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Reddoch-Cardenas KM, Cancelas JA, Nestheide S, Rugg N, Peña K, McIntosh CS, Ferdin J, Talackine J, Parker J, Jensen LA, Gonzales R, Hess JR, Zia M. Novel anticoagulant-preservative solution maintained the hemostatic function of cold stored whole blood for 56 days. Transfusion 2025; 65 Suppl 1:S185-S192. [PMID: 40134105 PMCID: PMC12080240 DOI: 10.1111/trf.18207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/28/2025] [Accepted: 03/01/2025] [Indexed: 03/27/2025]
Abstract
BACKGROUND Whole blood (WB) is an efficient product for field medical resuscitation because of its unitary composition, tolerance for storage on ice and in field refrigerators, and simplicity of use. We measured quality parameters of a novel 8-week WB storage system. STUDY DESIGN AND METHODS Here, 500 mL of WB from healthy donors was collected in 70 mL of CPDA-1, leukoreduced with a platelet-sparing filter, pooled into ABO-compatible two-unit pools, and split into matched pairs of equal volume designated as Test or Control units. Test units received an additional 50 mL of a novel WB preservative solution (APEX units, Hemerus Medical, St Paul, MN). A total of 15 paired WB units were evaluated at Day 0 (D0) and periodically up to Day 56 (D56) of storage at 1-6°C across two centers. Quality testing included cellularity, ATP concentrations, hemolysis, blood gases, metabolites, coagulation factor levels, thromboelastography (TEG), and bacterial culture. RESULTS At D56, APEX units displayed higher RBC ATP concentration (3.14 vs. 2.18 μmol/gHb, p = 0.001), pH (6.53 vs. 6.50, p = 0.01), and higher bicarbonate reserve (8 vs. 5.4, p < 0.0001). D56 APEX units had greater platelet contribution to TEG clot strength (p < 0.01) and better preservation of red cell ATP (p < 0.001). Activities of fibrinogen, factor VIII, factor V, and protein S activity in APEX units remained within the reference levels on D56. No bacterial contamination was detected at the end of storage. DISCUSSION These findings suggest that APEX preserves RBCs effectively and maintains platelet and plasma coagulation functions for up to 56 days.
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Affiliation(s)
| | - J. A. Cancelas
- Hoxworth Blood Center, Cincinnati, Ohio, USA
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | | | - N. Rugg
- Hoxworth Blood Center, Cincinnati, Ohio, USA
| | - K. Peña
- Hoxworth Blood Center, Cincinnati, Ohio, USA
| | - C. S. McIntosh
- U.S. Army Institute of Surgical Research (USAISR), Sam Houston, Texas, USA
| | - J. Ferdin
- U.S. Army Institute of Surgical Research (USAISR), Sam Houston, Texas, USA
| | - J. Talackine
- U.S. Army Institute of Surgical Research (USAISR), Sam Houston, Texas, USA
| | - J. Parker
- Hoxworth Blood Center, Cincinnati, Ohio, USA
| | - L. A. Jensen
- Hemerus Medical, LLC, Saint Paul, Minnesota, USA
| | - R. Gonzales
- Hemerus Medical, LLC, Saint Paul, Minnesota, USA
| | - J. R. Hess
- Hemerus Medical, LLC, Saint Paul, Minnesota, USA
| | - M. Zia
- Hemerus Medical, LLC, Saint Paul, Minnesota, USA
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2
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D’Alessandro A. Red blood cell metabolism: a window on systems health towards clinical metabolomics. Curr Opin Hematol 2025; 32:111-119. [PMID: 40085132 PMCID: PMC11949704 DOI: 10.1097/moh.0000000000000863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
PURPOSE OF REVIEW This review focuses on recent advances in the understanding of red blood cell (RBC) metabolism as a function of hypoxia and oxidant stress. In particular, we will focus on RBC metabolic alterations during storage in the blood bank, a medically relevant model of erythrocyte responses to energy and redox stress. RECENT FINDINGS Recent studies on over 13 000 healthy blood donors, as part of the Recipient Epidemiology and Donor Evaluation Study (REDS) III and IV-P RBC omics, and 525 diversity outbred mice have highlighted the impact on RBC metabolism of biological factors (age, BMI), genetics (sex, polymorphisms) and exposure (dietary, professional or recreational habits, drugs that are not grounds for blood donor deferral). SUMMARY We review RBC metabolism from basic biochemistry to storage biology, briefly discussing the impact of inborn errors of metabolism and genetic factors on RBC metabolism, as a window on systems metabolic health. Expanding on the concept of clinical chemistry towards clinical metabolomics, monitoring metabolism at scale in large populations (e.g., millions of blood donors) may thus provide insights into population health as a complementary tool to genetic screening and standard clinical measurements.
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Affiliation(s)
- Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
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3
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Xu J, Lei C, Zhu W. Nanomaterial-Enhanced Red Blood Cell Biopreservation: From Refrigeration to Cryopreservation. Chembiochem 2025; 26:e202400827. [PMID: 39632268 DOI: 10.1002/cbic.202400827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/07/2024]
Abstract
Red blood cell (RBC) transfusions represent a cornerstone of clinical practice, with RBCs constituting the primary component in transfusion therapy. Extending the preservation of RBCs while maintaining their functional integrity would offer considerable advancements for both transfusion medicine and military healthcare. Despite decades of research, progress in achieving long-term RBC preservation has been limited. A key challenge is the range of physical and biochemical damage RBCs incur during storage, leading to marked changes in their morphology, physiological function, and viability. While traditional preservation techniques have provided partial mitigation of these damages, their efficacy remains suboptimal. In contrast, nanomaterials, with their distinctive spatial architectures and surface properties, offer a promising avenue for minimizing storage-related damage and extending RBC preservation. This review provides an overview of the major categories of damage encountered during RBC biopreservation, classified into storage lesions and cryolesions. We also highlight the key role of nanomaterials in enhancing the storage quality of RBCs and prolonging their preservation duration. Finally, we discuss the current challenges and pressing issues faced by nanomaterial-based RBCs biopreservation.
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Affiliation(s)
- Jun Xu
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, P. R. China
| | - Chuanyi Lei
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, P. R. China
| | - Wei Zhu
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, P. R. China
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4
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Alajeyan IA, Alsughayyir J, Alfhili MA. Zeatin Elicits Premature Erythrocyte Senescence Through Calcium and Oxidative Stress Mediated by the NOS/PKC/CK1α Signaling Axis. Dose Response 2025; 23:15593258251314825. [PMID: 39823073 PMCID: PMC11733885 DOI: 10.1177/15593258251314825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/11/2024] [Accepted: 12/15/2024] [Indexed: 01/19/2025] Open
Abstract
Objectives: Cytokinins are plant hormones that regulate cell growth and differentiation. In particular, zeatin (ZTN) delays cellular senescence of human fibroblasts and keratinocytes and exhibits anticancer activity. Chemotherapy-induced anemia is a major side effect of anticancer therapy secondary to premature senescence of red blood cells (RBCs). Herein, we investigated the biochemical and molecular mechanisms underlying ZTN action in human RBCs. Methods: Colorimetric assays were used to quantify hemolysis and related markers and flow cytometric analysis was applied to examine eryptosis through phosphatidylserine (PS) exposure by annexin-V-FITC, intracellular Ca2+ by Fluo4/AM, reactive oxygen species (ROS) by H2DCFDA, and cell size from forward scatter (FSC). Results: ZTN at 200 μM induced significant hemolysis and K+, Na+, AST, and LDH leakage. ZTN also caused a significant increase in annexin-V-positive cells along with increased Fluo4 and DCF fluorescence and reduced FSC. Importantly, L-NAME, staurosporin, D4476, urea, sucrose, and polyethylene glycol 8000 (PEG) significantly ameliorated ZTN cytotoxicity. Conclusion: ZTN stimulates PS exposure, intracellular Ca2+ elevation, oxidative stress, and cell shrinkage. The hemolytic potential of ZTN, mediated through nitric oxide synthase/protein kinase C/casein kinase 1α signaling axis, is sensitive to isosmotic urea, sucrose, and PEG availability. Altogether, the anticancer potential of ZTN must be reconsidered with prudence.
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Affiliation(s)
- Iman A. Alajeyan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Jawaher Alsughayyir
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad A. Alfhili
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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5
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Rabcuka J, Smethurst PA, Dammert K, Saker J, Aran G, Walsh GM, Tan JCG, Codinach M, McTaggart K, Marks DC, Bakker SJL, McMahon A, Di Angelantonio E, Roberts DJ, Blonski S, Korczyk PM, Shirakami A, Cardigan R, Swietach P. Assessing the kinetics of oxygen-unloading from red cells using FlowScore, a flow-cytometric proxy of the functional quality of blood. EBioMedicine 2025; 111:105498. [PMID: 39674089 PMCID: PMC11730303 DOI: 10.1016/j.ebiom.2024.105498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 12/16/2024] Open
Abstract
BACKGROUND Metrics evaluating the functional quality of red blood cells (RBCs) must consider their role in oxygen delivery. Whereas oxygen-carrying capacity is routinely reported using haemoglobin assays, the rate of oxygen exchange is not measured, yet also important for tissue oxygenation. Since oxygen-unloading depends on the diffusion pathlength inside RBCs, cell geometry offers a plausible surrogate. METHODS We related the time-constant of oxygen-unloading (τ), measured using single-cell oxygen saturation imaging, with flow-cytometric variables recorded on a haematology analyser. Experiments compared freshly-drawn RBCs with stored RBCs, wherein metabolic run-down and spherical remodelling hinder oxygen unloading. FINDINGS Multivariable regression related τ to a ratio of side- and forward-scatter, referred to herein as FlowScore. FlowScore was able to distinguish, with sensitivity and specificity >80%, freshly drawn blood from blood that underwent storage-related kinetic attrition in O2-handling. Moreover, FlowScore predicted τ restoration upon biochemical rejuvenation of stored blood. Since RBC geometry and metabolic state are related, variants of FlowScore estimated [ATP] and [2,3-diphosphoglycerate]. The veracity of FlowScore was confirmed by four blood-banking systems (Australia, Canada, England, Spain). Applying FlowScore to data from the COMPARE study revealed a positive association with the time-delay from sample collection to measurement, which was verified experimentally. The LifeLines dataset revealed age, sex, and smoking among factors affecting FlowScore. INTERPRETATION We establish FlowScore as a widely-accessible and cost-effective surrogate of RBC oxygen-unloading kinetics. As a metric of a cellular process that is sensitive to storage and disease, we propose FlowScore as an RBC quality marker for blood-banking and haematology. FUNDING See Acknowledgements.
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Affiliation(s)
- Julija Rabcuka
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK
| | - Peter A Smethurst
- Component Development Laboratory, NHS Blood and Transplant, Cambridge, UK
| | | | - Jarob Saker
- Sysmex Europe SE, Bornbarch 1, Norderstedt, 22848, Germany
| | - Gemma Aran
- Cell Laboratory, Banc de Sang i Teixits, Barcelona, Spain
| | - Geraldine M Walsh
- Product and Process Development, Canadian Blood Services, Vancouver, Canada
| | - Joanne C G Tan
- Research and Development, Australian Red Cross Lifeblood, Sydney, Australia; Sydney Medical School, University of Sydney, Camperdown, Australia
| | - Margarita Codinach
- Cell Laboratory, Banc de Sang i Teixits, Barcelona, Spain; Transfusional Medicine Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ken McTaggart
- Product and Process Development, Canadian Blood Services, Ottawa, Canada
| | - Denese C Marks
- Research and Development, Australian Red Cross Lifeblood, Sydney, Australia; Sydney Medical School, University of Sydney, Camperdown, Australia
| | - Stephan J L Bakker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Amy McMahon
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health & Primary Care, University of Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK
| | - Emanuele Di Angelantonio
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health & Primary Care, University of Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK; Health Data Science Research Centre, Human Technopole, Milan, Italy
| | - David J Roberts
- NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK; Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Slawomir Blonski
- Institute of Fundamental Technological Research Polish Academy of Sciences, Warsaw, Poland
| | - Piotr M Korczyk
- Institute of Fundamental Technological Research Polish Academy of Sciences, Warsaw, Poland
| | | | - Rebecca Cardigan
- Component Development Laboratory, NHS Blood and Transplant, Cambridge, UK; Department of Haematology, University of Cambridge, UK
| | - Pawel Swietach
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK.
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Alshalani A, AlSudais H, Binhassan S, Juffermans NP. Sex discrepancies in blood donation: Implications for red blood cell characteristics and transfusion efficacy. Transfus Apher Sci 2024; 63:104016. [PMID: 39423667 DOI: 10.1016/j.transci.2024.104016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2024]
Abstract
Red blood cell (RBC) transfusions carry risks, and the mechanisms mediating adverse transfusion outcomes are not fully understood. This review explores the impact of donor sex and donor-recipient sex mismatch on RBC characteristics and transfusion outcomes. Females, at least those in their reproductive age, have a higher proportion of young RBCs in the circulation when compared to males, associated with higher post transfusion recovery. Also, female RBCs exhibit a greater resilience to the storage lesion, with lower hemolysis rates and better rheologic properties. Despite these qualities, transfusion of female RBCs may be associated with adverse transfusion outcomes, such as pulmonary injury, increased mortality, and immunomodulatory effects, which may differ depending on the sex of the recipient, although not all observations are consistent. As a potential mechanism, the presence of immature RBCs, especially reticulocytes, in transfused blood is associated with immunomodulatory effects. Reticulocytes contain residual cellular components which can interact with surrounding blood cells and endothelial cells, in particular in neonates and cancer patients. Understanding the influence of donor sex and RBC age-subpopulation on RBC quality, and investigating the risks and benefits of immature RBCs in transfusions, offers opportunities for optimizing transfusion practices.
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Affiliation(s)
- Abdulrahman Alshalani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
| | - Hamood AlSudais
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sarah Binhassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Nicole P Juffermans
- Department of Intensive Care and Translational Laboratory of Intensive Care, Erasmus Medical Center, Rotterdam, the Netherlands
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7
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Wang Y, Ma Y, Sun L, Rao Q, Yuan X, Chen Y, Li X. Profiles of differential expression of miRNAs in the late stage of red blood cell preservation and their potential roles. Transfus Clin Biol 2024; 31:229-236. [PMID: 39341351 DOI: 10.1016/j.tracli.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/01/2024]
Abstract
OBJECTIVE To detect the differentially expressed regulatory miRNAs in the late stage of red blood cell (RBC) preservation and predict their roles. METHODS Suspended RBCs with different storage periods of 35 day, 42 day, and 50 day were collected for routine blood tests, RNA extraction, and preparation of small RNA sequencing libraries. The constructed libraries were sequenced and the biological functions of differential miRNAs in RBCs in the late storage were analyzed by bioinformatics. RESULTS Routine indicators of RBCs in the late stage were not significantly affected by preservation time. The Pearson correlation analysis performing on RBC miRNAs with different storage days revealed that RBC miRNAs changed with the increase of storage days. RBC miRNAs from day 35 (D35), day 42 (D42) and day 50 (D50) showed significant differences (P < 0.05). Compared RBC miRNAs from D42 with these from D35, there were 690 up-regulated miRNAs and 82 down-regulated miRNAs; compared RBC miRNAs from D50 with these from D35, there were 638 up-regulated miRNAs and 123 down-regulated miRNAs; compared RBC miRNAs from D42 with these from D50, there were 271 up-regulated miRNAs and 515 down-regulated miRNAs. GO enrichment analysis of target genes of differential miRNAs were mainly involved in cell metabolism, biosynthesis, protein modification, gene expression and transcriptional regulation of biological processes. KEGG pathway enrichment analysis of miRNA target genes showed that differential miRNA target genes were closely related to pathways in cancer. CONCLUSION MiRNAs were differentially expressed in the late stage of RBC preservation, and may be involved in various biological processes, especially cancer.
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Affiliation(s)
- Yajie Wang
- Department of Blood Transfusion, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yiming Ma
- Department of Blood Transfusion, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Liping Sun
- Department of Transfusion Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Quan Rao
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Xiaozhou Yuan
- Department of Blood Transfusion, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yan Chen
- Department of Blood Transfusion, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Xiaofei Li
- Department of Blood Transfusion, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
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8
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Caughey MC, Francis RO, Karafin MS. New and emerging technologies for pretransfusion blood quality assessment: A state-of-the-art review. Transfusion 2024; 64:2196-2208. [PMID: 39325509 PMCID: PMC11573642 DOI: 10.1111/trf.18019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/14/2024] [Accepted: 09/07/2024] [Indexed: 09/27/2024]
Affiliation(s)
- Melissa C. Caughey
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University; Chapel Hill, NC
| | - Richard O. Francis
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center; New York, New York
| | - Matthew S. Karafin
- Department of Pathology and Laboratory Medicine, University of North Carolina; Chapel Hill, NC
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9
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Koo YK, Choi SJ, Kwon SS, Myung J, Kim S, Park I, Chung HS. Effect of storage duration on outcome of patients receiving red blood cell in emergency department. Sci Rep 2024; 14:23463. [PMID: 39379435 PMCID: PMC11461482 DOI: 10.1038/s41598-024-74114-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 09/24/2024] [Indexed: 10/10/2024] Open
Abstract
The effect of the duration of red blood cell (RBC) storage on the outcomes of transfused patients remains controversial, and studies on patients in the emergency department (ED) are limited. This study aimed to determine the association between RBC storage duration and outcomes of patients receiving transfusions in the ED. For RBCs issued to patients in the ED between 2017 and 2022, the storage period of the RBC and data on the transfused patient were obtained. Patients were divided into fresh (≤ 7 days) and old (> 7 days) RBC groups, and the associations between storage duration, outcomes, and laboratory changes were evaluated. There was no significant difference in outcomes between the two groups in the 28-day mortality (adjusted odds ratio [OR] 0.91, 95% confidence interval [CI] 0.75-1.10, P = 0.320) and the length of stay (fresh 13.5 ± 18.1 vs. old 13.3 ± 19.8, P = 0.814). Regarding changes in laboratory test results, the increase in hemoglobin and hematocrit levels was not affected by the storage durations. The study revealed that transfusion of older RBCs is not associated with inferior outcomes or adverse clinical consequences when compared to that of fresh RBCs in patients in the ED.
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Affiliation(s)
- Yu-Kyung Koo
- Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Sol Ji Choi
- Department of Emergency Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Soon Sung Kwon
- Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Jinwoo Myung
- Department of Emergency Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Sinyoung Kim
- Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Incheol Park
- Department of Emergency Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hyun Soo Chung
- Department of Emergency Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
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10
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Masannagari P, Rajashekaraiah V. Attenuation of Oxidative Stress in Erythrocytes Stored with Vitamin C and l-Carnitine in Additive Solution-7. Biopreserv Biobank 2024; 22:497-505. [PMID: 38452159 DOI: 10.1089/bio.2023.0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2024] Open
Abstract
Background: Blood transfusion has advanced toward component therapy for specific requirements during trauma and surgery. Oxidative stress is induced in erythrocytes during storage. Hence, antioxidants as additives can be employed to counteract oxidative stress and enhance antioxidant defenses. Therefore, this study investigates the combinatorial effects of vitamin C and l-carnitine on erythrocytes during storage. Methodology: Erythrocyte samples were categorized into control and experimental groups-vitamin C (10 mM) and l-carnitine (10 mM) and stored under blood bank conditions (at 4°C) for 35 days. Hemoglobin (Hb), antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT] and glutathione peroxidase [GPX]), lipid peroxidation products (conjugate dienes and thiobarbituric acid reactive substances [TBARSs]), protein oxidation products, metabolic markers (glucose, lactate dehydrogenase), glutathione (GSH), superoxides, and hemolysis were assessed at weekly intervals. Results: SOD activity increased on day 7 in the controls, whereas it increased on days 7 and 14 in the experimental groups. CAT activity increased on day 35 in both the groups. GPX activity increased on day 7 in the controls. Hb levels decreased on days 14 and 35 in the controls and on day 35 in the experimental groups. Hemolysis increased from day 7 onward in both the groups. Protein oxidation products were maintained throughout the storage. GSH levels increased on day 21 in the controls and on days 14 and 21 in the experimental groups. Superoxides and conjugate dienes decreased from day 14 in both the groups. TBARSs decreased on day 7 in the experimental groups. Conclusion: Vitamin C and l-carnitine have synergistically enhanced the efficacy of stored erythrocytes in terms of Hb, antioxidant enzymes, and lipid peroxidation.
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Affiliation(s)
- Pallavi Masannagari
- Department of Biotechnology, School of Sciences, JAIN (Deemed-to-be University), Bangalore, India
| | - Vani Rajashekaraiah
- Department of Biotechnology, School of Sciences, JAIN (Deemed-to-be University), Bangalore, India
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11
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Obonyo NG, Dhanapathy V, White N, Sela DP, Rachakonda RH, Tunbridge M, Sim B, Teo D, Nadeem Z, See Hoe LE, Bassi GL, Fanning JP, Tung JP, Suen JY, Fraser JF. Effects of red blood cell transfusion on patients undergoing cardiac surgery in Queensland - a retrospective cohort study. J Cardiothorac Surg 2024; 19:475. [PMID: 39090687 PMCID: PMC11293042 DOI: 10.1186/s13019-024-02974-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 07/13/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Packed red blood cell (pRBC) transfusion is a relatively safe and mainstay treatment commonly used in cardiac surgical patients. However, there is limited evidence on clinical effects of transfusing blood nearing end-of shelf life that has undergone biochemical changes during storage. OBJECTIVE To investigate evidence of associations between morbidity/mortality and transfusion of blood near end of shelf-life (> 35 days) in cardiac surgical patients. METHODS Data from the Queensland Health Admitted Patient Data Collection database 2007-2013 was retrospectively analysed. Coronary artery bypass graft and valvular repair patients were included. Multivariable logistic regression was used to examine the effect of pRBC age (< 35 days vs. ≥ 35 days) on in-hospital mortality and morbidity. As secondary analysis, outcomes associated with the number of pRBC units transfused (≤ 4 units vs. ≥ 5 units) were also assessed. RESULTS A total of 4514 cardiac surgery patients received pRBC transfusion. Of these, 292 (6.5%) received pRBCs ≥ 35 days. No difference in in-hospital mortality or frequency of complications was observed. Transfusion of ≥ 5 units of pRBCs compared to the ≤ 4 units was associated with higher rates of in-hospital mortality (5.6% vs. 1.3%), acute renal failure (17.6% vs. 8%), infection (10% vs. 3.4%), and acute myocardial infarction (9.2% vs. 4.3%). Infection carried an odds ratio of 1.37 between groups (CI = 0.9-2.09; p = 0.14) and stroke/neurological complications, 1.59 (CI = 0.96-2.63; p = 0.07). CONCLUSION In cardiac surgery patients, transfusion of pRBCs closer to end of shelf-life was not shown to be associated with significantly increased mortality or morbidity. Dose-dependent differences in adverse outcomes (particularly where units transfused were > 4) were supported.
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Affiliation(s)
- Nchafatso G Obonyo
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
- Initiative to Develop African Research Leaders (IDeAL), KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
- Wellcome Trust Centre for Global Health Research, Imperial College London, London, UK.
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
| | - Vikash Dhanapathy
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- School of Medicine, Griffith University, Gold Coast, QLD, Australia
| | - Nicole White
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, QLD, Australia
| | - Declan P Sela
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Reema H Rachakonda
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Matthew Tunbridge
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Beatrice Sim
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Derek Teo
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Zohaib Nadeem
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Louise E See Hoe
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, QLD, Australia
| | - Gianluigi Li Bassi
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- Wesley Medical Research, The Wesley Foundation, Auchenflower, Brisbane, QLD, Australia
- Intensive Care Unit, St Andrew's War Memorial Hospital, Spring Hill, Brisbane, QLD, Australia
- Intensive Care Unit, The Wesley Hospital, Auchenflower, Brisbane, QLD, Australia
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Jonathon P Fanning
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - John-Paul Tung
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- Clinical Services and Research, Australian Red Cross Lifeblood, Brisbane, QLD, Australia
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Jacky Y Suen
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- Intensive Care Unit, St Andrew's War Memorial Hospital, Spring Hill, Brisbane, QLD, Australia
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
- School of Medicine, Griffith University, Gold Coast, QLD, Australia
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12
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Zhu H, Auten RL, Whorton AR, Mason SN, Bock CB, Kucera GT, Kelleher ZT, Vose AT, McMahon TJ. Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo. Thromb Haemost 2024; 124:656-668. [PMID: 38519039 PMCID: PMC11199053 DOI: 10.1055/s-0044-1782182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 01/03/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND Increased adhesivity of red blood cells (RBCs) to endothelial cells (ECs) may contribute to organ dysfunction in malaria, sickle cell disease, and diabetes. RBCs normally export nitric oxide (NO)-derived vascular signals, facilitating blood flow. S-nitrosothiols (SNOs) are thiol adducts formed in RBCs from precursor NO upon the oxygenation-linked allosteric transition in hemoglobin. RBCs export these vasoregulatory SNOs on demand, thereby regulating regional blood flow and preventing RBC-EC adhesion, and the large (system L) neutral amino acid transporter 1 (LAT1; SLC7A5) appears to mediate SNO export by RBCs. METHODS To determine the role of LAT1-mediated SNO import by ECs generally and of LAT1-mediated SNO import by ECs in RBC SNO-dependent modulation of RBC sequestration and blood oxygenation in vivo, we engineered LAT1fl/fl; Cdh5-Cre+ mice, in which the putative SNO transporter LAT1 can be inducibly depleted (knocked down, KD) specifically in ECs ("LAT1ECKD"). RESULTS We show that LAT1 in mouse lung ECs mediates cellular SNO uptake. ECs from LAT1ECKD mice (tamoxifen-induced LAT1fl/fl; Cdh5-Cre+) import SNOs poorly ex vivo compared with ECs from wild-type (tamoxifen-treated LAT1fl/fl; Cdh5-Cre-) mice. In vivo, endothelial depletion of LAT1 increased RBC sequestration in the lung and decreased blood oxygenation after RBC transfusion. CONCLUSION This is the first study showing a role for SNO transport by LAT1 in ECs in a genetic mouse model. We provide the first direct evidence for the coordination of RBC SNO export with EC SNO import via LAT1. SNO flux via LAT1 modulates RBC-EC sequestration in lungs after transfusion, and its disruption impairs blood oxygenation by the lung.
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Affiliation(s)
- Hongmei Zhu
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
- Durham VA Health Care System, Durham North Carolina, United States
| | - Richard L. Auten
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States
| | - Augustus Richard Whorton
- Department of Pharmacology, Duke University Medical Center, Durham, North Carolina, United States
| | - Stanley Nicholas Mason
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States
| | - Cheryl B. Bock
- Rodent Cancer Models Shared Resource, Duke University Medical Center, Durham, North Carolina, United States
| | - Gary T. Kucera
- Rodent Cancer Models Shared Resource, Duke University Medical Center, Durham, North Carolina, United States
| | - Zachary T. Kelleher
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
| | - Aaron T. Vose
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
- Durham VA Health Care System, Durham North Carolina, United States
| | - Tim J. McMahon
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
- Durham VA Health Care System, Durham North Carolina, United States
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13
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Isiksacan Z, William N, Senturk R, Boudreau L, Wooning C, Castellanos E, Isiksacan S, Yarmush ML, Acker JP, Usta OB. Extended supercooled storage of red blood cells. Commun Biol 2024; 7:765. [PMID: 38914723 PMCID: PMC11196592 DOI: 10.1038/s42003-024-06463-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 06/16/2024] [Indexed: 06/26/2024] Open
Abstract
Red blood cell (RBC) transfusions facilitate many life-saving acute and chronic interventions. Transfusions are enabled through the gold-standard hypothermic storage of RBCs. Today, the demand for RBC units is unfulfilled, partially due to the limited storage time, 6 weeks, in hypothermic storage. This time limit stems from high metabolism-driven storage lesions at +1-6 °C. A recent and promising alternative to hypothermic storage is the supercooled storage of RBCs at subzero temperatures, pioneered by our group. Here, we report on long-term supercooled storage of human RBCs at physiological hematocrit levels for up to 23 weeks. Specifically, we assess hypothermic RBC additive solutions for their ability to sustain supercooled storage. We find that a commercially formulated next-generation solution (Erythro-Sol 5) enables the best storage performance and can form the basis for further improvements to supercooled storage. Our analyses indicate that oxidative stress is a prominent time- and temperature-dependent injury during supercooled storage. Thus, we report on improved supercooled storage of RBCs at -5 °C by supplementing Erythro-Sol 5 with the exogenous antioxidants, resveratrol, serotonin, melatonin, and Trolox. Overall, this study shows the long-term preservation potential of supercooled storage of RBCs and establishes a foundation for further improvement toward clinical translation.
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Affiliation(s)
- Ziya Isiksacan
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's, Boston, MA, USA
| | - Nishaka William
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Rahime Senturk
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's, Boston, MA, USA
- Department of Chemical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands
| | - Luke Boudreau
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's, Boston, MA, USA
| | - Celine Wooning
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's, Boston, MA, USA
- Department of Human Biology, Scripps College, Claremont, CA, USA
| | - Emily Castellanos
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's, Boston, MA, USA
- Department of Psychology, Amherst College, Amherst, MA, USA
| | - Salih Isiksacan
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's, Boston, MA, USA
- Department of Electrical-Electronics Engineering, Bilkent University, Ankara, Turkey
| | - Martin L Yarmush
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's, Boston, MA, USA
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Jason P Acker
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
- Innovation and Portfolio Management, Canadian Blood Services, Edmonton, AB, Canada.
| | - O Berk Usta
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Shriners Children's, Boston, MA, USA.
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14
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Wise TJ, Ott ME, Joseph MS, Welsby IJ, Darrow CC, McMahon TJ. Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport. Front Physiol 2024; 15:1394650. [PMID: 38915775 PMCID: PMC11194670 DOI: 10.3389/fphys.2024.1394650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 04/24/2024] [Indexed: 06/26/2024] Open
Abstract
Efficient distribution of oxygen (O2) to the tissues in mammals depends on the evolved ability of red blood cell (RBC) hemoglobin (Hb) to sense not only O2 levels, but metabolic cues such as pH, PCO2, and organic phosphates, and then dispense or take up oxygen accordingly. O2 delivery is the product of not only oxygen release from RBCs, but also blood flow, which itself is also governed by vasoactive molecular mediators exported by RBCs. These vascular signals, including ATP and S-nitrosothiols (SNOs) are produced and exported as a function of the oxygen and metabolic milieu, and then fine-tune peripheral metabolism through context-sensitive vasoregulation. Emerging and repurposed RBC-oriented therapeutics can modulate either or both of these allosteric and vasoregulatory activities, with a single molecule or other intervention influencing both arms of O2 transport in some cases. For example, organic phosphate repletion of stored RBCs boosts the negative allosteric effector 2,3 biphosphoglycerate (BPG) as well as the anti-adhesive molecule ATP. In sickle cell disease, aromatic aldehydes such as voxelotor can disfavor sickling by increasing O2 affinity, and in newer generations, these molecules have been coupled to vasoactive nitric oxide (NO)-releasing adducts. Activation of RBC pyruvate kinase also promotes a left shift in oxygen binding by consuming and lowering BPG, while increasing the ATP available for cell health and export on demand. Further translational and clinical investigation of these novel allosteric and/or vasoregulatory approaches to modulating O2 transport are expected to yield new insights and improve the ability to correct or compensate for anemia and other O2 delivery deficits.
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Affiliation(s)
- Thomas J. Wise
- Duke University School of Medicine, Durham, NC, United States
| | - Maura E. Ott
- Duke University School of Medicine, Durham, NC, United States
| | - Mahalah S. Joseph
- Duke University School of Medicine, Durham, NC, United States
- Florida International University School of Medicine, Miami, FL, United States
| | - Ian J. Welsby
- Duke University School of Medicine, Durham, NC, United States
| | - Cole C. Darrow
- Duke University School of Medicine, Durham, NC, United States
| | - Tim J. McMahon
- Duke University School of Medicine, Durham, NC, United States
- Durham VA Health Care System, Durham, NC, United States
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15
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Montano-Pedroso JC, Biagini S, Macedo MCMDA, Ribeiro G, Comenalli Marques Junior JF, Rizzo SRCP, Rabello G, Langhi Junior DM. Consensus of the Brazilian association of hematology, hemotherapy and cellular therapy on patient blood management: History and scenario of patient blood management in the world and in Brazil. Hematol Transfus Cell Ther 2024; 46 Suppl 1:S1-S4. [PMID: 38508946 PMCID: PMC11069064 DOI: 10.1016/j.htct.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 02/18/2024] [Indexed: 03/22/2024] Open
Abstract
Patient Blood Management (PBM) is a multidimensional approach that seeks to optimize the use of blood and its components in patients. This matter emerged as a response to the need to reduce unnecessary exposure to blood transfusions and their potential risks. In the past, blood transfusion was often overused resulting in complications and high costs. The advent of Patient Blood Management has caused a paradigm shift, highlighting anemia prevention, bleeding control and maximizing the production of blood cells by the organism itself. Patient Blood Management guidelines include the early identification of anemia, strategies to minimize blood loss during surgery, intraoperative blood conservation techniques, preoperative hemoglobin optimization and evidence-based approaches to the rational use of blood transfusions. Aiming to improve clinical outcomes, decrease transfusion-related complications and reduce associated costs, this multidisciplinary approach counts on doctors, nurses, pharmacists and other healthcare professionals. Based on research and clinical evidence, Patient Blood Management continues to evolve thereby promoting safer, more effective patient-centered practices. Its implementation has proven beneficial in various medical contexts thereby contributing to improvements in the quality of care provided to patients. Our goal with this Consensus is to present readers with a broad and diverse view of Patient Blood Management so that they have the building blocks to implement this new technique.
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Affiliation(s)
- Juan Carlos Montano-Pedroso
- Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil; Instituto de Assistência Médica do Servidor Público Estadual (Iamspe), São Paulo, SP, Brazil
| | - Silvana Biagini
- Hospital Guilherme Álvaro e Complexo Hospitalar dos Estivadores, Santos, SP, Brazil
| | | | - Glaciano Ribeiro
- Hospital das Clínicas da Universidade Federal de Minas Gerais (HC UFMG), Belo Horizonte, MG, Brazil; Grupo HHEMO, São Paulo, SP, Brazil
| | | | | | - Guilherme Rabello
- Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (Incor - HCFMUSP), São Paulo, SP, Brazil.
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16
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Chatzinikolaou PN, Margaritelis NV, Paschalis V, Theodorou AA, Vrabas IS, Kyparos A, D'Alessandro A, Nikolaidis MG. Erythrocyte metabolism. Acta Physiol (Oxf) 2024; 240:e14081. [PMID: 38270467 DOI: 10.1111/apha.14081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/11/2023] [Accepted: 01/01/2024] [Indexed: 01/26/2024]
Abstract
Our aim is to present an updated overview of the erythrocyte metabolism highlighting its richness and complexity. We have manually collected and connected the available biochemical pathways and integrated them into a functional metabolic map. The focus of this map is on the main biochemical pathways consisting of glycolysis, the pentose phosphate pathway, redox metabolism, oxygen metabolism, purine/nucleoside metabolism, and membrane transport. Other recently emerging pathways are also curated, like the methionine salvage pathway, the glyoxalase system, carnitine metabolism, and the lands cycle, as well as remnants of the carboxylic acid metabolism. An additional goal of this review is to present the dynamics of erythrocyte metabolism, providing key numbers used to perform basic quantitative analyses. By synthesizing experimental and computational data, we conclude that glycolysis, pentose phosphate pathway, and redox metabolism are the foundations of erythrocyte metabolism. Additionally, the erythrocyte can sense oxygen levels and oxidative stress adjusting its mechanics, metabolism, and function. In conclusion, fine-tuning of erythrocyte metabolism controls one of the most important biological processes, that is, oxygen loading, transport, and delivery.
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Affiliation(s)
- Panagiotis N Chatzinikolaou
- Department of Physical Education and Sports Science at Serres, Aristotle University of Thessaloniki, Serres, Greece
| | - Nikos V Margaritelis
- Department of Physical Education and Sports Science at Serres, Aristotle University of Thessaloniki, Serres, Greece
| | - Vassilis Paschalis
- School of Physical Education and Sport Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasios A Theodorou
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
| | - Ioannis S Vrabas
- Department of Physical Education and Sports Science at Serres, Aristotle University of Thessaloniki, Serres, Greece
| | - Antonios Kyparos
- Department of Physical Education and Sports Science at Serres, Aristotle University of Thessaloniki, Serres, Greece
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Michalis G Nikolaidis
- Department of Physical Education and Sports Science at Serres, Aristotle University of Thessaloniki, Serres, Greece
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17
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Dumbill R, Rabcuka J, Fallon J, Knight S, Hunter J, Voyce D, Barrett J, Ellen M, Weissenbacher A, Kurniawan T, Blonski S, Korczyk PM, Ploeg R, Coussios C, Friend P, Swietach P. Impaired O2 unloading from stored blood results in diffusion-limited O2 release at tissues: evidence from human kidneys. Blood 2024; 143:721-733. [PMID: 38048591 PMCID: PMC10900257 DOI: 10.1182/blood.2023022385] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/26/2023] [Accepted: 11/03/2023] [Indexed: 12/06/2023] Open
Abstract
ABSTRACT The volume of oxygen drawn from systemic capillaries down a partial pressure gradient is determined by the oxygen content of red blood cells (RBCs) and their oxygen-unloading kinetics, although the latter is assumed to be rapid and, therefore, not a meaningful factor. Under this paradigm, oxygen transfer to tissues is perfusion-limited. Consequently, clinical treatments to optimize oxygen delivery aim at improving blood flow and arterial oxygen content, rather than RBC oxygen handling. Although the oxygen-carrying capacity of blood is increased with transfusion, studies have shown that stored blood undergoes kinetic attrition of oxygen release, which may compromise overall oxygen delivery to tissues by causing transport to become diffusion-limited. We sought evidence for diffusion-limited oxygen release in viable human kidneys, normothermically perfused with stored blood. In a cohort of kidneys that went on to be transplanted, renal respiration correlated inversely with the time-constant of oxygen unloading from RBCs used for perfusion. Furthermore, the renal respiratory rate did not correlate with arterial O2 delivery unless this factored the rate of oxygen-release from RBCs, as expected from diffusion-limited transport. To test for a rescue effect, perfusion of kidneys deemed unsuitable for transplantation was alternated between stored and rejuvenated RBCs of the same donation. This experiment controlled oxygen-unloading, without intervening ischemia, holding all non-RBC parameters constant. Rejuvenated oxygen-unloading kinetics improved the kidney's oxygen diffusion capacity and increased cortical oxygen partial pressure by 60%. Thus, oxygen delivery to tissues can become diffusion-limited during perfusion with stored blood, which has implications in scenarios, such as ex vivo organ perfusion, major hemorrhage, and pediatric transfusion. This trial was registered at www.clinicaltrials.gov as #ISRCTN13292277.
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Affiliation(s)
- Richard Dumbill
- Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Julija Rabcuka
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
| | - John Fallon
- Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Simon Knight
- Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - James Hunter
- Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom
- University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | | | | | | | - Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Tetuko Kurniawan
- Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland
- President University, Kota Jababeka, Bekasi, Indonesia
| | - Slawomir Blonski
- Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland
| | - Piotr Michal Korczyk
- Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland
| | - Rutger Ploeg
- Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Constantin Coussios
- OrganOx Limited, Oxford, United Kingdom
- Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom
| | - Peter Friend
- Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
- OrganOx Limited, Oxford, United Kingdom
| | - Pawel Swietach
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom
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18
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Hu Y, Liu X, Zhang W, Chen J, Chen X, Tan S. Inulin Can Improve Red Blood Cell Cryopreservation by Promoting Vitrification, Stabilizing Cell Membranes, and Inhibiting Ice Recrystallization. ACS Biomater Sci Eng 2024; 10:851-862. [PMID: 38176101 DOI: 10.1021/acsbiomaterials.3c01463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2024]
Abstract
In transfusion medicine, the cryopreservation of red blood cells (RBCs) is of major importance. The organic solvent glycerol (Gly) is considered the current gold-standard cryoprotectant (CPA) for RBC cryopreservation, but the deglycerolization procedure is complex and time-consuming, resulting in severe hemolysis. Therefore, it remains a research hotspot to find biocompatible and effective novel CPAs. Herein, the natural and biocompatible inulin, a polysaccharide, was first employed as a CPA for RBC cryopreservation. The presence of inulin could improve the thawed RBC recovery from 11.83 ± 1.40 to 81.86 ± 0.37%. It was found that inulin could promote vitrification because of its relatively high viscosity and glass transition temperature (Tg'), thus reducing the damage during cryopreservation. Inulin possessed membrane stability, which also had beneficial effects on RBC recovery. Moreover, inulin could inhibit the mechanical damage induced by ice recrystallization during thawing. After cryopreservation, the RBC properties were maintained normally. Mathematical modeling analysis was adopted to compare the performance of inulin, Gly, and hydroxyethyl starch (HES) in cryopreservation, and inulin presented the best efficiency. This work provides a promising CPA for RBC cryopreservation and may be beneficial for transfusion therapy in the clinic.
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Affiliation(s)
- Yuying Hu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Xiangjian Liu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Wenqian Zhang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Jiangming Chen
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Xiaoxiao Chen
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Songwen Tan
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
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19
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Ma Y, Li C, Sun L, Li X. The Ratio of Intraoperative Red Blood Cell Transfusion to Blood Loss Associated with Early Postoperative Complications in Pediatric Liver Transplantation Patients. Transfus Med Hemother 2024; 51:41-47. [PMID: 38314246 PMCID: PMC10836861 DOI: 10.1159/000530290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 03/20/2023] [Indexed: 02/06/2024] Open
Abstract
Introduction Liver transplantation (LT) is an operation purposed to save the lives of children with acute or chronic liver diseases, hepatic tumors, and some genetic and metabolic diseases. However, patients who underwent LT have a significant risk of intraoperative blood loss and red blood cell (RBC) transfusion, especially in pediatric patients. Methods In this study, 569 pediatric patients (<18 years old) who underwent LT at a tertiary university hospital between 2013 and 2020 were included. Multiple logistic regression was used to analyze the association between the ratio of intraoperative RBC transfusion to blood loss (IRTBL) and the complications after LT in pediatric patients. IRTBL was divided into quartiles in the adjusted model. Odds ratios, 95% confidence intervals, and p values for trends were calculated. Restricted cubic spline (RCS) regression was used to evaluate the nonlinear association between IRTBL and complications. Results Compared with the lowest level and the highest level of IRTBL, Q2 and Q3 quartiles of IRTBL showed significantly positive association with early complications. A significantly nonlinear association was observed between the IRTBL and early complications in the RCS model with the multiple adjustments of potential covariates (P overall<0.01, P nonlinear<0.01). However, no significant association was observed between late complications and IRTBL. Conclusion In this study, we found there was a nonlinear relationship between the ratio of IRTBL and early postoperative complications in pediatric LT patients, which provides a theoretical basis for RBC transfusion in pediatric LT patients.
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Affiliation(s)
- Yiming Ma
- Department of Blood Transfusion, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Cheng Li
- Department of Clinical Nutrition, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Liying Sun
- Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Xiaofei Li
- Department of Blood Transfusion, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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20
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Gagen B, Duchesne J, Ghio M, Duplechain A, Krakosky D, Simpson JT, Tatum D. PROSPECTIVE EXAMINATION OF THE K/ICA RATIO AS A PREDICTOR FOR MORTALITY IN SEVERE HEMORRHAGE. Shock 2024; 61:34-40. [PMID: 37752083 DOI: 10.1097/shk.0000000000002238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Abstract
ABSTRACT Background: Patients receiving massive transfusion protocol (MTP) are at risk for posttransfusion hypocalcemia and hyperkalemia. Previous retrospective analysis has suggested the potassium/ionized calcium (K/iCa) ratio as a prognostic indicator of mortality. This prospective study sought to validate the value of the K/iCa ratio as a predictor for mortality in patients receiving MTP. Methods: This was a prospective analysis of adult trauma patients who underwent MTP activation from May 2019 to March 2021 at an urban level 1 trauma center. Serum potassium and iCa levels within 0 to 1 h of MTP initiation were used to obtain K/iCa. Receiver operator characteristic curve analysis assessed predictive capacity of K/iCa on mortality. Kaplan-Meier survival analysis and Cox regression examined the effect of K/iCa ratio on survival. Results: A total of 110 of 300 MTP activation patients met inclusion criteria. Overall mortality rate was 31.8%. No significant differences between the elevated K/iCa and lower K/iCa groups were found for prehospital or emergency department initial vitals, shock index, or injury severity. However, nonsurvivors had a significantly higher median K/iCa ratio compared with those who survived ( P < 0.01). Multivariable logistic regression revealed the total number of blood products to be significantly associated with elevated K/iCa (odds ratio, 1.02; 95% CI, 1.01-1.04; P = 0.01). The Kaplan Meier survival curve demonstrated a significantly increased rate of survival for those with an elevated K/iCa ratio ( P < 0.01). Multivariable Cox regression adjusted for confounders showed a significant association between K/iCa and mortality (Hazard Ratio, 4.12; 95% CI, 1.89-8.96; P < 0.001). Conclusion: This evidence further highlights the importance of the K/iCa ratio in predicting mortality among trauma patients receiving MTP. Furthermore, it demonstrates that posttransfusion K levels along with iCa levels should be carefully monitored in the MTP setting. Level of Evidence: Level II. Study Type: Prognostic/epidemiological.
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Affiliation(s)
- Brennan Gagen
- Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana 70112
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21
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Skrajewski-Schuler LA, Soule LD, Geiger M, Spence D. UPLC-MS/MS method for quantitative determination of the advanced glycation endproducts Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2023; 15:6698-6705. [PMID: 38047493 PMCID: PMC10720951 DOI: 10.1039/d3ay01817b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 11/24/2023] [Indexed: 12/05/2023]
Abstract
During blood storage, red blood cells (RBCs) undergo physical, chemical, and metabolic changes that may contribute to post-transfusion complications. Due to the hyperglycemic environment of typical solutions used for RBC storage, the formation of advanced glycation endproducts (AGEs) on the stored RBCs has been implicated as a detrimental chemical change during storage. Unfortunately, there are limited studies involving quantitative determination and differentiation of carboxymethyl-lysine (CML) and carboxyethyl-lysine (CEL), two commonly formed AGEs, and no reported studies comparing these AGEs in experimental storage solutions. In this study, CML and CEL were identified and quantified on freshly drawn blood samples in two types of storage solutions, standard additive solution 1 (AS-1) and a normoglycemic version of AS-1 (AS-1N). To facilitate detection of the AGEs, a novel method was developed to reliably extract AGEs from RBCs, provide Food and Drug Administration (FDA) bioanalytical guidance criteria, and enable acceptable selectivity for these analytes. Ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) was utilized to identify and quantify the AGEs. Results show this method is accurate, precise, has minimal interferences or matrix effects, and overcomes the issue of detecting AGE byproducts. Importantly, AGEs can be detected and quantified in both types of blood storage solutions (AS-1 and AS-1N), thereby enabling long-term (6 weeks) blood storage related studies.
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Affiliation(s)
- Lauren A Skrajewski-Schuler
- Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
- Institute for Quantitative Health, Michigan State University, East Lansing, MI 48824, USA.
| | - Logan D Soule
- Institute for Quantitative Health, Michigan State University, East Lansing, MI 48824, USA.
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Morgan Geiger
- Institute for Quantitative Health, Michigan State University, East Lansing, MI 48824, USA.
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Dana Spence
- Institute for Quantitative Health, Michigan State University, East Lansing, MI 48824, USA.
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
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22
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Oladokun R, Adekanmbi EO, An V, Gangavaram I, Srivastava SK. Dielectrophoretic profiling of erythrocytes to study the impacts of metabolic stress, temperature, and storage duration utilizing a point-and-planar microdevice. Sci Rep 2023; 13:17281. [PMID: 37828082 PMCID: PMC10570315 DOI: 10.1038/s41598-023-44022-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 10/03/2023] [Indexed: 10/14/2023] Open
Abstract
Dielectrophoresis (DEP) is widely utilized for trapping and sorting various types of cells, including live and dead cells and healthy and infected cells. This article focuses on the dielectric characterization of erythrocytes (red blood cells or RBCs) by quantifying DEP crossover frequency using a novel point-and-planar microwell device platform. Numerical simulations using COMSOL Multiphysics software demonstrate that the distribution of the DEP force is influenced by factors such as the shape of the point electrode, spacing between the point and planar electrodes, and the type of bioparticle being investigated. The dependency on electrode spacing is experimentally evaluated by analyzing the DEP crossover response of erythrocytes. Furthermore, the results are validated against the traditional electrical characterization technique called electrorotation, which typically requires laborious fabrication and operation using quadrupole electrodes. Other significant factors, including erythrocyte storage age and the changes in cell properties over time since collection, osmolarity, and temperature, are also assessed to determine the optimal conditions for erythrocyte characterization. The findings indicate a significant difference between fresh and stored erythrocyte samples (up to 4 days), highlighting the importance of maintaining an isotonic medium for cell storage.
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Affiliation(s)
- Raphael Oladokun
- Department of Chemical and Biomedical Engineering, West Virginia University, 1306 Evansdale Dr., PO Box 6102, Morgantown, WV, 26506-6102, USA
| | | | - Vanessa An
- Summer 2022 High School Intern, Department of Chemical and Biomedical Engineering, West Virginia University, Morgantown, WV, USA
| | - Isha Gangavaram
- Summer 2022 High School Intern, Department of Chemical and Biomedical Engineering, West Virginia University, Morgantown, WV, USA
| | - Soumya K Srivastava
- Department of Chemical and Biomedical Engineering, West Virginia University, 1306 Evansdale Dr., PO Box 6102, Morgantown, WV, 26506-6102, USA.
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23
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Isiksacan Z, D’Alessandro A, Wolf SM, McKenna DH, Tessier SN, Kucukal E, Gokaltun AA, William N, Sandlin RD, Bischof J, Mohandas N, Busch MP, Elbuken C, Gurkan UA, Toner M, Acker JP, Yarmush ML, Usta OB. Assessment of stored red blood cells through lab-on-a-chip technologies for precision transfusion medicine. Proc Natl Acad Sci U S A 2023; 120:e2115616120. [PMID: 37494421 PMCID: PMC10410732 DOI: 10.1073/pnas.2115616120] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023] Open
Abstract
Transfusion of red blood cells (RBCs) is one of the most valuable and widespread treatments in modern medicine. Lifesaving RBC transfusions are facilitated by the cold storage of RBC units in blood banks worldwide. Currently, RBC storage and subsequent transfusion practices are performed using simplistic workflows. More specifically, most blood banks follow the "first-in-first-out" principle to avoid wastage, whereas most healthcare providers prefer the "last-in-first-out" approach simply favoring chronologically younger RBCs. Neither approach addresses recent advances through -omics showing that stored RBC quality is highly variable depending on donor-, time-, and processing-specific factors. Thus, it is time to rethink our workflows in transfusion medicine taking advantage of novel technologies to perform RBC quality assessment. We imagine a future where lab-on-a-chip technologies utilize novel predictive markers of RBC quality identified by -omics and machine learning to usher in a new era of safer and precise transfusion medicine.
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Affiliation(s)
- Ziya Isiksacan
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO80045
| | - Susan M. Wolf
- Law School, Medical School, Consortium on Law and Values in Health, Environment & the Life Sciences, University of Minnesota, Minneapolis, MN55455
| | - David H. McKenna
- Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN55455
| | - Shannon N. Tessier
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
| | | | - A. Aslihan Gokaltun
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
- Department of Chemical Engineering, Hacettepe University, Ankara06532, Turkey
| | - Nishaka William
- Laboratory Medicine and Pathology, University of Alberta, Edmonton, ABT6G 2R8, Canada
| | - Rebecca D. Sandlin
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
| | - John Bischof
- Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN55455
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN55455
| | | | - Michael P. Busch
- Vitalant Research Institute, San Francisco, CA94105
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA94105
| | - Caglar Elbuken
- Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center, Bilkent University, Ankara06800, Turkey
- Faculty of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Oulu, 90014Oulu, Finland
- Valtion Teknillinen Tutkimuskeskus Technical Research Centre of Finland Ltd., 90570Oulu, Finland
| | - Umut A. Gurkan
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH44106
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH44106
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH44106
| | - Mehmet Toner
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
| | - Jason P. Acker
- Laboratory Medicine and Pathology, University of Alberta, Edmonton, ABT6G 2R8, Canada
- Innovation and Portfolio Management, Canadian Blood Services, Edmonton, ABT6G 2R8, Canada
| | - Martin L. Yarmush
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ08854
| | - O. Berk Usta
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
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24
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Lopes MG, Recktenwald SM, Simionato G, Eichler H, Wagner C, Quint S, Kaestner L. Big Data in Transfusion Medicine and Artificial Intelligence Analysis for Red Blood Cell Quality Control. Transfus Med Hemother 2023; 50:163-173. [PMID: 37408647 PMCID: PMC10319094 DOI: 10.1159/000530458] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 03/27/2023] [Indexed: 07/07/2023] Open
Abstract
Background "Artificial intelligence" and "big data" increasingly take the step from just being interesting concepts to being relevant or even part of our lives. This general statement holds also true for transfusion medicine. Besides all advancements in transfusion medicine, there is not yet an established red blood cell quality measure, which is generally applied. Summary We highlight the usefulness of big data in transfusion medicine. Furthermore, we emphasize in the example of quality control of red blood cell units the application of artificial intelligence. Key Messages A variety of concepts making use of big data and artificial intelligence are readily available but still await to be implemented into any clinical routine. For the quality control of red blood cell units, clinical validation is still required.
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Affiliation(s)
- Marcelle G.M. Lopes
- Experimental Physics, Saarland University, Saarbrücken, Germany
- Cysmic GmbH, Saarbrücken, Germany
| | | | - Greta Simionato
- Experimental Physics, Saarland University, Saarbrücken, Germany
- Institute for Clinical and Experimental Surgery, Saarland University, Saarbrücken, Germany
| | - Hermann Eichler
- Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University, Saarbrücken, Germany
| | - Christian Wagner
- Experimental Physics, Saarland University, Saarbrücken, Germany
- Physics and Materials Science Research Unit, University of Luxembourg, Luxembourg City, Luxembourg
| | | | - Lars Kaestner
- Experimental Physics, Saarland University, Saarbrücken, Germany
- Theoretical Medicine and Biosciences, Saarland University, Saarbrücken, Germany
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25
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Camargo Castillo MA, de Almeida BA, Wissmann D, Moreira RF, Okano FY, Gonzalez FHD, Soares JF, de Faria Valle S. Viability of erythrocytes in canine packed red blood cells stored in CPDA-1 is related to the presence of Mycoplasma haemocanis. Comp Immunol Microbiol Infect Dis 2023; 97:101982. [PMID: 37120937 DOI: 10.1016/j.cimid.2023.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 04/12/2023] [Indexed: 05/02/2023]
Abstract
Hemotropic mycoplasmas are associated with subclinical disease in dogs and should be identified in blood donors. The objective was to investigate the presence and effect of M. haemocanis in units of packed red blood cells (pRBC) during storage. Canine donors (n = 10) were screened for M. haemocanis by quantitative real-time PCR. pRBCs were obtained from 5 hemoplasma negative dogs and 5 hemoplasma positive dogs. Each pRBC was aliquoted into two 100 mL transfer bags and stored at 4 °C. M. haemocanis loads and biochemical variables (pH, bicarbonate, potassium, sodium, chlorite, glucose, lactate, ammonia, PCV, and % hemolysis) were evaluated on days 1, 7, 18, and 29. M. haemocanis loads increased in pRBC from day 1-29 of storage. Glucose decreased and lactate increase faster in pRBC with M. haemocanis. This study contributes to understand hemoplasma metabolism and reinforces that dog donors should be tested for hemoplasmas.
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Affiliation(s)
- Monica A Camargo Castillo
- Department of Veterinary Clinical Pathology, School of Veterinary Medicine, UFRGS, Porto Alegre RS, Brazil
| | | | - Daiani Wissmann
- Department of Veterinary Clinical Pathology, School of Veterinary Medicine, UFRGS, Porto Alegre RS, Brazil
| | - Renata Fagundes Moreira
- Department of Veterinary Clinical Pathology, School of Veterinary Medicine, UFRGS, Porto Alegre RS, Brazil
| | - Felipe Yuki Okano
- Department of Veterinary Clinical Pathology, School of Veterinary Medicine, UFRGS, Porto Alegre RS, Brazil
| | - Felix H D Gonzalez
- Department of Veterinary Clinical Pathology, School of Veterinary Medicine, UFRGS, Porto Alegre RS, Brazil
| | - João Fábio Soares
- Department of Veterinary Clinical Pathology, School of Veterinary Medicine, UFRGS, Porto Alegre RS, Brazil
| | - Stella de Faria Valle
- Department of Veterinary Clinical Pathology, School of Veterinary Medicine, UFRGS, Porto Alegre RS, Brazil.
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26
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Claus MA, Smart L, Raisis AL, Sharp CR, Abraham S, Gummer JPA, Mead MK, Bradley DL, Van Swelm R, Wiegerinck ETG, Litton E. Effect of Deferoxamine on Post-Transfusion Iron, Inflammation, and In Vitro Microbial Growth in a Canine Hemorrhagic Shock Model: A Randomized Controlled Blinded Pilot Study. Vet Sci 2023; 10:vetsci10020121. [PMID: 36851425 PMCID: PMC9962370 DOI: 10.3390/vetsci10020121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/27/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Red blood cell (RBC) transfusion is associated with recipient inflammation and infection, which may be triggered by excessive circulating iron. Iron chelation following transfusion may reduce these risks. The aim of this study was to evaluate the effect of deferoxamine on circulating iron and inflammation biomarkers over time and in vitro growth of Escherichia coli (E. coli) following RBC transfusion in dogs with atraumatic hemorrhage. Anesthetized dogs were subject to atraumatic hemorrhage and transfusion of RBCs, then randomized to receive either deferoxamine or saline placebo of equivalent volume (n = 10 per group) in a blinded fashion. Blood was sampled before hemorrhage and then 2, 4, and 6 h later. Following hemorrhage and RBC transfusion, free iron increased in all dogs over time (both p < 0.001). Inflammation biomarkers interleukin-6 (IL6), CXC motif chemokine-8 (CXCL8), interleukin-10 (IL10), and keratinocyte-derived chemokine (KC) increased in all dogs over time (all p < 0.001). Logarithmic growth of E. coli clones within blood collected 6 h post-transfusion was not different between groups. Only total iron-binding capacity was different between groups over time, being significantly increased in the deferoxamine group at 2 and 4 h post-transfusion (both p < 0.001). In summary, while free iron and inflammation biomarkers increased post-RBC transfusion, deferoxamine administration did not impact circulating free iron, inflammation biomarkers, or in vitro growth of E. coli when compared with placebo.
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Affiliation(s)
- Melissa A. Claus
- School of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia
- Perth Veterinary Specialists, Osborne Park, WA 6017, Australia
- Correspondence:
| | - Lisa Smart
- School of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia
- Small Animal Specialist Hospital, Tuggerah, NSW 2259, Australia
| | - Anthea L. Raisis
- School of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia
| | - Claire R. Sharp
- School of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia
| | - Sam Abraham
- School of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia
| | - Joel P. A. Gummer
- Forensic Sciences Laboratory, ChemCentre, Resources and Chemistry Precinct, Bentley, WA 6102, Australia
- School of Science, Edith Cowan University, Joondalup, WA 6027, Australia
| | - Martin K. Mead
- School of Veterinary Medicine, Murdoch University, Murdoch, WA 6150, Australia
| | - Damian L. Bradley
- Intensive Care Unit, Rockingham General Hospital, Cooloongup, WA 6168, Australia
| | - Rachel Van Swelm
- Hepcidinanalysis.com, Department of Laboratory Medicine, Translational Metabolic Laboratory (TML 830), Radboud University Medical Center, 6525 Nijmegen, The Netherlands
| | - Erwin T. G. Wiegerinck
- Hepcidinanalysis.com, Department of Laboratory Medicine, Translational Metabolic Laboratory (TML 830), Radboud University Medical Center, 6525 Nijmegen, The Netherlands
| | - Edward Litton
- Intensive Care Unit, Fiona Stanley Hospital, Murdoch, WA 6150, Australia
- School of Medicine, University of Western Australia, Crawley, WA 6009, Australia
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27
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Zürn C, Höhn R, Hübner D, Umhau M, Kroll J, Kari FA, Humburger F, Maier S, Stiller B. Risk Assessment of Red Cell Transfusion in Congenital Heart Disease. Thorac Cardiovasc Surg 2022; 70:e15-e20. [PMID: 36179762 PMCID: PMC9536749 DOI: 10.1055/s-0042-1756493] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Background The storage time of packed red blood cells (pRBC) is an indicator of
change in the product's pH, potassium, and lactate levels. Blood–gas analysis is a readily
available bedside tool on every intensive care ward to measure these factors prior to
application, thus facilitating a calculated decision on a transfusion's quantity and
duration. Our first goal is to assess the impact of storage time on pH, potassium, and lactate
levels in pRBC. The influence of those parameters in the transfused children will then be
evaluated. Methods In this retrospective study, we conducted blood–gas analyses of pRBC units
before they were administered over 4 hours to neonates, infants, and children in our
pediatric cardiac intensive care ward. All patients underwent regular blood–gas analyses
themselves, before and after transfusion. Results We observed a highly significant correlation between the storage time of
pRBC units and a drop in pH, as well as an increase in potassium and lactate of stored red
cells ( p < 0.0001). Median age of recipients with a complete blood–gas dataset
was 0.1 (interquartile range [IQR] = 0.0–0.7) years; median pRBC storage duration was 6
(IQR = 5–8) days. Further analyses showed no statistically significant effect on
children's blood gases within 4 hours after transfusion, even after stratifying for pRBC
storage time ≤7 days and >7 days. Conclusion Stored red blood cells show a rapid decrease in pH and increase in
potassium and lactate. Slow transfusion of these units had no adverse effects on the
recipients' pH, potassium, and lactate levels.
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Affiliation(s)
- Christoph Zürn
- Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Centre Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - René Höhn
- Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Centre Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - David Hübner
- Department of Machine Learning for Medical Applications, Averbis GmbH, Freiburg, Germany
| | - Markus Umhau
- Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Johannes Kroll
- Department of Cardiovascular Surgery, University Heart Centre Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Fabian A Kari
- Department of Cardiovascular Surgery, University Heart Centre Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Frank Humburger
- Department of Anesthesiology and Critical Care, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Sven Maier
- Department of Cardiovascular Surgery, University Heart Centre Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Brigitte Stiller
- Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Centre Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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28
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Pandey S, Mahato M, Srinath P, Bhutani U, Goap TJ, Ravipati P, Vemula PK. Intermittent scavenging of storage lesion from stored red blood cells by electrospun nanofibrous sheets enhances their quality and shelf-life. Nat Commun 2022; 13:7394. [PMID: 36450757 PMCID: PMC9712616 DOI: 10.1038/s41467-022-35269-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 11/24/2022] [Indexed: 12/03/2022] Open
Abstract
Transfusion of healthy red blood cells (RBCs) is a lifesaving process. However, upon storing RBCs, a wide range of damage-associate molecular patterns (DAMPs), such as cell-free DNA, nucleosomes, free-hemoglobin, and poly-unsaturated-fatty-acids are generated. DAMPs can further damage RBCs; thus, the quality of stored RBCs declines during the storage and limits their shelf-life. Since these DAMPs consist of either positive or negative charged species, we developed taurine and acridine containing electrospun-nanofibrous-sheets (Tau-AcrNFS), featuring anionic, cationic charges and an DNA intercalating group on their surfaces. We show that Tau-AcrNFS are efficient in scavenging DAMPs from stored human and mice RBCs ex vivo. We find that intermittent scavenging of DAMPs by Tau-AcrNFS during the storage reduces the loss of RBC membrane integrity and reduces discocytes-to-spheroechinocytes transformation in stored-old-RBCs. We perform RBC-transfusion studies in mice to reveal that intermittent removal of DAMPs enhances the quality of stored-old-RBCs equivalent to freshly collected RBCs, and increases their shelf-life by ~22%. Such prophylactic technology may lead to the development of novel blood bags or medical device, and may therefore impact healthcare by reducing transfusion-related adverse effects.
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Affiliation(s)
- Subhashini Pandey
- grid.475408.a0000 0004 4905 7710Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore, 560065 Karnataka India ,grid.502290.c0000 0004 7649 3040The University of Trans-Disciplinary Health Sciences and Technology, Attur (post), Yelahanka, Bangalore, 560064 Karnataka India
| | - Manohar Mahato
- grid.475408.a0000 0004 4905 7710Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore, 560065 Karnataka India
| | - Preethem Srinath
- grid.475408.a0000 0004 4905 7710Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore, 560065 Karnataka India
| | - Utkarsh Bhutani
- grid.475408.a0000 0004 4905 7710Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore, 560065 Karnataka India
| | - Tanu Jain Goap
- grid.475408.a0000 0004 4905 7710Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore, 560065 Karnataka India ,grid.502290.c0000 0004 7649 3040The University of Trans-Disciplinary Health Sciences and Technology, Attur (post), Yelahanka, Bangalore, 560064 Karnataka India
| | - Priusha Ravipati
- grid.475408.a0000 0004 4905 7710Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore, 560065 Karnataka India
| | - Praveen Kumar Vemula
- grid.475408.a0000 0004 4905 7710Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post, Bellary Road, Bangalore, 560065 Karnataka India
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29
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Berndt M, Buttenberg M, Graw JA. Large Animal Models for Simulating Physiology of Transfusion of Red Cell Concentrates-A Scoping Review of The Literature. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:1735. [PMID: 36556937 PMCID: PMC9787038 DOI: 10.3390/medicina58121735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/15/2022] [Indexed: 11/29/2022]
Abstract
Background and Objectives: Transfusion of red cell concentrates is a key component of medical therapy. To investigate the complex transfusion-associated biochemical and physiological processes as well as potential risks for human recipients, animal models are of particular importance. This scoping review summarizes existing large animal transfusion models for their ability to model the physiology associated with the storage of erythrocyte concentrates. Materials and Methods: The electronic databases PubMed, EMBASE, and Web of Science were systematically searched for original studies providing information on the intravenous application of erythrocyte concentrates in porcine, ovine, and canine animal models. Results: A total of 36 studies were included in the analysis. The majority of porcine studies evaluated hemorrhagic shock conditions. Pig models showed high physiological similarities with regard to red cell physiology during early storage. Ovine and canine studies were found to model typical aspects of human red cell storage at 42 days. Only four studies provided data on 24 h in vivo survival of red cells. Conclusions: While ovine and canine models can mimic typical human erythrocyte storage for up to 42 days, porcine models stand out for reliably simulating double-hit pathologies such as hemorrhagic shock. Large animal models remain an important area of translational research since they have an impact on testing new pharmacological or biophysical interventions to attenuate storage-related adverse effects and allow, in a controlled environment, to study background and interventions in dynamic and severe disease conditions.
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Affiliation(s)
- Melanie Berndt
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Maximilian Buttenberg
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Jan A. Graw
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Anesthesiology and Intensive Care Medicine, Ulm University, 89081 Ulm, Germany
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30
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Vijayan V, Greite R, Schott S, Doricic J, Madyaningrana K, Pradhan P, Martens J, Blasczyk R, Janciauskiene S, Immenschuh S. Determination of free heme in stored red blood cells with an apo-horseradish peroxidase-based assay. Biol Chem 2022; 403:1091-1098. [PMID: 36054292 DOI: 10.1515/hsz-2022-0184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/15/2022] [Indexed: 12/19/2022]
Abstract
Transfusion effectiveness of red blood cells (RBCs) has been associated with duration of the storage period. Storage-dependent RBC alterations lead to hemolysis and release of toxic free heme, but the increase of free heme levels over time is largely unknown. In the current study, an apo-horseradish peroxidase (apoHRP)-based assay was applied to measure levels of free heme at regular intervals or periodically in supernatants of RBCs until a maximum storage period of 42 days. Free heme levels increased with linear time-dependent kinetics up to day 21 and accelerated disproportionally after day 28 until day 42, as determined with the apoHRP assay. Individual time courses of free heme in different RBC units exhibited high variability. Notably, levels of free hemoglobin, an established indicator of RBC damage, and those of total heme increased with continuous time-dependent linear kinetics over the entire 42 day storage period, respectively. Supernatants from RBC units with high levels of free heme led to inflammatory activation of human neutrophils. In conclusion, determining free heme in stored RBCs with the applied apoHRP assay may become feasible for testing of RBC storage quality in clinical transfusion medicine.
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Affiliation(s)
- Vijith Vijayan
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | - Robert Greite
- Department of Nephrology, Hannover Medical School, D-30625 Hannover, Germany
| | - Sebastian Schott
- Department of Nephrology, Hannover Medical School, D-30625 Hannover, Germany
| | - Julian Doricic
- Department of Nephrology, Hannover Medical School, D-30625 Hannover, Germany
| | - Kukuh Madyaningrana
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.,Faculty of Biotechnology, Universitas Kristen Duta Wacana, 55224 Yogyakarta, Indonesia
| | - Pooja Pradhan
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | - Jörg Martens
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | | | - Stephan Immenschuh
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
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31
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Premature Macrophage Activation by Stored Red Blood Cell Transfusion Halts Liver Regeneration Post-Partial Hepatectomy in Rats. Cells 2022; 11:cells11213522. [DOI: 10.3390/cells11213522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/03/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Liver resection is a common treatment for various conditions and often requires blood transfusions to compensate for operative blood loss. As partial hepatectomy (PHx) is frequently performed in patients with a pre-damaged liver, avoiding further injury is of paramount clinical importance. Our aim was to study the impact of red blood cell (RBC) resuscitation on liver regeneration. We assessed the impact of RBC storage time on liver regeneration following 50% PHx in rats and explored possible contributing molecular mechanisms using immunohistochemistry, RNA-Seq, and macrophage depletion. The liver was successfully regenerated after PHx when rats were transfused with fresh RBCs (F-RBCs). However, in rats resuscitated with stored RBCs (S-RBCs), the regeneration process was disrupted, as detected by delayed hepatocyte proliferation and lack of hypertrophy. The delayed regeneration was associated with elevated numbers of hemorrhage-activated liver macrophages (Mhem) secreting HO-1. Depletion of macrophages prior to PHx and transfusion improved the regeneration process. Gene expression profiling revealed alterations in numerous genes belonging to critical pathways, including cell cycle and DNA replication, and genes associated with immune cell activation, such as chemokine signaling and platelet activation and adhesion. Our results implicate activated macrophages in delayed liver regeneration following S-RBC transfusion via HO-1 and PAI-1 overexpression.
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32
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Hansen S, Wood DK. Simultaneous quantification of blood rheology and oxygen saturation to evaluate affinity-modifying therapies in sickle cell disease. LAB ON A CHIP 2022; 22:4141-4150. [PMID: 36134535 PMCID: PMC10165883 DOI: 10.1039/d2lc00623e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Sickle cell blood demonstrates oxygen-dependent flow behavior as a result of HbS polymerization during hypoxia, and these rheological changes provide a biophysical metric that can be used to quantify the pathological behavior of the blood. Relating these rheological changes directly to hemoglobin oxygen saturation would improve our understanding of SCD pathogenesis and the potential effects of therapeutic drugs. Towards this end, we have developed a microfluidic platform capable of spectrophotometric quantification of Hb-O2 saturation and simultaneous evaluation of the accompanying rheological changes in SCD blood flow. We demonstrated the ability to measure changes in Hb-O2 affinity and a restoration of oxygen-independent blood flow behavior after incubation with voxelotor, an oxygen affinity modifying drug approved for use in SCD. We also identified regimes in Hb-O2 saturation where the effects of HbS polymerization begin to take effect in contributing to pathological flow behavior, independent of voxelotor treatment. In contrast, incubation with voxelotor recovered oxygen-dependent blood flow over a range of PO2, providing a framework for understanding voxelotor's therapeutic effect in lowering the PO2 at which the requisite Hb-O2 saturation is reached to observe pathological blood flow. These results help explain the mechanistic effects of voxelotor and show the potential of this platform to identify affinity-modifying compounds and evaluate their therapeutic effect on blood flow.
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Affiliation(s)
- Scott Hansen
- Department of Biomedical Engineering, University of Minnesota, Minneapolis 55409, USA.
| | - David K Wood
- Department of Biomedical Engineering, University of Minnesota, Minneapolis 55409, USA.
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33
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Vardaki MZ, Georg Schulze H, Serrano K, Blades MW, Devine DV, F B Turner R. Assessing the quality of stored red blood cells using handheld Spatially Offset Raman spectroscopy with multisource correlation analysis. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2022; 276:121220. [PMID: 35395462 DOI: 10.1016/j.saa.2022.121220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/23/2022] [Accepted: 03/29/2022] [Indexed: 06/14/2023]
Abstract
In this work we employ Spatially Offset Raman Spectroscopy (SORS) to non-invasively identify storage-related changes in red blood cell concentrate (RCC) in-situ within standard plastic transfusion bags. To validate the measurements, we set up a parallel study comparing both bioanalytical data (obtained by blood-gas analysis, hematology analysis and spectrophotometric assays), and Raman spectrometry data from the same blood samples. We then employ Multisource Correlation Analysis (MuSCA) to correlate the different types of data in RCC. Our analysis confirmed a strong correlation of glucose, methemoglobin and oxyhemoglobin with their respective bioassay values in RCC units. Finally, by combining MuSCA with k-means clustering, we assessed changes in all Raman wavenumbers during cold storage in both RCC Raman data from the current study and parallel RCC supernatant Raman data previously acquired from the same units. Direct RCC quality monitoring during storage, would help to establish a basis for improved inventory management of blood products in blood banks and hospitals based on analytical data.
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Affiliation(s)
- Martha Z Vardaki
- Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens 11635, Greece
| | - H Georg Schulze
- Monte do Tojal, Caixa Postal 128, Hortinhas, Terena 7250-069, Portugal
| | - Katherine Serrano
- Department of Pathology and Laboratory Medicine, The University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6 T 2B5, Canada; Centre for Blood Research, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6 T 1Z3, Canada; Centre for Innovation, Canadian Blood Services
| | - Michael W Blades
- Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6 T 1Z1, Canada
| | - Dana V Devine
- Department of Pathology and Laboratory Medicine, The University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6 T 2B5, Canada; Centre for Blood Research, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6 T 1Z3, Canada; Centre for Innovation, Canadian Blood Services
| | - Robin F B Turner
- Michael Smith Laboratories, The University of British Columbia, 2185 East Mall, Vancouver, BC V6 T 1Z4, Canada; Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6 T 1Z1, Canada; Department of Electrical and Computer Engineering, The University of British Columbia, 2332 Main Mall, Vancouver, BC V6 T 1Z4, Canada
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34
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A Nano Erythropoiesis Stimulating Agent (Nano-ESA) for the Treatment of Anemia and Associated Disorders. iScience 2022; 25:105021. [PMID: 36111254 PMCID: PMC9468392 DOI: 10.1016/j.isci.2022.105021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/20/2022] [Accepted: 08/19/2022] [Indexed: 11/24/2022] Open
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35
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Garcia‐Herreros A, Yeh Y, Peng Z, del Álamo JC. Cyclic Mechanical Stresses Alter Erythrocyte Membrane Composition and Microstructure and Trigger Macrophage Phagocytosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201481. [PMID: 35508805 PMCID: PMC9284186 DOI: 10.1002/advs.202201481] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 06/01/2023]
Abstract
Red blood cells (RBCs) are cleared from the circulation when they become damaged or display aging signals targeted by macrophages. This process occurs mainly in the spleen, where blood flows through submicrometric constrictions called inter-endothelial slits (IES), subjecting RBCs to large-amplitude deformations. In this work, RBCs are circulated through microfluidic devices containing microchannels that replicate the IES. The cyclic mechanical stresses experienced by the cells affect their biophysical properties and molecular composition, accelerating cell aging. Specifically, RBCs quickly transition to a more spherical, less deformable phenotype that hinders microchannel passage, causing hemolysis. This transition is associated with the release of membrane vesicles, which self-extinguishes as the spacing between membrane-cytoskeleton linkers becomes tighter. Proteomics analysis of the mechanically aged RBCs reveals significant losses of essential proteins involved in antioxidant protection, gas transport, and cell metabolism. Finally, it is shown that these changes make mechanically aged RBCs more susceptible to macrophage phagocytosis. These results provide a comprehensive model explaining how physical stress induces RBC clearance in the spleen. The data also suggest new biomarkers of early "hemodamage" and inflammation preceding hemolysis in RBCs subjected to mechanical stress.
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Affiliation(s)
- Antoni Garcia‐Herreros
- Department of Mechanical and Aerospace EngineeringUniversity of California9500 Gilman Dr.La JollaCA92093USA
| | - Yi‐Ting Yeh
- Department of Mechanical and Aerospace EngineeringUniversity of California9500 Gilman Dr.La JollaCA92093USA
- Department of BioengineeringUniversity of California9500 Gilman Dr.La JollaCA92093USA
- Institute of Engineering in MedicineUniversity of California9500 Gilman Dr.La JollaCA92093USA
| | - Zhangli Peng
- Department of BioengineeringUniversity of Illinois at Chicago1200 W Harrison StChicagoIL60607USA
| | - Juan C. del Álamo
- Department of Mechanical and Aerospace EngineeringUniversity of California9500 Gilman Dr.La JollaCA92093USA
- Institute of Engineering in MedicineUniversity of California9500 Gilman Dr.La JollaCA92093USA
- Department of Mechanical EngineeringUniversity of Washington850 Republican StSeattleWA98109USA
- Center for Cardiovascular BiologyUniversity of Washington850 Republican StSeattleWA98109USA
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36
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Signori D, Magliocca A, Hayashida K, Graw JA, Malhotra R, Bellani G, Berra L, Rezoagli E. Inhaled nitric oxide: role in the pathophysiology of cardio-cerebrovascular and respiratory diseases. Intensive Care Med Exp 2022; 10:28. [PMID: 35754072 PMCID: PMC9234017 DOI: 10.1186/s40635-022-00455-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 06/08/2022] [Indexed: 11/23/2022] Open
Abstract
Nitric oxide (NO) is a key molecule in the biology of human life. NO is involved in the physiology of organ viability and in the pathophysiology of organ dysfunction, respectively. In this narrative review, we aimed at elucidating the mechanisms behind the role of NO in the respiratory and cardio-cerebrovascular systems, in the presence of a healthy or dysfunctional endothelium. NO is a key player in maintaining multiorgan viability with adequate organ blood perfusion. We report on its physiological endogenous production and effects in the circulation and within the lungs, as well as the pathophysiological implication of its disturbances related to NO depletion and excess. The review covers from preclinical information about endogenous NO produced by nitric oxide synthase (NOS) to the potential therapeutic role of exogenous NO (inhaled nitric oxide, iNO). Moreover, the importance of NO in several clinical conditions in critically ill patients such as hypoxemia, pulmonary hypertension, hemolysis, cerebrovascular events and ischemia-reperfusion syndrome is evaluated in preclinical and clinical settings. Accordingly, the mechanism behind the beneficial iNO treatment in hypoxemia and pulmonary hypertension is investigated. Furthermore, investigating the pathophysiology of brain injury, cardiopulmonary bypass, and red blood cell and artificial hemoglobin transfusion provides a focus on the potential role of NO as a protective molecule in multiorgan dysfunction. Finally, the preclinical toxicology of iNO and the antimicrobial role of NO-including its recent investigation on its role against the Sars-CoV2 infection during the COVID-19 pandemic-are described.
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Affiliation(s)
- Davide Signori
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Aurora Magliocca
- Department of Medical Physiopathology and Transplants, University of Milan, Milan, Italy
| | - Kei Hayashida
- Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health System, Manhasset, NY, USA
- Department of Emergency Medicine, North Shore University Hospital, Northwell Health System, Manhasset, NY, USA
- Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jan A Graw
- Department of Anesthesiology and Operative Intensive Care Medicine, CCM/CVK Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany
- ARDS/ECMO Centrum Charité, Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Rajeev Malhotra
- Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Giacomo Bellani
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Department of Emergency and Intensive Care, San Gerardo Hospital, Monza, Italy
| | - Lorenzo Berra
- Harvard Medical School, Boston, MA, USA
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
- Respiratory Care Department, Massachusetts General Hospital, Boston, MA, USA
| | - Emanuele Rezoagli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
- Department of Emergency and Intensive Care, San Gerardo Hospital, Monza, Italy.
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Metabolic reprogramming under hypoxic storage preserves faster oxygen unloading from stored red blood cells. Blood Adv 2022; 6:5415-5428. [PMID: 35736672 DOI: 10.1182/bloodadvances.2022007774] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/11/2022] [Indexed: 11/20/2022] Open
Abstract
Stored red blood cells (RBCs) incur biochemical and morphological changes, collectively termed the storage lesion. Functionally, the storage lesion manifests as slower oxygen unloading from RBCs, which may compromise the efficacy of transfusions where the clinical imperative is to rapidly boost oxygen delivery to tissues. Recent analysis of large real-world data linked longer storage with increased recipient mortality. Biochemical rejuvenation with a formulation of adenosine, inosine, and pyruvate can restore gas-handling properties, but its implementation is impractical for most clinical scenarios. We tested whether storage under hypoxia, previously shown to slow biochemical degradation, also preserves gas-handling properties of RBCs. A microfluidic chamber, designed to rapidly switch between oxygenated and anoxic superfusates, was used for single-cell oxygen saturation imaging on samples stored for up to 49 days. Aliquots were also analyzed flow-cytometrically for side-scatter (a proposed proxy of O2 unloading kinetics), metabolomics, lipidomics and redox proteomics. For benchmarking, units were biochemically rejuvenated at four weeks of standard storage. Hypoxic storage hastened O2 unloading in units stored to 35 days, an effect that correlated with side-scatter but was not linked to post-translational modifications of hemoglobin. Although hypoxic storage and rejuvenation produced distinct biochemical changes, a subset of metabolites including pyruvate, sedoheptulose 1-phosphate, and 2/3 phospho-D-glycerate, was a common signature that correlated with changes in O2 unloading. Correlations between gas-handling and lipidomic changes were modest. Thus, hypoxic storage of RBCs preserves key metabolic pathways and O2 exchange properties, thereby improving the functional quality of blood products and potentially influencing transfusion outcomes.
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Manis C, Manca A, Murgia A, Uras G, Caboni P, Congiu T, Faa G, Pantaleo A, Cao G. Understanding the Behaviour of Human Cell Types under Simulated Microgravity Conditions: The Case of Erythrocytes. Int J Mol Sci 2022; 23:ijms23126876. [PMID: 35743319 PMCID: PMC9224527 DOI: 10.3390/ijms23126876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/09/2022] [Accepted: 06/15/2022] [Indexed: 12/10/2022] Open
Abstract
Erythrocytes are highly specialized cells in human body, and their main function is to ensure the gas exchanges, O2 and CO2, within the body. The exposure to microgravity environment leads to several health risks such as those affecting red blood cells. In this work, we investigated the changes that occur in the structure and function of red blood cells under simulated microgravity, compared to terrestrial conditions, at different time points using biochemical and biophysical techniques. Erythrocytes exposed to simulated microgravity showed morphological changes, a constant increase in reactive oxygen species (ROS), a significant reduction in total antioxidant capacity (TAC), a remarkable and constant decrease in total glutathione (GSH) concentration, and an augmentation in malondialdehyde (MDA) at increasing times. Moreover, experiments were performed to evaluate the lipid profile of erythrocyte membranes which showed an upregulation in the following membrane phosphocholines (PC): PC16:0_16:0, PC 33:5, PC18:2_18:2, PC 15:1_20:4 and SM d42:1. Thus, remarkable changes in erythrocyte cytoskeletal architecture and membrane stiffness due to oxidative damage have been found under microgravity conditions, in addition to factors that contribute to the plasticity of the red blood cells (RBCs) including shape, size, cell viscosity and membrane rigidity. This study represents our first investigation into the effects of microgravity on erythrocytes and will be followed by other experiments towards understanding the behaviour of different human cell types in microgravity.
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Affiliation(s)
- Cristina Manis
- Department of Life and Environmental Sciences, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy; (C.M.); (A.M.); (P.C.)
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Piazza d’Armi, 09123 Cagliari, Italy
| | - Alessia Manca
- Department of Biomedical Science, University of Sassari, Viale San Pietro, 07100 Sassari, Italy;
| | - Antonio Murgia
- Department of Life and Environmental Sciences, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy; (C.M.); (A.M.); (P.C.)
| | - Giuseppe Uras
- Department of Clinical and Movement Neurosciences, Institute of Neurology, University of College London, London NW3 2PF, UK;
| | - Pierluigi Caboni
- Department of Life and Environmental Sciences, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy; (C.M.); (A.M.); (P.C.)
| | - Terenzio Congiu
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato’s Campus, 09042 Monserrato, Italy; (T.C.); (G.F.)
| | - Gavino Faa
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato’s Campus, 09042 Monserrato, Italy; (T.C.); (G.F.)
| | - Antonella Pantaleo
- Department of Biomedical Science, University of Sassari, Viale San Pietro, 07100 Sassari, Italy;
- Correspondence: (A.P.); (G.C.)
| | - Giacomo Cao
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Piazza d’Armi, 09123 Cagliari, Italy
- Center of Advanced Studies, Research and Development in Sardinia (CRS4), Loc. Piscina Manna, Building 1, 09050 Pula, Italy
- Sardinia AeroSpace District (DASS), at Sardegna Ricerche, Via G. Carbonazzi 14, 09123 Cagliari, Italy
- Correspondence: (A.P.); (G.C.)
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Jain V, Yang WH, Wu J, Roback JD, Gregory SG, Chi JT. Single Cell RNA-Seq Analysis of Human Red Cells. Front Physiol 2022; 13:828700. [PMID: 35514346 PMCID: PMC9065680 DOI: 10.3389/fphys.2022.828700] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/21/2022] [Indexed: 02/02/2023] Open
Abstract
Human red blood cells (RBCs), or erythrocytes, are the most abundant blood cells responsible for gas exchange. RBC diseases affect hundreds of millions of people and impose enormous financial and personal burdens. One well-recognized, but poorly understood feature of RBC populations within the same individual are their phenotypic heterogeneity. The granular characterization of phenotypic RBC variation in normative and disease states may allow us to identify the genetic determinants of red cell diseases and reveal novel therapeutic approaches for their treatment. Previously, we discovered diverse RNA transcripts in RBCs that has allowed us to dissect the phenotypic heterogeneity and malaria resistance of sickle red cells. However, these analyses failed to capture the heterogeneity found in RBC sub-populations. To overcome this limitation, we have performed single cell RNA-Seq to analyze the transcriptional heterogeneity of RBCs from three adult healthy donors which have been stored in the blood bank conditions and assayed at day 1 and day 15. The expression pattern clearly separated RBCs into seven distinct clusters that include one RBC cluster that expresses HBG2 and a small population of RBCs that express fetal hemoglobin (HbF) that we annotated as F cells. Almost all HBG2-expessing cells also express HBB, suggesting bi-allelic expression in single RBC from the HBG2/HBB loci, and we annotated another cluster as reticulocytes based on canonical gene expression. Additional RBC clusters were also annotated based on the enriched expression of NIX, ACVR2B and HEMGN, previously shown to be involved in erythropoiesis. Finally, we found the storage of RBC was associated with an increase in the ACVR2B and F-cell clusters. Collectively, these data indicate the power of single RBC RNA-Seq to capture and discover known and unexpected heterogeneity of RBC population.
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Affiliation(s)
- Vaibhav Jain
- Department of Neurology, Durham, NC, United States.,Duke Molecular Physiology Institute, Durham, NC, United States
| | - Wen-Hsuan Yang
- Department of Molecular Genetics and Microbiology, Durham, NC, United States.,Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, United States
| | - Jianli Wu
- Department of Molecular Genetics and Microbiology, Durham, NC, United States.,Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, United States
| | - John D Roback
- Center for Transfusion and Cellular Therapies, Durham, NC, United States.,Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Simon G Gregory
- Department of Neurology, Durham, NC, United States.,Duke Molecular Physiology Institute, Durham, NC, United States
| | - Jen-Tsan Chi
- Department of Molecular Genetics and Microbiology, Durham, NC, United States.,Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, United States
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40
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Recktenwald SM, Lopes MGM, Peter S, Hof S, Simionato G, Peikert K, Hermann A, Danek A, van Bentum K, Eichler H, Wagner C, Quint S, Kaestner L. Erysense, a Lab-on-a-Chip-Based Point-of-Care Device to Evaluate Red Blood Cell Flow Properties With Multiple Clinical Applications. Front Physiol 2022; 13:884690. [PMID: 35574449 PMCID: PMC9091344 DOI: 10.3389/fphys.2022.884690] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022] Open
Abstract
In many medical disciplines, red blood cells are discovered to be biomarkers since they "experience" various conditions in basically all organs of the body. Classical examples are diabetes and hypercholesterolemia. However, recently the red blood cell distribution width (RDW), is often referred to, as an unspecific parameter/marker (e.g., for cardiac events or in oncological studies). The measurement of RDW requires venous blood samples to perform the complete blood cell count (CBC). Here, we introduce Erysense, a lab-on-a-chip-based point-of-care device, to evaluate red blood cell flow properties. The capillary chip technology in combination with algorithms based on artificial neural networks allows the detection of very subtle changes in the red blood cell morphology. This flow-based method closely resembles in vivo conditions and blood sample volumes in the sub-microliter range are sufficient. We provide clinical examples for potential applications of Erysense as a diagnostic tool [here: neuroacanthocytosis syndromes (NAS)] and as cellular quality control for red blood cells [here: hemodiafiltration (HDF) and erythrocyte concentrate (EC) storage]. Due to the wide range of the applicable flow velocities (0.1-10 mm/s) different mechanical properties of the red blood cells can be addressed with Erysense providing the opportunity for differential diagnosis/judgments. Due to these versatile properties, we anticipate the value of Erysense for further diagnostic, prognostic, and theragnostic applications including but not limited to diabetes, iron deficiency, COVID-19, rheumatism, various red blood cell disorders and anemia, as well as inflammation-based diseases including sepsis.
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Affiliation(s)
| | - Marcelle G. M. Lopes
- Experimental Physics, Saarland University, Saarbruecken, Germany
- Cysmic GmbH, Saarbruecken, Germany
| | - Stephana Peter
- Experimental Physics, Saarland University, Saarbruecken, Germany
- Theoretical Medicine and Biosciences, Saarland University, Saarbruecken, Germany
| | - Sebastian Hof
- Experimental Physics, Saarland University, Saarbruecken, Germany
- Theoretical Medicine and Biosciences, Saarland University, Saarbruecken, Germany
| | - Greta Simionato
- Experimental Physics, Saarland University, Saarbruecken, Germany
- Institute for Clinical and Experimental Surgery, Saarland University, Campus University Hospital, Homburg, Germany
| | - Kevin Peikert
- Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
| | - Andreas Hermann
- Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
- DZNE, Deutsches Zentrum für Neurodegenerative Erkrankungen, Research Site Rostock/Greifswald, Rostock, Germany
- Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany
| | - Adrian Danek
- Neurologische Klinik und Poliklinik, Ludwig-Maximilians-University, Munich, Germany
| | | | - Hermann Eichler
- Institute for Clinical Hemostaseology and Transfusion Medicine, Saarland University and Saarland University Hospital, Homburg, Germany
| | - Christian Wagner
- Experimental Physics, Saarland University, Saarbruecken, Germany
- Department of Physics and Materials Science, University of Luxembourg, Luxembourg City, Luxembourg
| | - Stephan Quint
- Experimental Physics, Saarland University, Saarbruecken, Germany
- Cysmic GmbH, Saarbruecken, Germany
| | - Lars Kaestner
- Experimental Physics, Saarland University, Saarbruecken, Germany
- Theoretical Medicine and Biosciences, Saarland University, Saarbruecken, Germany
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Marcucci R, Mannini L, Andrei V, Bandinelli B, Gori AM, Fatucchi S, Giglioli C, Romano SM, Piazzai C, Marchionni N, Cecchi E. Transient stress-related hyperviscosity and endothelial dysfunction in Takotsubo syndrome: a time course study. Heart Vessels 2022; 37:1776-1784. [PMID: 35451602 DOI: 10.1007/s00380-022-02071-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/31/2022] [Indexed: 11/04/2022]
Abstract
Takotsubo syndrome (TTS) is an acute and usually reversible heart failure syndrome, frequently associated with emotional or physical stress. Its pathophysiology remains largely unclear, although several mechanisms related to catecholaminergic storm have been proposed. In this study we analyzed during the acute phase of TTS and at follow-up both hemorheological parameters and biomarkers of endothelial damage, whose time course has never been fully explored. In 50 TTS women, we analyzed several hemorheological parameters [whole blood viscosity (WBV) at 0.512 s-1 and at 94.5 s-1, plasma viscosity (PLV), erythrocyte deformability and aggregation index] as well as biomarkers of endothelial dysfunction [von Willebrand Factor (vWF), Plasminogen activator inhibitor-1 and factor VIII levels] during the acute phase and after a median 6 months follow-up. These variables were also assessed in 50 age-matched healthy women. Respect to follow-up, in the acute phase of TTS we observed higher values of white blood cell count, fibrinogen, WBV at low and high shear rates, PLV, erythrocyte aggregation index and lower values of erythrocyte elongation index. Moreover, all biomarkers of endothelial dysfunction resulted significantly higher in the acute phase. During follow-up WBV at 94.5 s-1, erythrocyte elongation index and vWF resulted significantly altered with respect to controls. The results of this study confirm the role of hyperviscosity and endothelial dysfunction in TTS pathophysiology. Moreover, they suggest the persistence of alterations of erythrocyte deformability and endothelial dysfunction even beyond the acute phase that could be the target of therapeutic strategies also during follow-up.
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Affiliation(s)
- Rossella Marcucci
- Department of Cardiac Thoracic and Vascular Medicine, Center for Atherothrombotic Diseases, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.,Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy
| | - Lucia Mannini
- Department of Cardiac Thoracic and Vascular Medicine, Center for Atherothrombotic Diseases, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Valentina Andrei
- General Cardiology Unit, Department of Cardiac Thoracic and Vascular Medicine, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni, 85, 50141, Florence, Italy
| | - Brunella Bandinelli
- Department of Cardiac Thoracic and Vascular Medicine, Center for Atherothrombotic Diseases, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Anna Maria Gori
- Department of Cardiac Thoracic and Vascular Medicine, Center for Atherothrombotic Diseases, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.,Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy
| | - Serena Fatucchi
- General Cardiology Unit, Department of Cardiac Thoracic and Vascular Medicine, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni, 85, 50141, Florence, Italy
| | - Cristina Giglioli
- General Cardiology Unit, Department of Cardiac Thoracic and Vascular Medicine, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni, 85, 50141, Florence, Italy
| | - Salvatore Mario Romano
- Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy.,General Cardiology Unit, Department of Cardiac Thoracic and Vascular Medicine, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni, 85, 50141, Florence, Italy
| | - Chiara Piazzai
- General Cardiology Unit, Department of Cardiac Thoracic and Vascular Medicine, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni, 85, 50141, Florence, Italy
| | - Niccolo' Marchionni
- General Cardiology Unit, Department of Cardiac Thoracic and Vascular Medicine, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni, 85, 50141, Florence, Italy
| | - Emanuele Cecchi
- General Cardiology Unit, Department of Cardiac Thoracic and Vascular Medicine, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni, 85, 50141, Florence, Italy.
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Redaelli S, Magliocca A, Malhotra R, Ristagno G, Citerio G, Bellani G, Berra L, Rezoagli E. Nitric oxide: Clinical applications in critically ill patients. Nitric Oxide 2022; 121:20-33. [PMID: 35123061 PMCID: PMC10189363 DOI: 10.1016/j.niox.2022.01.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/19/2022] [Accepted: 01/31/2022] [Indexed: 12/19/2022]
Abstract
Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss an innovative proposed strategy to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO.
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Affiliation(s)
- Simone Redaelli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Aurora Magliocca
- Department of Medical Physiopathology and Transplants, University of Milan, Milano, Italy
| | - Rajeev Malhotra
- Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Giuseppe Ristagno
- Department of Medical Physiopathology and Transplants, University of Milan, Milano, Italy; Department of Anesthesiology, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Citerio
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Neuroscience Department, NeuroIntensive Care Unit, San Gerardo Hospital, ASST Monza, Monza, Italy
| | - Giacomo Bellani
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Department of Emergency and Intensive Care, ECMO Center, San Gerardo University Hospital, Monza, Italy
| | - Lorenzo Berra
- Harvard Medical School, Boston, MA, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Respiratory Care Department, Massachusetts General Hospital, Boston, MA, USA
| | - Emanuele Rezoagli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Department of Emergency and Intensive Care, ECMO Center, San Gerardo University Hospital, Monza, Italy.
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Premont RT, Singel DJ, Stamler JS. The enzymatic function of the honorary enzyme: S-nitrosylation of hemoglobin in physiology and medicine. Mol Aspects Med 2022; 84:101056. [PMID: 34852941 PMCID: PMC8821404 DOI: 10.1016/j.mam.2021.101056] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022]
Abstract
The allosteric transition within tetrameric hemoglobin (Hb) that allows both full binding to four oxygen molecules in the lung and full release of four oxygens in hypoxic tissues would earn Hb the moniker of 'honorary enzyme'. However, the allosteric model for oxygen binding in hemoglobin overlooked the essential role of blood flow in tissue oxygenation that is essential for life (aka autoregulation of blood flow). That is, blood flow, not oxygen content of blood, is the principal determinant of oxygen delivery under most conditions. With the discovery that hemoglobin carries a third biologic gas, nitric oxide (NO) in the form of S-nitrosothiol (SNO) at β-globin Cys93 (βCys93), and that formation and export of SNO to dilate blood vessels are linked to hemoglobin allostery through enzymatic activity, this title is honorary no more. This chapter reviews evidence that hemoglobin formation and release of SNO is a critical mediator of hypoxic autoregulation of blood flow in tissues leading to oxygen delivery, considers the physiological implications of a 3-gas respiratory cycle (O2/NO/CO2) and the pathophysiological consequences of its dysfunction. Opportunities for therapeutic intervention to optimize oxygen delivery at the level of tissue blood flow are highlighted.
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Affiliation(s)
- Richard T Premont
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - David J Singel
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 59717, USA
| | - Jonathan S Stamler
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
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44
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Matthews K, Lamoureux ES, Myrand-Lapierre ME, Duffy SP, Ma H. Technologies for measuring red blood cell deformability. LAB ON A CHIP 2022; 22:1254-1274. [PMID: 35266475 DOI: 10.1039/d1lc01058a] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Human red blood cells (RBCs) are approximately 8 μm in diameter, but must repeatedly deform through capillaries as small as 2 μm in order to deliver oxygen to all parts of the body. The loss of this capability is associated with the pathology of many diseases, and is therefore a potential biomarker for disease status and treatment efficacy. Measuring RBC deformability is a difficult problem because of the minute forces (∼pN) that must be exerted on these cells, as well as the requirements for throughput and multiplexing. The development of technologies for measuring RBC deformability date back to the 1960s with the development of micropipette aspiration, ektacytometry, and the cell transit analyzer. In the past 10 years, significant progress has been made using microfluidics by leveraging the ability to precisely control fluid flow through microstructures at the size scale of individual RBCs. These technologies have now surpassed traditional methods in terms of sensitivity, throughput, consistency, and ease of use. As a result, these efforts are beginning to move beyond feasibility studies and into applications to enable biomedical discoveries. In this review, we provide an overview of both traditional and microfluidic techniques for measuring RBC deformability. We discuss the capabilities of each technique and compare their sensitivity, throughput, and robustness in measuring bulk and single-cell RBC deformability. Finally, we discuss how these tools could be used to measure changes in RBC deformability in the context of various applications including pathologies caused by malaria and hemoglobinopathies, as well as degradation during storage in blood bags prior to blood transfusions.
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Affiliation(s)
- Kerryn Matthews
- Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada.
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
| | - Erik S Lamoureux
- Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada.
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
| | - Marie-Eve Myrand-Lapierre
- Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada.
| | - Simon P Duffy
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- British Columbia Institute of Technology, Vancouver, BC, Canada
| | - Hongshen Ma
- Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada.
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada
- Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
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45
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Islamzada E, Matthews K, Lamoureux ES, Duffy SP, Scott MD, Ma H. Degradation of red blood cell deformability during cold storage in blood bags. EJHAEM 2022; 3:63-71. [PMID: 35846223 PMCID: PMC9176030 DOI: 10.1002/jha2.343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 02/02/2023]
Abstract
Red blood cells (RBCs) stored in blood bags develop a storage lesion that include structural, metabolic, and morphologic transformations resulting in a progressive loss of RBC deformability. The speed of RBC deformability loss is donor-dependent, which if properly characterized, could be used as a biomarker to select high-quality RBC units for sensitive recipients or to provide customized storage timelines depending on the donor. We used the microfluidic ratchet device to measure the deformability of red blood cells stored in blood bags every 14 days over a span of 56 days. We observed that storage in blood bags generally prevented RBC deformability loss over the current standard 42-day storage window. However, between 42 and 56 days, the deformability loss profile varied dramatically between donors. In particular, we observed accelerated RBC deformability loss for a majority of male donors, but for none of the female donors. Together, our results suggest that RBC deformability loss could be used to screen for donors who can provide stable RBCs for sensitive transfusion recipients or to identify donors capable of providing RBCs that could be stored for longer than the current 42-day expiration window.
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Affiliation(s)
- Emel Islamzada
- Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Centre for Blood ResearchUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Kerryn Matthews
- Centre for Blood ResearchUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of Mechanical EngineeringUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Erik S. Lamoureux
- Centre for Blood ResearchUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of Mechanical EngineeringUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Simon P. Duffy
- Centre for Blood ResearchUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- British Columbia Institute of TechnologyBurnabyBritish ColumbiaCanada
| | - Mark D. Scott
- Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Centre for Blood ResearchUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Canadian Blood ServicesOttawaOntarioCanada
| | - Hongshen Ma
- Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Centre for Blood ResearchUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of Mechanical EngineeringUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- School of Biomedical EngineeringUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Vancouver Prostate CentreVancouver General HospitalVancouverBritish ColumbiaCanada
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Graw JA, Bünger V, Materne LA, Krannich A, Balzer F, Francis RCE, Pruß A, Spies CD, Kuebler WM, Weber-Carstens S, Menk M, Hunsicker O. Age of Red Cells for Transfusion and Outcomes in Patients with ARDS. J Clin Med 2022; 11:jcm11010245. [PMID: 35011986 PMCID: PMC8745782 DOI: 10.3390/jcm11010245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 12/12/2022] Open
Abstract
Packed red blood cells (PRBCs), stored for prolonged intervals, might contribute to adverse clinical outcomes in critically ill patients. In this study, short-term outcome after transfusion of PRBCs of two storage duration periods was analyzed in patients with Acute Respiratory Distress Syndrome (ARDS). Patients who received transfusions of PRBCs were identified from a cohort of 1044 ARDS patients. Patients were grouped according to the mean storage age of all transfused units. Patients transfused with PRBCs of a mean storage age ≤ 28 days were compared to patients transfused with PRBCs of a mean storage age > 28 days. The primary endpoint was 28-day mortality. Secondary endpoints included failure-free days composites. Two hundred and eighty-three patients were eligible for analysis. Patients in the short-term storage group had similar baseline characteristics and received a similar amount of PRBC units compared with patients in the long-term storage group (five units (IQR, 3-10) vs. four units (2-8), p = 0.14). The mean storage age in the short-term storage group was 20 (±5.4) days compared with 32 (±3.1) days in the long-term storage group (mean difference 12 days (95%-CI, 11-13)). There was no difference in 28-day mortality between the short-term storage group compared with the long-term storage group (hazard ratio, 1.36 (95%-CI, 0.84-2.21), p = 0.21). While there were no differences in ventilator-free, sedation-free, and vasopressor-free days composites, patients in the long-term storage group compared with patients in the short-term storage group had a 75% lower chance for successful weaning from renal replacement therapy (RRT) within 28 days after ARDS onset (subdistribution hazard ratio, 0.24 (95%-CI, 0.1-0.55), p < 0.001). Further analysis indicated that even a single PRBC unit stored for more than 28 days decreased the chance for successful weaning from RRT. Prolonged storage of PRBCs was not associated with a higher mortality in adults with ARDS. However, transfusion of long-term stored PRBCs was associated with prolonged dependence of RRT in critically ill patients with an ARDS.
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Affiliation(s)
- Jan A. Graw
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
- ARDS/ECMO Centrum Charité, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Berlin Institute of Health (BIH), Charitéplatz 1, 10117 Berlin, Germany
- Correspondence:
| | - Victoria Bünger
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
| | - Lorenz A. Materne
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
| | - Alexander Krannich
- Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Felix Balzer
- Institute of Medical Informatics, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany;
| | - Roland C. E. Francis
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
- ARDS/ECMO Centrum Charité, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Axel Pruß
- Institute of Transfusion Medicine, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Claudia D. Spies
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
- ARDS/ECMO Centrum Charité, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Wolfgang M. Kuebler
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Steffen Weber-Carstens
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
- ARDS/ECMO Centrum Charité, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Mario Menk
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
- ARDS/ECMO Centrum Charité, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Oliver Hunsicker
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (V.B.); (L.A.M.); (R.C.E.F.); (C.D.S.); (S.W.-C.); (M.M.); (O.H.)
- ARDS/ECMO Centrum Charité, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
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Bertolone L, Shin HKH, Baek JH, Gao Y, Spitalnik SL, Buehler PW, D'Alessandro A. ZOOMICS: Comparative Metabolomics of Red Blood Cells From Guinea Pigs, Humans, and Non-human Primates During Refrigerated Storage for Up to 42 Days. Front Physiol 2022; 13:845347. [PMID: 35388289 PMCID: PMC8977988 DOI: 10.3389/fphys.2022.845347] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 02/10/2022] [Indexed: 01/07/2023] Open
Abstract
Unlike other rodents, guinea pigs (Cavia porcellus) have evolutionarily lost their capacity to synthesize vitamin C (ascorbate) de novo and, like several non-human primates and humans, rely on dietary intake and glutathione-dependent recycling to cope with oxidant stress. This is particularly relevant in red blood cell physiology, and especially when modeling blood storage, which exacerbates erythrocyte oxidant stress. Herein we provide a comprehensive metabolomics analysis of fresh and stored guinea pig red blood cell concentrates (n = 20), with weekly sampling from storage day 0 through 42. Results were compared to previously published ZOOMICS studies on red blood cells from three additional species with genetic loss of L-gulonolactone oxidase function, including humans (n = 21), olive baboons (n = 20), and rhesus macaques (n = 20). While metabolic trends were comparable across all species, guinea pig red blood cells demonstrated accelerated alterations of the metabolic markers of the storage lesion that are consistent with oxidative stress. Compared to the other species, guinea pig red blood cells showed aberrant glycolysis, pentose phosphate pathway end product metabolites, purine breakdown products, methylation, glutaminolysis, and markers of membrane lipid remodeling. Consistently, guinea pig red blood cells demonstrated higher end storage hemolysis, and scanning electron microscopy confirmed a higher degree of morphological alterations of their red blood cells, as compared to the other species. Despite a genetic inability to produce ascorbate that is common to the species evaluated, guinea pig red blood cells demonstrate accelerated oxidant stress under standard storage conditions. These data may offer relevant insights into the basal and cold storage metabolism of red blood cells from species that cannot synthesize endogenous ascorbate.
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Affiliation(s)
- Lorenzo Bertolone
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, United States
| | - Hye Kyung H Shin
- Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Jin Hyen Baek
- Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Yamei Gao
- Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Steven L Spitalnik
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
| | - Paul W Buehler
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, United States.,Department of Pediatrics, Center for Blood Oxygen Transport and Hemostasis, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, United States.,Department of Medicine, Division of Hematology, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, United States
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48
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Islamzada E, Matthews K, Lamoureux E, Duffy SP, Scott MD, Ma H. Blood unit segments accurately represent the biophysical properties of red blood cells in blood bags but not hemolysis. Transfusion 2021; 62:448-456. [PMID: 34877683 DOI: 10.1111/trf.16757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/25/2021] [Accepted: 11/19/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND The biophysical properties of red blood cells (RBCs) provide potential biomarkers for the quality of donated blood. Blood unit segments provide a simple and nondestructive way to sample RBCs in clinical studies of transfusion efficacy, but it is not known whether RBCs sampled from segments accurately represent the biophysical properties of RBCs in blood bags. STUDY DESIGN AND METHODS RBCs were sampled from blood bags and segments every two weeks during 8 weeks of storage at 4°C. RBC deformability was measured by deformability-based sorting using the microfluidic ratchet device in order to derive a rigidity score. Standard hematological parameters, including mean corpuscular volume (MCV), red cell distribution width (RDW), mean cell hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and hemolysis were measured at the same time points. RESULTS Deformability of RBCs stored in blood bags was retained over 4 weeks storage, but a progressive loss of deformability was observed at weeks 6 and 8. This trend was mirrored in blood unit segments with a strong correlation to the blood bag data. Strong correlations were also observed between blood bag and segment for MCV, MCHC, and MCH but not for hemolysis. CONCLUSION RBCs sampled from blood unit segments accurately represent the biophysical properties of RBCs in blood bags but not hemolysis. Blood unit segments provide a simple and nondestructive sample for measuring RBC biophysical properties in clinical studies.
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Affiliation(s)
- Emel Islamzada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kerryn Matthews
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada
| | - Erik Lamoureux
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada
| | - Simon P Duffy
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,British Columbia Institute of Technology, Vancouver, British Columbia, Canada
| | - Mark D Scott
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,Canadian Blood Services, Vancouver, British Columbia, Canada
| | - Hongshen Ma
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.,Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
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49
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Comparison of Two Alternative Procedures to Obtain Packed Red Blood Cells for β-Thalassemia Major Transfusion Therapy. Biomolecules 2021; 11:biom11111638. [PMID: 34827635 PMCID: PMC8615631 DOI: 10.3390/biom11111638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 11/16/2022] Open
Abstract
β-thalassemia major (βTM) patients require frequent blood transfusions, with consequences that span from allogenic reactions to iron overload. To minimize these effects, βTM patients periodically receive leucodepleted packed red blood cells (P-RBCs) stored for maximum 14 days. The aim of this study was to compare two alternative routine procedures to prepare the optimal P-RBCs product, in order to identify differences in their content that may somehow affect patients’ health and quality of life (QoL). In method 1, blood was leucodepleted and then separated to obtain P-RBCs, while in method 2 blood was separated and leucodepleted after removal of plasma and buffycoat. Forty blood donors were enrolled in two independent centers; couples of phenotypically matched whole blood units were pooled, divided in two identical bags and processed in parallel following the two methods. Biochemical properties, electrolytes and metabolic composition were tested after 2, 7 and 14 days of storage. Units prepared with both methods were confirmed to have all the requirements necessary for βTM transfusion therapy. Nevertheless, RBCs count and Hb content were found to be higher in method-1, while P-RBCs obtained with method 2 contained less K+, iron and storage lesions markers. Based on these results, both methods should be tested in a clinical perspective study to determine a possible reduction of transfusion-related complications, improving the QoL of βTM patients, which often need transfusions for the entire lifespan.
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50
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Barshtein G, Pajic-Lijakovic I, Gural A. Deformability of Stored Red Blood Cells. Front Physiol 2021; 12:722896. [PMID: 34690797 PMCID: PMC8530101 DOI: 10.3389/fphys.2021.722896] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/18/2021] [Indexed: 12/24/2022] Open
Abstract
Red blood cells (RBCs) deformability refers to the cells’ ability to adapt their shape to the dynamically changing flow conditions so as to minimize their resistance to flow. The high red cell deformability enables it to pass through small blood vessels and significantly determines erythrocyte survival. Under normal physiological states, the RBCs are attuned to allow for adequate blood flow. However, rigid erythrocytes can disrupt the perfusion of peripheral tissues and directly block microvessels. Therefore, RBC deformability has been recognized as a sensitive indicator of RBC functionality. The loss of deformability, which a change in the cell shape can cause, modification of cell membrane or a shift in cytosol composition, can occur due to various pathological conditions or as a part of normal RBC aging (in vitro or in vivo). However, despite extensive research, we still do not fully understand the processes leading to increased cell rigidity under cold storage conditions in a blood bank (in vitro aging), In the present review, we discuss publications that examined the effect of RBCs’ cold storage on their deformability and the biological mechanisms governing this change. We first discuss the change in the deformability of cells during their cold storage. After that, we consider storage-related alterations in RBCs features, which can lead to impaired cell deformation. Finally, we attempt to trace a causal relationship between the observed phenomena and offer recommendations for improving the functionality of stored cells.
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Affiliation(s)
- Gregory Barshtein
- Biochemistry Department, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - Alexander Gural
- Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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