemoglobin. Adequate vascular access is essential for erythrocytapheresis to allow for high flow rates and various forms of access are used including peripheral veins and central venous access devices. Our center typically uses a single vortex port (Angiodynamics, Walnut Creek, CA) with placement of a peripheral IV at time of procedure in order to maintain a circuit for exchange. Using peripheral access reliably becomes particularly difficult in young patients and those that require multiple access over time due to scaring. To ensure a successful procedure in patients with poor peripheral access, a single-needle (SN) option for TPE (SN-TPE) that is available on Spectra Optia (Terumo BCT, Lakewood, CO) was used. The single-needle procedure utilizes intermittent, rather than continuous, flow, and thus requires extra procedure run time. One discontinuous cycle consists of "exchanging red cells," which is the drawing of blood and removal of the red cells, and "adjusting the volume in the reservoir," which is the returning of blood. These cycles continue until the procedure is complete. This procedure allows us to continue RCE in a select number of patients with poor vascular access. Methods: We evaluated our institutional experience on patients treated using single-needle RCE. In addition, information regarding each RCE session was collected including duration of procedure and inlet flow rate. Results: An average of 45 RCE procedures are performed each month. Patients are scheduled every 3 to 8 weeks, with an average of every 4-5 week frequency. We started the Single Needle option in July of 2019 on 3 patients: one adult aged patient and 2 pediatric patients. By the end of 2019 we had perform a total of 27 SN procedures. In 2020, we performed a total of 112 SN procedures, average of 9 procedures each month. As of the first 6 months of 2021, we have completed 35 SN procedures, averages 6 a month. In patients undergoing single needle exchange we were able to increase inlet flow rates from an average of 30-50ml/min to 60-80ml/min. This decreased the duration of run times from 120-198 min to 77- 119 min. Pre and post hemoglobin S% was comparable between dual and single exchange patients and there was no change in the interval between RCE sessions. Conclusion: With our increasing experience with single-needle RCE, our findings suggest that RCE can be successfully completed using the single-needle option with no impact on pre- and post-exchange hemoglobin S% levels. There was a reduction in the total length of procedure due to ability to maintain higher inlet rates and decreased time to obtain access for RCE. The single needle option also improved patient satisfaction due to more reliable access and negating need for peripheral IV access. Disclosures Munson: Terumo Medical Corporation: Consultancy, Honoraria, Speakers Bureau. Raj: Forma therapeutics: Consultancy; Terumo Medical Corporation: Honoraria, Speakers Bureau; Global biotherapeutics: Speakers Bureau.
Abstract Background: Chronic transfusion therapy in sickle cell disease is used to prevent complications of sickle cell disease by reducing hemoglobin S levels, most commonly used for primary or secondary stroke prophylaxis, amongst other indications. Transfusions can be completed as simple, partial manual exchange or automated exchange.Comparative evidence on the long term efficacy of simple, partial manual or automated exchange in the management of children with sickle cell disease is lacking. Methods: A retrospective study of patients aged less than 18 years with a diagnosis of sickle cell disease on a chronic transfusion program (simple top-up transfusion, partial manual exchange or automated exchange transfusion), followed at the Hospital for Sick Children, Toronto, Ontario from January 2003- July 2020.We excluded patients who received transfusions for acute complications. Data collected included: demographics, indication for transfusion, type of transfusion (simple, partial manual exchange or automated exchange), access for transfusion (peripheral intravenous (PIV), central venous line (CVL)), pre-transfusion hemoglobin and hemoglobin S values. Analysis: Exploratory data analysis was conducted where descriptive statistics were used to summarize data for both continuous and categorical variables. Continuous variables were summarized using measures of central tendency and dispersion where mean and standard deviations for normally distributed data and medians and interquartile ranges were used where the data was skewed. Chi-squared tests were employed when demonstrating relationships between two categorical variables. All statistical analyses were two-sided tests with 0.05 as the critical level of significance. Ethics: This study was approved by The Hospital of Sick Children Research Ethics Board(REB). Results: Sixty-one participants were observed between January 2003 and July 2020. Majority 38 out of (62.3%) of the participants were male. The most common indication for transfusion was primary stroke prevention (following abnormal transcranial doppler (TCD) 36 %) followed by vasculopathy 11 (%, stroke 9 % , abnormal TCD & silent infarct 8 %, and splenic sequestration 2 %) There were 744 total transfusions. 491/744 (66%) transfusions were simple transfusions, 168/744 (22.6%) were PMEs while 85/744 (11.4%) were apheresis transfusions. Average pre-transfusion hemoglobin S (HbS) was similar between the two types of access (p=0.416) and also across the three types of transfusion (p=0.158). The type of access did not appear to have an effect on the changes in HbS per transfusion(p=0.561.) The trends of pre-transfusion HbS %were similar over time between participants whose access was PIV and those whose access was CVL/ PORT.(Figure 1 below). Achievement of target HbS was similar between peripheral intravenous and central venous line access (p=0.337) and across the three types of transfusion (p=0.086).See Table 1 below. The type of transfusion had an effect on the reduction in HBS with simple transfusion having the highest percentage change of HbSS(-3.69%) followed by Apheresis (-1.32%) and PME (-0.75%), p=0.018., that is per every transfusion. The reason for this is that is the values being compared are quite different. The automated exchange values are on established patients (pre transfusion hemoglobin S had already been lowered), while the simple transfusion values are on new to transfusion patients (pre transfusion S high), the patients on partial manual exchange started off with lower HbS levels, so consequently their change was less. Conclusion: All three types of transfusion had equal efficiency in reducing HbS over time. Apheresis showed a quicker reduction in the hemoglobin S level in the initial transfusions. Simple transfusions and PME are as efficient as apheresis in achieving target HbS levels to prevent complications associated with SCD. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
Abstract Hemoglobin S (HbS) beta thalassemias (thal) are types of sickle cell disease (SCD) that result from the inheritance of one HbS gene and one β thalassemia gene. Red Blood Cell (RBC) alloimmunization is believed to be a major complication of transfusion therapy for HbS-thal patients. Indeed, among SCD patients generally, alloimmunization not only complicates the procurement of blood, but can also lead to life threatening delayed hemolytic transfusion reactions, and can be associated with a host of negative health outcomes including a higher risk of death. It is generally accepted that some alloimmunization events can be prevented via donor-recipient antigen matching, although this strategy is associated with higher costs and utilization of scarce resources (i.e.. antigen negative RBC units). The present study aimed to assess the clinical and economic implications of alloimmunization in HbS-thal patients. The Premier Hospital chargemaster dataset was used to perform a cross-sectional study matching alloimmunized and non-alloimmunized patients based on sex, age, date of admission, and type of visit (outpatient vs. inpatient). All outpatient and inpatient discharges from Jan 2015 to Jun 2019 were included in the study. Because there is not a specific laboratory code to designate alloimmunization, presence of both "antiglobulin crossmatch" and "RBC antibody identification" codes in a record was used as a surrogate for alloimmunization. Accuracy of this approach was validated by comparing the frequency of these codes among the hereditary hemorrhagic telangiectasia (HHT) and myelodysplastic syndromes (MDS) populations within the Premier dataset to the reported rates of alloimmunization for these entities in the medical literature (Zheng Transfusion. 2018;58(3):775-780, Singhal Haematologica. 2017;102(12):2021-2029). This comparison predicted a 16.8% alloimmunization rate in the HHT population (similar to the 15.3% reported in the literature) and an 11.5% alloimmunization prevalence in the MDS population (similar to the 11% reported in the literature). HbS-thal patients were identified based on diagnostic coding (ICD-10 code D57.4). Demographic, clinical and billing characteristics were retrieved. Cost per outpatient and inpatient discharge, hospital and intensive care unit (ICU) length of stay (LoS) and inpatient mortality were assessed for both alloimmunized and non-alloimmunized HbS-thal patients. Bivariate comparisons were performed, assuming a two-tailed test of significance and an α level of 0.05. Multivariable regression models adjusting for diagnosis-related groups with ≥1% incidence were performed. This approach permitted a total of 999 discharges corresponding to alloimmunized HbS-thal patients (cases) to be matched to 550 HbS-thal controls. Mean (SD) age was 35.1 (18.8) and 30.1 (18.6) for cases and controls, respectively. The percentage of females was slightly higher within the alloimmunized group (63.66% vs. 57.45%), and higher rates of inpatient visits were observed for the alloimmunized population compared to controls (67.9% vs. 33.1%). The multivariate models showed that alloimmunized HbS-thal patients presented significantly worse economic and clinical outcomes compared to their non-alloimmunized controls through all variables assessed. Median cost per discharge was $5,313 (p<0.0001) higher for alloimmunized inpatients and $1,014 (p<0.0001) higher for alloimmunized outpatients, compared to non-alloimmunized controls. Alloimmunized HbS-thal patients also experienced a 63% increase in hospital LoS (4.5 vs 7.4 days;; p<0.0001) and nearly over a 2.5-fold increase in ICU LoS (4.2 vs 10.0 days; p=0.0257). Alloimmunization in this population was also associated with a 3-fold increased risk of admission to intensive care (p=0.0032), longer stays in the ICU (p-0.0257), and a 3-fold increase in inpatient death (p<0.0001) (Table 1). The present study reveals that alloimmunization is associated with significantly longer hospitalizations and ICU stays, higher risk of ICU admission, greater inpatient death, and higher healthcare costs among patients with ICD-10 diagnosis of HbS-thal. These data seem to support the incremental costs and resource allocation decisions required to provide prophylactic antigen matching to HbS-thal patients, in an effort to diminish the risk of alloimmunization. Figure 1 Figure 1. Disclosures Gehrie: Grifols SSNA: Consultancy, Honoraria. Viayna: Grifols S.A.: Current Employment. Blanchette: Grifols SSNA: Consultancy; Novo Nordisk Inc.: Current Employment. Meny: Grifols SSNA: Current Employment. Noumsi: Grifols SSNA: Current Employment. Huber: Grifols SSNA: Current Employment. Runken: Grifols SSNA: Current Employment.
Abstract Background SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β- globin gene, with either homozygous inheritance, or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. This point mutation results in the production of hemoglobin S, which polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. In addition to VOEs, patients with SCD may experience severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. The current treatment strategy for patients with SCD includes hydroxyurea, along with newer treatments such as L-glutamine, crizanlizumab, and voxelotor. However, despite the availability of these treatments, considerable morbidity and mortality among patients with SCD represents a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crisis, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. Crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety in a Phase I/II study (Röth et al. Blood 2020), in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder. Study Design and Methods CROSSWALK-c (NCT number pending) is a placebo-controlled, randomized, double-blind, Phase IIa study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0), and presenting with ≥ 2 to ≤ 10 VOEs are eligible for this study. Patients on concurrent SCD-directed therapies are also eligible. Vaccination against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumonia are required for enrollment. Patients with a history of hematopoietic stem cell transplant are excluded from the study. Eligible patients will be randomized 1:1 to the crovalimab or placebo treatment arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be administered on Day 1 Week 1, followed by four weekly SC doses on Day 2 Week 1, and then on Weeks 2-4. Maintenance dosing will be administered from Week 5, followed by once every 4 weeks thereafter, for 48 weeks. All patients will receive study treatment according to a weight-based tiered dosing schedule. The primary objective is to evaluate the efficacy of crovalimab compared with placebo, based on the annualized rate of medical facility VOEs. Secondary efficacy objectives include the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin-creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetics, immunogenicity, and exploratory biomarker objectives will also be evaluated. Figure 1 Figure 1. Disclosures Callaghan: Agios Pharmaceuticals: Current Employment; Roche/Genentech: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy, Speakers Bureau; Forma: Consultancy; Hema Biologics: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; BioMarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Chiesi: Consultancy; Kedrion: Consultancy; Pfizer: Consultancy. Ataga: Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: CSL Behring: Other: Endpoint adjudicator ; Forma: Consultancy; Novo Nordisk: Consultancy; Chiesi: Consultancy; Bluebird Bio: Other: Endpoint adjudicator ; Novartis: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy. Balachandran: F. Hoffmann-La Roche Ltd: Current Employment. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Perretti: F. Hoffmann-La Roche Ltd: Current Employment. Ramos: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Bartolucci: Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; INNOVHEM: Other: Co-founder; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Hemanext: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy.
Abstract Background SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. Despite the majority of VOEs being managed at home, they remain the most common reason for emergency department (ED) visits and hospitalization among patients with SCD, with > 70% of ED visits and > 90% of hospital admissions for SCD being related to VOEs (Ballas et al. Am J Hematol 2005; Lanzkron et al. Am J Hematol 2010). One of the most severe complications of VOEs is acute chest syndrome, which is a leading cause of mortality among patients with VOEs (Vichinsky et al. N Engl J Med 2000; Bartolucci et al. eBioMedicine 2016). In the absence of targeted therapies for the management of VOEs in patients with SCD, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, representing a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crises, and in patients with delayed hemolytic transfusion reaction. Accumulating nonclinical data have suggested a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase I/II study (Röth et al. Blood 2020) in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety. Study Design and Methods CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase Ib study evaluating the safety of crovalimab for the management of acute uncomplicated VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0) are eligible for the study (Figure). Patients must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be up to date. Eligible patients will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. Patients in both study arms will continue to undergo pain management and receive other supportive care for their VOE and may also continue to receive ongoing concurrent SCD-directed therapies. Patients will be followed during the hospitalization until discharge and will continue to be followed post-discharge during an observational period. The maximum total study duration for an individual patient will be 12 weeks, which includes the hospitalization and observational periods. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Figure 1 Figure 1. Disclosures Bartolucci: F. Hoffmann-La Roche Ltd: Consultancy; Bluebird: Consultancy, Research Funding; Emmaus: Consultancy; Hemanext: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; GBT: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; INNOVHEM: Other: Co-founder; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Ataga: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Callaghan: Alnylum: Current equity holder in publicly-traded company; Roche/Genentech: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; Pfizer: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; uniQure: Consultancy; Spark: Consultancy; Biomarin: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Forma: Consultancy; Chesei: Consultancy; Agios Pharmaceuticals: Current Employment. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: F. Hoffmann-La Roche: Consultancy; Bluebird Bio: Other: Endpoint adjudicator; Forma: Consultancy; GBT: Consultancy; Novo Nordisk: Consultancy; CSL Behring: Other: Endpoint adjudicator; Novartis: Consultancy; Chiesi: Consultancy. Alexandrou: F. Hoffmann-La Roche Ltd: Consultancy, Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Fox: Parexel International: Current Employment; Genentech, Inc.: Current Employment. Patel: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment.
Abstract Introduction/Objective Quantitation by high-performance liquid chromatography (HPLC) of hemoglobin %A2 is often not used in evaluation for thalassemia of hemoglobin S-trait patients, due to analytical interference from glycated hemoglobin S1d to increase %A2. In contrast, an increase in %A2 for S-trait when measured by capillary electrophoresis (CE) has been reported, without known analytical interference. This observation has not been re- evaluated in modern versions of CE, however. For validation exercises associated with startup of CE at our institution, we compared distributions of %A2 among A patients and S-trait patients using Sebia “Capillarys® 2” CE. Methods/Case Report %A2 is provided in two Sebia “Capillarys® 2” methods: analysis of A1c (method 1, M1) and analysis of hemoglobin variants (method 2, M2). To minimize effect of potential preselection for thalassemia among M2 samples, we first evaluated distributions of %A2 for A and S-trait among M1 samples. We then evaluated correlation of A2 measurements between M1 and M2. Statistical analyses were conducted using R programming. Results (if a Case Study enter NA) Using M1, %A2 for S-trait patients (2.61±0.31%, n=116) was higher than for A patients (2.11±0.27%, n=108) (p<0.001), with difference=0.42-0.57 %A2 (95% confidence interval, CI). %A2 by M1 was consistently less than %A2 by M2, for both A and S-trait (p>0.25): for A, M1/M2=0.89±0.05 (n=35); for S-trait, M1/M2=0.88±0.05 (n=32). Decreased %A2 by M1 compared to M2 may in part be due to separation in M1 of a glycated form of A2. Using M2, %A2 for S-trait patients (3.05±0.29%, n=32) was higher than for A patients (2.41±0.29%, n=35) (p<0.001), with difference=0.50-0.76 %A2 (CI). M2 results were consistent with M1 data when combined with the observed M1/M2 ratios. Conclusion Results suggest a physiological increase in %A2 in S-trait patients compared to A patients, not likely to be attributable to thalassemia. The average increase is ~0.6 %A2 for hemoglobin variant analysis by CE.
Sickle cell disease is an inherited hemoglobinopathy leading to the synthesis of hemoglobin S. Hemoglobin S results in the formation of abnormal sickle-shaped erythrocytes that lead to hematologic abnormalities such as hemolytic anemia and increased risks of thrombosis. Another particular problem encountered with the disease is pulmonary hypertension. The objective of this narrative review is to discuss the prevalence, pathophysiology mechanisms, diagnostic techniques, treatment options, and prognostic indicators in the setting of sickle cell disease with pulmonary hypertension. Additionally, the review also highlights other advancements that are being investigated. Considering the significant morbidity, mortality, and prevalence of pulmonary hypertension in patients with sickle cell disease, it is important to account for the aforementioned domains in the future guidelines to provide optimal and individualized care to the high-risk individuals as well as reduce the progression of disease, morbidity, and mortality rates.
A anemia falciforme (AF) é uma doença autossômica recessiva, que leva à produção de hemoglobina anormal, denominada hemoglobina S (HbS). Seus portadores sofrem com o crescimento deficiente, desde a infância, além de disfunções endócrinas, baixo consumo alimentar, alto requerimento energético, deficiência de minerais, que podem resultar em desnutrição. Durante a gestação, está associada ao aumento de complicações relacionadas à própria doença, morbimortalidade materna e perinatal mais elevada, nascimento de crianças com baixo peso e maiores taxas de complicações infecciosas puerperais. O objetivo do estudo foi buscar, através de uma revisão integrativa, esclarecer sobre o estado nutricional e as complicações clínicas de gestantes com anemia falciforme. Para tanto, realizou-se um estudo exploratório, por meio de pesquisa bibliográfica. Sendo a seleção e a localização das referências retiradas das bases de dados PubMed/LILACS, Plos One e da biblioteca eletrônica SciELO, utilizando também a Biblioteca Virtual em Saúde (BVS), a fim de identificar artigos científicos publicados no período entre 2008 e 2020, utilizando os seguintes descritores: anemia falciforme e intercorrências obstétricas; anemia falciforme e gestante; hemoglobina S e gestante e versões em inglês. Verificou-se que gestantes portadoras de anemia falciforme possuem maior propensão a complicações, como aborto espontâneo, crescimento intra-uterino restrito, aumento da mortalidade fetal intra-útero, recém-nascido de baixo peso, trabalho de parto pré-termo, somados à deficiência de macro e micronutrientes durante o período gestacional, podendo chegar à desnutrição materna e à morbimortalidade materna e neonatal. Em suma, a suscetibilidade à desnutrição materna, infecções, complicações hemolíticas e vaso-oclusivas de gestantes com anemia falciforme mostrou-se um prognóstico desfavorável, trazendo consigo complicações para a mãe e o neonato. Reforçando a importância do acompanhamento nutricional como estratégia de prevenção e orientação relativas às alterações nutricionais das gestantes portadoras da doença, como alternativa para a minimização dos resultados adversos e garantir melhoria da saúde materna e fetal. Sickle cell anemia (SCA) is an autosomal recessive disease that leads to the production of abnormal hemoglobin called hemoglobin S (HbS). Their carriers suffer from deficient growth, since childhood, in addition to endocrine dysfunction, low food consumption, high energy requirement, mineral deficiency, which can result in malnutrition. During pregnancy, it is associated with an increase in complications related to the disease itself, higher maternal and perinatal morbidity and mortality, birth of low birth weight children and higher rates of puerperal infectious complications. The aim of the study was to seek, through an integrative review, to clarify the nutritional status and clinical complications of pregnant women with sickle cell anemia. For that, an exploratory study was carried out, through bibliographical research. With the selection and location of references taken from the PubMed/LILACS, Plos One and SciELO electronic library databases, also using the Virtual Health Library (VHL), in order to identify scientific articles published in the period between 2008 and 2020, using the following descriptors: sickle cell anemia and obstetric complications; sickle cell anemia and pregnant women; hemoglobin S and pregnant women and English versions. It was found that pregnant women with sickle cell anemia are more prone to complications, such as miscarriage, restricted intrauterine growth, increased intrauterine fetal mortality, low birth weight newborn, preterm labor, in addition to disability of macro and micronutrients during the gestational period, which can lead to maternal malnutrition and maternal and neonatal morbidity and mortality. In short, the susceptibility to maternal malnutrition, infections, hemolytic and vaso-occlusive complications of pregnant women with sickle cell anemia proved to be an unfavorable prognosis, bringing with it complications for the mother and the newborn. Reinforcing the importance of nutritional monitoring as a prevention and guidance strategy regarding nutritional changes in pregnant women with the disease, as an alternative to minimizing adverse outcomes and ensuring improved maternal and fetal health.
