Sickle Cell Pain Research Articles

8194 Extramedullary Hematopoiesis Involving Bilateral Adrenal Glands In A Patient With Sickle Cell Anemia

Abstract Disclosure: V.T. Pham: None. L.N. Sendos: None. Title: Extramedullary hematopoiesis involving bilateral adrenal glands in a patient with sickle cell anemia Background: Extramedullary hematopoiesis refers to blood cell production occurring outside the bone marrow. It is a reactive process caused by inadequate production or excessive destruction of blood cells typically seen in patients with hereditary anemias or infiltrative bone marrow disorders. Extramedullary hematopoiesis usually occurs in the spleen, liver and lymph nodes, but it can also very rarely arise from the adrenal glands. Case Presentation:We present a case of a 42-year-old male with a history of sickle cell anemia who presented with chest pain and shortness of breath and had a chest CT angiography which incidentally showed a 5.6 x 3.8 cm left adrenal mass and a 2.9 x 2.1 cm right adrenal mass. Further evaluation with an MRI abdomen with and without contrast revealed a 5.5 cm lobulated left adrenal mass with patchy areas of microscopic fat and faint delayed heterogeneous enhancement as well as a 2.2 cm right adrenal nodule. The nodules were described as markedly T2 hypointense with heterogeneous T1 hyperintense/isointense signal on MRI with a broad differential diagnosis including extramedullary hematopoiesis in bilateral adrenal glands, lipid poor adenoma or neoplasm. Regarding his sickle cell disease history, the patient was diagnosed as an infant and had very rare episodes of sickle cell pain crisis as a child. However, once he entered adulthood, he began to have multiple episodes of sickle cell pain crisis requiring hospitalizations and transfusions. On further review of patient’s prior imaging scans during these previous hospitalizations, he was first noted to have bilateral sub centimeter adrenal nodules on a CT Abdomen without contrast done almost a decade prior to his current presentation. We ordered biochemical evaluation which did not show any evidence of adrenal hormonal hypersecretion. His case was discussed at our multidisciplinary conference with the radiology and surgery team and it was concluded that the imaging characteristics were most consistent with extramedullary hematopoiesis in the setting of bilateral adrenal gland involvement and patient’s history of sickle cell anemia. Therefore, no immediate surgical resection was recommended. Given the size of the left adrenal mass being greater than 4 cm in size, we advised follow-up imaging for surveillance. Discussion:There has been a rise in detection of adrenal incidentalomas due to the increased use of advanced diagnostic imaging in healthcare settings. When patients with hematologic diseases are found to have adrenal incidentalomas, it is important to consider extramedullary hematopoiesis in the differential diagnosis to avoid unnecessary invasive procedures and surgeries. Presentation: 6/2/2024

Abstract 4031: P-selectin as an emerging target for the treatment of primary and secondary brain tumors

Abstract Glioblastoma (GB) is an aggressive type of brain cancer with a high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells that have been shown to facilitate GB cell invasion and immune suppression. The mechanism by which GB cells alter microglia behavior is yet to be fully understood. One proposed mechanism involves adhesion molecules such as the Selectins family of proteins which are expressed on the surface of endothelial and immune cells and are involved in immune modulation and cancer immunity. We have previously shown that one member of the Selectin family, P-Selectin (SELP), is expressed by GB cells. Here, we investigated the functional role of SELP in GB-microglia interactions. First, we found that microglia cells facilitate the expression and secretion of SELP by GB cells, and that GB cells facilitate the expression of P-Selectin ligand-1 (PSGL-1) by Glioma-associated microglia/macrophages (GAMs). We then showed that SELP mediates GAMs-enhanced GB invasion and proliferation in our unique 3D-bioprinted ex vitro models and has a role in GAMs activation state. These findings were validated in vivo, showing that inhibition or downregulation of SELP leads to reduced tumor growth, increased overall survival, and improved immune response. Single-cell RNA-seq analysis of the tumors revealed an increase in pro-inflammatory GAMs signature, reduction in cancer cell tumorigenesis potential, and improved T cell activation. Thus, combining SELP inhibition with other immune checkpoint inhibitors, such as anti-PD-1, may have a synergistic effect by harnessing both the innate and the adaptive immune systems against the tumor. Furthermore, we found SELP/PSGL-1 axis to be involved in the progression of brain metastasis originating from melanoma, and breast, and lung cancer. Thus, we have begun an investigator-initiated clinical trial, testing the efficacy of the anti-SELP antibody, Crizanlizumab, alone or in combination with anti-PD-1 antibody, Nivolumab, for GB and melanoma brain metastasis patients (NCT05909618). Crizanlizumab, approved by the FDA and EMA for sickle cell pain crisis (VOC, Vaso-Occlusive Crisis) of sickle-cell anemia patients, was proven to be safe for human use, and efficient in inhibiting SELP function. As such, it has the potential to reduce tumor burden and improve patient outcomes. This work can improve our understanding of GAMs function, which may pave the way for new and effective treatments for primary and secondary brain tumors. Citation Format: Eilam Yeini, Ronnie Frommer-Shapira, Alisa Talianski, Paula Ofek, Sabina Pozzi, Nitzan Albeck, Dikla Ben-Shushan, Galia Tiram, Sapir Golan, Ron Kleiner, Ron Sheinin, Shlomit Reich-Zeliger, Rachel Grossman, Zvi Ram, Henry Brem, Thomas M. Hyde, Prerna Magod, Dinorah Friedmann-Morvinski, Asaf Madi, Ronit Satchi-Fainaro. P-selectin as an emerging target for the treatment of primary and secondary brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4031.

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

Management of Acute Sickle Cell Disease Pain.

Pain is a common complication of sickle cell disease. Sickle cell pain can often be effectively managed by pediatricians in outpatient and hospital settings. Acute pain management should be initiated quickly. Patients need to be evaluated for sickle cell complications and other causes of pain. Nonsteroidal anti-inflammatory drugs and opioids are the mainstay of pain treatment, but additional therapies include hydration, local pain control, muscle relaxants, and nonpharmacologic approaches. Healthy lifestyle habits and good behavioral and mental health are important for preventing and coping with sickle cell disease pain. Disease-modifying therapies, such as hydroxyurea, can help prevent sickle hemoglobin polymerization and acute pain episodes. Because sickle cell disease largely affects people who are racialized minorities in the United States, health-care providers need to be aware of how their own personal biases may affect care of these patients.

Improved Management of sickle cell pain crisis in a Pediatric Emergency Department through Use of Intranasal Fentanyl.

Introduction: National Heart, Lung, and Blood Institute recommends giving the first dose of opioids within 30 minutes of presentation to the emergency department for sickle cell disease patients with moderate to severe vaso-occlusive crisis. Intranasal fentanyl has been used extensively and shown to reduce time to the first dose of analgesic, improve pain scores at 20 minutes, and increase the odds of getting discharged from the emergency department. Material and methods: For phase one of the project, baseline data was collected. The new pain algorithm was introduced at the start of the second phase, which involved giving intranasal fentanyl as the first analgesic for vaso-occlusive crisis in the emergency department. After the intervention, the second analysis compared outcomes with phase one. Wilcoxon-Mann-Whitney tests were used for comparing data between phase one and phase two and Wilcoxon signed-rank tests (paired version) were used for comparing pain scores before and after analgesic. Results: Visits at phase two had significantly lower hospitalization rate [phase one 53.5% vs. phase two 34.2%(p value 0.005)], more fentanyl use [phase one 1.5% vs. phase two 50.6% (p< 0.001)], less patient-controlled-analgesia (PCA) opioid use after admission [phase one 13.0% vs. phase two 2.53% (p= 0.016)], higher compliance with outpatient visits [phase one 61.3% vs. phase two 98.7% (p < 0.001)], shorter length of hospital stay [phase one 117.6 ± 112.7 hours vs. phase two 68.3 ± 47.2 hours (p-value 0.01)], decrease in the time to first analgesic after coming to the emergency department (phase one 78.2 ± 131.2 minutes vs. phase two 38.3 ± 31.2 minutes (p 0.85)], and decrease in the mean pain score after first medication in the emergency department [phase one 5.48 ± 3.12 vs. phase two 4.46 ± 2.88 (p value 0.021)] Conclusion: Intranasal fentanyl led to more effective and timely management of vaso-occlusive crisis with improvement in clinical outcomes compared to standard management.

Role of Menstrual Bleeding Assessments in Sickle Cell Clinics in Improving Quality of Care for Women- a Multicenter Approach

Introduction: Reproductive health education is lacking among individuals with sickle cell disease (SCD) despite many females reporting increased pain during menstruation. Research suggests that SCD-related pain associated with menstruation may be regulated with the use of hormonal therapy. Yet, education about safe and available contraceptive therapies is often lacking during routine sickle cell visits, leading to increased pain-related healthcare utilization and suboptimal management of menses and contraception. In this prospective cross-sectional study, we hypothesized that menstrual bleeding assessments, in the form of surveys conducted during sickle cell clinic visits would prompt timely identification and management of menstruation complications in females with SCD. Methods: The study was primarily conducted by members of the Foundation for Women & Girls with Blood Disorders' Women & Girls SCD Learning Action Network (WGSCD LAN) and Pacific Sickle Cell Regional Collaborative (PSCRC). The menstrual bleeding assessment consisted of 4 surveys; a patient survey and provider survey both created by the WGSCD LAN, a validated menstrual bleeding questionnaire (MBQ) and a validated measure of global health from the Patient Reported Outcomes Measurement Information System (PROMIS). The patient survey included questions about the patients' experience with sickle cell pain in relation to menstruation, medications being used, their education, access to, and utilization of reproductive health services. The provider survey was completed after the provider reviewed the patient MBQ and surveys and included questions about the providers' access to reproductive health services, the patients' medical data, and the providers' plans of care for that patient. Sickle cell centers across the U.S. were recruited to participate through the WGSCD LAN and the PSCRC. Consented females who reached menarche for >12 months, had menses in the past 12 months, and were not pregnant or breastfeeding were requested to complete the patient, MBQ and PROMIS surveys by their sickle cell providers. For every patient survey filled, provider surveys were encouraged but not required. Results: After IRB approval at 9 U.S. sickle cell centers, 6 institutions enrolled 56 females with SCD for the MBQs and patient surveys, with 45 (80%) provider surveys and 32 (57%) short PROMIS surveys completed. Most patients had hemoglobin SS disease (71%). Thirty-six (64%) females were ≥ 18 years old (range 18-48 years), and 20 (36%) were 13-17 years old. Mean MBQ score for adults with SCD was 17.3 (SD 9.6) (mean validated score 10.8,SD 8.8) and for adolescents with SCD was 16.1 (SD 7.5) (mean validated score 19.6, SD 7.6). Thirty-five (63%) females reported sickle cell pain with menstrual cycles. Despite this, only 7 females (12.5%) reported using one or more hormonal therapies in the 3 months prior, including oral contraceptives (n= 4), Depo injections (n =5), and/or an intrauterine device (IUD) (n =1). Only one female reported using condoms. Most sickle cell providers (38/45) were not prescribing hormonal therapies to their patients, however, all providers reported having access to reproductive health specialists in their institutions. Seven females reported not having heard of hormonal therapy, including 3 females >18 years of age. NSAID use of ≥5 days in a 2-week period was reported by 22% of females (12/54). In the PROMIS survey, only 28% females reported very good to excellent physical health and only 47% reported very good to excellent mental health. After review of MBQ, PROMIS and patient surveys, provider surveys (n = 32) noted intent to or provision of one or more of these services: verbal education about hormonal therapy by 25 (66%) providers, referral to a reproductive health specialist by 14 providers (37%), work-up for iron deficiency by 6 providers (22.2%), and work up for bleeding disorders by 4 providers (14.8%). Conclusion: Patient reportedsickle cell pain with menstruation is quite prevalent, but hormonal therapy use is minimal despite availability of reproductive health specialists in most U.S. sickle cell centers. Menstrual bleeding assessments in the sickle cell clinic can facilitate a dialogue and recognition of reproductive health concerns among females with SCD and enhance medical attention and care from hematologists and reproductive health specialists in collaborative models of care.

Targeting p38 Mitogen Activated Protein Kinase to Ameliorate Pain in SCD

Pain is a major comorbidity of sickle cell disease (SCD). Central sensitization is associated with chronic sickle cell pain. Earlier studies showed that p38 mitogen activated protein kinase (MAPK) is activated in the spinal cords of sickle mice with nociceptor sensitization of 2˚ neurons (Cataldo et al., Pain 2015). Novel approaches targeting p38 MAPK phosphorylation or its upstream targets may alleviate chronic pain. Cannabinoids represent a novel approach for ameliorating pain, including the endogenous cannabinoid-like lipid mediator palmitoylethanolamide (PEA). PEA has been shown to reduce neuropathic pain and depression scores, while improving sleep concomitant with reduced c-reactive protein (CRP) in a clinical evaluation of diabetic peripheral neuropathic pain and inflammation (Pickering et al., Inflammopharmacology 2022). We therefore examined if, [i] p38 MAPK is activated in dorsal root ganglion (DRG) which transmits action potentials to spinal neurons; [ii] if PEA administration reduces spinal neuroinflammation, oxidative stress and neuronal p38 MAPK phosphorylation; and [iii] inhibition of p38 MAPK phosphorylation ameliorates chronic pain in SCD. Female Berkeley (BERK) sickle (HbSS) expressing >99% human sickle hemoglobin and/or control (HbAA) expressing normal human HbA, mice (3.5-5.0 months) were treated for 14-days with PEA (i.p., 20 mg/kg/d) or vehicle (veh; i.p., 7.5% DMSO, 7.5% Tween 20, in sterile PBS). At endpoint, spinal cords and plasma were collected. HbSS mice have constitutively higher spinal malondialdehyde (MDA) levels, a marker of oxidative stress, compared to HbAA mice (~50%, P<.05), and PEA treatment significantly reduced HbSS spinal MDA levels (~53%, P<.05, vs veh); pro-apoptotic caspase-3 (~91%, P<.01) and pro-inflammatory interleukin (IL)-1β (~42%, P<.05), which are constitutively elevated in HbSS compared to HbAA mice (~45%, P<.05). Concomitant with reduced spinal inflammation, PEA reduced global marker of inflammation, serum amyloid P (~42%, P<.01) in the circulation, an analog for human CRP, which is significantly higher in HbSS compared to HbAA mice (~700%, P<.01). Thus, PEA ameliorates spinal inflammation and oxidative stress, and inhibits apoptosis. DRG neurons in vitro isolated from sickle mice were treated with tumor necrosis factor α (TNF α; 1 ng/mL) and hemin (40 mM) to create a sickle microenvironment replete with inflammation and oxidative stress, which significantly increased p38 MAPK phosphorylation (~494%, P<.001). PEA (30 mM) treatment of the neurons significantly inhibited TNF α and hemin-induced MAPK phosphorylation and its nuclear translocation (~65%, P<.001). Thus, it is likely that both peripheral and central mechanisms mediated by p38 MAPK signaling contribute to the initiation and maintenance of pain in SCD which are inhibited by PEA. Neflamapimod (Nef) is a novel inhibitor of p38 MAPK phosphorylation with significant anti-inflammatory effects, mediated by IL-1β and TNF α. Nef is orally bioavailable and has been suggested to improve synaptic transmission. We evaluated the effect of orally administered Nef (6 and 12 mg/kg 2x daily; veh 0.1% pluronic acid in sterile H 2O) in female sickle mice (9.0 months) with hyperalgesia. Treatment with Nef 12 mg/kg/d for 7-days reduced mechanical (~42% & ~34%, both P<.01, vs veh & baseline, respectively) and cold hyperalgesia (~46% & ~34%, both P<.001, vs veh & baseline, respectively). A decrease was also observed in mechanical (~29%, P<.05, vs veh) and cold hyperalgesia (~24%, P<.05, vs veh) after 7 days with 6 mg/kg Nef treatment. These data suggest p38 MAPK signaling contributes to chronic pain in SCD. Together, our observations demonstrate the therapeutic potential of PEA and Nef in targeting p38 MAPK as novel interventions to ameliorate sickle cell pain and central sensitization. PEA is a safe nutraceutical which has shown effectiveness in many pain conditions including osteoarthritis. Nef has shown efficacy in improving cognitive function in Phase II clinical trials in dementia patients. Pain and cognitive impairment co-exist in SCD. Therefore, Nef has the potential to reduce pain and improve cognitive function in SCD.

Mechanism-Based Targeting of Sickle Cell Pathobiology and Pain with Novel Transdermal Curcumin

Pain is a debilitating consequence of sickle cell disease (SCD). We examined the potential of novel topical transdermal curcumin (TDC) gel with transdermal systemic delivery to target pain and SCD pathobiology. Curcumin is an antioxidant and anti-inflammatory polyphenol with therapeutic potential but has poor oral bioavailability. TDC gel (Vasceptor TM, Vascarta Inc.), containing 0.1 M of curcuminoids (derived from Curcugen, Dolcas-Biotech, LLC), or vehicle were applied (0.1 mL) topically by gentle rubbing to the abdomen on alternating days for 3 weeks followed by analysis of blood, organ pathology and skin secretome. Using high-performance liquid chromatography, we found that curcumin levels peaked in the plasma (7.87 µg/mL) and blood cells (6.78 µg/mL) 60 min following administration in C57BL/6 mice, thus, showing efficient bioavailability. Next, we used humanized ‘ sickle‘, homozygous transgenic mice ( HbSS-BERK) expressing >99% human sickle hemoglobin (HbSS) without mouse α- and β-globins. These mice mimic the pathobiology and features of pain observed in persons with SCD. We observed that TDC application in male and female HbSS led to a significant decrease in hyperalgesia over the 21 days (D) of treatment. Mechanical hyperalgesia significantly decreased after 14D of treatment in males and after 21D in females (p<.05 and p<.01, respectively Vs. BL). Similarly, cold hyperalgesia (paw withdrawal frequency on cold plate at 4˚C) decreased significantly in males after 24 hours and in females after 7D of TDC treatment (p<.05 and .01, respectively Vs. BL). Non-evoked cold avoidance showed that males spent significantly more time in the colder chamber at 23ºC on 14D, and females did so on 21D after TDC treatment (p<.001 & p<.01, respectively Vs. BL). Throughout 21D TDC treatment, females showed significantly lower analgesic response in cold hyperalgesia compared to male HbSS, similar to relatively poor response to analgesia in female Vs. male individuals with SCD. The amelioration of hyperalgesia for 21D with TDC suggests a disease-modifying effect. Indeed, we observed a significant increase in hematocrit (p<.05), a reduction in reticulocytes (p<.05), and an appreciable increase (43.2%) in Hb and decreased lactate dehydrogenase activity in the blood of TDC-treated HbSS mice Vs. vehicle (p<.01). RBCs from TDC treated HbSS mice showed enhanced ATP levels (p <.01) and reduced protein carbonylation, both biomarkers of protein oxidation (p<.045) Vs RBCs from vehicle-treated HbSS. Histopathology showed a significant reduction in vascular congestion and iron deposits in TDC-treated male HbSS compared to vehicle in the spleen (p<.0003 & p<.001, respectively) and in % fields involved in hepatic infarcts and iron deposits (p<.02 & p<.044, respectively). Together, decreased hemolysis, increased Hb, hematocrit, and ATP suggest RBC stabilization, improved mitochondrial metabolism, and reduced oxidative stress and organ damage, leading to a disease-modifying effect of TDC. TDC also significantly reduced global inflammatory marker serum amyloid-P (p<.05) and inflammatory cytokines in the skin secretome with a concomitant reduction in interleukins [2 (p<.05), 4 (p<.01), and 6 (p<.01)], monocyte chemoattractant protein 1 (MCP-1; p<.01), interferon-gamma (IFN-γ; p<.05), granulocyte macrophage-colony stimulating factor (GM-CSF; p<.01), and regulated on activation, normal T-cell expressed and secreted protein (RANTES; p<.05) compared to vehicle. MCP-1 contributes to neuropathic pain and inflammation; GM-CSF stimulates granulocyte differentiation and growth. Both RANTES and MCP-1 may also activate mast cells. TDC led to a significant decrease in cutaneous mast cell degranulation (p<.001) Vs. vehicle in sickle mice. These data strongly suggest an anti-inflammatory effect of TDCby targeting the release of cytokines and inhibiting granulocyte activity. TDC significantly ameliorates hyperalgesia (chronic pain), inflammation, hemolysis, oxidative stress, and organ damage and improves mitochondrial function and hematological parameters of SCD pathobiology, indicative of disease modifying and anti-nociceptive effects. The results suggest if started early in life, the use of an easy-to-deploy novel TDC formulation, with increased bioavailability and non-toxic properties that directly target sickle cell pathobiology, may prevent chronic pain in SCD.

Characteristics and Trends of Hospitalizations for Sickle-Cell Related Complications

Introduction There are approximately 100,000 people living with sickle cell disease (SCD) in the United States. As per the Center for Disease Control estimates, almost all patients with SCD will require hospitalization more than once a year and visit the emergency department at least 2-3 times a year on average. Previous studies have shown that SCD hospitalization trends are steadily increasing in the country. In November of 2019, two new drugs, crizanlizumab (to decrease the frequency of vaso-occlusive crises) and voxelotor (to increase hemoglobin response), were approved by the Food and Drug Administration (FDA) for the treatment of sickle cell disease. Around the same time, the entire health care system experienced disruption in the form of the COVID-19 pandemic. Hence, we conducted this retrospective study to assess SCD hospitalization trends from 2016-2020 and stratified them across various demographic factors to analyze the underlying causes. Methods We conducted a retrospective study from the National Inpatient Sample (NIS), which is a large all-payer database created by the Health Care Cost and Utilization Project (HCUP). We included all adult patients with a diagnosis of SCD (HbSS, HbSC, Sickle/b thal, and other variants) and identified their trends of hospitalizations for various SCD-related complications like vaso-occlusive crises, heart failure exacerbation, acute kidney injury, stroke, sepsis with and without septic shock, bacteremia, pneumonia, osteomyelitis, acute chest syndrome, splenic sequestration, and priapism. We then did a linear-to-linear analysis and ANOVA test to stratify these trends across various age, gender, income, and location groups. SPSS was used for the statistical analysis. Results Our study included a total of 19,250 patients who had at least one admission for sickle cell-related complications during 2016-2020. The average number of admissions for sickle cell pain crisis steadily increased from 10.2 per 100,000 in 2016 to 14.7 in 2019 and then decreased to 13.9 in 2020. Priapism steadily declined from 2.3% in 2016 to 1.4% in 2020 (p<0.001). Acute kidney injury complicated 4.9% of admissions in 2016 and steadily rose to 5.2% of admissions in 2020 (p = 0.88). Admissions complicated by bacteremia peaked in 2017 (0.9%) but have since been on a decline (0.5% in 2020) (p-0.02). Admissions complicated by pneumonia showed a steady decline from 6% in 2016 to 4.3% in 2020 (p<0.001). Admissions with osteomyelitis, splenic sequestration, acute chest syndrome, heart failure exacerbation, stroke, and sepsis complicated <1% of all admissions and were not statistically relevant. When stratified by age, it was noted that the age group of 18-39 had the most admissions. Females consistently had more admissions than males. Medicaid was the predominant insurance among all the admissions, followed by Medicare. Around 50% of the patients admitted for SCD-related complications were in the 0-25th percentile of median household income quartiles. The majority of admissions were seen in urban teaching hospitals. The majority of these admissions were also seen in the Southern regions. Conclusion Our results show that female patients in the age group 18-39 years, those covered by Medicaid and Medicare, and those in lower income quartiles comprised the majority of admissions for SCD-related complications. This demonstrates disparities in SCD care, wherein patients in lower socio-economic strata may not have access to newer advances in SCD treatment. Although it is optimistic to note that admissions for pain crises had a significant decline from 2019-2020, it remains to be seen whether these numbers are due to new therapies or due to the disruption of healthcare services caused by the pandemic. Analyzing more long-term trends after the year 2020 will help us understand this impact. The overall trend of infections and sepsis has been low, likely due to widespread vaccinations and early antibiotic treatments. It is interesting to note that although there was a downtrend for the majority of SCD complications, the incidence of AKI during admissions is steadily rising, validating the need to focus more on renal care in sickle cell patients.

Patient, Caregiver, and Healthcare Provider Perspectives on Pharmacologic and Non-Pharmacologic Therapies for Pain in Sickle Cell Disease

Background: Pain is the main cause of poor quality of life among patients with sickle cell disease (SCD). While opioid therapy is the mainstay of treatment for acute SCD pain, it can be complicated by side effects and toxicities. A multimodal, multidisciplinary approach to pain management that promotes non-pharmacologic therapies can improve the quality of care for patients with SCD by addressing biopsychosocial components of the pain experience. Guided by the Consolidated Framework for Implementation Research (CFIR), this study utilized qualitative interviews with patients, caregivers, and healthcare providers at our institution to assess barriers to the use of non-pharmacologic and pharmacologic therapies for pain in SCD. Methods: Semi-structured qualitative interviews were conducted with adolescents and young adults (AYAs; ages 13-21) with SCD, caregivers of AYAs with SCD, and healthcare providers at our institution. AYAs had either a documented history of chronic pain and/or ≥1 admission/year for vaso-occlusive crises (VOCs) for at least one year from 2016-2022. After informed assent and/or consent were obtained, individual semi-structured interviews were conducted. Open-ended interview questions explored existing knowledge, perceptions, and barriers to pharmacologic and non-pharmacologic therapies for pain in SCD. Interviews proceeded until no new themes emerged in each group (i.e., thematic saturation). Interviews were analyzed using descriptive content analysis facilitated by Dedoose software. The CFIR and prior research informed a preliminary codebook, which was revised as new themes emerged. The coders independently coded transcripts and then met to discuss and resolve any discrepancies in coding. Results: Demographics: Eighteen AYAs, 17 caregivers, and 22 healthcare providers were interviewed. Of the AYAs, 61% were female, mean age was 17 years, and the most common SCD genotype was HgbSS (56%). Of the caregivers, 88% were mothers, with a mean age of 43 years. There were 15 AYA/caregiver dyads who participated. The following healthcare providers who care for patients with SCD were interviewed: physicians (31%), nurse practitioners (14%), nurses (14%), child life specialists (14%), psychologists (9%), art therapists (4.5%), healing touch providers (4.5%), physical therapists (4.5%), and social work (4.5%). Themes: Barriers to the use of non-pharmacologic therapies for pain management in SCD can broadly be grouped into two major themes: lack of knowledge about options and lack of access to non-pharmacologic options. Regarding lack of knowledge, most AYAs and caregivers endorsed a lack of knowledge about specific non-pharmacologic therapies (e.g., yoga therapy, healing touch, acupuncture), including their benefits, risks, and their abilities to reduce pain. Like AYAs and caregivers, many healthcare providers had limited knowledge about specific non-pharmacologic therapies and the evidence in support of their usage. Regarding lack of access to specific options, the majority of participants questioned the ability of patients to access non-pharmacologic options for pain management including availability of options and cost of access. Additional themes included a desire for more education about pain and pain management options. AYAs and caregivers were particularly interested in more information about yoga. Additionally, AYAs and caregivers were interested in education early in life before pain episodes occurred. Conclusions: Emerging themes among all groups include an interest in non-pharmacologic therapies for pain in SCD, but with limited knowledge on benefits, risks, options, and access to these therapies. As the American Society of Hematology (ASH) guidelines recommend non-pharmacologic therapies for sickle cell pain, it is crucial to implement these therapies into the management of pain in SCD. Education about different options paired with implementation options for ways to incorporate non-pharmacologic therapies is necessary to optimize pain control and improve quality of life. A particular focus on yoga therapy, with availability of a yoga therapist in medical settings, and organized yoga education events specific for SCD may be beneficial to engage individuals in yoga therapy with a trained yoga-therapist. As a next step, evaluation of these potential implementation strategies will occur within our health system.

Implementation of a Best Practice Alert and Dedicated Hematology Consultation on Hospitalization Outcomes of Patients with Sickle Cell Disease

Introduction The American Society of Hematology (ASH) guidelines recommend rapid (within 1 hour) administration of tailored pain medication and frequent reassessments to optimize pain control in persons with sickle cell disease (SCD) presenting with acute pain related to SCD (Brandow et al., 2020). Implementation of an individualized pain plan (IPP) has been associated with decreased length of stay and lower rate of 7-day readmissions (Welch-Coltrane et al., 2021).Early initiation of sustained analgesia results in more rapid resolution of vaso-occlusive crises (VOC) in 80% patients. While all of our patients have an IPP, provider knowledge of the existence of IPPs and where to find them has been challenging to properly implement this practice. All inpatient SCD patients receive hematology consults but lack of continuity and experience with patients can be challenging for them. The study aimed to investigate the impact of implementing a Best Practice Alert (BPA) and introduction of dedicated SCD nurse practitioner (NP) on consults on various clinical metrics related to patients with sickle cell disease during hospitalization. Methods We created a best practice alert (BPA) that is triggered when a patient with SCD is admitted to the inpatient service. It directs the admitting team and nursing staff to the IPP and an order set for sickle cell pain crisis. The nursing interface of the BPA also includes a link to an educational module. Data was collected pertaining to length of stay, readmission, and percentage of admissions with a hematology consult placed from before and after implementation of the BPA. Around the same time, a dedicated nurse practitioner managed consults for patients hospitalized with sickle cell VOC and provided education to the primary team. We then conducted a retrospective chart review of all sickle cell patients at the University of Wisconsin from January 1, 2021, to December 31, 2023. We included all patients 18 years and greater with a sickle cell disease diagnosis as identified by the ICD-10 code (D57.00) and excluded patients with restricted research participation. We used descriptive statistics to obtain summaries of patient demographics as percentages for categorical variables and mean values for continuous data. Results Preliminary data demonstrated that the number of distinct patients with admissions decreased from 47 pre-BPA to 30 post-BPA (Table 1, Figure 1). The average length of stay in days decreased with 7.87 days pre-BPA to 6.35 days post-BPA. The average number of days between previous discharge and readmission increased from 45.65 to 85.65 after implementation. Readmissions at 7 and 30 days decreased by 17% and 4%, respectively. Conclusion The goal of this QI initiative was to improve IPP implementation by introducing a BPA in the chart directing admitting providers to the plan for efficient use. Dedicated SCD NP provided continuity and ensured IPPs were followed. While we could not directly measure the implementation of IPP with each BPA trigger, relevant patient-related outcomes such as readmissions and length of stay were reduced with meaningful reduction in LOS by 1.52 days during the first 9 months of these changes. In the future, we plan to further refine this process and expand our outcomes data by obtaining patient and provider feedback via surveys to fully understand the impact of this process and continue improvements. The role of SCD NP will be expanded due to encouraging results. In summary, BPA alerts in the chart for rapid implementation of IPPs, along with a knowledgeable SCD consult provider to ensure proper follow up of plans is a feasible strategy to improve patient outcomes when admitted with VOC.

Advancing Care of Patients with Sickle Cell Disease through a Transformative Quality Improvement Initiative

Background Managing sickle cell disease (SCD) and its associated complications requires specialized knowledge often limited in primary and emergency care settings. Despite the availability of guideline recommendations and an expanding therapeutic landscape, hematologists experience challenges in managing sickle cell pain and implementing multidisciplinary care coordination that improves morbidity, overall disease management, and quality of life. To improve SCD care, we conducted a quality improvement (QI) study, bringing together healthcare professionals (HCPs) from established SCD centers to assess current practice patterns and develop strategies to overcome barriers to acute pain management and transitions of care for patients with SCD. Methods This QI initiative is comprised of baseline surveys (n = 115), pre- and post-surveys (n = 71) from the small-group, team-based audit-feedback (AF) sessions (Table 1), and 90-day follow-up surveys of HCPs from the four enrolled centers. Survey questions were designed to assess knowledge, confidence, and experiences managing acute pain, transitioning care, and keeping up with the latest clinical evidence and guideline recommendations for SCD. Care teams from each clinic, along with a nationally renowned expert SCD physician, participated in audit and feedback sessions to (a) assess system-specific practice gaps identified via the provider surveys, (b) prioritize areas for improvement, and (c) develop action plans for addressing root causes. Results Baseline surveys results revealed providers' top challenge encountered in managing patients with SCD as managing acute complications (40%) (Figure 1). Gaps were observed in clinicians reporting high/very high confidence in their ability to adequately manage SCD patients' acute pain episodes (51%), align clinical practices with evidence-based SCD guidelines (44%), and coordinate transitions of care (33%). Furthermore, baseline surveys showed only 19% of providers reported they are very/extremely satisfied with their current process for transitioning patients, noting top challenges in patient's difficulty navigating the adult healthcare system (47%) and deficiency of providers caring for patients with SCD near me (26%). Following participation in the AF sessions, clinicians indicated gains in high/very high confidence in their ability to adequately manage an acute pain episode for a patient with SCD (52% to 69%) and ability to coordinate transitions of care for patients with SCD (44% to 56%). During the AF sessions, Care teams set goals to improve provider education, appropriate acute care management of SCD and patient engagement. Action plans to achieve these goals include sharing the action plan with additional clinical team members (47%), collaborating among clinical teams to improve pain management plans for patients with SCD (39%) and improving patient education about SCD (31%). In 90-day follow up surveys, 75% of clinics reported improvements in acute pain management and transitions of care for patients with SCD. Furthermore, the top 3 areas of most improvement at the time of follow-up were enhancing sickle cell education provided to patients (75%), supporting teenage and young adult patients in independently managing their own care (50%), and coordinating meetings with local adult sickle cell providers and teenage/young adult patients and families (50%). Conclusions Through this QI initiative, clinical teams identified barriers to optimal SCD care, creating and implementing specific action plans to increasing knowledge of SCD and evidence-based therapies, optimizing transitions of care and improving acute pain management. While meaningful confidence and action plan gains were demonstrated, these data underscore clinical practice gaps to address in future initiatives to support safe, effective, and evidence-based processes for managing SCD to prevent complications and optimize outcomes and quality of life. Study Sponsor Statement The study reported in this abstract was funded by educational grants from Vertex Pharmaceuticals Incorporated and Agios Pharmaceuticals, Inc. The grantors had no role in the study design, execution, analysis, or reporting.

Telemedicine Triage Model for Infusion Center-Based Management of Uncomplicated Acute Sickle Cell Pain Episodes

Introduction: Patients with sickle cell disease (SCD) develop acute episodes of pain for which they seek care in the hospital emergency department (ED). Infusion center (IC)-based care is an effective alternate treatment strategy for management of uncomplicated pain episodes. However, at our center, we could not obtain institutional buy in for dedicated IC resources. Hence, we developed a telemedicine-guided “add on” IC model, embedded within our institution's cancer infusion services. Here, we evaluate the feasibility of our telemedicine-guided IC model and its effectiveness in managing acute pain episodes and impact on SCD patient care. Methods: A multi-disciplinary team consisting of the SCD clinical team including Nurse Case Manager, Advanced Practice Provider (APP), MD and the IC team including IC leadership, IC charge RN, IC scheduler was assembled. An agreement was made between the SCD team and IC leadership that at least one “add on slot” would be made available for an acute SCD pain visit every day. A workflow was created integrating telemedicine for communication with patients and team members alike, and all team members were educated regarding the workflow (Figure 1). IC leadership was re-engaged when changes needed to be made to the workflow to accommodate more IC visits. Visit numbers for IC visits, emergency department (ED) same day discharges and inpatient (IP) hospitalizations were collected from the electronic medical record and compared for pre-IC development (Jan 1, 2017- Dec 31, 2018) and post IC (January 1, 2021 - Dec 31, 2022). Statistical analysis was performed using Graphpad/Prism assuming nonparametric distribution where applicable. Results: We were able to successfully implement our telemedicine-based IC workflow for management of acute SCD pain. Given the rapid increase in IC requests and need for accommodating more than one patient a day, we engaged nursing leadership and re-designed the workflow to identify additional “add on” slots at various IC locations in our health system, added extended hours and weekend capacity. IC visits for uncomplicated pain episodes increased nearly 9 fold, from 132 visits in the pre-IC period to 1151 visits in the post IC period. Seventeen patients used the IC in the pre-telemedicine period and 53 patients used the IC in the post-telemedicine period. The number of ED same day discharges decreased by 35.2%, from 372 visits in pre-IC phase to 241 visits in post IC period. The number of IP hospitalizations went from 281 to 278. ED visits per IC user per year decreased from 10.9 to 2.4 and IP hospitalizations per IC user per year decreased from 8.3 to 2.6. There was a positive correlation between number of IC visits and ED discharges (Spearman r 0.27, p= 0.06) and between number of IC visits and inpatient hospitalizations (Spearman r 0.4, p=0.006), indicating that the patients who were high users of IC based services also had high rates of ED use and hospitalizations. Twenty four patients who used the IC in 2022 did not have same day ED discharges, 15 patients did not have IP stays and 10 patients did not have IP or ED visits in 2022. Among these 10 patients, 8 had their first IC contact under the telemedicine triage IC model (2021-2022). Conclusions: Telemedicine based IC triage can be a successful model for delivery of IC based care for management of acute SCD pain and of great value in settings where dedicated resources are not available. The total number of ED discharges decreased after incorporation of our model, as did both ED discharges and IP hospitalizations per IC user per year. Patients with high numbers of IC visits were also high utilizers of hospital-based services. A cohort of patients were able to use the IC alone for pain management and did not use the ED or get hospitalized.

Building Adaptive Coping and Knowledge to Improve Daily Life (Back2Life): A Pilot Feasibility Trial for Youth with Chronic Sickle Cell Pain

Introduction: Cognitive-behavioral therapy (CBT) for pain is an effective non-pharmacological treatment for chronic pain management, yet can have limited generalizability, access, and reach for underrepresented populations like youth with sickle cell disease (SCD). We aimed to conduct a single-arm proof-of-concept clinical trial to evaluate the feasibility, acceptability, and preliminary efficacy of Back2Life, an adapted, culturally congruent CBT intervention for youth with chronic SCD pain and their parents. We hypothesized that Back2Life would be feasible and acceptable as demonstrated by high levels of treatment engagement (≥80% attendance of treatment sessions) and satisfaction. We also expected clinically significant reductions in pain and pain interference and improvements in pain coping efficacy from baseline to 3-month follow-up (primary endpoint) and 6-month follow-up (maintenance endpoint). Methods: Youth receiving care at comprehensive SCD clinics at 3 tertiary care locations within a southeast children's hospital were included if they were aged 10-18 years, any SCD genotype, reported chronic pain (i.e., pain on most days per month for at least 3 months), had English fluency, and had stable disease-modifying treatments in the past 3 months. Youth were excluded if they had comorbid medical conditions typically associated with pain but unrelated to SCD, had significant cognitive or developmental limitations that would interfere with study procedures, or received ≥ 3 sessions of outpatient psychological therapy for pain management in the preceding 6 months. Patients completed assessments at baseline, post-treatment, 3-month follow-up, and 6-month follow-up. Primary outcomes included pain characteristics (i.e., intensity, frequency, burden), pain interference, and coping self-efficacy. Secondary outcomes included depressive symptoms, pain catastrophizing, and sleep quality. The Back2Life program included evidence-based CBT treatment manuals that were adapted based on qualitative feedback from patient and parent stakeholders to optimize the cultural congruence and relevance to chronic SCD pain. Back2Life was an adaptive treatment comprised of 6-10 module-based sessions delivered by a behavioral health coach via telehealth. All participants received 6 core sessions and up to 4 additional sessions were included to optimize tailored treatment components to address individual family needs. Tailored sessions targeted common co-morbidities associated with chronic pain and were identified based on findings of the baseline assessment. Families also could opt-in to tailored sessions based on interest. Descriptive statistics were conducted to evaluate feasibility and acceptability metrics as well as clinically significant changes in primary and secondary clinical outcomes. Results: Youth (n=20) were on average 15.9 years old (SD=1.6), 50% female, 100% Black or African American, and 95% Non-Hispanic/Latinx. Most (80%) had hemoglobin types HbSS or HbSβ 0. Feasibility and acceptability ratings were high, including 85% consent rate, 80% initiated study procedures, 100% treatment session completion, 93% intervention fidelity, 100% reported moderate-high treatment satisfaction, and strong qualitative feedback suggested treatment acceptance. Patients reported clinically significant changes from baseline to 6-month follow-up in pain frequency (>35% reduction), worst and typical pain intensities (>30% reduction), SCD pain burden (>30% reduction), pain interference (moderate to mild severity), and improvement in pain coping self-efficacy (see Table 1). Patients also reported changes in pain catastrophizing (high to moderate severity), depressive symptoms (mild severity to within normal limits), and no change in sleep quality. Conclusions: The Back2Life treatment program demonstrated high feasibility and acceptability, participant engagement, participant retention, and meaningful changes in patient-reported outcomes. An adapted, culturally congruent, telehealth-delivered CBT for pain intervention tailored to meet the unique needs experienced by youth with chronic SCD pain can promote increased access, reach, and health equity in SCD.

Use of IV Hydration Instead of Exchange Transfusion for Prophylactic Management of Pain Crisis in Homozygous (SS) Sickle Cell Disease Helps Maintain Hgb Levels and Prevents Further Escalation of Iron Overload

Introduction: Indications for exchange transfusion in the management of sickle cell disease and its complications are over time becoming limited. Currently accepted indications include acute chest syndrome and cerebrovascular accidents only. However, there is often consideration of using exchange transfusions for management of sickle cell pain crisis episodes resistant to opioid-based pain management. This is, however, of questionable efficacy due to concerns of iron overload as well as alloimmunization. The excessive utilization of blood products also presents a significant challenge. Therefore, it is important to explore alternatives to exchange transfusion in the management of pain crisis in sickle cell disease. Method: This study aimed at investigating the effects of transitioning patients with homozygous SS disease from routine exchange transfusions to IV hydration protocols. The main objective was to examine the changes in Hgb levels and the status of iron overload in these patients. A cohort of 16 patients with a Ferritin level above 1000 ng/ml, who were already receiving regular exchange transfusions, were included in the study. Their Hgb levels and Ferritin levels were measured periodically. This group was then given IV hydration twice a week, regardless of whether they were experiencing pain issues. We then compared the Hgb and Ferritin levels during a 6-month period of active exchange transfusions and 6-month period of being on IV hydration protocols. Both periods were a year apart, allowing for adequate homeostatic changes to take place. Additionally, we compared the number of simple transfusions during both these periods. Result: The mean ferritin level in patients getting exchange transfusions was 6097 ng/mL with the mean Hgb level maintained at 7.48 g/dL. During the initial study period, there were 14 exchange transfusion sessions involving 96 units of packed red blood cells (PRBCs). Additionally, 8 units of simple transfusion units were administered during the same period. Interestingly, as this cohort transitioned away from exchange transfusions, the number of simple transfusions increased to 30. Only one exchange transfusion occurred during the second 6-month observation period. During this time, ferritin level stopped increasing, and the mean was measured at 6076 ng/ml. The Hgb levels did show a slight decrease, with the mean being 6.90 g/dL, but the difference was not statistically significant. Conclusion: The findings of this study suggest that the use of IV hydration protocol is effective in managing iron overload issues and maintaining an adequate Hgb level in patients who were previously undergoing routine exchange transfusions to prevent or manage pain crisis episodes. The results indicate that IV hydration should be initiated when ferritin levels increase beyond 1000 ng/ml, rather than waiting for more advanced stages. Moreover, the study shows that even when IV hydration is started at a later stage of iron overload, it still appears to limit further iron accumulation, as evidenced by the stabilization of ferritin levels. Overall, the use of IV hydration as an alternative to routine exchange transfusions holds promise in managing pain crisis and iron overload in sickle cell disease.

A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study of Mitapivat in Patients with Sickle Cell Disease: RISE UP Phase 2 Results

Background: Sickle cell disease (SCD) is characterized by the presence of hemoglobin S (HbS), a structural variant caused by a mutation in the HBB gene. Deoxygenated HbS molecules polymerize into “fibers”, causing red blood cells (RBCs) to sickle and hemolyze. Sickled RBCs have a shortened lifespan and impede blood flow to tissues, causing painful vaso-occlusive crises. Recurrent microvascular damage and chronic hemolytic anemia result in progressive multi-organ damage. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase, a key enzyme in RBC metabolism, with a dual mechanism of action under investigation in SCD: it increases adenosine triphosphate (ATP) in RBCs, improving survival, and decreases 2,3−diphosphoglycerate, increasing Hb oxygen affinity and thus diminishing HbS polymerization and RBC sickling. RISE UP is a global Phase (Ph) 2/3 double-blind, randomized, placebo (PBO)-controlled trial evaluating the efficacy and safety of mitapivat in patients (pts) with SCD (NCT05031780). Methods: In the Ph 2 double-blind period (DBP), 2 dose levels of mitapivat were evaluated against PBO for 12 weeks (wks). Eligible pts were ≥16 years with ≥5.5 to ≤10.5 g/dL Hb and ≥2 to ≤10 sickle cell pain crises (SCPCs, including pain, priapism, acute chest syndrome, hepatic sequestration, and splenic sequestration) in year prior to entry. Pts were randomized 1:1:1 to mitapivat 50 mg twice daily (BID), mitapivat 100 mg BID, or matched PBO. Pts completing the DBP were eligible to receive mitapivat in a 216-wk open-label extension. Primary endpoints were Hb response (≥1.0 g/dL increase in average Hb concentrations from Wks 10 through 12 compared with baseline [BL], tested with Fisher's exact test at 2-sided 0.05 significance level) and adverse events (AEs), including the type, severity, and relationship to study drug. Prespecified secondary endpoints included average change from BL from Wks 10 through 12 in Hb, markers of hemolysis, markers of erythropoiesis, and pt-reported fatigue score, as well as annualized rate of SCPCs. Results: In the Ph 2 DBP, 79 pts were randomized and treated with mitapivat 50 mg BID (n=26), mitapivat 100 mg BID (n=26), or PBO (n=27). In the 50 mg BID, 100 mg BID, and PBO arms, mean (SD) age was: 29.9 (7.79), 30.2 (10.52), and 28.5 (10.30) years; female: 57.7%, 61.5%, and 74.1%; mean (SD) BL Hb: 8.76 (1.295), 8.82 (0.898), and 8.49 (1.141) g/dL; mean (SD) number of SCPCs during previous year: 3.1 (1.83), 3.2 (1.65), and 3.4 (1.91), respectively. The primary endpoint was achieved; 46.2% (12/26) of pts in the 50 mg BID arm and 50.0% (13/26) in the 100 mg BID arm demonstrated a significant increase in Hb response compared with 3.7% (1/27) of pts in the PBO arm (2-sided p=0.0003 and p=0.0001, respectively). Mitapivat was generally well tolerated; observed safety profile was consistent with previously reported data of mitapivat in SCD and other hemolytic anemias. No serious treatment-emergent AEs were related to study drug; no AEs led to study drug discontinuation or death. Least-squares mean (LSM [95% CI]) for average change from BL in Hb levels from Wks 10 through 12 was 1.11 (0.77, 1.45) g/dL, 1.13 (0.79, 1.47) g/dL, and 0.05 (−0.28, 0.39) g/dL for 50 mg BID, 100 mg BID, and PBO arms, respectively ( Figure). Improvements were observed in markers of hemolysis and erythropoiesis. SCPCs annualized rates (95% CI) were 0.83 (0.34, 1.99) and 0.51 (0.16, 1.59) for 50 mg BID and 100 mg BID arms, respectively, compared to 1.71 (0.95, 3.08) for PBO. LSM (95% CI) for average changes from BL in pt-reported fatigue score from Wks 10 through 12 was −3.80 (−7.16, −0.45), −0.10 (−3.27, 3.08), and −0.17 (−3.40, 3.07) for 50 mg BID, 100 mg BID, and PBO arms, respectively ( Table). Conclusion: During the Ph 2 DBP of RISE UP, treatment with mitapivat demonstrated statistically significant and clinically meaningful improvement in Hb response at both dose levels (50 mg BID and 100 mg BID) compared to PBO. Improvements in markers of hemolysis/erythropoiesis and annualized rate of SCPCs were observed for both doses as compared with PBO; the magnitude of improvement in markers of hemolysis and annualized rate of SCPCs was larger in the mitapivat 100 mg BID arm. Mitapivat was well tolerated with a safety profile consistent with previous studies. These data suggest that mitapivat, through its dual mechanism of action, may provide clinical benefit to pts with SCD and support continued development in the Ph 3 portion of the RISE UP trial.

Evaluating the feasibility of delivering a pain management programme for adults living with sickle cell disease.

Pain is the prominent feature of sickle cell disease (SCD) and negatively affects quality of life. Delivery of pain management programmes (PMPs) has been suggested in clinical guidelines for pain management in SCD; however, further evidence of the feasibility and effectiveness of PMPs in this population is needed. This study explored the feasibility of delivering a sickle cell pain management programme (SCPMP) for adults within a haemoglobinopathies service. A single arm, repeated-measures observational design was used to determine feasibility of delivering the SCPMP at one study site. Primary feasibility outcomes were recruitment, completion of treatment and outcome measures, satisfaction, credibility and acceptability to participants. Secondary feasibility outcomes were treatment outcomes and processes, frequency of vaso-occlusive crisis (VOC) and healthcare utilisation. Four of five feasibility criteria were met. Annual recruitment of eight participants to a SCPMP was not achieved. Twenty-nine people began a SCPMP during the study period. Twenty-five (86.2%) participants attended ≥5/8 sessions and 21(84%) programme completers provided all end of programme questionnaires. Mean scores of >7 on ten-point scales were seen across satisfaction and credibility questions. At least moderate (Hedges g >0.5) effect sizes were seen in pre-post SCPMP measures of pain interference, anxiety, depression, self-efficacy, pain-related worry and acceptance. A small (Hedges g 0.4) effect size was seen in HRQoL. Following SCPMP attendance, mean frequency of self-reported VOC and hospital admissions reduced. This study suggests that, given an adequate source of referrals, a SCPMP is feasible to deliver and appears acceptable and credible to participants. Exploration of influences on recruitment, such as barriers to group interventions, would be illuminating, prior to investigating feasibility of an adequately powered randomised-controlled trial.

An alcohol dehydrogenase 7 gene polymorphism associates with both acute and chronic pain in sickle cell disease.

Introduction: As the most distressing complication of sickle cell disease (SCD), pain is marked by considerable heterogenicity. In this study we explored the potential association of alcohol dehydrogenase 7 gene (ADH7) polymorphismrs971074 with sickle cell pain. Methods: We analyzed clinical phenotypes and thers971074 single-nucleotide polymorphismin ADH7 by MassARRAY-iPlex analysis in a cohort of SCD patients. Results: The synonymous rs971074 wassignificantly associated with both acute and chronic pain in SCD. Patients withthe minor T allele(s) recorded significantly more crisis episodes and severe chronic pain symptoms. Conclusion: Our study has identified the rs971074 minor T allele as a genetic biomarker potentially influencing acute and chronic pain. These findings may ultimately help inform strategies to develop precision pain therapies in SCD.

Major Advances for Sickle Cell Pain Crisis

Major Advances for Sickle Cell Pain Crisis

Sickle Cell Anemia and Pain Management in Children

Introduction: Sickle cell anemia is one of the most common hemoglobinopathies in the world. This chronic disease is characterized by acute complications and chronic organ damage. Objective: The aim of this review is to examine the effective management of painful crises in children with sickle cell anemia in the light of the literature, and to provide nurses and other healthcare professionals with information on effective pain control in these children. One of the most important problems faced by children with sickle cell anemia is the occlusion of the vessels due to sickling and the painful crises caused by tissue ischemia due to the crisis. These life-threatening crises need to be intervened as soon as possible. In cases where it is not intervened in a timely and rapid manner, painful crises cause short and long-term negative consequences. Conclusion: The aim of treatment in a child diagnosed with Sickle Cell Anemia is to prevent crises, reduce symptoms and prevent complications. The best management of this process includes nursing practices that are necessary for the frequent evaluation of pain and keeping the child's quality of life at the highest level.