bims-sicedi 2025-02-23 papers

Am J Hematol. 2025 Feb 21.

FDA Approval Based on Novel Surrogate Endpoints: Lessons From the Voluntary Withdrawal of Voxelotor in Sickle Cell Disease.

Myung Sun Kim, Vinay Prasad.

Keywords: FDA; outcomes research; sickle cell disease

DOI: https://doi.org/10.1002/ajh.27635

Am J Hematol. 2025 Feb 17.

Steady-State Ratio of von Willebrand Factor Antigen to ADAMTS13 Activity Predicts Low Platelet Count at Hospitalization for Sickle Cell Disease Vaso-Occlusive Episodes.

Xu Zhang, Binal N Shah, Jin Han, José A López, Dominic W Chung, Junmei Chen, Santosh L Saraf, Victor R Gordeuk.

Keywords: platelets‐adhesion; sickle cell disease

DOI: https://doi.org/10.1002/ajh.27636

Hemoglobin. 2025 Feb 20. 1-7

Hypersplenism Affects Growth and Haematology in HbSS: Observations from the Jamaican Birth Cohort.

Ian Hambleton, Karlene Mason, Beryl Serjeant, Graham Serjeant.

In 296 patients with homozygous sickle cell disease (HbSS) detected during the screening of 100,000 deliveries between 1973-1981, chronic hypersplenism defined as a spleen measuring ≥4 cm below the costal margin with evidence of prolonged red cell sequestration occurred in 30 (10.1%) subjects, 23 resolved by splenectomy and 7 resolved spontaneously. Median age at splenectomy was 4.8 years and following splenectomy, median values for hemoglobin increased by 2.3 g/dL, reticulocytes fell by 8.3%, total nucleated cells fell by 2.2%, and platelets increased by 29,813 × 109/dL. Mean splenic weight at splenectomy was 340 g representing 0.5%-4.9% of post-splenectomy body weight. Following splenectomy, height increased at a greater rate than in a matching period for controls (95% CI 0.11-4.06. p = 0.04). Risk factors for hypersplenism, did not differ among commonly used determinants of sickling, fetal hemoglobin (HbF), α globin gene number, or β globin haplotype. A history of acute splenic sequestration preceded hypersplenism more commonly among splenectomized cases (20/23 compared with 0 of 7 resolving spontaneously (Fishers exact test p < 0.001). Factors causing hypersplenism remain largely unknown but splenectomy after a period of monitoring for spontaneous regression, improves hematology and growth.

Keywords: Birth cohort; Jamaica; hypersplenism; sickle cell disease

DOI: https://doi.org/10.1080/03630269.2025.2461075

bioRxiv. 2025 Feb 09. pii: 2025.02.08.636742. [Epub ahead of print]

Senolytics restore hematopoietic stem cell function in sickle cell disease.

Sickle Cell Disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, possibly due to pathological stress on bone marrow. To investigate this further, we interrogated mice and individuals with SCD and observed extended cell cycle times, oxidative stress, DNA damage, senescence, and dysregulation of molecular programs associated with these processes in bone marrow hematopoietic stem and progenitor cells (HSPCs). Human SCD HSPCs displayed poor hematopoietic potential ex vivo . SCD mice displayed a dramatic loss of transplantable bone marrow HSPCs, which was reversed upon treatment of SCD mice with the senolytic agent, ABT-263 (navitoclax). Thus, senolytics restore bone marrow function during SCD in mice and represent a novel strategy to improve bone marrow health in individuals with SCD and improve the safety of potentially curative gene therapies that utilize autologous HSPCs from individuals with SCD.

DOI: https://doi.org/10.1101/2025.02.08.636742

Am J Hematol. 2025 Feb 21.

Pyruvate Kinase Function Correlates With Red Blood Cell Properties and Clinical Manifestations in Sickle Cell Disease.

M J M Traets, J F Bos, S van der Veen, L van Pelt, M J van Dijk, B A van Oirschot, J R A de Wilde, J J Jans, W W van Solinge, S E M Schols, M N Lauw, M H Cnossen, E Nur, B J Biemond, A W Rijneveld, E J van Beers, R van Wijk, M A E Rab.

Pyruvate kinase (PK) is a key enzyme involved in the final step of glycolysis, essential to produce adenosine triphosphate (ATP). Relatively decreased red blood cell (RBC) PK activity (reflected by a lower PK/hexokinase [HK] ratio) and PK thermostability (PK activity after exposure to heat) were recently identified as pathophysiological features of sickle cell disease (SCD). In this study, we investigated whether impaired PK function is associated with sickle RBC properties and SCD-related clinical manifestations. This study included 97 non-transfused patients with SCD (88 HbSS, 9 HbS/β0 thalassemia). PK thermostability was correlated with RBC parameters such as reticulocyte count (r = -0.402, p < 0.0001) and hemoglobin F (r = 0.394, p < 0.0001), and indicators of impaired functional properties of sickle RBCs, such as the point of sickling (r = -0.417, p < 0.0001), oxygen affinity (r = 0.408, p < 0.001) and RBC adhesion to laminin (r = -0.322, p = 0.024). Additionally, a low PK/HK ratio correlated with decreased PK thermostability (r = 0.308, p = 0.002), decreased RBC deformability (r = 0.268, p = 0.009), and elevated 2,3-diphosphoglycerate levels (r = -0.244, p = 0.016). Multivariate Poisson regression analysis demonstrated that reduced PK thermostability and PK/HK ratio were associated with a higher incidence of SCD-related clinical complications. For every 10-unit decrease in PK thermostability and 1-unit decrease in PK/HK ratio, the incidence of SCD-related clinical complications increased by 11% (p = 0.012) and 10% (p = 0.019), respectively. Altogether, these findings indicate that impaired PK function is related to compromised sickle RBC properties and SCD-related clinical manifestations. This supports the relevance and underlines the potential of PK activation therapy.

Keywords: pyruvate kinase; red cells metabolism; sickle cell disease

DOI: https://doi.org/10.1002/ajh.27644

Ann Hematol. 2025 Feb 19.

Plasma free hemoglobin is associated with LDH, AST, total bilirubin, reticulocyte count, and the hemolysis score in patients with sickle cell anemia.

Angela Liu, Charleen Jacobs-McFarlane, Paola Sebastiani, Jeffrey Glassberg, Sarah McCuskee, Susanna Curtis.

Plasma free hemoglobin (PFH) is a direct biomarker for hemolysis that has been associated with clinical complications such as pulmonary hypertension and death in patients with sickle cell disease (SCD). We sought to characterize the relationship between PFH and more clinically available hemolytic markers including lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, reticulocyte percentage and to derive a composite hemolysis score derived from principal component analysis (PCA) of these biomarkers. In 68 adult patients (median age 31 years old, IQR 25-39) with HbSS or HbSβ0-thalassemia enrolled in the IMPROVE II study, median PFH was elevated at 21.9 mg/dL (IQR 9.9-44.9 mg/dL) at steady state. Using Pearson correlation analysis, PFH had a stronger relationship to LDH (R = 0.699), AST (R = 0.587), and total bilirubin (R = 0.475), compared to reticulocyte count (R = 0.316). The hemolysis score was significantly associated with PFH (R = 0.677). When compared with other laboratory measures, PFH correlated with hemoglobin (R= -0.275) and HbS (R = 0.277), but did not correlate with white blood cell count (WBC) or HbF. The hemolysis score was significantly associated with WBC (R = 0.307), hemoglobin (R = -0.393), HbF (R=- 0.424), and HbS (R = 0.423). This study confirms that the conventional hemolytic biomarkers LDH, AST, bilirubin, and reticulocyte percentage correlate with PFH. Additionally, the hemolysis score is a valid tool to measure hemolysis and that it may be a marker of global hemolysis as opposed to PFH, which quantifies intravascular hemolysis. Further studies will be needed to elucidate the role of PFH and intravascular hemolysis in the development of clinical complications of sickle cell disease. Statements and Funding Declarations: The research leading to these results received funding from the National Heart, Lung, and Blood Institute (NHLBI) R01 HL142671 Grant under J.G. J.G. has also served as a consultant for CSL Behring, Novartis, and Novo Nordisk synteract DSMB and is supported by NHLBI RO1HL159116, R01 HL142671, R01 ES030717, UG1 HL138645, UH3 HL143192, U01HL167036, and the Doris Duke Charitable Foundation Advancing Cures grant. S.C. has served as a consultant for Pfizer and is supported by the NHLBI 5K23HL151884 grant. A.L. is supported by the NHLBI 5T32HL129974-05. C.J.M is supported by the NHLBI 5T32HL129974-05. P.S., and S.M. declare no conflicts and/or funding.

Keywords: Hemolysis; Hemolysis score; Plasma free hemoglobin; Sickle cell disease

DOI: https://doi.org/10.1007/s00277-025-06253-w

Blood Adv. 2025 Feb 19. pii: bloodadvances.2023012546. [Epub ahead of print]

Implementing ASH's Guidelines for Acute Medical Care for Children and Adults with Sickle Cell Disease in Custody.

Michael R DeBaun, Michelle Staples-Horne, Radha Sadacharan, Paula Braverman, Nirmish Shah, John J Strouse, Deana Orsini, Charles D Lee, Elizabeth S Barnert.

Between 2019 and 2021, the American Society of Hematology (ASH) developed clinical guidelines for managing sickle cell disease (SCD), covering acute pain, acute neurological events, and other complications. However, these guidelines lacked implementation strategies for incarcerated individuals, a vulnerable group with unique challenges. In 2024, an ASH special panel of SCD and carceral health experts convened to address acute SCD care in custody settings, emphasizing timely access to emergency care, including acute management for acute strokes, pain management, and fever evaluation. The ASH special panel recommended pre-arranged emergency plans for transfer to specialized facilities, continuity of care with SCD specialists, and adherence to community-level care standards. Limitations included insufficient population data and absent chronic care guidelines. The ASH special panel urged that future ASH guidelines address SCD management tailored to carceral settings to reduce morbidity and ensure equitable care.

DOI: https://doi.org/10.1182/bloodadvances.2023012546

Br J Haematol. 2025 Feb 21.

Maternal and perinatal outcomes of sickle cell disease in pregnancy: A nationwide study in France.

Alice Corsia, Laure Joseph, Nathanael Beeker, Sandra Manceau, Marine Driessen, Benoit Meunier, Marina Cavazzana, Mathis Collier, Jean-Marc Treluyer.

This nationwide cohort study provides a comprehensive overview of maternal and perinatal outcomes associated with sickle cell disease (SCD) during pregnancy. Using the French national health database, all singleton pregnancy-related hospital discharges from 2013 to 2020 in women aged 15-55 (n = 5 752 080) were selected. Of these, 1022 births were to women with SCD, 308 of whom were on long-term treatment, that is, hydroxyurea (HU) and/or transfusion programme. Pregnancies with SCD were more likely to involve pre-eclampsia (9.6% vs. 1.7%; p < 0.001), pulmonary embolism (0.70% vs. 0.02%; p < 0.001), caesarean sections (52.8% vs. 18.2%; p < 0.001) and postpartum haemorrhage (8.3% vs. 4.1%; p < 0.001) compared to pregnancies without SCD. Preterm birth (<37 weeks) was much more common in women with SCD (28.5% vs. 5.6%). Infants born to women with SCD faced greater adverse neonatal outcomes (22.4% vs. 8.0%; p < 0.001). Although untreated SCD was linked to fewer complications than long-term treated SCD, both conditions presented greater risks compared with pregnancies without SCD. Unexpectedly, babies born to women with SCD had a higher incidence of congenital abnormalities (6.3% vs. 3.4%; p < 0.001), not attributed to HU use. Overall, despite advances in SCD management, pregnancy in SCD remains a high-risk condition, for both mothers and babies.

Keywords: adverse neonatal outcome; aspirin; congenital abnormalities; hydroxyurea; perinatal and maternal outcomes; pregnancy; prematurity; pre‐eclampsia; sickle cell disease; transfusion

DOI: https://doi.org/10.1111/bjh.20009

Blood Adv. 2025 Feb 25. 9(4): 933-934

The transplant debate: defining innovation for sickle cell.

Cécile Karsenty, Titilope Fasipe, Alexander I Ngwube.

DOI: https://doi.org/10.1182/bloodadvances.2024015400