Crisis In Sickle Cell Disease Research Articles

Total Hip Arthroplasty Complications in Sickle Cell Disease: Systematic Review and Meta-Analysis

Background: Microvascular occlusions caused by sickle-shaped erythrocytes in patients with sickle cell disease (SCD) can lead to increased intraoperative and postoperative complications during total hip arthroplasty (THA). This systematic review and meta-analysis aimed to estimate the overall rate of complications following THA in patients with SCD and to identify the predictors of these complications including the surgical approach. Methods: The search was conducted across the grey literature, Google Scholar, and seven databases: Scopus, MEDLINE Central/PubMed, ProQuest, SciELO, SAGE, and Web of Science. All observational studies reporting the proportional THA complications in SCD were included. The Newcastle–Ottawa Scale quality assessment tool was used to assess the quality of the studies. The random effect model was applied to estimate the pooled outcomes. A sub-group analysis for the different approaches was performed. A sensitivity analysis and meta-regression were used to explain heterogeneity and to identify the THA complication predictors. Results: Of 3230 citations, only 23 studies were eligible for the meta-analysis. The pooled proportion of total primary THA complications in patients with SCD was 42% (95% CI: 30–56%, I2 = 95%). The sub-group analysis highlighted the anterolateral approach as the approach accompanied with the least complications. The meta-regression revealed that the anterolateral approach decreases the complications significantly, −28.67 (95%CI, −56.45–−0.88, p = 0.044), while the number of hips increased the complications by 0.43 (95%CI, 0.30–0.57, p < 0.001). Male gender, age, lateral approach, and HbSS non-significantly affect the THA complications in SCD 52.05, 0.18, 6.06, and 55.78, respectively. The pooled proportions for an SCD crisis 9% (95%CI, 5–14%, I2 = 61%), dislocation 4% (95%CI: 2–7%, I2 = 66%), aseptic loosening 12% (95%CI, 7–20%, I2 = 91%), revision 6% (3–11, I2 = 92%), heterotopic ossification 12% (95%CI, 3–35%, I2 = 95%), and prosthetic joint infection (PJI) 6% (95%CI, 3–11%, I2 = 92%). The most fitted model of meta-regression illustrated that HbSS significantly increases PJI, 0.05 (95%CI: 0.02–0.08, p = 0.009), and male gender and age non-significantly increase PJI, 2.28 (95%CI: −4.99–13.56, p = 0.311) and 0.001 (95%CI: −0.27–0.27, p = 0.990), respectively. Meanwhile, the anterolateral, lateral, and posterior approaches non-significantly decrease PJI, −3.55, −0.92, and −1.27, respectively. The pooled proportion for a sickle cell disease crisis after revision was 16% (95%CI: 6–36%, I2 = 0) and for aseptic loosening after revision, it was 24% (95%CI: 12–43%, I2 = 0). Conclusions: This study revealed the high rate of complications in patients with SCD and highlighted that the anterolateral approach was associated with the lowest rate of complications. Furthermore, this study illustrated that homozygous (HbSS) individuals are more susceptible to prosthetic joint infection.

Secretory Phospholipase A2 Levels Are High in Women with Sickle Cell Disease and Menstruation-Induced Vaso-Occlusive Crises

Menstruation-induced vaso-occlusive crisis (MIVOC) is a significant cause of morbidity in women with sickle cell disease (SCD). Secretory phospholipase A2 (sPLA2) is an inflammatory biomarker that is elevated in vaso-occlusive events such as acute chest syndrome (ACS), but its role in MIVOC is not previously studied. This study compared the serum level of sPLA2 among women with MIVOC and those without MIVOC. This is a comparative cross-sectional study. 354 women with SCD were screened for MIVOC using a structured questionnaire. sPLA2 levels were assayed using a standard ELISA while full blood counts were performed on an automated hematology analyzer. Data were analyzed using the SPSS software v26.0. Results were summarized as frequencies, percentages, and mean ± standard deviation. Variables were compared using the Student’s t-test and Pearson’s correlation. A p-value of <.05 was considered significant. The prevalence of MIVOC was 26.8%. Participants with MIVOC (n = 95) had significantly lower mean hemoglobin concentration (8.00 ± 2.03g/dL vs. 9.95 ± 4.15g/dL, p < .000), significantly higher mean platelets count (518.71 ± 84.58 × 109/L vs 322.21 ± 63.80 × 109/L, p < .000) and higher sPLA2 level (6.58 ± 1.94 IU vs 6.03 ± 0.42 IU, p = .008) compared to those without MIVOC (n = 95). Among participants with MIVOC, sPLA2 levels positively correlated with total white blood cell, absolute neutrophil, and lymphocyte counts. This study demonstrates that MIVOC is common among women with SCD and that the pathophysiology of MIVOC may have an inflammatory basis similar to that of ACS. The potential role of anti-inflammatory and antiplatelet agents in preventing and treating MIVOC may be explored.

Homelessness and Its Impact on the Management of Vaso-Occlusive Crises in Sickle Cell Disease.

Homelessness and Its Impact on the Management of Vaso-Occlusive Crises in Sickle Cell Disease.

Factors Associated with Sickle Cell Crisis Among Sickle Cell Disease Patients Aged ≤15 Years in Three Kenyan Health Facilities

In view of the dearth of definitive therapeutic measures for sickle cell disease (SCD) and its associated crises, the resulting financial burden on parents and caregivers, coupled with psychological distress, social stigma, and other far-reaching consequences, remains incalculable. This research assessed the determinants of sickle cell crises among individuals with SCD aged 15 years and below, focusing on three healthcare facilities in Nairobi County. Using a descriptive cross-sectional design, the study aimed to establish the correlation between SCD crises and various variables in this specific age group within the selected health facilities. Structured interviewer-administered questionnaires, featuring both open-ended and dichotomous questions, were meticulously validated, optimized, and employed to gather pertinent data from the participants. The findings revealed that a majority of SCD patients below 15 years in sampled hospitals were female (52.85%), and the highest incidence of SCD occurred in the age range of 0-5 years (46.63%). Educational attainment among patients predominantly peaked at the primary school level (65.80%), with a minimal 7.77% reaching a secondary school level. Moreover, female caregivers (92.23%) were prevalent among those responsible for SCD patients aged 15 years and below. Primary caregivers, aged between 26- 30 years (37.82%) and 31-35 years (26.42%) were predominately married (75.13%) and engaged in agricultural activities (63.73%). This study revealed that out of the sampled SCD patients under 15 years old, a staggering 83.94% experienced crises related to their sickle cell disease, manifesting as abdominal pains for nearly 70 %, joint discomfort for over 72.22%, acute chest pain occurring approximately 25 %, with bone ache accounting about 32 %. Multiple logistic regression analysis demonstrated that female gender, the age group of 6-10 years, and frequent hospital visits (more than twice a month) significantly increased the log odds for severe SCD crises. Therefore, this study underscores the impact of patient and caregiver factors on the severity of SCD and its crises. Modifying these factors appropriately holds the potential to enhance the prognosis and wellbeing of both patients and caregivers, and strategic interventions must be devised to improve adherence to treatment protocols for SCD patients aged 15 years and below, thereby enhancing prognosis and overall quality of life.

Unraveling the Complexity of Vaso-Occlusive Crises in Sickle Cell Disease: Insights from a Resource-Limited Setting.

Background/Objectives: This study investigated vaso-occlusive crises (VOCs) in sickle cell disease in Lubumbashi, Democratic Republic of Congo, aiming to understand the disease complexities amidst limited resources. With sickle cell hemoglobinopathies on the rise in sub-Saharan Africa, this nine-year study explored factors associated with VOCs and hematological components. Methods: This study comprised 838 patients, analyzing VOCs and hematological changes over time. Demographic characteristics and blood composition changes were carefully categorized. A total of 2910 crises were observed and managed, with analyses conducted on severity, localization, and age groups using statistical methods. Results: The majority of crises were mild or moderate, primarily affecting osteoarticular regions. Statistical analysis revealed significant disparities in crisis intensity based on location and age. The association between blood samples and the number of comorbidities was investigated. Significant positive associations were found for all parameters, except monocytes, indicating a potential link between blood variables and complication burden. Survival analysis using Cox regression was performed to predict the probability of experiencing a second crisis. No significant effects of medication or localization were observed. However, intensity (p < 0.001), age (p < 0.001), and gender (p < 0.001) showed significant effects. Adjusted Hazard Ratios indicated increased risk with age and male gender and reduced risk with mild or severe crisis intensity compared to light. Conclusions: This research sheds light on the complexities of VOCs in resource-limited settings where sickle cell disease is prevalent. The intricate interplay between clinical, laboratory, and treatment factors is highlighted, offering insights for improved patient care. It aims to raise awareness of patient challenges and provide valuable information for targeted interventions to alleviate their burden.

Expert consensus on the management of infusion-related reactions (IRRs) in patients with sickle cell disease (SCD) receiving crizanlizumab: a RAND/UCLA modified Delphi panel.

Crizanlizumab, a monoclonal antibody against P-selectin, has been shown to reduce vaso-occlusive crises (VOCs) compared to placebo in patients ≥ 16 years with sickle cell disease (SCD). However, there have been rare reports of patients experiencing severe pain and subsequent complications within 24hours of crizanlizumab infusions. These events are defined as infusion-related reactions (IRRs). Informed by current literature and clinical experience, a group of content experts developed clinical guidelines for the management of IRRs in patients with SCD. We used the RAND/University of California, Los Angeles (UCLA) modified Delphi panel method, a valid, reproducible technique for achieving consensus. We present our recommendations for managing IRRs, which depend on patient characteristics including: prior history of IRRs to other monoclonal antibodies or medications, changes to crizanlizumab infusion rate and patient monitoring, pain severity relative to patient's typical SCD crises, and severe allergic symptoms. These recommendations outline how to evaluate and manage IRRs in patients receiving crizanlizumab. Future research should validate this guidance using clinical data and identify patients at risk for these IRRs.

Brain network hypersensitivity underlies pain crises in sickle cell disease

Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

Endari treatment ameliorates sickle cell-related disruption in intestinal barrier functions and is associated with prolonged survival in sickle cell mice

ABSTRACT Background Endari (L-glutamine) is a conditional amino acid that reduces the frequency of vaso-occlusive crisis (VOC) in sickle cell disease (SCD). Aim To investigate whether Endari could ameliorate intestinal barrier function and improve survival outcomes in SCD. Methods We treated female Townes SCD mice with Endari and evaluated their intestinal barrier functions by measuring the recovery of orally administered fluorescein isothiocyanate (FITC)-conjugated dextran 4 kDa in serum, and serum intestinal fatty acid binding proteins (iFABP) and lipopolysaccharide (LPS) concentrations by ELISA. We also explored the impact the Endari has on the survival of the SCD mice that underwent repeated experimentally-induced VOC. Results Compared to SCD mice treated with water only, Endari-treated mice showed improved intestinal barrier functions, with decrease in the barrier permeability and reduction in the translocation of lipopolysaccharides from the intestinal lumen into the circulation. These changes occurred after only 4 weeks of Endari treatment. Improved intestinal barrier function was also associated with prolonged survival in Endari-treated SCD mice after repeated experimentally-induced VOC. Conclusion Our findings provide the evidence supporting the beneficial effects of Enadri in improving intestinal barrier function and associated survival outcomes in SCD.

Plant-Produced Therapeutic Crizanlizumab Monoclonal Antibody Binds P-Selectin to Alleviate Vaso-occlusive Pain Crises in Sickle Cell Disease.

Sickle Cell Disease (SCD) is a severe genetic disorder causing vascular occlusion and pain by upregulating the adhesion molecule P-selectin on endothelial cells and platelets. It primarily affects infants and children, causing chronic pain, circulatory problems, organ damage, and complications. Thus, effective treatment and management are crucial to reduce SCD-related risks. Anti-P-selectin antibody Crizanlizumab (Crimab) has been used to treat SCD. In this study, the heavy and light chain (HC and LC) genes of anti-P-Selectin antibody Crimab were cloned into a plant expression binary vector. The HC gene was under control of the duplicated 35S promoter and nopaline synthase (NOS) terminator, whereas the LC gene was under control of the potato proteinase inhibitor II (PIN2) promoter and PIN2 terminator. Agrobacterium tumefaciens LBA4404 was used to transfer the genes into the tobacco (Nicotiana tabacum cv. Xanthi) plant. In plants the genomic PCR and western blot confirmed gene presence and expression of HC and LC Crimab proteins in the plant, respectively. Crimab was successfully purified from transgenic plant leaf using protein A affinity chromatography. In ELISA, plant-derived Crimab (CrimabP) had similar binding activity to P-selectin compared to mammalian-derived Crimab (CrimabM). In surface plasmon resonance, the KD (dissociation binding constant) and response unit values were lower and higher than CrimabP, respectively. Taken together, these results demonstrate that the transgenic plant can be applied to produce biofunctional therapeutic monoclonal antibody.

Plasma sphingolipids in patients with sickle cell disease: Multiple-site vaso-occlusive crises could be associated with lower sphingolipid levels.

Although sickle cell disease (SCD) and its manifestations have been associated with various lipid alterations, there are a few studies exploring the impact of sphingolipids in SCD. In this study, we determined plasma ceramide (Cer) and sphingomyelin (CerPCho) species and investigated their association with the crisis in SCD. SCD patients (N = 27) suffering from vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) were involved in this study. Blood samples were drawn at crisis and later at steady state periods. Clinical history, white blood cell count (WBC), C-reactive protein and lactate dehydrogenase (LDH) levels were recorded. 16:0, 18:0, 20:0, 22:0 Cer and 16:0, 18:0, 24:0 CerPCho were measured via LC-MS/MS. All measured Cer and CerPCho levels of SCD patients at crisis and steady-state were found to be similar. Inflammation-related parameters were significantly higher in patients with ACS compared to single-site VOC. Patients with multiple-site VOC were found to have significantly lower sphingolipid levels compared with those with single-site VOC, at crisis (16, 18, 24 CerPCho and 18, 22 Cer) and at steady-state (24:0 CerPCho and 18 Cer). Our results show that sphingolipid levels in SCD patients are similar during crisis and at steady state. However, lower sphingolipid levels appear to be associated with the development of multiple-site VOC. Since the differences were observed at both crisis and steady-state, sphingolipid level could be an underlying factor associated with crisis characteristics in patients with SCD.

Oxygen saturation thresholds in managing sickle cell disease at US children's hospitals.

Adequate oxygen saturation (SpO2 ) is crucial for managing sickle cell disease (SCD). Children with SCD are at increased risk for occult hypoxemia; therefore, understanding SpO2 threshold practices would help identify barriers to oxygen optimization in a population sensitive to oxyhemoglobin imbalances. We investigated SpO2 cutoff levels used in clinical algorithms for management of acute SCD events at children's hospitals across the United States, and determined their consistency with recommended national guidelines (SpO2 >95%). Clinical pathways and algorithms used for the management of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) in SCD were obtained and reviewed from large children's hospitals in the United States. Responses were obtained from 94% (140/149) of eligible children's hospitals. Of these, 63 (45%) had available clinical algorithms to manage VOC and ACS. SpO2 cutoff was provided in 71.4% (45/63) of clinical algorithms. Substantial variation in SpO2 cutoff levels was noted, ranging from ≥90% to more than 95%. Only seven hospitals (5% of total hospitals and 15.6% of hospitals with clinical algorithms available) specified oxygen cutoffs that were consistent with national guidelines. Hospitals geographically located in the South (46.8%; n=29/62) and Midwest (54.8%; n=17/31) were more likely to have VOC and ACS clinical algorithms, compared to the Northeast (26.5%; n=9/34) and West (36.4%; n=8/22). There is inconsistency in the use of clinical algorithms and oxygen thresholds for VOC and ACS across US children's hospitals. Children with SCD could be at risk for insufficient oxygen therapy during adverse acute events.

Knowledge, Awareness and Opinion Related to Sickle Cell Disease Among the Professional College Students of Amravati, Maharashtra

The aim of this study is to investigate the awareness, clinical manifestations, treatment and populations at risk of Sickle Cell Disease (SCD) amongst the professional college students of Amravati district. This study was also focus on knowledge about carriers (HbAA) and sufferers (HbSS). The total 842 students from technical streams such as engineering, pharmacy and biotech were enrolled. All participants were assessed on their general knowledge of the disease. The structured questionnaire containing the questions on origin, prevalence, incidences, life expectancy, painful crisis, counseling methods, treatments, management, attitude and behavior towards SCD were provided to all participants. The results had shown that, only 144(17.1%) subjects were found to be known about SCD. Out of them, 56(38.8%) individuals had appreciable knowledge, 80(55.5%) had limited knowledge and 8(5.5%) had marginal knowledge of SCD. The 30.5%(n=44) respondents were known about need of blood transfusion and 18.75%(n=27) participants had knowledge of interrelation between sickle cell anemia and the disease jaundice be an important clinical complaint in SCD. 25.69% (n=37) respondents known to have about intimate relationship between sickle cell disease and pain crisis. Majority of respondents (512/842) was believed that, people should have knowledge and awareness about the genetic diseases that helps to restrict its further spread. Keywords: Sickle cell disease, Professional college, Amravati, Maharashtra

Hydroxyurea is associated with later onset of acute splenic sequestration crisis in sickle cell disease: Lessons from the European Sickle Cell Disease Cohort-Hydroxyurea (ESCORT-HU) study.

Acute splenic sequestration crisis (ASSC) is a potentially life-threatening complication of sickle cell disease (SCD), typically occurring in young patients under 5 years of age, with a median age at first episode of less than 2 years. Because a beneficial effect of hydroxyurea (HU) on spleen perfusion and splenic function has been suspected, we hypothesized that HU treatment might be associated with later onset of ASSC in patients with SCD. To investigate this hypothesis, we analyzed data from the ESCORT-HU study on a large cohort of patients with SCD receiving HU, enrolled between January 2009 and June 2017 with a follow-up of 7309 patient-years of observation. The median age at ASSC of the 14 patients who experienced a first episode of ASSC during the study period was 8.0 [IQR: 5.0-24.1] years. The median age at HU initiation was significantly lower in these 14 patients (4.8 [IQR: 3.3-18.7] years) compared to the 1664 patients without ASSC (19.9 [8.8-33.4] years, p = .0008). These findings suggest that ASSC may occur at an unusually late age in patients receiving HU, possibly reflecting longer preservation of spleen perfusion and function secondary to early initiation of HU. Further studies are needed to better characterize the effects of HU on spleen perfusion/function and on the occurrence of ASSC in patients with SCD (ClinicalTrials.gov identifier: NCT02516579; European registry ENCEPP/SDPP/10565).

Sudden Death due to Acute Splenic Sequestration Crisis in Sickle Cell Disease: A Case Report with Active Post-mortem Follow up

Sudden Death due to Acute Splenic Sequestration Crisis in Sickle Cell Disease: A Case Report with Active Post-mortem Follow up

Lactate dehydrogenase and hemolysis index to predict vaso-occlusive crisis in sickle cell disease

Sickle cell disease (SCD) is an inherited hemoglobinopathy disorder associated with chronic hemolysis. A major complication is vaso-occlusive crisis (VOC), associating frequent hospitalization, morbidity and mortality. The aim of this study was to investigate whether hemolysis biomarkers were able to predict VOC risk in adult patients with SCD requiring hospitalization within 1 year. This single-center prospective study included adult patients with SCD at steady state or during VOC. A total of 182 patients with SCD were included, 151 at steady state and 31 during VOC. Among the 151 patients at steady state 41 experienced VOC within 1 year (median: 3.0 months [2.0–6.5]). We observed an increase of lactate dehydrogenase (LDH) (p = 0.01) and hemolysis index (HI) (p = 0.0043) during VOC compared to steady state. Regarding patients with VOC requiring hospitalization, LDH (p = 0.0073) and HI (p = 0.04) were increased. In unadjusted logistic regression, LDH > median (> 260 U/L) (RR = 3.6 [1.29–10.88], p = 0.0098) and HI > median (> 8 UA/L) (RR = 3.13 [1.91–5.33]; p < 0.001) were associated with VOC. The association of LDH > 260 U/L and HI > 12 UA/L presented a sensitivity of 90%, and a specificity of 72.9% to predict VOC. The association of LDH and HI cut-off was able to predict VOC risk in SCD.

Exploring Factors Linked to Home-Reported Acute Pain Events and Pain Crises in Sickle Cell Disease (SCD) through Flare Tracking in the Ascend Study

Introduction: Pain is a prominent symptom in sickle cell disease (SCD) and often broadly categorized as persistent chronic pain or more intense acute pain episodes compared to regular chronic pain experiences. Many research studies focus solely on pain events requiring healthcare utilization, neglecting those experienced at home, which may cloud the understanding of an individual's daily experience in managing their symptoms. Capturing home-reported evidence is crucial for comprehending SCD's impact on patients and potential effects of medical interventions. Objective: The objective of the Ascend Study was to collect individuals' experiences with pain events in SCD, employing a flexible, home-reported outcomes data collection methodology in Folia Health's mobile and web-based platform. Methods: The Advarra IRB-approved study recruited individuals with any genotype of SCD in the U.S., aged 13 and above, and caregivers of children aged 4 to 12. E-consent and data collection occurred through the Folia platform, where participants selected and tracked relevant symptoms (including, but not limited, to pain-specific symptoms) and treatments, along with health-related quality of life, over the course of 3 months per participant. Baseline severity scores were collected on a 1 to 10 Likert scale for symptoms that were pre-selected by participants at the start of the study. Participants also directly reported potential acute pain events and pain crises experienced in monthly surveys. Detailed flare tracking was set up for four symptom types (chronic pain, acute pain, pain crises, pain and discomfort), enabling structured follow-up questions on select pain flare events. Flare tracking was activated if participants reported a 2-point increase in severity compared to self-identified baselines or opted to track a pain symptom outside of their pre-selected routine. Overall pain burden was collected by participants who routinely tracked all of these various pain experiences, comprising the Ascend Study's home-reported pain hierarchy (Figure A). Results: 89% (n=59) of tracking participants reported experiencing a potential pain crisis for at least 1 month through monthly surveys. Analysis using the flare threshold applied to all pain symptoms tracked (sensitivity 77.5%; specificity 44.9%) identified 2,660 potential pain flare events. Among participants, 86% (n=57) experienced at least one flare event based on the flare threshold. On average, each participant had 24.9 flare days. Flare events identified by the threshold included 9 pain types tracked on a 1-10 Likert scale and 26 pain types tracked as binary “yes/no.” A total of 812 potential pain flare events reported by 46 participants prompted flare tracking follow-up questions (Table 1). Increases in chronic pain were more common than new types. 74% of these participants (n=34) opted to provide additional information through flare tracking in 282 pain flare events. Real-time flare tracking was reported in 85% of flare tracking events. From follow-up responses, most common classifications of pain were stabbing(188, 30.3%), pulsing or throbbing(144, 23.2%), and dull or aching(143, 23.0%). The back (155, 15.7%) and leg (268, 27.2%) were the most prevalent pain locations, with weather (177) and seasonal change (92) identified as potential triggers. Top flare descriptors included ‘can't do normal activities’ (84, 24.4%) and ‘not getting better with home pain meds’ (78, 22.7%). Conclusion: The Ascend Study provides detailed insights into SCD acute pain experiences, showing a high percentage of real-time flare tracking. Chronic pain flares were frequently reported, back and leg pain being the most prevalent locations, and seasonal changes identified as potential triggers. While the flare threshold analysis identified many potential pain flare events, the method's sensitivity might lead to lower specificity for pain flare events and the inclusion of potentially non-flare events. Findings provide valuable insights into the acute pain experiences of individuals with SCD, emphasizing the significance of capturing home-reported evidence to improve patient care and SCD therapies.

Predicting Vaso-Occlusive Crises in Sickle Cell Disease through Digital, Longitudinal Tracking of Wearable Metrics and Patient-Reported Outcomes

Background Sickle Cell Disease (SCD) is a genetic disorder caused by an HBB gene mutation and resulting structural variant haemoglobin (HbS) that polymerises upon deoxygenation, leading to a sickled morphology of red blood cells ( Chakravorty et al., Arch Dis Child 2015). This causes acute pain episodes, known as vaso-occlusive crises (VOC), that can result in severe end-organ damage in the long-term and a shortened lifespan ( Jang et al., J Transl Med 2021). Responsible for an estimated 95% of SCD hospitalisations and as a key predictor of death ( Darbari et al., Eur J Haematol 2020, Ballas et al., Am J Hematol 2005), it is critical to find new ways to drive early detection of VOCs in order to support preventative interventions. Aims This work aimed to develop a machine learning (ML) algorithm capable of predicting the potential onset of a VOC, using physiological data captured longitudinally by a wearable smartwatch, as well as patient-reported outcomes (PROs) entered via a specialised mobile phone application. Methods Following informed patient consent, participants gained access to a mobile phone application, or “digital patient wallet”, encompassing their health data and access to a PRO entry portal ( Summers et al., HemaSphere 2023). This allowed for daily recording of PROs including EQ-5D-5L, pain, mood, and fatigue scores, alongside self-reported VOCs. Participants were also provided with a Withings ScanWatch to be worn day and night, capturing physical activity, sleep quality, and heart rate data in an automated manner. Medical record data including healthcare utilisation, pathology, and demographic data was obtained through participant completion of a Subject Access Request form. Data for a snapshot cohort of 186 patients over a 1-month period (May-June 2023) were analysed through an ensemble of ML models: gradient boosting machine, neural network, and k-means clustering. All collated metrics were fed into the model, with the exclusion of hospitalisation as an 'a posteriori' variable, to ensure predictions were based on appropriate variables and not strengthened by self-confirming factors. The resulting predicted likelihood of a VOC for each participant was calculated on each day and given as a scale from 0-100%, with a likelihood of 75% or higher deemed to be a predicted VOC. This was then assessed against the true incidence of the participants' self-reported VOCs. Results The mean age was 36 (SD 11.6) years, and most patients were female (70%). The HbSS genotype was most common (75%), followed by HbSC (16%), and HbS Beta + Thalassemia (5%). 82,804 datapoints were collated for all participants across this period, encompassing 90 different variables. 69 instances of a VOC were self-reported by patients during the period of analysis, 58 (84%) of which were accurately predicted by the algorithm. 2,366 instances of no VOC were self-recorded, giving a negative predicted value of 83% (1,958/2,366 predicted). Further breakdown by the predicted likelihood score is displayed in Figure 2, highlighting the spread of individually calculated VOC likelihood scores per day against the incidence of patient-reported VOCs. Summary/Conclusions This work provides an important translation of daily trackable metrics through a remote, digital ecosystem, to the real-world prediction of potential VOC events in SCD. The purpose of this algorithm is, at its core, to act as a pre-emptive warning system from which proactive behavioural changes or interventions can be enacted. As such, the prediction of additional potential risk scores above the 75% threshold reflects an approach of ‘over-predicting’ considered to be a preferable strategy for the algorithm, given the severe nature of VOCs and the health impacts of missing a potential event. Our ongoing aim is to further develop the algorithm and its contributing metrics against medical data, in addition to patient self-reported events, to further optimise the predictor. This includes the curation of core metrics requiring minimal patient input, in order to reduce missing datapoints across those that feed into the algorithm and thereby reduce unpredicted VOCs. Ultimately, we hope to provide an early alert system that will help patients to identify their VOCs sooner, and thus action the next steps that may prevent possible hospital admissions.

Alkaline Phosphatase As a Marker for Acute Complications in Sickle Cell Disease

Background: Sickle cell disease (SCD) can result in complications affecting multiple organ systems, including renal, pulmonary, and central nervous system. Alkaline phosphatases (ALP) comprise a group of isoenzymes which function to catalyze the hydrolysis of inorganic phosphate monoesters, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal-5′-phosphate. Predominantly, serum ALP is derived from the liver and bone (1). An elevation in serum ALP primarily signifies hepatobiliary disorders, wherein cholestasis and bile duct damage results in increased enzyme synthesis as a compensatory mechanism. Increased ALP levels can also be an indication of bone disease associated with increased osteoblast activity (2). ALP has been linked to the severity of the pain crisis in SCD (3), and there is also evidence that ALP is a predictor for increased mortality risk in SCD (4-6). This study aims to investigate ALP as a biomarker of SCD severity and acute organ complications (VOE). Methods: This retrospective study included 252 patients aged 18 years or older with SCD who were admitted to the University of Illinois Chicago (UIC) hospital for the management of vasoocclusive pain events (VOEs) between July 1, 2017, and June 30, 2018. The study recorded the following complications during hospitalization: acute chest syndrome, acute kidney injury, acute liver injury, thrombotic or hemorrhagic stroke, deep vein thrombosis or thromboembolism, the need for transfer to the intensive care unit, the need for exchange blood transfusion, or death during hospitalization. Data analyses were performed using the Kruskal-Wallis test, Chi-square test, linear or a stepwise ordinal logistic regression analysis. Results: The median age of this cohort was 31 years (interquartile range 26-42 years), 36% were males and 72% had hemoglobin SS/Sβ0 with 33% on hydroxyurea. In this cohort, 105 patients experienced at least one complication during at least one hospitalization(s) within the one-year study period, while 147 were hospitalized but did not experience complications during the hospitalization (Table 1). A comparison of clinical characteristics between the two cohorts revealed that patients with complications had a higher prevalence of HgbSS/Sβ0-genotype; had higher ALP, total bilirubin, and AST concentrations; Patients with complications had a greater number of hospitalizations and longer length of stay in both the median length and the total length over the study period (Table 2). In a multivariable model comparing baseline characteristics, HgbSS/Sβ0-genotype and increased ALP levels at baseline were significant predictors of complications during hospitalization, after adjusting for other variables as listed in the table (Table 3). Furthermore, in a subgroup analysis of patients with HgbSS/Sβ0-genotype, this relationship was even stronger: higher baseline ALP levels were significantly associated with acute complications during the study period (OR 7.3, 95% CI: 2.2 - 24.1, p = 0.001). Summary: Our findings suggest that SCD patients with longer hospital stay and higher numbers of admissions tend to have acute complications during hospitalization. Individuals with the HgbSS/Sbeta0 genotype and higher levels of ALP are at an increased risk of developing acute complications, which could potentially account for the increased mortality risk associated with alkaline phosphatase reported by previous literature. K. Makris, C. Mousa, E. Cavalier, Alkaline Phosphatases: Biochemistry, Functions, and Measurement. Calcif Tissue Int112, 233-242 (2023).J. Masrour Roudsari, S. Mahjoub, Quantification and comparison of bone-specific alkaline phosphatase with two methods in normal and paget's specimens. Caspian J Intern Med3, 478-483 (2012).J. I. Brody, W. N. Ryan, M. A. Haidar, Serum alkaline phosphatase isoenzymes in sickle cell anemia. JAMA232, 738-741 (1975).J. J. Feld et al., Liver injury is associated with mortality in sickle cell disease. Aliment Pharmacol Ther42, 912-921 (2015).S. A. Curtis, N. Danda, Z. Etzion, H. W. Cohen, H. H. Billett, Longitudinal Analysis of Patient Specific Predictors for Mortality in Sickle Cell Disease. PLoS One11, e0164743 (2016).V. Sachdev et al., A phenotypic risk score for predicting mortality in sickle cell disease. Br J Haematol192, 932-941 (2021).

Population Pharmacokinetic Modeling of Different Formulations of Inclacumab Using Phase 1 Data in Healthy Participants

Introduction: P-selectin is a cell adhesion molecule that contributes to vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Inclacumab is a recombinant, fully human, immunoglobulin G4 monoclonal antibody that selectively binds to P-selectin to prevent binding with P-selectin glycoprotein ligand-1. Inclacumab was previously evaluated by Roche in clinical trials with healthy participants and patients with cardiovascular disease and is now being developed as a potential treatment to reduce the frequency of VOCs in individuals with SCD. Changes in the manufacturing of inclacumab have resulted in 3 formulations/drug materials: Roche v0.1, Roche v0.2, and Global Blood Therapeutics (GBT). GBT-manufactured inclacumab utilizes a similar formulation and the same cell line as Roche v0.2 (Roche v0.1 utilizes a different cell line), and analytical and nonclinical comparability between Roche v0.2 and GBT inclacumab have been demonstrated (Mihaila et al. Expert Opin Biol Ther 2022). Here we report results from a population pharmacokinetic (PopPK) model developed to compare the pharmacokinetics (PK) of different formulations using data from 4 phase 1 clinical studies in healthy participants administered Roche v0.1, Roche v0.2, or GBT inclacumab. The objectives were to develop a PopPK model to describe inclacumab PK in healthy adult participants and to quantify potential differences in inclacumab PK associated with different formulations/drug materials. Methods: A PopPK model was developed using single- and multiple-dose PK data from healthy participants who received intravenous (IV) inclacumab across 4 studies (BP21112 [Roche v0.1, single ascending dose (SAD)], BP21617 [Roche v0.1, multiple ascending dose], BP28134 [Roche v0.2, SAD], and GBT2104-111 [GBT, SAD]). Evaluable participants had ≥1 measurable postdose concentration with an associated sample time, relevant dosing information prior to each measurable concentration, and no protocol violation that could confound PK analyses. A nonlinear mixed effects model was fit to the inclacumab plasma concentration-time data using first-order conditional estimation with eta-epsilon interaction in NONMEM ® (v7.3). Model selection was based on the plausibility of parameter estimates, goodness-of-fit plots, and the objective function value. The final model was evaluated using a prediction-corrected visual predictive check (pcVPC). Results: The PopPK dataset comprised 145 healthy participants, of which 2622 inclacumab plasma concentrations (84.9%) from 143 participants were evaluable (Roche v0.1: n=68 [47.6%]; Roche v0.2: n=60 [42.0%]; GBT: n=15 [10.5%]). Median (range) age and body weight were 42 (21-63) years and 73.2 (45.8-109) kg, respectively. Nominal doses ranged from 0.03 to 40 mg/kg IV; 23.8% of participants received 3 mg/kg and 29.4% received 20 mg/kg. A 3-compartment disposition model with parallel linear clearance (CL=0.125 L/d) and nonlinear (concentration-dependent; V max=1.19 mg/d; K m=0.784 μg/mL) clearance from the central compartment described the plasma concentration-time data. The effect of drug material was incorporated a priori as relative bioavailability term F in the base model using exploratory analyses of observed exposures. Dosing of Roche v0.1 and Roche v0.2 inclacumab resulted in 23% and 2% higher exposure than GBT inclacumab, respectively. Between-subject variability was estimated for linear clearance, nonlinear clearance, and all volume parameters, and residual error was described using a proportional model (Table). Of the tested covariates, baseline body weight was a statistically significant covariate effect and was included on all linear clearance and volume terms. Model qualification by pcVPC showed good predictive performance of the final model. Conclusions: The PopPK of IV inclacumab in healthy participants was described by a 3-compartment disposition model with parallel linear and nonlinear clearances. Estimated relative exposure of Roche v0.2 and GBT-manufactured inclacumab was similar, indicating comparability in drug exposure. Understanding the relationship between exposure and dose for different formulations facilitates more accurate assessment of safety data across multiple clinical studies. These data provide support for the ongoing phase 3 clinical development in SCD using GBT-manufactured inclacumab without further clinical comparability testing.

Pain Frequency and Health Care Utilization Patterns in Women with Sickle Cell Disease Experiencing Menstruation-Associated Pain Crises.

Background: Pain crises in sickle cell disease (SCD) lead to high rates of health care utilization. Historically, women have reported higher pain burdens than men, with recent studies showing a temporal association between pain crisis and menstruation. However, health care utilization patterns of SCD women with menstruation-associated pain crises have not been reported. We studied the frequency, severity, and health care utilization of menstruation-associated pain crises in SCD women. Materials and Methods: A multinational, cross-sectional cohort study of the SCD phenotype was executed using a validated questionnaire and medical chart review from the Consortium for the Advancement of Sickle Cell Research (CASiRe) cohort. Total number of pain crises, emergency room/day hospital visits, and hospitalizations were collected from a subcohort of 178 SCD women within the past 6 months and previous year. Results: Thirty-nine percent of women reported menstruation-associated pain crises in their lifetime. These women were significantly more likely to be hospitalized compared with those who did not (mean 1.70 vs. 0.67, p = 0.0005). Women reporting menstruation-associated pain crises in the past 6 months also experienced increased hospitalizations compared with those who did not (mean 1.71 vs. 0.75, p = 0.0016). Forty percent of women reported at least four menstruation-associated pain crises in the past 6 months. Conclusions: Nearly 40% of SCD women have menstruation-associated pain crises. Menstruation-associated pain crises are associated with high pain burden and increased rates of hospitalization. Strategies are needed to address health care disparities within gynecologic care in SCD.