bims-sicedi 2026-02-22 papers

Expert Rev Hematol. 2026 Feb 17.

Improving endpoints for sickle cell disease clinical trials: retaining consistency and clinical benefit.

Slimane Allali, Martina Bevacqua, Mariane de Montalembert.

Keywords: chronic hemolytic anemia; clinical trials; endpoints; health-related quality of life; patient-reported outcomes; sickle cell disease; vaso-occlusive crisis

DOI: https://doi.org/10.1080/17474086.2026.2634282

Expert Rev Hematol. 2026 Feb 17.

The emerging role of complement inhibitory approaches in the treatment of acute sickle cell disease complications.

Haley Cowan, Ronak Dave, Akshaya Arjunan, Maya Maarouf, Gabrielle Dean, Sara Graciaa, Michelle L Schoettler, Satheesh Chonat.

INTRODUCTION: Sickle cell disease (SCD) is a common and life-threatening hematological disorder that affects almost 100,000 people in the United States and millions worldwide. The wide phenotypic variability of SCD results from a complex pathophysiology involving coagulation, inflammation, leukocyte and endothelial cell activation, and other cellular and humoral mechanisms. To improve the prognosis of SCD patients, we must gain a better understanding of the underlying molecular pathogenesis and offer new therapies.
AREAS COVERED: In SCD and other hemolytic disorders, continual red blood cell breakdown generates free plasma hemoglobin and free heme. Plasma free heme directly activates the complement cascade, resulting in further hemolysis. Complement pathway activation has been linked to SCD; however, the exact mechanism and role of this activation in the pathophysiology of SCD are still being studied. We performed a literature review identifying studies describing complement activation or the impact of complement inhibition in SCD.
EXPERT OPINION: Emerging preclinical and clinical data support the role of complement in SCD. Thorough and careful investigation of the efficacy and safety of proximal and distal complement inhibitors in SCD is warranted. This novel pathway has a tremendous potential to pave the way for innovative therapies to prevent and treat SCD complications.

Keywords: Sickle cell disease; complement; complement inhibitor; complications; delayed hemolytic transfusion reaction; eculizumab; hemolysis; vaso occlusive episode

DOI: https://doi.org/10.1080/17474086.2026.2634277

Blood Adv. 2026 Feb 20. pii: bloodadvances.2025018869. [Epub ahead of print]

Sickle Cell Vaso-Occlusive Episodes Correlates with the Magnetic Heterogeneity of Red Blood Cell.

Jacob Strayer, Xian Wu, Hyeon Choe, Poornima Ramesh Iyer, Jenifer Gómez-Pastora, William Joseph Moorman, Joseph Cefaratti, Alec West, Jacob Doon-Ralls, Kristina Landes, Sherraine Della-Moretta, Andre F Palmer, Maciej Zborowski, Paul W Buehler, Jeffrey J Chalmers, Payal Chandarana Desai.

Sickle cell disease (SCD) is a complex condition that results in low oxygen affinity and oxidative damage within red blood cells (RBCs), which contributes to serious complications such as vaso-occlusive episodes (VOEs). Given the well-established theoretical and experimental evidence that oxygenated hemoglobin is diamagnetic, while deoxygenated hemoglobin and methemoglobin are paramagnetic, this study aims to investigate whether RBCs from patients with SCD exhibit progressively increased magnetic susceptibility in correlation with disease severity. In this study, we employed cell tracking velocimetry (CTV) to perform single-cell analysis of RBC magnetic properties under both oxygenated and deoxygenated states. CTV quantifies the oxygen saturation of each cell by measuring their magnetically induced cell velocities in conjunction with known cell properties. Subsequent statistical analysis revealed that although the mean oxygen saturation of the RBCs from SCD patients did not differ significantly from that of healthy donors, the magnetic velocities at the 1st and 99th percentile of RBC samples from SCD patients were significantly reduced and elevated, respectively. These elevated and reduced velocities correlate directly to the magnetic susceptibility of the cell, which corresponds to the hemoglobin state. Moreover, we identified a correlation (p < 0.01) between the magnetic heterogeneity in the top and bottom 1% and pain severity, particularly in SCD patients experiencing acute VOEs. This study underscores the potential of RBC magnetic properties as biophysical markers for identifying the pain severity of SCD patients and opening avenues for personalized therapeutic interventions.

DOI: https://doi.org/10.1182/bloodadvances.2025018869

Ann Hematol. 2026 Feb 16. 105(4): 115

Laboratory and genetic characteristic associated with gallbladder-related outcomes in sickle cell disease in Brazil: results from the REDS-III multicenter cohort study.

REDS-III Brazil SCD Cohort study and the TOPMed consortium

Keywords: Cholelithiasis; Genome-wide association study; Hemolysis; Sickle cell disease; UGT1A1 variants

DOI: https://doi.org/10.1007/s00277-026-06800-z

Blood Adv. 2026 Feb 17. pii: bloodadvances.2025018992. [Epub ahead of print]

Safety and effectiveness of voxelotor in individuals with sickle cell disease in the RETRO and PROSPECT US registries.

Biree Andemariam, Nirmish Shah, William B Ershler, Edward Donnell Ivy, Deepika S Darbari, Alan R Anderson, Parul Rai, Ted Wun, Ching-Ray Yu, David M Purdie, Colleen M Valenzuela, Michelle Xu.

Two registry studies, RETRO and PROSPECT, were conducted to evaluate real-world effectiveness and safety outcomes in US participants with sickle cell disease (SCD) who received voxelotor as standard of care. RETRO collected retrospective data of participants aged ≥12 years at 9 US sites for ~1 year after voxelotor initiation. PROSPECT collected retrospective and prospective data of participants aged ≥4 years at 24 US sites, with 5-years planned follow-up. Both studies collected data for 1-year pre-voxelotor initiation. RETRO enrolled 216 participants. PROSPECT enrolled 265 participants before voxelotor was withdrawn from global markets in September 2024; of these, 260 participants received voxelotor. The mean±SD duration of voxelotor treatment was 50.52±25.1 and 143.2±65.6 weeks in RETRO and PROSPECT, respectively. Safety analyses included all participants who received voxelotor. Mean±SD observed change in hemoglobin from baseline was from 0.6±1.6 to 0.8±1.5 g/dL in RETRO (~1-year) and from 0.1±1.7 to 0.7 ±1.5 g/dL in PROSPECT (54 months). Decreases from baseline in hemolysis markers (absolute/percentage reticulocyte counts, total/indirect bilirubin) post-voxelotor were observed across all time points in RETRO and across most time points in PROSPECT. Acute pain crisis (APC) was the most common SCD complication, with annualized incidence rates (total number of events/total patient-years) pre- and post-voxelotor of 1.33 and 1.54 in RETRO and 4.78 and 3.15 in PROSPECT. No new safety findings were identified. Despite inherent limitations of registry studies, voxelotor treatment increased hemoglobin and decreased hemolysis markers in US clinical practice, with no evidence of an increased frequency of APC.

DOI: https://doi.org/10.1182/bloodadvances.2025018992

Br J Haematol. 2026 Feb 19.

Circulating angiogenesis-related biomarkers in sickle cell retinopathy and maculopathy.

Rajani P Brandsen, Ingeborg Klaassen, Renée de Caluwe, Erfan Nur, Bart J Biemond, Roselie M H Diederen, Reinier O Schlingemann.

Sickle cell disease (SCD), encompassing genotypes such as HbSS and HbSC, leads to retinal complications such as sickle cell retinopathy (SCR) and maculopathy (SCM) through poorly understood mechanisms. This study explored associations of a panel of circulating angiogenesis-related factors with SCR and SCM. Adult HbSS (homozygous SCD; n = 33) and HbSC (compound heterozygous SCD; n = 33) patients underwent ophthalmic examination, including optical coherence tomography angiography, to assess SCR stage and presence of SCM. Plasma levels of circulating angiogenesis-related factors were analysed, with selected markers (angiopoietin-2, vascular endothelial growth factor [VEGF], granulocyte colony-stimulating factor, endoglin, endostatin, interleukin [IL]-6 and IL-10) assessed using enzyme-linked immunosorbent assay. Proliferative SCR (PSCR) was present in 5 (15.2%) HbSS and 21 (63.6%) HbSC patients. Foveal avascular zone abnormalities and macular thinning were present in 50.8% and 48.4% of patients respectively. Most vascular factors, including VEGF, showed no association with SCR or SCM. However, angiopoietin-2 was higher in HbSS patients, independent of SCR stage or SCM, and correlated with IL-6, IL-10, VEGF, reticulocyte counts, and lactate dehydrogenase (LDH). In HbSC patients, endostatin levels were highest in those with PSCR (p = 0.030). While most proteins were unrelated to retinal outcomes, angiopoietin-2 elevation may reflect HbSS-specific systemic hypoxia. Elevated endostatin in HbSC patients with PSCR suggests a potential role in PSCR development. These findings offer new leads for understanding SCD-related retinal disease.

Keywords: angiogenesis; sickle cell disease; sickle cell maculopathy; sickle cell retinopathy

DOI: https://doi.org/10.1111/bjh.70385

Lancet Glob Health. 2026 Mar;pii: S2214-109X(25)00455-3. [Epub ahead of print]14(3): e386-e394

Low-dose aspirin for preventing intrauterine growth restriction and pre-eclampsia in sickle cell pregnancy in Nigeria (PIPSICKLE): a randomised controlled trial.

PIPSICKLE trial study group

BACKGROUND: Pregnant women with sickle cell disease are at increased risk of intrauterine growth restriction (IUGR), pre-eclampsia, and sickle-related conditions. Low-dose aspirin might reduce some of these complications but has not been tested in sickle cell pregnancy. We aimed to investigate the effectiveness and safety of low-dose aspirin for preventing complications during pregnancy.
METHODS: In a double-blind randomised controlled trial in 16 public health facilities in southwest Nigeria, pregnant women (aged ≥18 years) with haemoglobin SS (HbSS) or SC (HbSC) and carrying a singleton fetus between 12 weeks' and 28 weeks' gestation received daily 100 mg aspirin or placebo until 36 weeks' gestation or delivery and were monitored until 6 weeks' postpartum. The composite primary outcome comprised IUGR, perinatal mortality, or miscarriage. Analysis was done in the intention-to-treat population. The trial was registered in the Pan African Clinical Trial Registry (PACTR202001787519553) and ClinicalTrials.gov (NCT05253781).
FINDINGS: Between July 1, 2020, and May 27, 2024, 619 pregnant women with HbSS and HbSC were screened, of whom 476 eligible women were recruited; 239 received aspirin 100 mg from a median gestational age of 19·0 (16·0-24·0) weeks and 237 received placebo from a median gestational age of 20·5 (15·5-25·0) weeks. 41 withdrew, died, or were lost to follow-up before 36 weeks' gestation. There was no significant difference in the risk of the primary endpoint: 59 (27·1%) of 218 women in the aspirin group versus 54 (25·8%) of 209 women in the placebo group (risk ratio 1·05 [95% CI 0·75-1·46]). More sickle-cell crises occurred with aspirin than with placebo (mean frequency of 32·64 [SD 71·17] per 100 women with aspirin versus 30·38 [75·95] per 100 women with placebo, incidence rate ratio 1·04 [95% CI 1·01-1·08]). There were ten (4·2%) maternal deaths in the aspirin group versus two (0·1%) in the placebo group (risk ratio 4·96 [95% CI 1·18-20·92]).
INTERPRETATION: Low-dose aspirin was not beneficial for preventing IUGR, perinatal mortality, or miscarriage in sickle cell pregnancy, although this conclusion is limited by late initiation of the medication after 16 weeks' gestation in three-quarters of the participants. Low-dose aspirin, however, increased sickle-related complications compared with placebo, thus studies to clarify its safety in pregnant women with sickle cell disease are required.
FUNDING: Tertiary Education Trust Fund Nigeria.

DOI: https://doi.org/10.1016/S2214-109X(25)00455-3