bims-sicedi 2025-02-16 papers

Transfusion. 2025 Feb;65(2): 325-332

Use of automated isovolemic hemodilution red-cell exchange in patients with sickle cell disease: A Canadian single center experience.

Kelsey Uminski, Iris Perelman, Alan T Tinmouth, Johnathan Mack.

BACKGROUND: Red cell exchange (RCE) is an important treatment for sickle cell disease (SCD). It is a resource-intensive intervention requiring large volumes of red blood cells (RBC), which are frequently antigen-matched. Efforts to reduce the volume of units transfused, while maintaining treatment efficacy is an important need. This study evaluates the impact of a change to isovolemic hemodilution (IHD)-RCE on RBC utilization in SCD patients at a Canadian center.
STUDY DESIGN AND METHODS: Adult SCD patients receiving chronic automated RCE at the Ottawa Hospital were approached for study inclusion. To safely attain a meaningful reduction in transfused RBCs, RCE parameters were individualized for each patient. IHD-RCE was performed only if an estimated reduction in RBC volume of at least 200 mL was expected, with hematocrit not allowed to decrease below 20%. Data were compared in the 6-months before and after the protocol change.
RESULTS: Twenty-two adult patients met the criteria for inclusion. There was a net reduction of 107 RBC units after the transition from standard RCE to IHD-RCE (1035 vs. 928 units; -10.3%). The mean number of RBC units transfused per patient decreased by 4.8 (47.0 vs. 42.2 units; p = .01). No difference in target post-RCE hemoglobin S levels was observed.
DISCUSSION: In this study IHD-RCE reduced RBC utilization without impacting efficacy or safety, conserving 107 RBC units (an annualized savings of $95,444 CAD). No adverse events due to saline replacement were observed. Increased awareness of the benefits of IHD-RCE through knowledge translation could promote greater uptake.

Keywords: isovolemic hemodilution; red‐cell exchange; sickle cell disease; transfusion

DOI: https://doi.org/10.1111/trf.18119

Blood Transfus. 2025 Feb 04.

The impact of red cell storage age on transfused patients with sickle cell disease: protocol of a pilot randomized clinical trial to evaluate changes in inflammation and clinical transfusion efficacy.

Matthew S Karafin, Ross M Fasano, Anton Illich, David Wichlan, Ada Chang, Sonjile M James, Hailly E Butler, Oleg Kolupaev, Melissa C Caughey, Nigel S Key, Joshua J Field, Jane A Little.

BACKGROUND: Despite fulfilling all requirements for donor blood units as defined by the FDA, a number of patients with sickle cell disease (SCD) are transfused with red blood cell (RBC) units that are near the end of their storage life, exposing them to the potentially adverse components of the red cell storage lesion. Due to their chronically inflamed state, patients with SCD may be particularly susceptible to these components. We present here a pilot study protocol for testing the impact of fresh vs older red cell units in chronically transfused adults with SCD.
MATERIALS AND METHODS: This is a randomized, prospective, clinical trial. We aimed to recruit forty chronically transfused adults or adolescents with SCD who receive regular RBC transfusions for their clinical care and randomize these patients to receive either units greater than or equal to 30 days, or units less than or equal to 10 days for 3 consecutive outpatient transfusion events.
RESULTS: The primary endpoint is the metabolic differences identified between units transfused that are greater than or equal to 30 days, and those units less than or equal to 10 days. The secondary endpoint evaluates the change in blood monocyte activation at 2 hours after transfusion between the two groups. Lastly, weevaluate unit RBC efficacy via changes in hemoglobin/day, hemoglobin A%/day, hospitalization rate, pain scores, and infections as documented via blood and urine cultures.
DISCUSSION: This study promises to provide evidence as to whether metabolically older red cell units affect the quality and efficacy of chronic transfusion therapy for adults with SCD and has the potential to guide the need for future study on this important clinical issue.

DOI: https://doi.org/10.2450/BloodTransfus.886

Biophys J. 2025 Feb 08. pii: S0006-3495(25)00062-1. [Epub ahead of print]

Hyperactive deoxy-PIEZO1 shapes the circulatory lifecycle of irreversibly sickled cells.

Virgilio L Lew, Simon D Rogers.

Sickle cell disease (SCD), affecting millions worldwide, is caused by the homozygous inheritance of the abnormal haemoglobin, HbS. Deoxygenation of HbS in the venous circulation permeabilizes sickle cells to calcium via PIEZO1 channels triggering a dehydration cascade driven by the outward electrochemical potassium gradient. This mechanism operates with particular intensity in a subpopulation of sickle RBCs, the irreversibly sickled cells (ISCs). The lifespan of ISCs is extremely short, about 4 to 7 days. Most of this time is spent in a profoundly dehydrated condition, the irreversibly sickled state, eliciting vaso-occlusion, which is considered the root cause of organ failure and pain crisis in SCD. There is a large experimental and clinical database on sickle cells and ISCs, but how ISCs form and evolve in the circulation remains a mystery. The present study is the first attempt to unravel the experimentally inaccessible lifecycle of ISCs in vivo applying a well-accredited model of red blood cell homeostasis and circulatory dynamics, using a vast array of validated experimental observations to tightly constrain the model parameters. The results showed that abnormally strong deoxy-PIEZO1 responses were needed for calcium to elicit a violent hyperdense collapse in ISC-destined stress reticulocytes within about a day in the circulation. The potassium-depleted ISCs remain in this maximally dehydrated but volume stable condition, the pathogenic state, sustained by vigorous pump-leak balanced sodium fluxes. Eventually, sodium pump decay initiates rapid terminal rehydration by the unbalanced net gain of NaCl and water. Analysis of the mechanisms behind this three-stage circulatory lifecycle of ISCs exposed a complex web of interactions among many components of the homeostatic fabric of RBCs. These findings point to the abnormally intense PIEZO1 response to deoxygenation in ISC-destined stress reticulocytes as a prime cause of ISC formation in vivo, a central target for future research.

Keywords: Gardos channels; PIEZO1; calcium transport; irreversibly sickled cells; plasma membrane calcium pump; sickle cell disease; sodium pump

DOI: https://doi.org/10.1016/j.bpj.2025.02.005

J Clin Med. 2025 Feb 01. pii: 948. [Epub ahead of print]14(3):

Thalassemias and Sickle Cell Diseases in Pregnancy: SITE Good Practice.

Valeria Maria Pinto, Rosanna Cima, Rosario Di Maggio, Maria Livia Alga, Antonia Gigante, Filomena Longo, Anna Maria Pasanisi, Donatella Venturelli, Elena Cassinerio, Maddalena Casale, Raffaella Origa, Giovanni Zanconato, Gian Luca Forni, Lucia De Franceschi.

Background: Hereditary hemoglobin disorders are the most common globally distributed monogenic red cell diseases. The rights of women with thalassemia or sickle cell disease (SCD) to motherhood need to be protected by creating a roadmap to guide her, and her family network, along all the phases of the event. In fact, pregnancy in these vulnerable patients requires special attention and guidelines from the counseling stage (giving information about the special requirement and risks posed by their pregnancy with respect to the general population) the pre-conception stage, the early and mid-late pregnancy stage, to labor and lactation. The biocomplexity of these diseases requires a multidisciplinary team synergizing with gynecologists and obstetricians. In addition, the presence of a multicultural scenario requires healthcare workers to overcome stereotypes and adopt appropriate anthropological tools that might help them integrate the different cultural models of disease and motherhood. Methods: The Management Committee of the Society for Thalassemia and Hemoglobinopathies (SITE) selected and brought together a multidisciplinary and multiprofessional group made up of experts in hemoglobinopathies and experts in anthropology, flanked along with by experts with methodological and organizational expertise in order to create recommendations based on the integration of available scientific evidence together with expert opinion. Results: The panelists critically analyzed the literature, combining in a single document practices developed over several years of managing young women with hemoglobinopathies in a sensitive phase of their lives. Conclusions: This good practice document is the result of a collegial effort by Italian experts on hemoglobinopathies who are members of SITE. (SITE).

Keywords: SCD; good practice; hemoglobin H disease; hemoglobinopathies; pregnancy; sickle cell disease; thalassemia

DOI: https://doi.org/10.3390/jcm14030948

Am J Clin Nutr. 2025 Feb 05. pii: S0002-9165(25)00069-3. [Epub ahead of print]

Folic acid supplementation in children with sickle cell disease: A randomized double-blind non-inferiority crossover trial.

Brock A Williams, Heather McCartney, Joel Singer, Angela M Devlin, Suzanne Vercauteren, Ali Amid, John K Wu, Crystal D Karakochuk.

BACKGROUND: Children with sickle cell disease in Canada are routinely supplemented with folic acid to provide sufficient folate for the increased demands of erythropoiesis. However, with mandatory folic acid fortification of refined grains and pharmacotherapies which extend the lifespan of sickled red blood cells (RBC), this clinical practice is in question.
OBJECTIVE: To determine the efficacy of folic acid supplementation by measuring the effect of 12±1 weeks of 1mg/d folic acid, compared to placebo, on concentrations of RBC folate (primary outcome), serum folate and one-carbon-related metabolites, and clinical outcomes in children with SCD.
METHODS: In this double-blind randomized controlled non-inferiority crossover trial, 31 children with sickle cell disease, aged 2-19 years, were enrolled and randomly assigned (1:1 with blocks of 4) to 1mg/d folic acid, the current standard of care, or a placebo for 12±1 weeks. Following a 12±1 week washout period, treatments were reversed.
RESULTS: The mean (95% CI) difference in endline RBC folate concentrations across treatments was -179 (-260, -99) nmol/L, with the lower boundary of the confidence interval exceeding non-inferiority but the upper boundary not (p=0.0001; modified intention-to-treat). There was no significant difference in the number of participants who had RBC folate deficiency after each treatment (p=0.059). No participants presented with serum folate deficiency (<7 nmol/L). There were no significant differences observed in one-carbon metabolite concentrations (total homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, vitamin B12, or methylmalonic acid), hematological measures, nor clinical outcomes (specifically acute pain episodes or megaloblastic changes) when individuals were supplemented with folic acid in comparison to placebo.
CONCLUSIONS: Despite mandatory food fortification and advances in the medical treatment of sickle cell disease, it appears that some children with this condition may still benefit from daily folic acid supplementation. Whether this translates to improved clinical outcomes remains uncertain. This trial was registered at ClinicalTrials.gov as NCT04011345 (https://clinicaltrials.gov/study/NCT04011345).

Keywords: folic acid; pediatrics; randomized control trial; sickle cell disease

DOI: https://doi.org/10.1016/j.ajcnut.2025.02.001