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.

Can we use biomarkers to identify those at risk of acute pain from sickle cell disease?

INTRODUCTION: Acute pain episodes, also known as vaso-occlusive crises (VOC), are a major symptom of sickle cell disease (SCD) and lead to frequent hospitalizations. The diagnosis of VOC can be challenging, particularly in adults with SCD, 50% of whom have chronic pain. Several potential biomarkers have been proposed for identifying individuals with VOC, including elevation above the baseline of various vascular growth factors, cytokines, and other markers of inflammation. However, none have been validated to date. AREAS COVERED: We summarize prospective biomarkers for the diagnosis of acute pain in SCD, and how they may be involved in the pathophysiology of a VOC. Previous and current strategies for biomarker discovery, including the use of omics techniques, are discussed. EXPERT OPINION: Implementing a multi-omics-based approach will facilitate the discovery of objective and validated biomarkers for acute pain.

Safety and efficacy of L-Glutamine in reducing the frequency of acute complications among patients with sickle cell disease: A randomized controlled study.

To evaluate the safety and efficacy of L-glutamine in reducing vaso-occlusive crisis (VOC) and improving cerebral arterial blood flow in children with sickle cell disease (SCD). This is an interventional randomized controlled trial that recruited sixty SCD patients, aged 9.2 ± 3.7 years, who had at least two VOCs during the last 12 months and on a stable dose of hydroxyurea. They were randomly assigned in a 1:1 ratio to receive glutamine (0.3 gm/kg/dose/12h) orally for 24 weeks or the standard of care (SOC). All patients had VOCs in the last year > 3, those on glutamine had a higher number of VOCs and hospitalization for VOC in the last year. There was a decreasing trend in the number, severity, and hospitalization of VOC and a significantly lower cumulative number of VOCs and hospitalizations in the glutamine group than in SOC (p = 0.008, p < 0.001 respectively). Time-averaged mean maximum velocity for the glutamine group had a marginal increase in both middle cerebral arteries, all values remained normal within a normal range, and in both internal carotid arteries, values increased from abnormally low to normal ranges at week 24. Glutamine reduced the number of VOCs and severity and may have a potentially favorable impact on the cerebral arterial flow velocities.

A critical review of therapeutic interventions in sickle cell disease: Progress and challenges.

Sickle cell disease (SCD) is an autosomal recessive genetic disorder that occurs due to the point mutation in the ß-globin gene, which results in the formation of sickle hemoglobin (HbS) in the red blood cells (RBCs). When HbS is exposed to an oxygen-depleted environment, it polymerizes, resulting in hemolysis, vaso-occlusion pain, and impaired blood flow. Still, there is no affordable cure for this inherited disease. Approved medications held promise but were met with challenges due to limited patient tolerance and undesired side effects, thereby inhibiting their ability to enhance the quality of life across various individuals with SCD. Progress has been made in understanding the pathophysiology of SCD during the past few decades, leading to the discovery of novel targets and therapies. However, there is a compelling need for research to discover medications with improved efficacy and reduced side effects. Also, more clinical investigations on various drug combinations with different mechanisms of action are needed. This review comprehensively presents therapeutic approaches for SCD, including those currently available or under investigation. It covers fundamental aspects of the disease, such as epidemiology and pathophysiology, and provides detailed discussions on various disease-modifying agents. Additionally, expert insights are offered on the future development of pharmacotherapy for SCD.

Unexpected Death of a Sickle Cell Disease Patient: A Case Report and Literature Review.

Sickle cell disease (SCD) is an autosomal recessive genetic disorder characterized by the abnormal formation of sickle hemoglobin (HbS). Under conditions of deoxygenation, HbS undergoes polymerization, resulting in microvascular occlusion, tissue hypoxia, and infarction. The elevated mortality rate associated with SCD is primarily attributed to complications such as sepsis, acute chest syndrome, stroke, acute multiorgan failure, and pulmonary hypertension. Despite advancements in awareness and treatments, preventing mortality in young individuals with SCD remains a formidable challenge. In an effort to shed light on these challenges, we present a case of unexpected death associated with SCD to emphasize the pressing need for continued research and intervention strategies to improve patient outcomes.

Crisis in the Chest: Acute Chest Syndrome as a Sequela of Tricuspid Valve Endocarditis.

The management of acute chest syndrome (ACS) in sickle cell disease occurring concurrently with pulmonary embolism resulting from tricuspid valve endocarditis poses an atypical challenge. We present a case in which this complex interaction occurs and the prompt interventions that were utilized to give the best possible outcome.

Applying Comfort Theory to Improve Outcomes for People in Sickle Cell Crisis.

When people with sickle cell disease in vaso-occlusive crisis need hospitalization, they often experience fragmented and disparate treatment. Racial, gender, and socioeconomic treatment bias by providers, including nurses, is complicated by the current reactionary United States (US) controlled substance policies. To provide high-quality and respectful care, nurses can use Kolcaba's Comfort Theory as the framework for a holistic plan to assess, deliver individualized interventions, and evaluate outcomes for people experiencing vaso-occlusive crisis. Once in the electronic medical record, it can guide care during future hospitalizations. By refocusing on the nursing value of providing comfort care to individuals in distress, nurses can change treatment outcomes for clients.

Cost-effectiveness of l-glutamine versus crizanlizumab for adults with sickle cell disease: model focused on reducing pain episode costs from Qatar's healthcare perspective.

Objectives: Treatment options for preventing vaso-occlusive crises among sickle cell disease patients are on the rise, especially if hydroxyurea treatment has failed. This economic analysis is conducted to assess the comparative clinical effectiveness, safety, and acquisition cost of l-glutamine and crizanlizumab for older adolescents and adults (⩾16 years old) with sickle cell disease in Qatar, with an emphasis on treatment costs and acute pain crises. Methods: We conduct a decision-tree model, where we compare the clinical and economic outcomes of two novel Food and drug administration (FDA)-approved medications which are available in Qatar; l-glutamine and crizanlizumab over a time horizon of 1 year in a hypothetical cohort of adult sickle cell disease patients from a Qatar healthcare perspective. The main outcome is incremental cost per sickle cell disease-related acute pain crises averted. Model clinical parameters were derived from individual drug randomized trials, published literature, whereas cost parameters from Qatar healthcare payer system (2020-2021). A sensitivity analysis was carried out, and the study results were robust around model inputs. Costs were converted to 2020 US dollars. Results: Study results showed that both treatment modalities' costs were the main driver of this analysis, with an average annual cost of the treatments per patient being $189,014 for crizanlizumab (5 mg/kg), $143,798 for crizanlizumab (2.5 mg/kg), and $74,323 for l-glutamine. The probability of no first-time sickle cell disease-related vaso-occlusive crises averted was 0.001/year for glutamine, 0.26/year for crizanlizumab (5 mg/kg), and 0.34/year for crizanlizumab (2.5 mg/kg). Lower dose crizanlizumab (2.5 mg/kg) dominated the higher one (5 mg/kg). The incremental cost-effectiveness ratio of crizanlizumab (2.5 mg/kg), when compared to l-glutamine was $81,265 per sickle cell disease-related vaso-occlusive crises averted. When comparing crizanlizumab (5 mg/kg) and l-glutamine, crizanlizumab (5 mg/kg) showed higher efficacy, yet the crizanlizumab incremental cost-effectiveness ratio was at $459,620 than l-glutamine. Conclusions: Crizanlizumab (2.5 mg/kg) may be a cost-effective intervention, yet it is not the approved dose for preventing vaso-occlusive crises in adolescents and adults with sickle cell disease. Crizanlizumab (5 mg/kg) was more cost-effective than the approved l-glutamine per sickle cell disease vaso-occlusive crisis prevented. Of note, we primarily focused on modeling acute vaso-occlusive pain, which limited our ability to consider other key outcomes in sickle cell disease.

Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study.

Background: Historically, sickle cell disease (SCD) patients experiencing frequent hospitalized vaso-occlusive crises (HVOC) have been associated with increased mortality, yet recent data reflecting the widespread use of hydroxyurea and advancements in disease management remain limited. Our study aims to assess the association between HVOC and mortality or severe complications in patients with SCD in this new treatment landscape. Methods: This was a retrospective observational cohort study using the French national health data system. Between 01-01-2012 and 12-31-2018, all SCD patients ≥16 years old (ICD-10 codes D57.0-2) were included and followed until 12-31-2018. HVOC was defined as a hospitalization of ≥1 night with primary diagnosis of SCD with crisis, following an emergency room visit. The association between HVOC and severe complications was assessed with a Cox proportional hazards model. Findings: In total, 8018 patients (56.6% females; 4538/8018) were included. The 2018 SCD standardized one-year period prevalence was 17.9 cases/100,000 person-years [17.4; 18.3]. The mean rate was 0.84 (1.88) HVOC/person-year. In 2018, 70% (5323/7605), 22% (1671/7605), and 8% (611/7605) of patients experienced 0, 1-2, or 3+ HVOCs, respectively. The median survival time between HVOCs was 415 days [386; 439]. Overall, 312 patients died (3.9%) with a mean age of 49.8 (19.4). Compared to patients without HVOC, the hazard ratios of death in patients with 1-2 or 3+ HVOCs the year prior to death were 1.67 [1.21; 2.30] and 3.70 [2.30; 5.93], respectively. Incidence of acute chest syndrome, pulmonary embolism, osteonecrosis, and sepsis increased with the HVOCs category, but not stroke. In 2018, 29.5% (180/611) of patients with 3+ HVOCs did not take hydroxyurea. Interpretation: Patients must be closely monitored during their hospitalizations to intensify treatment and check treatment compliance. Innovative therapies are also required. Funding: The study was funded by Novartis.

Sickle Cell Disease in Brazil: Current Management.

Sickle cell disease (SCD) comprises inherited red blood cell disorders due to a mutation in the ß-globin gene (c20A > T, pGlu6Val) and is characterized by the presence of abnormal hemoglobin, hemoglobin S, hemolysis, and vaso-occlusion. This mutation, either in a homozygous configuration or in compound states with other ß-globin mutations, leads to polymerization of hemoglobin S in deoxygenated conditions, causing modifications in red blood cell shape, particularly sickling. Vaso-occlusive crisis (VOC) is the hallmark of the disease, but other severe complications may arise from repeated bouts of VOCs. SCD is considered a global health problem, and its incidence has increased in some areas of the world, particularly the Americas and Africa. Management of the disease varies according to the region of the world, mainly due to local resources and socioeconomic status. This review aimed to describe more recent data on SCD regarding available treatment options, especially in Brazil. New treatment options are expected to be available to all patients, particularly crizanlizumab, which is already approved in the country.

Vaso-Occlusive Crises in Sickle Cell Trait Patients With Blood Loss Anemia: A Report of Two Cases.

This report of two cases confronts the longstanding perception of Sickle Cell Trait (SCT) as a clinically benign condition, highlighting its complex and severe clinical manifestations, particularly in the context of blood loss anemia and vaso-occlusive crises (VOCs). The hallmark of sickle cell disease is the severe pain caused by acute vaso-occlusion of the microvasculature that leads to bone marrow infarction. We report two cases of patients with SCT and severe anemia in the setting of blood loss secondary to uterine fibroids subsequently causing VOCs with likely bone sequestration. The occurrence of VOCs in SCT, while infrequent, can be serious and demands a high index of suspicion, particularly when patients appear in significant distress and cardiac or vascular etiologies are ruled out as a source. Reversal of anemia in this case provided quick resolution to symptoms, and we recommend other clinicians not disregard a differential of VOC in SCT carriers, and urge to treat patients as they would if they had sickle cell disease. This report challenges the conventional view of SCT as a condition of clinical benignity, calling for a recalibration in the clinical understanding, management strategies, and focus on this genetic trait under similar circumstances.

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.

A Novel Mechanistic Model for Future Research in the Elements of the ERAS Program in Patients With Sickle Cell Disease.

Enhanced recovery after surgery (ERAS) is a patient-centered, evidence-based, multidisciplinary team-developed approach to a surgical stress response that is implemented to optimize physiological function and facilitate recovery for the best possible outcomes from surgery. Although there are currently well-known published guidelines for the perioperative management of patients with sickle cell disease, there are currently no specific and evidencebased ERAS protocols that address the needs of these patients. A novel mechanistic model has recently been found that could change ERAS protocols for patients with sickle cell disease with regard to a current preoperative carbohydrate loading drink recommendation, nutrition and intravenous fluid management. ERAS has great benefits for most patient populations, but emerging research suggests that patients with sickle cell disease may process and respond differently to varying concentrations of serum glucose and serum cations (hyperglycemia and hypertonic states). This adverse response involves actin, a cytoskeletal protein, in the red blood cell and how increased hemoglobin glycosylation may lead to a malfunction in this protein and a transition to vaso-occlusive crises in patients with sickle cell disease. Further research is warranted with this new mechanistic model to develop more meticulous and customized perioperative management plans to address risk mitigation in patients with sickle cell disease.

Assessment of hypoxemia among young adults with sickle cell anaemia in steady state in southwestern Nigeria: a crosssectional study.

OBJECTIVES: Hypoxia is a known feature of sickle cell anaemia (SCA) which results from chronic anaemia and recurrent vaso-occlusive crisis (VOC) which can cause tissue ischaemia that leads to an end organ damage. The hallmark of SCA is chronic anaemia and recurrent vaso-occlusive crisis. The aim of this study is to compare the oxygen saturation of sickle cell anaemic individuals with the normal haemoglobin type (Hb AA) control and also to determine the prevalence of hypoxemia among SCA. RESULTS: Two-hundred and twenty-two (136 Hb SS and 86 Hb AA) participated in the study. The mean ± SD of age (years), oxygen saturation (%) and pulse rate (bpm) of participants with sickle cell anaemia and Hb AA control were 21.85 ± 3.04 and 22.14 ± 3.18 (t = 0.701, p = 0.436), 95.21 ± 3.02 and 98.07 ± 0.81 (t=-8.598, p < 0.0001) and 77.10 ± 9.28 and 73.16 ± 8.52 (t = 3.173, p = 0.002) respectively. The prevalence of hypoxemia among SCA participants was 47.1%. Prevalence of hypoxemia in males with SCA was 60.9% while 39.1% of the females had hypoxemia.

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

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.

Intravenous Hydration and Associated Outcomes in Patients With Sickle Cell Disease Admitted With Vaso-Occlusive Crises: A Systematic Review.

Acute painful vaso-occlusive crisis (VOC) is the common presentation of sickle cell disease (SCD) leading to emergency room visits, admissions, morbidity, mortality, and negative impacts on quality of life. Among various treatment approaches commonly employed to manage the condition, intravenous (IV) hydration is also frequently used in emergency and inpatient settings. Although helpful to overcome dehydration, IV hydration often leads to adverse outcomes like fluid overload, pulmonary edema, increased length of stay, transfer to intensive care unit, new oxygen requirement, etc. Small-scale retrospective studies are conducted to study the outcomes of IV hydration but have failed to conclusively demonstrate its benefits as well as choice of IV fluids, rate of IV fluid replacement, etc. We conduct this review as an attempt to summarize the available evidence on the role and utility of IV hydration in sickle cell crises along with reported adverse outcomes.

A Rare Case of Brodie's Abscess in the Tibial Diaphysis Masquerading as a Vaso-occlusive Sickle Crisis.

We present the case of a 19-year-old male with a history of sickle cell anemia who presented to the hospital with worsening lower extremity pain. Given his acute presentation and history of recurrent pain crises, he was admitted to the hospital for management of a suspected acute pain crisis. However, due to continued pain, imaging was obtained which revealed a different diagnosis for the cause of his symptoms. MRI of the left lower leg revealed heterogenous T1 and T2 hyperintense signals within the proximal tibial diaphysis measuring 6.6 × 1.6 × 2.2 cm with a thick rim of peripheral irregular enhancement with surrounding periosteal reaction and soft tissue edema, concerning for osteomyelitis and developing Brodie's abscess. The patient underwent tibia irrigation and debridement with the placement of vancomycin and tobramycin beads. Perioperatively, no purulence was noted within the soft tissues, and no organisms were grown on tissue cultures. The patient's pain improved and he was discharged home with a plan to complete six weeks of intravenous antibiotics. This case represents the need to differentiate Brodie's abscess from a sickle cell crisis. Clinicians should also be aware that patients with sick cell disease are prone to Brodie's abscess and it should be a differential for symptoms of relenting bone pain.

LentiGlobin Administration to Sickle Cell Disease Patients: Effect on Serum Markers and Vaso-Occlusive Crisis.

LentiGlobin, an innovative gene therapy, introduces a modified beta-globin gene that yields an anti-sickling hemoglobin variant. It boosts total hemoglobin levels, mitigates hemolysis, curtails inflammation, and addresses iron overload by reducing transfusion requirements. These changes, in turn, provide insights into disease mechanisms and treatment outcomes. Alterations in serum markers, such as hemoglobin levels and inflammatory biomarkers, can illuminate the therapeutic effectiveness of LentiGlobin and its impact on mitigating complications such as vaso-occlusive crises. Therefore, the purpose of this narrative review is to discuss the effects of LentiGlobin administration on diverse serum biomarkers and its correlation with vaso-occlusive crises in individuals with sickle cell disease (SCD).

Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity.

This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients' well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 35 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT05045820.