bims-sicedi 2025-06-15 papers

Am J Health Syst Pharm. 2025 Jun 12. pii: zxaf114. [Epub ahead of print]

Clinical consultation: The pharmacist's role in hydroxyurea management for sickle cell disease.

Cameron Roessner, Kelsey Uminski, Dawn Goodyear, Natalia Rydz.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
PURPOSE: Sickle cell disease (SCD) is a genetic disorder caused by a mutation in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS). This clinical consultation explores the pivotal role of hydroxyurea as a disease-modifying therapy in SCD and examines how pharmacist-led interventions can optimize its use to improve patient outcomes.
SUMMARY: Hydroxyurea increases fetal hemoglobin (HbF) production, reducing HbS polymerization and lowering the frequency of vaso-occlusive crises, acute chest syndrome, and other complications. Despite its proven efficacy, barriers such as poor adherence, inadequate patient education, and suboptimal dosing hinder its effective use. Pharmacists, as integral members of the multidisciplinary care team, are ideally positioned to address these challenges. By providing patient education, regular laboratory monitoring, and dose titration to the maximum tolerated dose (MTD), pharmacists can enhance hydroxyurea's therapeutic benefits. Studies have shown that pharmacist-managed protocols significantly improve adherence, increase the proportion of patients achieving MTD, and lead to better clinical outcomes, such as higher HbF levels and fewer hospitalizations. Although emerging treatments such as gene therapies offer promise, hydroxyurea remains the most accessible and effective option for many patients.
CONCLUSION: Pharmacists play a crucial role in optimizing hydroxyurea therapy for patients with SCD by improving adherence and maximizing dosing strategies. Their involvement ensures that more patients experience the full therapeutic benefits of hydroxyurea, contributing to better long-term outcomes. Expanding pharmacist engagement in SCD management will continue to be essential, particularly as new treatments are developed.

Keywords: dose optimization; gene therapy; hydroxyurea; medication adherence; pharmacist-led intervention; sickle cell disease

DOI: https://doi.org/10.1093/ajhp/zxaf114

bioRxiv. 2025 May 31. pii: 2025.05.27.656389. [Epub ahead of print]

Targeting PIEZO1-TMEM16F Coupling to Mitigate Sickle Cell Disease Complications.

Pengfei Liang, Yui-Chun Serena Wan, Ke Zoe Shan, Ryan Chou, Yang Zhang, Martha Delahunty, Sanjay Khandelwal, Samuel J Francis, Gowthami M Arepally, Marilyn J Telen, Huanghe Yang.

A deeper understanding of sickle cell disease (SCD) pathophysiology is critical for identifying novel therapeutic targets. A hallmark of SCD is abnormal phosphatidylserine (PS) exposure on sickle red blood cells (RBCs), which contributes to anemia, thrombosis, and vaso-occlusive crises (VOC). However, the mechanisms underlying this excessive PS exposure remain unclear. Here, we identify TMEM16F, a Ca 2+ -activated lipid scramblase, as a key mediator of PS exposure downstream of Ca 2+ influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging and flow cytometry reveal that deoxygenation-induced sickling promotes PIEZO1 activation, triggering Ca 2+ entry, TMEM16F activation, and PS exposure. This cascade enhances PS + microparticle release, thrombin generation, and RBC adhesion to endothelial cells. Notably, partial PIEZO1 inhibition with benzbromarone, an anti-gout drug, suppresses these changes. Our findings thus define a previously unrecognized mechanotransduction pathway in sickle RBCs and propose a unique therapeutic strategy to mitigate hypercoagulability and vaso-occlusion associated with SCD.
Brief Summary: Enhanced PIEZO1 activation in sickle red blood cells promotes TMEM16F scramblase-mediated phosphatidylserine exposure and subsequent sickle cell disease complications. Disrupting this coupling presents a potential therapeutic strategy.

DOI: https://doi.org/10.1101/2025.05.27.656389

J Hematol. 2025 Jun;14(3): 124-132

Inflammatory Cytokines in Association With High Fetal Hemoglobin Level Reduce the Episodes of Vaso-Occlusive Crisis in Sickle Cell Patients.

Sujata Dixit, Arundhuti Das, Priyanka Samal, Sonali Sandeepta, Swati Sudeshna Panigrahi, Hitesh Kumar Jain, Subhojeet Biswas, Mrutyunjay Suar, Sanghamitra Pati, Manoranjan Ranjit, Madhusmita Bal.

Background: Vaso-occlusive crisis (VOC), a common clinical manifestation of sickle cell disease (SCD), is mediated by a series of inflammatory responses. Conversely, a high fetal hemoglobin (Hb F) level is a known factor that reduces the severity of clinical presentations associated with SCD. Since the association between cytokine profiles and high Hb F levels in SCD is not well studied, this study aims to investigate the interaction between cytokines and Hb F levels in SCD patients from Odisha, India.
Methods: A total of 276 patients with SCD were recruited for the study, including 180 in steady state and 90 in crisis state. Additionally, 117 individuals with sickle cell trait (SCT) and 128 healthy controls were included for comparison.
Results: The study revealed that the total white blood cell count and interleukin (IL)-6 levels were significantly higher in crisis state SCD patients, while the red cell distribution width, IL-10, and Hb F level were significantly higher in steady state SCD patients. Most importantly, the logistic regression analysis showed that the interaction of Hb F with the cytokines IL-10, IL-1β, and IL-17 provided three times greater protection from crisis in SCD patients.
Conclusion: The significance of these preliminary findings has been discussed in terms of prognostic markers and supplements to increase the efficacy of hydroxyurea used to enhance Hb F production.

Keywords: Cytokine; Fetal hemoglobin; IL-6; Sickle cell disease; VOC

DOI: https://doi.org/10.14740/jh1353

Am J Hum Genet. 2025 May 30. pii: S0002-9297(25)00189-2. [Epub ahead of print]

Complexity within simplicity: Exploring the multifactorial nature of sickle cell disease.

Athena Starlard-Davenport.

Sickle cell disease, though monogenic, exhibits complex clinical variability driven by genetic, epigenetic, and environmental factors. This commentary highlights advances in precision therapies and underscores the urgent need for equitable access, global collaboration, and personalized approaches to address the significant health disparities impacting individuals with sickle cell disease worldwide.

DOI: https://doi.org/10.1016/j.ajhg.2025.05.008

Blood Cells Mol Dis. 2025 Jun 09. pii: S1079-9796(25)00031-2. [Epub ahead of print]113-114 102939

Impact of elevated red blood cell membrane cholesterol in sickle cell anemia patients: Effects of BRN-002, a 2-hydroxypropyl-β-cyclodextrin derivate, on red blood cell lipids, deformability, sickling and hemolysis.

Claire Bordat, Philippe Connes, Philippe Joly, Solene Poutrel, Carine Halfon-Domenech, Anne Perez, Eric Niesor, Elie Nader.

Sickle cell anemia (SCA) patients are characterized by poorly deformable and fragile red blood cells (RBCs). Few studies reported an increased cholesterol content in SCA RBC membrane. However, the consequences of this elevated cholesterol level in the above-mentioned RBC alterations are currently unknown. The aim of this study was to assess, in vitro, the effects of BRN-002 (2-Hydroxypropyl-β-cyclodextrin derivate (HPBCD)), a cholesterol-depleting molecule, on RBC membrane cholesterol, hemolysis and RBC sickling and deformability in SCA patients. Forty patients with SCA and 10 healthy individuals (AA) were included in the different experiments of the study. SCA RBCs were incubated with BRN-002 and the following parameters were assessed: i) RBC and supernatant cholesterol content; ii) RBC deformability by oxygen-gradient ektacytometry; iii) hemolysis by measuring free hemoglobin concentration. Results confirmed that SCA patients have increased RBC membrane cholesterol compared to AA. BRN-002 effectively removed cholesterol in SCA RBC membrane and reduced free hemoglobin release during incubation. BRN-002 also increased RBC deformability in hypoxia and decreased the pO2 at which sickling occurs. These findings suggest that excess of RBC membrane cholesterol may participate in the typical RBC alterations found in SCA patients. Therefore, interventions focusing on RBC-cholesterol removal may be beneficial for SCA patients.

Keywords: Cholesterol; Cyclodextrin; Lipids; RBC rheology; Sickle cell anemia

DOI: https://doi.org/10.1016/j.bcmd.2025.102939

Pediatr Blood Cancer. 2025 Jun 12. e31857

Pregnancy- and Disease-Related Morbidity Among Medicaid Enrollees With Sickle Cell Disease.

Mariam Kayle, Mei Zhou, Brandon K Attell, Jhaqueline Valle, Sarah L Reeves, Hannah K Peng, Mathew Smeltzer, Ayesha Mukhopadhyay, Tobi Adeyeye Amosun, Jill Sergison, Angela B Snyder.

BACKGROUND: Whereas pregnancy in sickle cell disease (SCD) is considered high risk, there is limited understanding of pregnancy- and SCD-related morbidity to inform clinical practice and health policy.
PROCEDURE: This retrospective cohort study aimed to describe pregnancy- and disease-related morbidity among individuals with SCD for up to 1 year postpartum using Medicaid claims (2010-2018) linked with newborn screening and clinical reports from four state Sickle Cell Data Collection programs. Medicaid enrollees aged 15-44 years with SCD were included. The most recent delivery hospitalization and associated complications were identified using the International Classification of Diseases nineth and tenth revisions. The main outcomes included pregnancy- and disease-related complications during pregnancy, at delivery, and up to 1 year post-delivery.
RESULTS: A total of 1286 individuals met the inclusion criteria (43% were 15-24 years old, 50% were 25-34 years old). Most (n = 957, 74%) were enrolled in Medicaid before pregnancy, 88% (n = 1132) were enrolled within their first 16 weeks of pregnancy, and 68% (n = 876) maintained Medicaid coverage for 1 year postpartum. High incidence of SCD-related morbidities including vaso-occlusive crisis (37.6%) and acute chest syndrome (5.8%), and obstetric complications-preeclampsia/eclampsia (9.6%), antepartum hemorrhage (24.2%), and preterm delivery (28.1%)-were reported through 60 days postpartum. Many individuals continued to have SCD-related complications beyond the 60-day postpartum period, including more than one-third having a vaso-occlusive crisis.
CONCLUSIONS: Individuals with SCD are at increased risk of pregnancy- and SCD-related morbidity throughout the perinatal period. Medicaid policies that ensure continuous coverage and encourage comprehensive multidisciplinary care models may reduce both SCD and obstetric complications and promote better maternal outcomes.

Keywords: Medicaid; Sickle Cell Data Collection; maternal morbidity; postpartum period; sickle cell disease

DOI: https://doi.org/10.1002/pbc.31857