Episodes Of Vaso-occlusive Crisis Research Articles

Single-centre case series report of regional anaesthesia for pain management in vaso-occlusive crisis.

Sickle cell disease is characterised by episodes of vaso-occlusive crisis, a painful complication. Regional anaesthesia has shown promising results in reducing opioid consumption and pain scores. Patients with vaso-occlusive crises who underwent regional anaesthesia in the paediatric intensive care unit were studied. Data regarding pain location, regional analgesia technique, the local anaesthetic used and dose, daily opioid consumption, daily pain scores, use of adjuvants and complications were recorded. The primary outcome was to evaluate the effect of regional anaesthesia on opioid consumption. In this study, we describe 10 cases, referring to six paediatric patients with the vaso-occlusive crisis who underwent regional anaesthesia for severe pain and were unresponsive to increasing doses of opioids. Six cases received epidural analgesia, three continuous peripheral nerve blocks and one received both techniques. Opioid consumption was reduced (58%), and pain scores decreased (72%), both statistically significant reductions.

Acute Chest Syndrome at the Emory University Georgia Comprehensive Sickle Cell Center at Grady Health System

Background: Individuals who have sickle cell disease (SCD) are susceptible to several severe consequences, such as vasoocclusive crisis (VOC), which may further develop into acute chest syndrome (ACS), a specific type of acute lung injury. Although VOC can result in substantial morbidity, it is important to note that ACS is the primary cause of mortality among individuals with SCD. Despite the devastating consequences of ACS, no interventions exist that directly treat this complication. Consequently, when patients present with ACS, their treatment options are frequently limited to supportive care. The absence of ideal therapeutic interventions for individuals with SCD who are experiencing ACS is a significant factor in their increased rates of illness and death. A cohort of adult patients diagnosed with ACS was examined with the objective to evaluate indicators of disease severity and identify risk factors associated with recurrent ACS. Methods: The Emory University Georgia Comprehensive Sickle Cell Center, located at Grady Health System, offers a dedicated acute care unit (ACU) that operates around the clock. This unit is specifically designed to assess and manage SCD patients who present with sickle cell crises. A pilot retrospective study was undertaken to analyze 25 patients with ACS. The evaluation included the examination of admission laboratory results, demographic information, past medical history, co-morbidity, interventions for each ACS admission for each patient (refer to Table 1). Descriptive statistics were used to report frequencies or median and range (Table 2). Patient characteristics of patients with 1 ACS event versus those with recurrent ACS (>=2) were compared using fishers exact test or the Wilcoxon-rank-sum test. Statistical significance was set at 0.05. Analysis was completed using SAS 9.4 (Cary, NC). Results: A total of 47 ACS episodes were detected in a cohort of 25 individuals, resulting in a median of 1 ACS event per patient (range of 1 to 6). A total of 85% of the patients included in this study had homozygosity for SCD, whereas 36% of the patients were receiving hydroxyurea treatment. Chronic pain was reported in three-fourth of the cohort. Out of all the ACS events observed, only 40% necessitated red cell exchange transfusion. A correlation between a minimum hemoglobin (Hb) level of 3.3 g/dL and lactate dehydrogenase (LDH) levels over 4000 U/L was noted during ACS admission. These findings indicate the presence of intravascular hemolysis. Three individuals died to ACS. Next, we conducted a comparison between a group of 10 patients who experienced recurring ACS events, with a minimum of 2 to a maximum of 6 occurrences, and another group of 15 patients who only had a single ACS episode. The group of patients with recurrent ACS exhibits a median of 5.5 episodes of VOC that necessitate visits to the acute care unit within the year prior. In contrast, the group with a single ACS episode has a median of 1 event. There was a notable disparity in the frequency of transfusions received by patients with recurrent ACS compared to those who experienced only a single episode over the past year. Although no other variable demonstrated statistical significance, the recurrent ACS group exhibited lower levels of hemoglobin and higher levels of LDH in comparison to the group with a single ACS episode. Further examination of our patients with SCD could provide valuable insights into the potential factors that may predict ACS episodes. These factors include a patient's genetic background, the frequency of VOC, the use of hydroxyurea, evidence of hemolysis, and previous blood transfusions. Furthermore, the utilization of acute care unit by patients with SCD has had a positive effect in our cohort, on the reduction of red cell exchange transfusions and mortality rates from ACS, possibly from early identification and episodic transfusion, in comparison to similar cohorts with ACS.

Omega-3 Fatty Acid Supplements in Reducing Vaso-Occlusive Crisis Hospitalizations in Patients with Sickle Cell Disease: A Systemic Review and Meta-Analysis

Introduction Omega-3 fatty acids (O3FA) have been evaluated in various clinical settings for sickle cell disease (SCD) patients with promising results. This study aims to assess the efficacy and safety of O3FA supplements in preventing SCD complications. Methods We systematically searched Embase, PubMed, and Cochrane Register of Controlled Trials from inception to May 26 th, 2023. Studies that met the following criteria were included: (1) randomized controlled trials (RCTs) or nonrandomized studies of interventions; (2) comparing O3FA supplements to the standard of care (with or without hydroxyurea treatment); (3) patients with sickle cell disease; (4) and reporting at least one clinical outcomes of interest. We excluded studies (1) with unstable treatment history 3-6 months before the beginning of the studies; or (2) with patients on regular blood transfusion. Our outcomes of interest included (1) the frequency of painful vaso-occlusive crisis or acute chest syndrome requiring hospitalization; and (2) hemoglobin level after intervention. We used Review manager software to perform statistical analyses. The random effect model was applied to all analyses due to anticipated heterogeneity. Pooled mean differences and 95% confidence intervals (CI) were used to assess outcomes. Results We screened 188 studies and included four RCTs and one self-controlled cohort in the meta-analysis. Our population included 349 patients aged between 2 years to adults; 54.7% received O3FA supplements. The docosahexaenoic acid (DHA) dose ranged from 10 to 60 mg per kilogram daily. Follow-up varied from 3 to 12 months. More than two-thirds were hemoglobin SS disease, as presented in Table 1. Other SCD syndromes included hemoglobin S-beta 0 thalassemia and hemoglobin SC disease. Severe baseline disease (³ 3 episodes of painful vaso-occlusive crisis per year requiring hospital admission) ranged between 23.5% and all patients among studies. The vaso-occlusive crisis episodes were significantly reduced in the O3FA group compared with standard treatment: mean difference (MD)-1.63 times (95% CI: -2.35 to -0.91; p = 0.00001; I 2 = 54%), as seen in Figure 1a. There was no difference in hemoglobin levels after intervention with O3FA versus standard treatment (MD: 0.03; 95% CI: -0.25 to 0.32; p = 0.82). In the subgroup of patients without hydroxyurea treatment, the mean frequency of vaso-occlusive crisis was significantly lower with O3FA supplements compared with standard treatment (MD: -1.60; 95% CI: -2.47 to -0.72; p = 0.0004; I 2 = 67%), as shown in Figure 1b. There were no significant adverse events (AE) in the O3FA group. The most common AE were increased appetite, dyspepsia, and occasional “fishy” smell. One patient discontinued O3FA supplements because of drug-related abdominal pain. Conclusion Our systematic review and meta-analysis support O3FA supplementation as a safe and effective complementary strategy to reduce painful vaso-occlusive crises in patients with SCD.

Acute Events Significantly Increase Risk for Long-Term End-Organ Sequelae in Sickle Cell Disease - a Retrospective Cohort Study Using Optum Electronic Health Records

Introduction: Sickle cell disease (SCD) is a hereditary red blood cell disorder characterized by hemolytic anemia and vaso-occlusive crisis (VOC), which are associated with acute organ insults and cumulative end-organ damage. However, real-world data (RWD) are lacking for a host of acute events and rates of long-term organ damage in people with SCD, including priapism and leg ulcers. The objective of this study was to use RWD from US patients to comprehensively assess the rates of acute and long-term SCD events, and to explore the association between acute events and the potential implications for long-term organ damage. Methods: This was a retrospective, non-interventional cohort study using Optum US-based Electronic Health Records data from January 1, 2007, to June 30, 2022. The index date followed a 183-day baseline period after initial diagnosis of SCD in the database. Patients with ≥1 inpatient or 2 outpatient SCD ICD-9-CM or ICD-10-CM codes ≥30 days apart were included. Follow-up for acute events and long-term organ damage started at the index date and continued until a patient was censored for lack of database activity, death, or the study period ended. The prevalences of acute events and long-term organ damage were estimated. Cox regression models were used to determine if acute events were associated with long-term organ damage. Acute events reported 1, 2, 3, and ≥4 times were captured and evaluated for their association with outcomes of long-term organ damage. Exposure was time-varying as patients contributed to the unexposed risk group prior to exposure (acute events) and then to subsequent risk groups after exposures accumulated. Hazard ratios (HR) for long-term organ damage between exposed acute event individuals and unexposed individuals with SCD were estimated. Results: A total of 19,214 patients with SCD were included in this study; median (range) age was 29 (0-88) years, 59% were women, and 81% were African American. The most common acute events were VOC episodes assessed through medical utilization (MU) in 39% of patients, acute chest syndrome (ACS) in 15%, and ischemic stroke and seizures, each in 8% of patients. The most common long-term events of organ damage were heart failure (HF) in 7% of patients, neurocognitive deficit in 6%, and pulmonary hypertension (PH) and chronic kidney disease in 5% of patients each (Table 1). After adjusting for age and sex, patients who at any time had an ischemic stroke had an increased risk of a recurrent event (HR=29.86, 95% CI 26.07-34.21), neurocognitive deficit (HR=8.67, 95% CI 7.22-10.40), and paralysis/hemiparesis (HR=21.19, 95% CI 17.25-26.04) compared with those with no pre-existing ischemic stroke event. Patients with ACS at any time had an increased risk of PH (HR=5.39, 95% CI 4.38-6.35), HF (HR=3.88, 95% CI 3.33-4.52), and oxygen dependency (HR=5.25, 95% CI 4.30-6.41) compared with those with no pre-existing ACS event. Patients who had leg ulcers at any time had an increased risk of amputation (HR=16.70, 95% CI 8.24-33.88) and osteomyelitis (HR=15.17, 95% CI 10.83-21.24) compared with those with no pre-existing leg ulcer event. In a similar manner, the risks were higher for long-term organ damage in corresponding organs among patients with an event of hemorrhagic stroke, avascular necrosis of the humerus or femur, gross hematuria, proteinuria, or priapism, than in patients with no pre-existing events. The risk of developing long-term organ damage following one or multiple acute events was assessed (Table 2). For all the HRs, both the upper and lower bounds of the 95% CI were greater than 1. Conclusions: Acute events remain common among patients with SCD, particularly for VOC episodes assessed via MU, ACS, ischemic stroke, and seizure. Compared with patients who never had acute events, those who had any acute events were at higher risk of long-term organ damage in the same organ. Despite improvements in clinical care, RWD in this study suggest patients with SCD who continue to experience a high rate of acute insults are at higher risk of long-term complications that can lead to organ damage. A limitation of this study is the results have not been corrected for hemoglobin (Hb), despite the known correlation between lower Hb levels and higher rates for some types of organ damage. With the development of new therapeutic interventions, it is critical to understand the impact of these new therapies on acute events and rates of long-term organ damage in patients with SCD.

Evaluation of treatment patterns, healthcare resource utilization and cost of illness for sickle cell disease in Ghana: a private medical insurance claims database study

BackgroundSickle cell disease (SCD) is a major public health concern in sub-Saharan Africa, accounting for nearly 75% of the global disease burden. The current analysis evaluated patient characteristics, treatment patterns, healthcare resource utilization (HCRU) and associated costs in patients with SCD based on a Private Medical Insurance Database in Ghana.MethodsThis retrospective longitudinal cohort study was conducted using an e-claims database from Ghana (01 January 2015 to 31 March 2021). Patients were stratified by age (0 month to < 2 years, ≥ 2 years to ˂6 years, ≥ 6 years to < 12 years, ≥ 12 years to < 16 years; ≥16 years), vaso-occlusive crisis (VOC) (< 1, ≥ 1 to < 3, and ≥ 3 per year), and continuous enrolment. Study outcomes related to patient characteristics, comorbidities, treatment pattern, HCRU were evaluated for pre- and post-index period (index period was between July 2015 to March 2020). Descriptive analysis was used to analyse different study variables.ResultsThe study included 2,863 patients (mean age: 20.1 years; Min age: 0; Max age: 83; females 56.1%). Overall, 52.2% (n = 1,495) of SCD patients were ≥ 16 years and 17.0% (n = 486) were in the ≥ 2 to ˂6-years age group. The majority of patients aged ≥ 16 years (62.5%) in the database did not have reported VOC episodes, 35.9% of patients had 1 to 3 VOCs per year and 1.5% had ≥ 3 VOCs per year during the follow-up period. Consultation-based prevalence of SCD was 0.5% [95% confidence interval (CI): 0-1.3%] − 1.4% [CI: 0.6-2.2%]. Malaria, upper respiratory tract infection (URTI) and sepsis were the common complications of SCD. Analgesics were the most frequently prescribed medications followed by anti-infectives, hematinics, and antimalarials. Hydroxyurea, a routine standard of care for SCD was under-utilized. SCD patients had median cost incurred for consultation/hospital services of $11.3 (Interquartile range [IQR] $6.2 - $27.2). For patients with VOC, maximum median cost was incurred for medications ($10.9 [IQR $5.0-$32.6]). Overall median healthcare cost was highest for individuals with ≥ 3 VOCs per year during the follow-up period ($166.8 [IQR $70.3-$223.5]).ConclusionIn this retrospective private insurance claims database analysis, SCD imposes a significant healthcare burden, especially in patients with VOC. There is a need for reimbursed treatment options that could reduce the long-term burden associated with SCD and VOC.

5610845 A PHASE 1 STUDY OF CSL888 (HEMOPEXIN) IN ADULT PATIENTS WITH SICKLE CELL DISEASE

Background: Episodes of vaso-occlusive crisis (VOC) are the primary reason for hospitalization among patients with sickle cell disease (SCD). The release of heme from the breakdown of damaged red blood cells is thought to play an important role in contributing to vaso-occlusion in SCD. Free heme promotes activation of endothelium, expression of endothelial cell adhesion molecules and activation of blood cells (neutrophils, monocytes, and platelets) which “stick” to the blood vessel walls. The net result is blockage of blood circulation, resulting in the characteristic pain of VOC. Hemopexin is a 60 kilodalton (kDa) plasma glycoprotein that is mainly expressed in the liver and belongs to the family of acute-phase proteins whose synthesis is induced after an inflammatory event. Hemopexin binds extracellular heme with the highest known affinity (KD < 1pM) of all plasma proteins. In patients with SCD, hemopexin levels are significantly reduced (approximately 85%) compared to healthy controls due to increased consumption. CSL889 is human plasma-derived hemopexin. It is hypothesized that pharmacological administration of CSL889 may decrease heme toxicity, restore normal blood circulation and therefore have beneficial effects in the management of acute VOC in SCD patients. Translation to the clinic is supported by studies performed in vitro demonstrating protection of heme-mediated endothelial cell damage and in vivo using the Townes mouse model of SCD, in which hemopexin was shown ameliorate vaso-occlusion following hemoglobin or hypoxia/reperfusion challenges (Gentinetta et al. 2022). Preclinical repeat dose toxicity studies in animals have evidenced favorable tolerability up to the highest dose level tested. Methods: We describe the design of a Phase 1, first in human, multicenter, open-label study to evaluate the safety, tolerability, and pharmacokinetics (PK) of CSL889 in adult patients with SCD following single intravenous (IV) doses of CSL889 [NCT04285827]. The study will comprise 2 parts. Part A will include patients with SCD in their usual health (not in VOC) who will receive a single dose of CSL889 at one of up to 6 different dose levels. In Part B, patients with SCD who present in VOC requiring intravenous (IV) opioid injections and admission to hospital for further management, will receive a single dose of CSL889 at a level that has been shown to be safe and tolerable in Part A within 36 hours of in-patient admission. All subjects will be followed up for 32 days post-infusion of CSL889. The range of doses to be studied is based on a translational PK model based on data derived from the study of CSL889 in the Townes mouse model of SCD. Results: The primary objective is to determine the safety and tolerability of single doses of CSL889 given to patients with SCD both without (Part A) and with (Part B) active VOC. The secondary objectives are to determine the PK and immunogenicity of CSL889. Exploratory objectives are to determine changes in biomarkers of target engagement (including changes in cell-free heme) and pharmacodynamic biomarkers related to the mechanism of action. Change in pain scores (as measured by Numeric Rating Scale [NRS]) will be additionally evaluated in Part B. Conclusions: Enrollment is in progress. No serious adverse events considered related to the administration of CSL889 have been reported as of 01-Sep-2022. Disclosures: F Wilson, J Jochems, L Lindqvist, K Jung,T Gentinetta, S Costin and GJ Kato are employed by CSL Reference 1. Gentinetta et al, J Clin Med 2022, 11:630

Clinical Correlates of Acute and Chronic Pulmonary Complications in Children with Sickle Cell Disease from Madhya Pradesh, India: A Cross-sectional Study

Introduction: Sickle Cell Disease (SCD) is one of the most common hereditary haemoglobinopathies globally. Patients with SCD are at a high risk of pulmonary complications. However, there have been very few studies in literature regarding the spectrum of pulmonary involvement and its association with clinicotherapeutic parameters in Indian patients. Aim: To study the incidence of acute and chronic pulmonary complications in children with SCD and to estimate the association of various risk factors with pulmonary complications. Materials and Methods: The present observational crosssectional study was conducted in the Department of Paediatrics, Mahatma Gandhi Memorial Medical College (tertiary care hospital) and Maharaja Yeshwantrao (MY) Hospital, Indore, Madhya Pradesh, India, from June 2021 to July 2022. A total of 100 patients with SCD below the age of 18 years attending sickle-thalassaemia Outpatient Department (OPD) and Inpatient Department (IPD) with pulmonary symptoms admitted were enrolled in the study. Clinical history, physical examination and laboratory findings were noted as per the preconstructed proforma. Data were statistically analysed with unpaired t-test and Pearson’s Chi- square test. Results: A total of 100 patients with SCD were enrolled and the mean age of the study subjects was 9.27±3.39 years. Nearly equal distribution of males (n=52) and females (n=48) were seen with male to female ratio of 1:1.08. Incidence of complications was seen very high in homozygous sickle disease (63%) followed by only 40% in Haemoglobin S (HbS) beta thalassaemia. Most common complication noted in our patients was Acute Chest Syndrome (ACS) (57.7%), followed pneumonia (20%), sympneumonic effusion (15.6%) while only 6.7% had pulmonary hypertension. A statistically significant association (p-value&lt;0.05) was found between compliance to Hydroxyurea therapy and frequency of Vaso-occlusive Crisis (VOC) episodes with pulmonary complications status. Conclusion: In the present study, most frequent acute pulmonary complication noted was ACS followed by pneumonia and sympneumonic effusion. Frequency of VOCs episodes was significantly associated with increased risk of developing pulmonary complications.

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

Introduction Acute kidney injury (AKI) in hospitalized patients is associated with a high morbidity and mortality. Individuals with sickle cell disease (SCD) frequently experience organ dysfunction, including AKI, during hospitalization for episodes of vaso-occlusive crisis (VOC). AKI can lead to progressive kidney disease and chronic kidney disease (CKD), which is associated with further increased morbidity and mortality. Identifying AKI early during hospitalizations can lessen the risk of progressive CKD and renal replacement therapy. Utilizing machine learning techniques, we hypothesized that risk of AKI can be identified in SCD patients before the onset of kidney injury, leading to earlier recognition of AKI. Methods This is a single-site, retrospective IRB-approved study of 6,278 patient encounters with SCD admitted across five regional hospitals in Memphis, TN, from July 2017 to December 2020. Of these, 1,178 patient encounters were selected for analysis by including encounters with continuous minute-by-minute physiological data availability and excluding dialysis-dependent patient encounters. Each patient admission was considered a separate patient encounter if the interval between admissions was at least 1 month. AKI was defined based on the 2012 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline. Physiomarkers, a set of signal processing features, derived from five physiological data streams from bedside monitors, including heart rate, respiratory rate, and blood pressure (systolic, diastolic, and mean), were used, along with clinical laboratory and demographic data. Missing laboratory values and vital sign measurements were first imputed using the last-one carry forward imputation. The remaining missing values were imputed by the global median of the associated variable in the training dataset. Logistic regression, support vector machine, random forest, and eXtream Gradient Boosting (XGBoost) classifiers were used for classification. Case (AKI) and control records were divided into 12 non-overlapping but consecutive 6-hour analysis time-windows (Figure 1). Prediction horizons (the time in advance each model bundle was asked to predict the AKI event) were increased by 6-hour until the beginning of the record. Controls were balanced with cases using a bootstrap method and randomized across each unique iteration to minimize selection bias. Statistical features were derived from the 6-hour analysis window immediately prior to each prediction horizon. Explainability of models generated at each time window was assessed using averaged Shapley Additive Explanations (SHAP) scores. Results A total of 82 (7%) patient encounters were identified as AKI cases based on the 2012 KDIGO guidelines. The other 1096 SCD patient encounters served as controls (Figure 1). Overall, there were more females (64.6%) than males among AKI cases (Table 1). A history of hypertension, pulmonary hypertension, CKD, and pneumonia were higher in AKI cases than in controls (Table 1). The XGBoost model most accurately predicted AKI up to 60 hours before AKI onset, with an average test sensitivity, specificity, and area under the receiver operating characteristics curve of 0.86, 0.72, and 0.80, respectively. Conclusions In this proof-of-concept study, we found that physio/biomarkers derived from continuous bedside monitoring and laboratory data are temporally and differentially expressed in SCD patients with AKI. A minimalistic artificial intelligence model can be developed using this information to predict AKI earlier in hospitalized SCD patients and may enable the development of innovative prevention strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intravenous Fluid Administration and the Risk of Adverse Outcomes in Sickle Cell Disease Patients Hospitalized for Vaso-Occlusive Crisis.

Vaso-occlusive crisis (VOC) is the leading cause of hospitalization in sickle cell disease (SCD). Intravenous fluid (IVF) administration is the usual practice during VOC episodes to slow the sickling process. In the absence of an evidence-based, clear-cut consensus on the optimal choice, route, and rate of fluid administration, there has been a wide variability in the practice of IVF administration in the treatment of VOC. However, there are growing concerns about the safety of this practice. This systematic review summarized the current evidence on the risk of negative outcomes in SCD patients treated for VOC with IVFs. A database search of Medline/PubMed, EMBASE, Scopus, Web of Science, CINAHL, Wiley Cochrane Library, Clinicaltrials.gov, and conference proceedings of the European Hematology Association (EHA) and American Society of Hematology (ASH) were performed. The results were presented using narrative analysis of quantitative data. Of the 2,821 identified records, a total of three eligible retrospective cohort studies with a total demographic population of 549 SCD patients were included in this review. Normal saline, a frequently used IVF for VOC may be associated with adverse outcomes such as poor pain control and volume overload. Volume overload, new oxygen requirement, acute chest syndrome, and acute kidney injury are potential adverse outcomes of inappropriate IVF use in VOC. There is limited evidence supporting the current practice of IVF use in VOC. Randomized controlled trials are required to fully clarify the place and safety of IVF in the management of VOC.

Assessing the Relationship between Plasma Von Willebrand Factor Antigen Levels, ABO and Rh (D) Blood Groups and Risk of Sickle Cell Anaemia Vaso – Occlusive Crisis

In sickle cell anaemia (SCA), continuous activation of the vascular endothelium by inflammatory cytokines leads to increased elaboration and secretion of von Willebrand Factor (vWF), a potent mediator of adhesive interactions involving the endothelium and circulating blood cells. Non-O blood groups are associated with the elevation of vWF concentration. Thus, SCA and non – O blood groups are determinants of increased levels of vWF, which plays a pivotal role in the pathophysiology of vaso-occlusive crisis (VOC). To determine the influence of plasma vWF:Ag levels, ABO and Rh (D) blood groups on the risk of occurrence of sickle cell vaso-occlusive crisis. We conducted a prospective study of frequencies of VOC with respect to plasma vWF:Ag levels, ABO and Rh (D) blood groups of 50 SCA patients. In comparison with blood group O, patients with non – O blood groups had significantly higher mean vWF concentration (4.17+3.16 IU/l vs 3.46+3.69 IU/l, p&lt; 0.001), with a significantly higher mean number of VOC episodes per patient (3.2 vs 1.3, p&lt;0.001). The relative risk of VOC for patients with non- O blood groups was 1.87 (95% confidence interval 1.5 - 2.2, p&lt;0.001). However, the association of Rh (D) blood group of the patients and their plasma vWF:Ag levels on the risk of occurrence and frequency of VOC was not statistically significant (P = 0.155). SCA patients with non – O blood groups had more episodes and higher risk of VOC that were likely due to the effect of higher plasma vWF concentration. These results indicate that the non- O blood group is a risk factor for frequent VOC and an unfavourable prognostic marker in SCA. We hereby recommend that a large multicentre prospective study be carried out to definitely determine the impact of ABO, Rh and other blood groups on the overall clinical course of SCA.

P-026: FACTORS ASSOCIATED WITH RENAL DYSFUNCTION AMONG CHILDREN WITH SICKLE CELL DISEASE

Purpose: Sickle cell nephropathy is a major complication of sickle cell disease and microalbuminuria is an early predictor of renal damage. Hence it is important to study the prevalence of renal dysfunction and its associated clinical, biochemical, and nutritional factors, benefitting patients in early identification and appropriate intervention thus, preventing the renal complications and associated morbidity. Materials and methods: A cross sectional study was conducted considering a total of 163 patients between 5-20 years, with SCD (homozygous) of either sex, diagnosed using HPLC attending outpatient clinic in their steady state for routine clinical care at a tertiary care hospital. Patients with history of blood transfusion within 2 weeks or in acute crisis or febrile illness were excluded from the study. Random spot urine sample was used for estimation of microalbuminuria by immunoturbidimetry method. Demographic details, clinical, biochemical, and nutritional parameters of each were recorded, analysed and compared. Microalbuminuria was said to be present if urine albumin creatinine ratio was between 30-300 mg/gm urine creatinine and value more than 300 mg/gm of urine creatinine was labelled as macroalbuminuria. A positive screening test was repeated twice with an early morning urine sample before labelling patient as having microalbuminuria. eGFR estimation was done using modified schwartz formula. Results: Out of total 163 patients (5-20 years), majority (32.52%) were in the age group of 6.1-9 years followed by 5-6 years (31.29%). Male female ratio was 1.3:1. Mean BMI was 14.67 ± 2.32. Mean VOC episodes and mean number of blood transfusions were 3.25 ± 2.91 and 3.23 ± 4.39 respectively. 3 patients had macroalbuminuria (1.84%), microalbuminuria was found in 24 patients (14.72%) while 83.44% patients were normal. 71.8% patients had normal eGFR, 18.4% had hyperfiltration while 9.8% had mild decrease in eGFR. The mean age was significantly higher in children with microalbuminuria than in those without microalbuminuria (11.69 ± 3.86 vs 8.55 ± 3.59 years; P=0.001), youngest patient being 6-year-old. Amongst positive patients, 66.67% were males and 33.33% were females. However, no significant correlation was found between gender and microalbuminuria (P= 0.293). 70.8% of positive patients had ≥3 episodes of vaso-occlusive crisis during their lifetime (P= 0.028) which was found to be statistically significant. Blood pressure taken at first visit were within normal limits for all the patients. 75% patients were already on hydroxyurea at the time of enrolment. 16.67% patients with microalbuminuria had hyperfiltration, 12.5% had mild decrease in eGFR while 70.83% had normal eGFR. No significant correlation was found between patient’s eGFR, nutritional status, blood transfusion frequencies, acute febrile illness episodes or any laboratory parameters with microalbuminuria. Conclusion: Age and frequent episodes of vaso-occlusive crises were found to be major factors associated with occurrence of microalbuminuria. These results confirm the need for early screening of microalbuminuria in patients with sickle cell disease and will be helpful in designing target strategy for early identification and introduction of appropriate timely intervention (drugs like ACE inhibitors) so that long term renal complications can be prevented. The authors do not declare any conflict of interest

P-058: INFLUENCE OF HEME OXYGENASE-I GENE PROMOTER POLYMORPHISM ON THE VASO OCCLUSIVE CRISIS OF SICKLE CELL ANEMIA PATIENTS OF EASTERN INDIA

Purpose: Intravascular hemolysis in sickle cell anemia (SCA) leads to release of heme into the circulation and oxidative stress predisposing to vaso occlusive crisis (VOC). Heme is metabolized by the Heme Oxygenase (HO) enzyme resulting in decrease in oxidative stress. The HO-1 expression is altered by HMOX-1 gene promoter polymorphism. We investigated the role of three HMOX-1 gene polymorphisms [two single nucleotide polymorphisms (SNP), 19(G>C)(rs2071747) and -413A>T(rs2071746), and one dinucleotide (GT)n length polymorphisms (rs3074372)] on VOC in SCA patients of eastern India. Materials and methods: A total of 170 SCA cases (80 mild and 90 severe phenotypes) and 101 healthy controls were considered for this study. Those without incidence of a single pain episode or VOC episode were considered as ‘mild phenotype’ of SCA while those who had three or more acute pain episodes in the last twelve months were considered as ‘severe phenotype’. Genotyping of HMOX-1 (19 G>C) polymorphism was done by ARMS-PCR. Whereas, -413A>T polymorphism and (GT)n repeats were done by DNA sequencing. In HMOX-1 gene promoter, the (GT)n repeats were categorized into three types: first, (GT)n≤27 is noted as ‘Small (S)’ repeats; second, (GT)n=28-32 as ‘Medium (M)’ repeats and third, (GT)n≥33 as ‘Large (L)’ repeats. We categorized repeats into two groups: group-I contains S/S and S/M; whereas, group-II contains L/L, L/M, M/M, and S/L. Genotypes and allele frequency were calculated and compared between cases and controls using SNPstarts. Fisher’s exact test, odds ratio (ORs) and 95% confidence intervals (95% CIs) were calculated by using GraphPad Prism v5.0. The p-value of <0.05 was considered statistically significant. Results: On analysis of HMOX-1 (19G>C) polymorphism (rs2071747) between the mild and severe phenotype of VOC, no significant (p>0.05) variation was found in the allele and genotype distribution. Whereas, in HMOX-1 (-413 A>T) polymorphism, a significantly higher mutant allele (T) (p=0.0185) and genotype were found [AA vs TT (p=0.011) and AA vs AT+TT (p=0.02)] in severe phenotype. However, there is no difference among AA vs AT (p=0.56). On (GT)n repeat analysis, it was found that small repeats were associated with the mild phenotype and large repeats with that of severe phenotype in SCA {Gp-I vs Gp-II [p=0.0014; OR(95%CI)- 3.143 (1.538-6.422)]}. The difference was significant when comparison of severe phenotype SCA was done with controls for (GT)n repeats with larger repeats being commoner in severe phenotype. Conclusion: No difference was noted between mild and severe SCA phenotypes HMOX-1 (19G>C) polymorphism. The prevalence of the small repeat (GT)n was found to be significantly higher in the mild SCA phenotypes and controls. Higher incidence of mutant allele and genotype of HMOX-1(-413T) polymorphism and larger (GT)n repeats in the promoter region of the HMOX-1 gene were associated with the severe phenotypes. Both have a negative effect on the HO-1 enzyme activity leading to increased VOC in severe SCA- phenotype. The capacity of HO-1 enzyme activity appears to be overwhelmed by heme-induced oxidative stress in severe phenotypes and the affected patients suffer more VOC compared to mild SCA phenotypes and controls. The authors do not declare any conflict of interest

PB2213: EFFECTIVENESS OF CRIZANLIZUMAB IN REDUCING VASO-OCCLUSIVE CRISIS IN PATIENTS WITH SICKLE CELL DISEASE IN BRAZIL: STUDY PROTOCOL FOR AN OBSERVATIONAL, RETROSPECTIVE, MULTICENTER, NATIONAL STUDY

Background: Sickle cell disease (SCD) is a genetic condition resulting in a structurally abnormal hemoglobin, that leads to a cascade of physiologic consequences, including erythrocyte rigidity, vaso-occlusion, chronic anemia, hemolysis, and vasculopathy. Its management can be intensive, time-consuming, and costly. Few effective treatment options are currently available for these patients, specially to control the vaso-occlusive crisis (VOC). In March 2020, crizanlizumab, a monoclonal antibody drug, was approved by the Brazilian Health Regulatory Agency (ANVISA) to reduce the frequency of VOCs in patients with SCD. Crizanlizumab has been provided through Novartis Managed Access Program (MAP), classified in Brazil as Expanded Access Program (EAP), as an alternative therapy for SCD patients with an immediately life-threatening condition or serious disease. So far, limited evidence is available on crizanlizumab effectiveness and safety profile in Brazil and no real-world evidence study was conducted in the country. In this scenario, real-world studies present an essential role on complementing efficacy and safety data from pivotal and randomized studies in a much broader population profile. Aims: To describe the study design and rationale for investigation for the first real-world study assessing crizanlizumab in SCD patients in Brazil. The study aims to describe the effectiveness and safety profile of crizanlizumab treatment in patients with SCD in Brazil. Methods: This is an observational, retrospective, multi-center study based on secondary data of SCD patients treated with crizanlizumab in Brazil. In total, 98 patients treated with crizanlizumab within the Novartis MAP (EAP) will be screened for the study. Patients aged ≥ 16 ≤ 70 years old, diagnosed with SCD and with documented history of at least one VOC episode up to abstraction data initiation will be included in the study. Patient known to be participating in an interventional study at any point of the two-year study period and/or on a chronic transfusion program will be excluded. Data will be retrospectively abstracted from medical chart, considering one-year prior to crizanlizumab onset and up to one year of crizanlizumab treatment to assess the pattern of VOCs. The annual rate of VOC experienced by the patient and leading to a healthcare visit within the preceding 12-months prior to crizanlizumab initiation and 12-month after will be assessed and compared as the primary outcome. Secondary outcomes include the overall effectiveness of crizanlizumab over 1 year of treatment; time to next VOCs in SCD patients; safety aspects – including the frequency of adverse events of interest, e.g.: arthralgia, nausea, back pain, pyrexia, abdominal pain and infusion-related reactions in SCD patients during crizanlizumab treatment; clinical parameters in SCD management as well as demographics and clinical characteristics of SCD patients who were treated with crizanlizumab. Results: Study in progress. Results not yet available. Image:Summary/Conclusion: This is the first real world study to assess the effectiveness and safety of crizanlizumab in Brazilian SCD patients. It is expected that the assessment of SCD patients under MAP in Brazil will provide valuable information closer to what is expected in the real-world scenario. The availability of more robust evidence can support decision-making process, from clinical assessment by providers, to implementation of public healthcare policies.

Effects of corticosteroids in patients with sickle cell disease and acute complications: a systematic review and meta-analysis.

Whether corticosteroids improve outcome in patients with acute complications of sickle cell disease (SCD) is still debated. We performed a systematic review of the literature with the aim of estimating effects of corticosteroids on the clinical course of vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) in patients with SCD. The primary outcome was transfusion requirement during hospitalization. Studies were identified by search of MEDLINE and CENTRAL database. Three randomized clinical trials (RCT) and three retrospective cohort studies (RCS) were included, involving 3,304 participants and 5,562 VOC or ACS episodes. There was no difference between corticosteroids and standard treatment regarding transfusion requirement overall (odds ratio [OR]=0.98, 95% confidence interval [CI]: 0.38-2.53) but there was a significant interaction of the study type (P<0.0001): corticosteroid therapy was associated with a lower risk of transfusion in RCT (OR=0.13, 95% CI: 0.04-0.45) and a higher risk of transfusion in RCS (OR=2.12, 95% CI: 1.33-3.40. In RCT, the length of hospital stay was lower with corticosteroids as compared with standard treatment: mean difference - 24 hours (95% CI: -35 to -14). Corticosteroids were associated with an increased risk of hospital readmission as compared with standard treatment, in RCT, RCS, and the entire cohort: OR=5.91, 95% CI: 1.40-24.83; OR=3.28, 95% CI: 1.46-7.36 and OR=3.21, 95% CI: 1.97-5.24, respectively. Corticosteroids were associated with reduced number of transfusions and length of stay in RCT but not in RCS, with more rehospitalizations overall. Additional RCT should be conducted while minimizing the risk of re-hospitalizations.

Reasons for Hospitalization of Sickle Cell Disease Patients in the Eastern Province of Saudi Arabia: A Single-Center Study.

Background: Sickle cell disease (SCD) is among the prevalent chronic diseases in the Eastern Province of Saudi Arabia. To our knowledge, there is no published research that reports the reasons for hospitalization in the Eastern Province of the country. Therefore, this study aimed to fill this gap.Design and methods: This is a retrospective cohort study that was conducted in the period from January 2018 to December 2019. Patients with sickle cell disease who were admitted and treated in the hospital were included in this study. Patients’ sociodemographic data and reasons for hospitalization were collected and analyzed using the statistical package for social sciences, version 21 (SPSS, Chicago, IL, USA).Results: There were 103 SCD patients, and the age range was from 18 to 62 years old. The majority of the patients were males (56.3%) and were in the younger age group (≤30 years old; 60.2%). The results showed that the most frequent cause of admission was a vaso-occlusive crisis (VOC) (n=94, 91.3%), followed by acute chest syndrome (ACS) (n=32, 31.1%), and then by hemolytic crisis (27 of the cases; 26.2%). However, we found that a higher number of hip avascular necrosis (AVN) cases were statistically significant in relation to the higher number of hospital admissions (p<0.05), whereas other reasons were not found to have a statistically significant association.Conclusion: The most frequent cause of admission was VOC episodes, followed by ACS, and then by hemolytic crises. Also, a higher number of hip AVN episodes were statistically significant with the higher number of hospital admissions.

Safety and Efficacy of Mitapivat (AG-348), an Oral Activator of Pyruvate Kinase R, in Subjects with Sickle Cell Disease: A Phase 2, Open-Label Study (ESTIMATE)

BackgroundSickle cell disease (SCD) is one of the most common and devastating inherited blood disorders characterized by a single nucleotide mutation in the beta-globin chain leading to the production of mutant hemoglobin S (HbS). HbS polymerizes upon deoxygenation causing red blood cells (RBC) to sickle which results in extremely painful episodes of vaso-occlusive crisis (VOC), severe hemolytic anemia, chronic multiorgan failure and a reduced life span. An important metabolic feature directly associated with RBC sickling is increased intracellular levels of the glycolytic intermediate 2,3-diphosphyglycerate (2,3-DPG) which promotes deoxygenation by lowering the oxygen affinity of hemoglobin (Hb). Pyruvate kinase R (PKR) is a key enzyme in RBC metabolism, generating adenosine triphosphate (ATP) to maintain energy homeostasis, membrane integrity and deformability, and modulates 2,3-DPG levels. Mitapivat (AG-348) is an oral, small molecule allosteric activator of PKR and shows promise as an anti-sickling agent in addition to its effect in PK deficiency and thalassemia. The safety and efficacy of mitapivat in subjects with SCD was evaluated in the dose finding period of this ongoing phase 2 study.MethodsThe ESTIMATE study is a phase 2, open-label study in which subjects ≥16 years with SCD (HbSS, HbS/β0, HbS/β+) with a baseline hemoglobin >6.1 g/dL and ≤11.1 g/dL, no chronic transfusion and adequate organ function were eligible. In the 8-week Dose Finding Period, initial dosing of mitapivat was 20 mg twice daily (BID). Subjects received a maximum of two sequential dose escalations of mitapivat (i.e. from 20 mg BID to 50 mg BID and 100 mg BID) depending on safety. The primary endpoints were safety, evaluated by frequency and severity of adverse events (AEs), and efficacy of mitapivat on RBC sickling. RBC sickling was evaluated by change in Point of Sickling (PoS), the pO2 at which sickling occurs as measured by oxygen gradient ektacytrometry on the Lorrca (RR Mechatronics). Secondary endpoints included changes in hematological parameters, levels of 2,3-DPG and ATP, Hb-oxygen affinity (p50) and surrogate markers of organ damage and mortality. Subjects who safely tolerated mitapivat and showed evidence of clinical improvement, were eligible to continue a 52-week follow-up period (Fixed Dose Extension Period).ResultsSix subjects have been enrolled as of September 2020 and completed the Dose Finding Period. All had homozygous HbSS except one patient who had HbS/β0-thalassemia. Baseline characteristics were: median age of 36 years (range 20-59 years), 4 (66.7%) were female and 5 (83.3%) were on stable-dose hydroxyurea. All subjects received dose escalation to a maximum dose of 100 mg BID. No serious adverse events (SAEs) occurred. Adverse events (AEs) were mild and often transient, with the most common treatment emergent AEs: transaminase increase (n=3 [50.0%], Grade 1), gastrointestinal disorders including dyspepsia, diarrhea and abdominal discomfort (n=3 [50.0%], Grade 1) and headache (n=2 [33.3%], Grade 1). One VOC occurred without hospital admission and did not require dose reduction or discontinuation. Table 1 summarizes the anti-sickling effect as well as the hematological and biochemical response to mitapivat treatment. Sickling occurred at lower pO2 levels in all 6 patients during the Dose Finding Period reflected by a significant decrease in treatment week 8 mean PoS compared to baseline. 5/6 subjects (83.3%) achieved a Hb increase of ≥1 g/dL during this period, which was accompanied by a decrease in hemolytic markers. Consistent with activation of PKR, 2,3-DPG levels decreased and ATP levels increased. Additional results including biomarker data will be presented.ConclusionMitapivat demonstrated an adequate safety profile during the 8-week Dose Finding Period in patients with SCD. The data show promising efficacy in terms of a decrease in the pO2 at which RBCs start to sickle, as well as increase in Hb from baseline and a concomitant decrease in markers reflecting hemolysis. The observed changes in 2,3-DPG and ATP levels are consistent with the proposed mechanism of the drug. The study is ongoing and further data including follow-up data, patient-reported outcomes, PKR activity and thermostability will be reported at a later stage. [Display omitted] Disclosuresvan Dijk: Agios Pharmaceuticals: Research Funding; Axcella Health: Research Funding. Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Rijneveld: Servier: Research Funding; Amgen: Research Funding. Nur: Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Roche: Speakers Bureau. Schutgens: CSL Behring: Research Funding; Novo Nordisk: Research Funding; OctaPharma: Research Funding; Pfizer: Research Funding; Shire/Takeda: Research Funding; Bayer: Research Funding. Wijk: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Beers: Pfizer: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding.

The Association between Adenotonsillectomy and Frequency of Vaso-Occlusive Crises in Patients with Sickle Cell Disease.

Sickle cell disease (SCD) typically manifests in early childhood as attacks of pain known as vaso-occlusive crises. Infection and hypoxemia have been linked with these recurrent episodes and with prolonged hospitalization in SCD patients. However, adenoids and tonsils as sources of infection and causes of hypoxemia have not been adequately investigated in association with vaso-occlusive crises in SCD. To assess the association between adenotonsillectomy and frequency of vaso-occlusive crisis in SCD patients who underwent this procedure at our Hospital, and between adenotonsillectomy and frequency of blood transfusions and emergency department and intensive care unit admissions. We used medical record data to conduct a retrospective review of SCD patients who underwent adenoidectomy and/or tonsillectomy between 2005 and 2017. Eligible subjects were assessed for frequency of vaso-occlusive crises, blood transfusions, and emergency department and intensive care unit admissions. Using the Wilcoxon signed rank test, we compared the frequencies of each outcome preoperatively and 1, 3, 5, and 10years postoperatively. Of 524 records reviewed, 40 eligible patients were included in the study. Minimal reduction was observed in the frequency of vaso-occlusive crisis episodes within 1 and 3years after adenotonsillectomy (p = 0.337 and p = 0.549, respectively). Although the 5- and 10-year postoperative vaso-occlusive crisis frequency tended to be higher than that in the preoperative period, none of the results reached statistical significance. The number of emergency department admissions showed a statistically significant increase 3years postoperatively compared with that in the preoperative period (P = 0.043). There were no statistically significant differences in perioperative blood transfusion frequency or number of intensive care unit admissions in any period. Adenotonsillectomy in SCD patients does not seem to be related to the frequency of vaso-occlusive crises, blood transfusions, or emergency department or intensive care unit admissions. Prospective studies with larger sample sizes are recommended to further evaluate these findings.

Effect of Weather on Frequency of Vaso-Occlusive Crisis in Children With Sickle Cell Disease.

IntroductionSickle cell disease (SCD) is characterized by acute vaso-occlusive crisis (VOC) often manifested as painful episodes. Environmental factors are known to play a role in the frequency and severity of VOC.MethodsThe aim of this study is to analyze the relationship between weather changes and VOC in children with SCD. Data on daily temperature, humidity, and wind speed in Brooklyn, New York was collected over one year. Daily census data of children < 20 years of age with SCD presenting with VOC during the study period was retrieved from the Health Information Systems database. Data was analyzed to determine correlations of daily temperature, humidity, and wind speed with the number of VOCs using Pearson correlation co-efficient and time-series statistics.ResultsThe total number of episodes of VOC was 344, with 218 outpatients and 126 inpatients. Total episodes of VOC peaked during January (n=44), while they were lowest in July (n=16). We observed a negative correlation of VOC with temperature (r= -0.05, p=0.04) and no correlation with humidity (r=0.01, p=0.85) was noted. Analysis of wind speed showed a negative correlation with VOC which is not significant.ConclusionNo significant correlation was found between changes in humidity or wind speed and VOC. As this study was performed in an urban environment with extreme weather changes, results may be different in other geographic areas.

Evaluation of Vaso-occlusive Crisis Management With Patient-Controlled Analgesia in Children With Sickle Cell Disease Requiring Hospitalization.

The aim of this study was to review the use of patient-controlled analgesia (PCA) in sickle cell disease (SCD) for pediatric patients with vaso-occlusive crisis (VOC) in our institution and to compare the effect of early vs late PCA start on pain relief and LOS. This retrospective study included all pediatric patients treated with PCA for a severe VOC from 2010 to 2016. "Early-PCA" was defined as start of PCA within 48 hours of arrival. Time to reach adequate analgesia was defined as the time to reach 2 consecutive pain scores less than 5/10 at 4-hour interval. During the study period, 46 patients presented 87 episodes of VOC treated with PCA. Sixty-three patients with VOC were treated with Early-PCA and 24 with Late-PCA. Both groups were comparable except for median pain score at admission; the Early-PCA group had higher scores: 9.0/10 vs 7.0/10. Time to reach adequate analgesia could be evaluated only in a subset of patients (n = 32) but was shorter in the Early-PCA group with a median difference of 41.0 hours (95% CI -82.0 to -6.0). Early-PCA was associated with a median reduction in LOS of 3.4 days (95% CI -4.9 to -1.9). There was no difference between the 2 groups in terms of side effects and occurrence of acute chest syndrome during hospitalization. In this study, a reduced time to reach adequate analgesia and LOS was noted in the Early-PCA group for severe VOC. A prospective study is required to confirm these results.

Multifocal Calvarial Infarction with Epidural Hemorrhage in a Patient with Sickle Cell Vaso-Occlusive Crisis: A Case Report

AbstractWhile primarily a hematologic disease, sickle cell anemia is notorious for its multisystemic manifestations, particularly in episodes of vaso-occlusive crisis. Multifocal acute calvarial infarction with associated epidural hemorrhage has rarely been reported in sickle cell vaso-occlusive crisis. In this article, we reported a unique case of a 15-year-old male presenting with sickle cell vaso-occlusive crisis and neuroimaging findings of multifocal calvarial bone infarction and epidural hemorrhage. Radiologists and clinicians should be cognizant of this rare complication of sickle cell anemia to ensure appropriate diagnosis and timely treatment.