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Winskel-Wood B, Marks DC, Johnson L. Storage Temperature Affects Platelet Activation and Degranulation in Response to Stimuli. Int J Mol Sci 2025; 26:2944. [PMID: 40243579 PMCID: PMC11989061 DOI: 10.3390/ijms26072944] [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: 02/11/2025] [Revised: 03/15/2025] [Accepted: 03/21/2025] [Indexed: 04/18/2025] Open
Abstract
The refrigeration (cold storage) of platelet components provides several benefits over room-temperature (RT) storage, extending the shelf-life up to 21 days. However, the effect of storage conditions on platelet activation in response to stimulation remains unclear. A paired study was conducted where buffy-coat platelet concentrates were pooled, split, and allocated to RT or cold storage (n = 6 in each group). Platelet samples were taken on days 1, 7, 14, and 21, which were tested without stimulation or following activation with TRAP-6, A23187, lipopolysaccharides, or Histone-H4. Imaging flow cytometry was used to assess the surface characteristics of platelets and extracellular vesicles (EVs). The supernatant concentration of EGF, RANTES, PF4, CD62P, IL-27, CD40L, TNF-α, and OX40L was examined using ELISA. Cold-stored platelets generated a greater proportion of procoagulant platelets and EVs than RT-stored platelets in response to stimulation. The supernatant of cold-stored components contained lower concentrations of soluble factors under basal conditions, suggesting that platelet granules were better retained. Cold-stored platelets released higher concentrations of soluble factors following stimulation with TRAP-6, A23187, or Histone-H4. Only cold-stored platelets responded to lipopolysaccharides. These data demonstrate that cold-stored platelets retain the capacity to respond to stimuli after 21 days of storage, which may facilitate improved functional post-transfusion.
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Affiliation(s)
- Ben Winskel-Wood
- Research and Development, Australian Red Cross Lifeblood, Sydney, NSW 2015, Australia; (D.C.M.); (L.J.)
| | - Denese C. Marks
- Research and Development, Australian Red Cross Lifeblood, Sydney, NSW 2015, Australia; (D.C.M.); (L.J.)
- Sydney Medical School, The University of Sydney, Sydney, NSW 2050, Australia
| | - Lacey Johnson
- Research and Development, Australian Red Cross Lifeblood, Sydney, NSW 2015, Australia; (D.C.M.); (L.J.)
- School of Science, RMIT University, Melbourne, VIC 3000, Australia
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Ueda Y, Kiyonaka S, Selfors LM, Inoue K, Harada H, Doura T, Onuma K, Uchiyama M, Kurogi R, Yamada Y, Sun JH, Sakaguchi R, Tado Y, Omatsu H, Suzuki H, Aoun M, Nakayama T, Kajimoto T, Yano T, Holmdahl R, Hamachi I, Inoue M, Mori Y, Takahashi N. Intratumour oxidative hotspots provide a niche for cancer cell dissemination. Nat Cell Biol 2025; 27:530-543. [PMID: 39984655 DOI: 10.1038/s41556-025-01617-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 01/10/2025] [Indexed: 02/23/2025]
Abstract
Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H2O2, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H2O2-rich microenvironments (H2O2 hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H2O2 underwent partial epithelial-mesenchymal transition through p38-MYC axis activation and migrated away from H2O2 hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H2O2 hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation.
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Affiliation(s)
- Yoshifumi Ueda
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Shigeki Kiyonaka
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan.
- Department of Biomolecular Engineering, Nagoya University, Nagoya, Japan.
- Research Institute for Quantum and Chemical Innovation, Nagoya University, Nagoya, Japan.
| | - Laura M Selfors
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Keisuke Inoue
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Hiroshi Harada
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Tomohiro Doura
- Department of Biomolecular Engineering, Nagoya University, Nagoya, Japan
| | - Kunishige Onuma
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Makoto Uchiyama
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Ryuhei Kurogi
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Yuji Yamada
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Jiacheng H Sun
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Reiko Sakaguchi
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Yuki Tado
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Haruki Omatsu
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Harufumi Suzuki
- Department of Biomolecular Engineering, Nagoya University, Nagoya, Japan
| | - Mike Aoun
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
| | - Takahiro Nakayama
- Department of Breast and Endocrine Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Taketoshi Kajimoto
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | | | - Rikard Holmdahl
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
| | - Itaru Hamachi
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
| | - Masahiro Inoue
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan.
| | - Nobuaki Takahashi
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan.
- The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan.
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Fang X, Mo C, Zheng L, Gao F, Xue F, Zheng X. Transfusion-Related Acute Lung Injury: from Mechanistic Insights to Therapeutic Strategies. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413364. [PMID: 39836498 PMCID: PMC11923913 DOI: 10.1002/advs.202413364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/08/2024] [Indexed: 01/23/2025]
Abstract
Transfusion-related acute lung injury (TRALI) is a potentially lethal complication of blood transfusions, characterized by the rapid onset of pulmonary edema and hypoxemia within six hours post-transfusion. As one of the primary causes of transfusion-related mortality, TRALI carries a significant mortality rate of 6-12%. However, effective treatment strategies for TRALI are currently lacking, underscoring the urgent need for a comprehensive and in-depth understanding of its pathogenesis. This comprehensive review provides an updated and detailed analysis of the current landscape of TRALI, including its clinical presentation, pathogenetic hypotheses, animal models, cellular mechanisms, signaling pathways, and potential therapeutic targets. By highlighting the critical roles of these pathways and therapies, this review offers valuable insights to inform the development of preventative and therapeutic strategies and to guide future research efforts aimed at addressing this life-threatening condition.
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Affiliation(s)
- Xiaobin Fang
- Department of Anesthesiology/Critical Care MedicineFuzhou University Affiliated Provincial HospitalSchool of MedicineFuzhou UniversityShengli Clinical Medical College of Fujian Medical UniversityFujian Provincial Key Laboratory of Critical Care MedicineFujian Provincial HospitalFuzhouFujian350001China
| | - Chunheng Mo
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOEState Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengdu610041China
| | - Ling Zheng
- Department of Anesthesiology/Critical Care MedicineFuzhou University Affiliated Provincial HospitalSchool of MedicineFuzhou UniversityShengli Clinical Medical College of Fujian Medical UniversityFujian Provincial Key Laboratory of Critical Care MedicineFujian Provincial HospitalFuzhouFujian350001China
| | - Fei Gao
- Department of Anesthesiology/Critical Care MedicineFuzhou University Affiliated Provincial HospitalSchool of MedicineFuzhou UniversityShengli Clinical Medical College of Fujian Medical UniversityFujian Provincial Key Laboratory of Critical Care MedicineFujian Provincial HospitalFuzhouFujian350001China
| | - Fu‐Shan Xue
- Department of Anesthesiology/Critical Care MedicineFuzhou University Affiliated Provincial HospitalSchool of MedicineFuzhou UniversityShengli Clinical Medical College of Fujian Medical UniversityFujian Provincial Key Laboratory of Critical Care MedicineFujian Provincial HospitalFuzhouFujian350001China
| | - Xiaochun Zheng
- Department of AnesthesiologyFujian Provincial HospitalShengli Clinical Medical College of Fujian Medical University & Fujian Emergency Medical CenterFujian Provincial Key Laboratory of Emergency MedicineFujian Provincial Key Laboratory of Critical MedicineFujian Provincial Co‐constructed Laboratory of “Belt and Road,”FuzhouFujianChina
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Chen J, Xiang Q, Zheng XJ, Jiang XY. Predictive model for postoperative pneumonia in patients with esophageal cancer after esophagectomy. Front Oncol 2025; 15:1529308. [PMID: 40027123 PMCID: PMC11868259 DOI: 10.3389/fonc.2025.1529308] [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: 12/04/2024] [Accepted: 01/31/2025] [Indexed: 03/05/2025] Open
Abstract
Background Pneumonia is one of the most common complications after esophagectomy and a risk factor affecting postoperative survival of esophageal cancer. The aim of this study was to identify risk factors and construct a predictive model for postoperative pneumonia (POP) in esophageal cancer. Methods This retrospective cohort study included esophageal cancer patients who underwent therapeutic esophagectomy from June 2019 to December 2023. Least absolute shrinkage and selection operator (LASSO) regression was used to screen predictive factors for POP, and a nomogram was constructed based on the selected predictive factors after screening. The performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). Results A total of 667 esophageal cancer patients who underwent esophagectomy were included, of whom 61 (9.1%) developed postoperative pneumonia. After LASSO regression analysis, factors independently associated with POP included mechanical ventilation for more than 2 days (P=0.000) and blood transfusion (P=0.003). A nomogram was constructed based on these independent risk factors. The AUC of the predictive model for POP was 0.839 (95%CI: 0.768-0.911). The internal verification result showed a good discriminative power and the DCA results demonstrated a good predictive value. Conclusion The predictive model constructed in this study can predict the risk of POP in patients with esophageal cancer, and may promote early intervention for high-risk patients by clinicians to reduce the incidence of POP.
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Affiliation(s)
| | | | | | - Xiao-yan Jiang
- Department of Healthcare-associated Infection Control Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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Adkins BD, Booth GS, Fasano RM, Gehrie EA, Gestring ML, Masel D, Nguyen PT, Refaai MA, Jacobs JW, Raza S, Vella MA, Tormey CA, Blumberg N. Eliminating leukocyte reduction for whole blood: Is it premature to consider this paradigm-changing practice? Transfusion 2025; 65:375-378. [PMID: 39709612 PMCID: PMC11826295 DOI: 10.1111/trf.18113] [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: 11/25/2024] [Accepted: 11/27/2024] [Indexed: 12/24/2024]
Affiliation(s)
- Brian D. Adkins
- Department of PathologyUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Garrett S. Booth
- Department of Pathology, Microbiology, & ImmunologyVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Ross M. Fasano
- Department of Pathology and Laboratory MedicineCenter for Transfusion and Cellular Therapy, Emory University School of MedicineAtlantaGeorgiaUSA
- Department of PediatricsAflac Cancer and Blood Disorders Center, Emory University School of MedicineAtlantaGeorgiaUSA
| | - Eric A. Gehrie
- The American Red Cross, Biomedical ServicesWashingtonDCUSA
| | - Mark L. Gestring
- Division of Acute Care Surgery, Department of SurgeryUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | - Debra Masel
- Transfusion Medicine Division, Department of Pathology and Laboratory MedicineUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | - Phuong‐Lan T. Nguyen
- Transfusion Medicine Division, Department of Pathology and Laboratory MedicineUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | - Majed A. Refaai
- Transfusion Medicine Division, Department of Pathology and Laboratory MedicineUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | - Jeremy W. Jacobs
- Department of Pathology, Microbiology, & ImmunologyVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Sheharyar Raza
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
- Canadian Blood Services, Medical Affairs and InnovationTorontoOntarioCanada
| | - Michael A. Vella
- Division of Acute Care Surgery, Department of SurgeryUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | | | - Neil Blumberg
- Transfusion Medicine Division, Department of Pathology and Laboratory MedicineUniversity of RochesterRochesterNew YorkUSA
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Bendas G, Gobec M, Schlesinger M. Modulating Immune Responses: The Double-Edged Sword of Platelet CD40L. Semin Thromb Hemost 2024. [PMID: 39379039 DOI: 10.1055/s-0044-1791512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
The CD40-CD40L receptor ligand pair plays a fundamental role in the modulation of the innate as well as the adaptive immune response, regulating monocyte, T and B cell activation, and antibody isotype switching. Although the expression and function of the CD40-CD40L dyad is mainly attributed to the classical immune cells, the majority of CD40L is expressed by activated platelets, either in a membrane-bound form or shed as soluble molecules in the circulation. Platelet-derived CD40L is involved in the communication with different immune cell subpopulations and regulates their functions effectively. Thus, platelet CD40L contributes to the containment and clearance of bacterial and viral infections, and additionally guides leukocytes to sites of infection. However, platelet CD40L promotes inflammatory cellular responses also in a pathophysiological context. For example, in HIV infections, platelet CD40L is supportive of neuronal inflammation, damage, and finally HIV-related dementia. In sepsis, platelet CD40L can induce extensive endothelial and epithelial damage resulting in barrier dysfunction of the gut, whereby the translocation of microbiota into the circulation further aggravates the uncontrolled systemic inflammation. Nevertheless, a distinct platelet subpopulation expressing CD40L under septic conditions can attenuate systemic inflammation and reduce mortality in mice. This review focuses on recent findings in the field of platelet CD40L biology and its physiological and pathophysiological implications, and thereby highlights platelets as vital immune cells that are essential for a proper immune surveillance. In this context, platelet CD40L proves to be an interesting target for various inflammatory diseases. However, either an agonism or a blockade of CD40L needs to be well balanced since both the approaches can cause severe adverse events, ranging from hyperinflammation to immune deficiency. Thus, an interference in CD40L activities should be likely done in a context-dependent and timely restricted manner.
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Affiliation(s)
- Gerd Bendas
- Department of Pharmacy, University of Bonn, Bonn, Germany
| | - Martina Gobec
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Martin Schlesinger
- Department of Pharmacy, University of Bonn, Bonn, Germany
- Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany
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7
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Hwang JH, Tung JP, Harkin DG, Flower RL, Pecheniuk NM. Extracellular vesicles in fresh frozen plasma and cryoprecipitate: Impact on in vitro endothelial cell viability. Transfusion 2024; 64:1709-1718. [PMID: 39021332 DOI: 10.1111/trf.17959] [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: 06/24/2024] [Accepted: 06/30/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND Transfusion-related acute lung injury (TRALI) remains a major contributor to transfusion-associated mortality. While the pathogenesis of TRALI remains unclear, there is evidence of a role for blood components. We therefore investigated the potential effects of fresh frozen plasma (FFP), cryoprecipitate, and extracellular vesicles (EVs) derived from these blood components, on the viability of human lung microvascular endothelial cells (HLMVECs) in vitro. METHODS EVs were isolated from FFP and cryoprecipitate using size-exclusion chromatography and characterized by nanoparticle tracking analysis, western blotting, and transmission electron microscopy. The potential effects of these blood components and their EVs on HLMVEC viability (determined by trypan blue exclusion) were examined in the presence and absence of neutrophils, either with or without prior treatment of HLMVECs with LPS. RESULTS EVs isolated from FFP and cryoprecipitate displayed morphological and biochemical properties conforming to latest international criteria. While FFP, cryoprecipitate, and EVs derived from FFP, each reduced HLMVEC viability, no effect was observed for EVs derived from cryoprecipitate. CONCLUSION Our findings demonstrate clear differences in the effects of FFP, cryoprecipitate, and their respective EVs on HLMVEC viability in vitro. Examination of the mechanisms underlying these differences may lead to an improved understanding of the factors that promote development of TRALI.
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Affiliation(s)
- Ji Hui Hwang
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
- Strategy and Growth, Australian Red Cross Lifeblood, Brisbane, Queensland, Australia
| | - John-Paul Tung
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
- Strategy and Growth, Australian Red Cross Lifeblood, Brisbane, Queensland, Australia
- Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
- School of Health, University of the Sunshine Coast, Sippy Downs, Queensland, Australia
| | - Damien G Harkin
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
- Strategy and Growth, Australian Red Cross Lifeblood, Brisbane, Queensland, Australia
| | - Robert L Flower
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
- Strategy and Growth, Australian Red Cross Lifeblood, Brisbane, Queensland, Australia
| | - Natalie M Pecheniuk
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
- Strategy and Growth, Australian Red Cross Lifeblood, Brisbane, Queensland, Australia
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8
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Kumaran D, Ramirez-Arcos S. Cutibacterium acnes contamination does not enhance the proinflammatory profile of platelet concentrates. Transfusion 2024; 64:1437-1446. [PMID: 38922882 DOI: 10.1111/trf.17931] [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: 04/26/2024] [Revised: 06/08/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Cutibacterium acnes, a common anaerobic platelet concentrate (PC) contaminant, has been associated with rare mild adverse transfusion reactions and is often considered a harmless commensal. Notably, C. acnes can cause chronic infections and has been shown to induce the release of proinflammatory cytokines by immune cells. Since elevated concentrations of proinflammatory factors in PCs have been linked to noninfectious adverse reactions, this study aimed to assess whether C. acnes could elicit the release and accumulation of proinflammatory factors during PC storage, thereby enhancing the risk of such reactions. STUDY DESIGN/METHODS Four ABO-matched buffy coat PCs were pooled and split into six units, each were inoculated with either saline (negative control), a Staphylococcus aureus isolate (positive control, 30 colony forming units [CFU]/unit), or four C. acnes PC isolates (10 CFU/mL) and stored at 20-24°C with agitation. Bacterial counts, platelet activation, and concentration of proinflammatory factors were assessed on days 0, 3, and 5. N = 3. RESULTS C. acnes counts remained stable, while S. aureus proliferated reaching 108CFU/mL by the end of PC storage. By day 5, no significant differences in platelet activation or proinflammatory cytokine profiles were observed in C. acnes-contaminated PCs compared to the negative control (p > .05), while there was a significant increase (p ≤ .05) in sCD40L concentration (day 3), and platelet activation and IL-8 concentration (day 5) in S. aureus-contaminated units. DISCUSSION C. acnes contamination does not promote the accumulation of proinflammatory factors in the absence of proliferation during storage and may not enhance the risk of inflammatory reactions when transfused to patients.
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Affiliation(s)
- Dilini Kumaran
- Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
- Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Sandra Ramirez-Arcos
- Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
- Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
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Andersson H, Nyesiga B, Hermodsson T, Enell Smith K, Hägerbrand K, Lindstedt M, Ellmark P. Next-generation CD40 agonists for cancer immunotherapy. Expert Opin Biol Ther 2024; 24:351-363. [PMID: 38764393 DOI: 10.1080/14712598.2024.2357714] [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: 02/16/2024] [Accepted: 05/16/2024] [Indexed: 05/21/2024]
Abstract
INTRODUCTION There is a need for new therapies that can enhance response rates and broaden the number of cancer indications where immunotherapies provide clinical benefit. CD40 targeting therapies provide an opportunity to meet this need by promoting priming of tumor-specific T cells and reverting the suppressive tumor microenvironment. This is supported by emerging clinical evidence demonstrating the benefits of immunotherapy with CD40 antibodies in combination with standard of care chemotherapy. AREAS COVERED This review is focused on the coming wave of next-generation CD40 agonists aiming to improve efficacy and safety, using new approaches and formats beyond monospecific antibodies. Further, the current understanding of the role of different CD40 expressing immune cell populations in the tumor microenvironment is reviewed. EXPERT OPINION There are multiple promising next-generation approaches beyond monospecific antibodies targeting CD40 in immuno-oncology. Enhancing efficacy is the most important driver for this development, and approaches that maximize the ability of CD40 to both remodel the tumor microenvironment and boost the anti-tumor T cell response provide great opportunities to benefit cancer patients. Enhanced understanding of the role of different CD40 expressing immune cells in the tumor microenvironment may facilitate more efficient clinical development of these compounds.
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Affiliation(s)
- Hampus Andersson
- Alligator Bioscience, Alligator Bioscience AB, Lund, Sweden
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Barnabas Nyesiga
- Alligator Bioscience, Alligator Bioscience AB, Lund, Sweden
- Department of Biomedical Science, Malmö University, Malmö, Sweden
| | - Tova Hermodsson
- Department of Immunotechnology, Lund University, Lund, Sweden
| | | | | | - Malin Lindstedt
- Alligator Bioscience, Alligator Bioscience AB, Lund, Sweden
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Peter Ellmark
- Alligator Bioscience, Alligator Bioscience AB, Lund, Sweden
- Department of Immunotechnology, Lund University, Lund, Sweden
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10
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Ebeyer-Masotta M, Eichhorn T, Fischer MB, Weber V. Impact of production methods and storage conditions on extracellular vesicles in packed red blood cells and platelet concentrates. Transfus Apher Sci 2024; 63:103891. [PMID: 38336556 DOI: 10.1016/j.transci.2024.103891] [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: 02/12/2024]
Abstract
The use of blood and blood products can be life-saving, but there are also certain risks associated with their administration and use. Packed red blood cells (pRBCs) and platelet concentrates are the most commonly used blood products in transfusion medicine to treat anemia or acute and chronic bleeding disorders, respectively. During the production and storage of blood products, red blood cells and platelets release extracellular vesicles (EVs) as a result of the storage lesion, which may affect product quality. EVs are subcellular structures enclosed by a lipid bilayer and originate from the endosomal system or from the plasma membrane. They play a pivotal role in intercellular communication and are emerging as important regulators of inflammation and coagulation. Their cargo and their functional characteristics depend on the cell type from which they originate, as well as on their microenvironment, influencing their capacity to promote coagulation and inflammatory responses. Hence, the potential involvement of EVs in transfusion-related adverse events is increasingly recognized and studied. Here, we review the knowledge regarding the effect of production and storage conditions of pRBCs and platelet concentrates on the release of EVs. In this context, the mode of processing and anticoagulation, the influence of additive solutions and leukoreduction, as well as the storage duration will be addressed, and we discuss potential implications of EVs for the clinical outcome of transfusion.
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Affiliation(s)
- Marie Ebeyer-Masotta
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria
| | - Tanja Eichhorn
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria
| | - Michael B Fischer
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria; Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Viktoria Weber
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria.
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11
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Liu C, Su Y, Guo W, Ma X, Qiao R. The platelet storage lesion, what are we working for? J Clin Lab Anal 2024; 38:e24994. [PMID: 38069592 PMCID: PMC10829691 DOI: 10.1002/jcla.24994] [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: 04/25/2023] [Revised: 11/04/2023] [Accepted: 11/26/2023] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Platelet concentrate (PC) transfusions are crucial in prevention and treatment of bleeding in infection, surgery, leukemia, and thrombocytopenia patients. Although the technology for platelet preparation and storage has evolved over the decades, there are still challenges in the demand for platelets in blood banks because the platelet shelf life is limited to 5 days due to bacterial contamination and platelet storage lesions (PSLs) at 20-24°C under constant horizontal agitation. In addition, the relations between some adverse effects of platelet transfusions and PSLs have also been considered. Therefore, understanding the mechanisms of PSLs is conducive to obtaining high quality platelets and facilitating safe and effective platelet transfusions. OBJECTIVE This review summarizes developments in mechanistic research of PSLs and their relationship with clinical practice, providing insights for future research. METHODS Authors conducted a search on PubMed and Web of Science using the professional terms "PSL" and "platelet transfusion." The obtained literature was then roughly categorized based on their research content. Similar studies were grouped into the same sections, and further searches were conducted based on the keywords of each section. RESULTS Different studies have explored PSLs from various perspectives, including changes in platelet morphology, surface molecules, biological response modifiers (BMRs), metabolism, and proteins and RNA, in an attempt to monitor PSLs and identify intervention targets that could alleviate PSLs. Moreover, novel platelet storage conditions, including platelet additive solutions (PAS) and reconsidered cold storage methods, are explored. There are two approaches to obtaining high-quality platelets. One approach simulates the in vivo environment to maintain platelet activity, while the other keeps platelets at a low activity level in vitro under low temperatures. CONCLUSION Understanding PSLs helps us identify good intervention targets and assess the therapeutic effects of different PSLs stages for different patients.
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Affiliation(s)
- Cheng Liu
- Peking University Third HospitalBeijingChina
| | - Yang Su
- Peking University Third HospitalBeijingChina
| | - Wanwan Guo
- Peking University Third HospitalBeijingChina
| | - Xiaolong Ma
- Peking University Third HospitalBeijingChina
| | - Rui Qiao
- Peking University Third HospitalBeijingChina
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12
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Carestia A, Godin LC, Jenne CN. Step up to the platelet: Role of platelets in inflammation and infection. Thromb Res 2023; 231:182-194. [PMID: 36307228 DOI: 10.1016/j.thromres.2022.10.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/28/2022] [Accepted: 10/03/2022] [Indexed: 11/18/2022]
Abstract
Platelets are anucleated cells derived from megakaryocytes that are primarily responsible for hemostasis. However, in recent years, these cytoplasts have become increasingly recognized as immune cells, able to detect, interact with, and kill pathogens. As platelets are involved in both immunity and coagulation, they have a central role in immunothrombosis, a physiological process in which immune cells induce the formation of microthrombi to both prevent the spread of pathogens, and to help facilitate clearance. In this review, we will highlight the role of platelets as key players in the inflammatory and innate immune response against bacterial and viral infection, including direct and indirect interactions with pathogens and other immune cells.
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Affiliation(s)
- Agostina Carestia
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
| | - Laura C Godin
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
| | - Craig N Jenne
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
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13
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Kuebler WM, William N, Post M, Acker JP, McVey MJ. Extracellular vesicles: effectors of transfusion-related acute lung injury. Am J Physiol Lung Cell Mol Physiol 2023; 325:L327-L341. [PMID: 37310760 DOI: 10.1152/ajplung.00040.2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/27/2023] [Accepted: 05/25/2023] [Indexed: 06/14/2023] Open
Abstract
Respiratory transfusion reactions represent some of the most severe adverse reactions related to receiving blood products. Of those, transfusion-related acute lung injury (TRALI) is associated with elevated morbidity and mortality. TRALI is characterized by severe lung injury associated with inflammation, pulmonary neutrophil infiltration, lung barrier leak, and increased interstitial and airspace edema that cause respiratory failure. Presently, there are few means of detecting TRALI beyond clinical definitions based on physical examination and vital signs or preventing/treating TRALI beyond supportive care with oxygen and positive pressure ventilation. Mechanistically, TRALI is thought to be mediated by the culmination of two successive proinflammatory hits, which typically comprise a recipient factor (1st hit-e.g., systemic inflammatory conditions) and a donor factor (2nd hit-e.g., blood products containing pathogenic antibodies or bioactive lipids). An emerging concept in TRALI research is the contribution of extracellular vesicles (EVs) in mediating the first and/or second hit in TRALI. EVs are small, subcellular, membrane-bound vesicles that circulate in donor and recipient blood. Injurious EVs may be released by immune or vascular cells during inflammation, by infectious bacteria, or in blood products during storage, and can target the lung upon systemic dissemination. This review assesses emerging concepts such as how EVs: 1) mediate TRALI, 2) represent targets for therapeutic intervention to prevent or treat TRALI, and 3) serve as biochemical biomarkers facilitating TRALI diagnosis and detection in at-risk patients.
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Affiliation(s)
- Wolfgang M Kuebler
- Institute of Physiology, Charité-Universitätsmedizin, Berlin, Germany
- Keenan Research Centre, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Nishaka William
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Martin Post
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Jason P Acker
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Innovation and Portfolio Management, Canadian Blood Services, Edmonton, Alberta, Canada
| | - Mark J McVey
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
- Translational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
- Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada
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14
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Szepanowski RD, Haupeltshofer S, Vonhof SE, Frank B, Kleinschnitz C, Casas AI. Thromboinflammatory challenges in stroke pathophysiology. Semin Immunopathol 2023:10.1007/s00281-023-00994-4. [PMID: 37273022 DOI: 10.1007/s00281-023-00994-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/27/2023] [Indexed: 06/06/2023]
Abstract
Despite years of encouraging translational research, ischemic stroke still remains as one of the highest unmet medical needs nowadays, causing a tremendous burden to health care systems worldwide. Following an ischemic insult, a complex signaling pathway emerges leading to highly interconnected thrombotic as well as neuroinflammatory signatures, the so-called thromboinflammatory cascade. Here, we thoroughly review the cell-specific and time-dependent role of different immune cell types, i.e., neutrophils, macrophages, T and B cells, as key thromboinflammatory mediators modulating the neuroinflammatory response upon stroke. Similarly, the relevance of platelets and their tight crosstalk with a variety of immune cells highlights the relevance of this cell-cell interaction during microvascular dysfunction, neovascularization, and cellular adhesion. Ultimately, we provide an up-to-date overview of therapeutic approaches mechanistically targeting thromboinflammation currently under clinical translation, especially focusing on phase I to III clinical trials.
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Affiliation(s)
- R D Szepanowski
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - S Haupeltshofer
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - S E Vonhof
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - B Frank
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - C Kleinschnitz
- Department of Neurology, University Hospital Essen, Essen, Germany.
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany.
| | - A I Casas
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
- Department of Pharmacology and Personalised Medicine, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands
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15
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Ishida Y, Nakazawa K, Itabashi T, Tomino M. Transfusion-related acute lung injury under general anesthesia successfully treated with extracorporeal membrane oxygenation: A case report. Clin Case Rep 2023; 11:e7386. [PMID: 37220518 PMCID: PMC10199813 DOI: 10.1002/ccr3.7386] [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: 03/24/2023] [Revised: 04/08/2023] [Accepted: 05/05/2023] [Indexed: 05/25/2023] Open
Abstract
Transfusion-related acute lung injury (TRALI) is a serious complication of blood transfusion and can also develop severe hypoxemia. In TRALI cases with difficult blood oxygenation on mechanical ventilation support, temporary veno-venous extracorporeal membrane oxygenation support appears to maintain oxygen levels.
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Affiliation(s)
- Yusuke Ishida
- Department of AnesthesiologyTokyo Medical UniversityTokyoJapan
| | - Koichi Nakazawa
- Department of AnesthesiologyTokyo Medical UniversityTokyoJapan
| | - Toshio Itabashi
- Department of AnesthesiologyTokyo Medical UniversityTokyoJapan
| | - Mikiko Tomino
- Department of AnesthesiologyTokyo Medical UniversityTokyoJapan
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16
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Chang M, Yi L, Zhou Z, Yi X, Chen H, Liang X, Jin R, Huang X. GEF-H1/RhoA signaling pathway mediates pro-inflammatory effects of NF-κB on CD40L-induced pulmonary endothelial cells. Mol Immunol 2023; 157:42-52. [PMID: 36989839 DOI: 10.1016/j.molimm.2023.03.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/19/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023]
Abstract
One of the key targets of the inflammatory response in acute lung injury (ALI) is the human pulmonary micro-vascular endothelial cells (HPMVECs). Owing to its role in the activation of endothelial cells (ECs), CD40L figures prominently in the pathogenesis of ALI. Increasing evidences have showed that CD40L mediates inflammatory effects on ECs, at least in part, by triggering NF-κB-dependent gene expression. However, the mechanisms of such signal transmission remain unknown. In this study, we found that CD40L stimulated the transactivation of NF-κB and expression of its downstream cytokines in a p38 MAPK-dependent mechanism in HPMVECs. In addition, CD40L-mediated inflammatory effects might be correlated with the activation of the IKK/IκB/NF-κB pathway and nuclear translocation of NF-κB, being accompanied by dynamic cytoskeletal changes. GEF-H1/RhoA signaling is best known for its role in regulating cytoskeletal rearrangements. An interesting finding was that CD40L induced the activation of p38 and IKK/IκB, and the subsequent transactivation of NF-κB via GEF-H1/RhoA signaling. The critical role of GEF-H1/RhoA in CD40L-induced inflammatory responses in the lung was further confirmed in GEF-H1 and RhoA knockout mouse models, both of which were established by adeno-associated virus (AAV)-mediated delivery of sgRNAs into mice with EC-specific Cas9 expression. These results taken together suggested that p38 and IKK/IκB-mediated signaling pathways, both of which lied downstream of GEF-H1/RhoA, may coordinately regulate the transactivation of NF-κB in CD40L-activated HPMVECs. These findings may help to determine key pharmacological targets of intervention for CD40L-activated inflammatory effects associated with ALI.
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17
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Lyu MA, Huang M, Zeng K, Li L, Khoury JD, Nishimoto M, Ma H, Sadeghi T, Mukherjee S, Slutsky AS, Flowers CR, Parmar S. Allogeneic cord blood regulatory T cells can resolve lung inflammation. Cytotherapy 2023; 25:245-253. [PMID: 36437190 DOI: 10.1016/j.jcyt.2022.10.009] [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: 06/08/2022] [Revised: 09/13/2022] [Accepted: 10/27/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND AIMS CD4+CD25+CD127lo regulatory T cells (Tregs) are responsible for maintaining immune homeostasis. Tregs can be rendered defective and deficient as a result of the immune imbalance seen in lung injury, and such dysfunction can play a major role in continued tissue inflammation. The authors hypothesized that adoptive therapy with healthy allogeneic umbilical cord blood (UCB)-derived Tregs may be able to resolve inflammation. RESULTS Ex vivo-expanded UCB Tregs exhibited a unique phenotype with co-expression of CD45RA+CD45RO+ >80% and lung homing markers, including CD49d. UCB Tregs did not turn pathogenic when exposed to IL-6. Co-culture with increasing doses of dexamethasone led to a synergistic increase in UCB Treg-induced apoptosis of conventional T cells (Tcons), which translated into significantly higher suppression of proliferating Tcons, especially at a lower Treg:Tcon ratio. Multiple injections of UCB Tregs led to their preferential accumulation in lung tissue in an immune injury xenogenic model. A significant decrease in lung resident cytotoxic CD8+ T cells (P = 0.0218) correlated with a sustained decrease in their systemic distribution compared with controls (P < 0.0001) (n = 7 per arm) as well as a decrease in circulating human soluble CD40 ligand level (P = 0.031). Tissue architecture was preserved in the treatment arm, and a significant decrease in CD3+ and CD8+ burden was evident in immunohistochemistry analysis. CONCLUSIONS UCB Treg adoptive therapy is a promising therapeutic strategy for treatment of lung injury.
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Affiliation(s)
- Mi-Ae Lyu
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Meixian Huang
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Ke Zeng
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Li Li
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Joseph D Khoury
- Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Mitsutaka Nishimoto
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Hongbing Ma
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | | | - Siddhartha Mukherjee
- Division of Hematology/Oncology, Department of Medicine, New York-Presbyterian Hospital, Columbia University Irving Medical Center, New York, New York, USA
| | - Arthur S Slutsky
- Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, Canada
| | - Christopher R Flowers
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Simrit Parmar
- Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
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18
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Linde IL, Prestwood TR, Qiu J, Pilarowski G, Linde MH, Zhang X, Shen L, Reticker-Flynn NE, Chiu DKC, Sheu LY, Van Deursen S, Tolentino LL, Song WC, Engleman EG. Neutrophil-activating therapy for the treatment of cancer. Cancer Cell 2023; 41:356-372.e10. [PMID: 36706760 PMCID: PMC9968410 DOI: 10.1016/j.ccell.2023.01.002] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 11/02/2022] [Accepted: 01/05/2023] [Indexed: 01/27/2023]
Abstract
Despite their cytotoxic capacity, neutrophils are often co-opted by cancers to promote immunosuppression, tumor growth, and metastasis. Consequently, these cells have received little attention as potential cancer immunotherapeutic agents. Here, we demonstrate in mouse models that neutrophils can be harnessed to induce eradication of tumors and reduce metastatic seeding through the combined actions of tumor necrosis factor, CD40 agonist, and tumor-binding antibody. The same combination activates human neutrophils in vitro, enabling their lysis of human tumor cells. Mechanistically, this therapy induces rapid mobilization and tumor infiltration of neutrophils along with complement activation in tumors. Complement component C5a activates neutrophils to produce leukotriene B4, which stimulates reactive oxygen species production via xanthine oxidase, resulting in oxidative damage and T cell-independent clearance of multiple tumor types. These data establish neutrophils as potent anti-tumor immune mediators and define an inflammatory pathway that can be harnessed to drive neutrophil-mediated eradication of cancer.
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Affiliation(s)
- Ian L Linde
- Program in Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Tyler R Prestwood
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Jingtao Qiu
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Genay Pilarowski
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Miles H Linde
- Program in Immunology, Stanford University, Stanford, CA 94305, USA
| | - Xiangyue Zhang
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Lei Shen
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | | | | | - Lauren Y Sheu
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Simon Van Deursen
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Lorna L Tolentino
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Wen-Chao Song
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Edgar G Engleman
- Program in Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
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19
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Valsami S, Grouzi E, Mochandreou D, Pouliakis A, Piroula-Godoy M, Kokori S, Pittaras T, Raikou A, Politou M. Effect of mirasol pathogen reduction technology system on immunomodulatory molecules of apheresis platelets. Transfus Apher Sci 2023; 62:103523. [PMID: 36041977 DOI: 10.1016/j.transci.2022.103523] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/28/2022] [Accepted: 08/07/2022] [Indexed: 11/28/2022]
Abstract
Pathogen inactivation for platelets by riboflavin system (MIRASOL) efficiently reduces transfusion related pathogen transmission. However little is known about its impact on platelets' immunomodulatory biochemical profile. We aimed was to assess the effects of MIRASOL treatment on platelet quality parameters and immunomodulatory molecules CD62P, RANTES, and CD40L in Single Donor Platelets (SDPs) resuspended in plasma (SDP-P) or T-PAS and additive solution (SDP-A). Twenty nine SDPs (15 SDP-P and 14 SDP-A) were included in the study. Samples were collected before, after MIRASOL treatment and just before transfusion. P-selectin (CD62P), RANTES, and CD40L were tested by ELISA. Platelet products quality assays were also performed. Platelet count/unit decreased after Mirasol treatment by 13 %. The pH of all units decreased over the 5-day storage period but remained above expected limits and the swirling test was positive throughout storage. P-selectin levels were not different between the three different time points in both SDPs-P and SDPs-A while RANTES levels were found to differ statistically significantly at the three different time points in all units and in the SPD-A subgroup. CD40L levels in all SDP products increased slightly during storage but this was not statistically significant. CD62P, RANTES, and CD40L in all time points were elevated in SDPs-A compared to SDPs-P but not at a statistically significant level. In conclusion MIRASOL treatment apart from RANTES increase does not seem to substantially affect platelets associated other cytokines and immunomodulatory molecules namely P-selectin and sCD40L which are implicated in immune transfusion reactions.
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Affiliation(s)
- S Valsami
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - E Grouzi
- Department of Transfusion Service and Clinical Hemostasis, "Agios Savvas" Regional Cancer Hospital, Athens, Greece
| | - D Mochandreou
- Department of Transfusion Service and Clinical Hemostasis, "Agios Savvas" Regional Cancer Hospital, Athens, Greece
| | - A Pouliakis
- Department of Cytopathology, University of Athens, "ATTIKON" University Hospital, Athens, Greece
| | - M Piroula-Godoy
- Masters of Science Programme "Thrombosis-Haemorrhage-Transfusion Medicine" of the National and Kapodistrian University of Athens, Greece
| | - S Kokori
- Laboratory of Haematology & Blood Bank Unit, "Attikon" University Hospital, National and Kapodistrian Athens, Athens, Greece
| | - T Pittaras
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - A Raikou
- Department of Transfusion Service and Clinical Hemostasis, "Agios Savvas" Regional Cancer Hospital, Athens, Greece
| | - M Politou
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece; Masters of Science Programme "Thrombosis-Haemorrhage-Transfusion Medicine" of the National and Kapodistrian University of Athens, Greece.
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20
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Cognasse F, Hamzeh Cognasse H, Eyraud MA, Prier A, Arthaud CA, Tiberghien P, Begue S, de Korte D, Gouwerok E, Greinacher A, Aurich K, Noorman F, Dumont L, Kelly K, Cloutier M, Bazin R, Cardigan R, Huish S, Smethurst P, Devine D, Schubert P, Johnson L, Marks DC. Assessment of the soluble proteins HMGB1, CD40L and CD62P during various platelet preparation processes and the storage of platelet concentrates: The BEST collaborative study. Transfusion 2023; 63:217-228. [PMID: 36453841 DOI: 10.1111/trf.17200] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 07/22/2022] [Accepted: 10/24/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Structural and biochemical changes in stored platelets are influenced by collection and processing methods. This international study investigates the effects of platelet (PLT) processing and storage conditions on HMGB1, sCD40L, and sCD62P protein levels in platelet concentrate supernatants (PCs). STUDY DESIGN/METHODS PC supernatants (n = 3748) were collected by each international centre using identical centrifugation methods (n = 9) and tested centrally using the ELISA/Luminex platform. Apheresis versus the buffy coat (BC-PC) method, plasma storage versus PAS and RT storage versus cold (4°C) were investigated. We focused on PC preparation collecting samples during early (RT: day 1-3; cold: day 1-5) and late (RT: day 4-7; cold: day 7-10) storage time points. RESULTS HMGB1, sCD40L, and sCD62P concentrations were similar during early storage periods, regardless of storage solution (BC-PC plasma and BC-PC PAS-E) or temperature. During storage and without PAS, sCD40L and CD62P in BC-PC supernatants increased significantly (+33% and +41%, respectively) depending on storage temperature (22 vs. 4°C). However, without PAS-E, levels decreased significantly (-31% and -20%, respectively), depending on storage temperature (22 vs. 4°C). Contrastingly, the processing method appeared to have greater impact on HMGB1 release versus storage duration. These data highlight increases in these parameters during storage and differences between preparation methods and storage temperatures. CONCLUSIONS The HMGB1 release mechanism/intracellular pathways appear to differ from sCD62P and sCD40L. The extent to which these differences affect patient outcomes, particularly post-transfusion platelet increment and adverse events, warrants further investigation in clinical trials with various therapeutic indications.
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Affiliation(s)
- Fabrice Cognasse
- Établissement Français du Sang Auvergne-Rhône-Alpes (Dpt scientifique), Saint-Étienne, France.,University of Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 SAINBIOSE, Saint-Étienne, France
| | - Hind Hamzeh Cognasse
- University of Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 SAINBIOSE, Saint-Étienne, France
| | - Marie Ange Eyraud
- Établissement Français du Sang Auvergne-Rhône-Alpes (Dpt scientifique), Saint-Étienne, France.,University of Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 SAINBIOSE, Saint-Étienne, France
| | - Amélie Prier
- Établissement Français du Sang Auvergne-Rhône-Alpes (Dpt scientifique), Saint-Étienne, France.,University of Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 SAINBIOSE, Saint-Étienne, France
| | - Charles Antoine Arthaud
- Établissement Français du Sang Auvergne-Rhône-Alpes (Dpt scientifique), Saint-Étienne, France.,University of Jean Monnet, Mines Saint-Étienne, INSERM, U 1059 SAINBIOSE, Saint-Étienne, France
| | - Pierre Tiberghien
- Etablissement Français du Sang (headquarters Dpt), La Plaine, St Denis, France.,UMR RIGHT 1098, Inserm, Etablissement Français du Sang, Université de Franche-Comté, Besançon, France
| | - Stephane Begue
- Etablissement Français du Sang (headquarters Dpt), La Plaine, St Denis, France
| | - Dirk de Korte
- Department of Product and Process Development, Sanquin Blood Bank, Amsterdam, The Netherlands
| | - Eric Gouwerok
- Department of Product and Process Development, Sanquin Blood Bank, Amsterdam, The Netherlands.,Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands
| | - Andreas Greinacher
- Institut für Immunologie und Transfusionsmedizin (Institute for Immunology and Transfusion Medicine), Universitätsmedizin Greifswald (Greifswald School of Medicine), Greifswald, Germany
| | - Konstanze Aurich
- Institut für Immunologie und Transfusionsmedizin (Institute for Immunology and Transfusion Medicine), Universitätsmedizin Greifswald (Greifswald School of Medicine), Greifswald, Germany
| | - Femke Noorman
- Military Blood Bank, Ministry of Defence, Utrecht, The Netherlands
| | - Larry Dumont
- Vitalant Research Institute, Denver, Colorado, USA.,School of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Kathleen Kelly
- Vitalant Research Institute, Denver, Colorado, USA.,School of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Marc Cloutier
- Héma-Québec, Affaires Médicales et Innovation (Medical Affairs and Innovation), Quebec, Quebec, Canada
| | - Renée Bazin
- Héma-Québec, Affaires Médicales et Innovation (Medical Affairs and Innovation), Quebec, Quebec, Canada
| | - Rebecca Cardigan
- Component Development Laboratory, NHS Blood and Transplant and Department of Haematology, University of Cambridge, Cambridge, UK
| | - Sian Huish
- Component Development Laboratory, NHS Blood and Transplant and Department of Haematology, University of Cambridge, Cambridge, UK
| | - Peter Smethurst
- Component Development Laboratory, NHS Blood and Transplant and Department of Haematology, University of Cambridge, Cambridge, UK
| | - Dana Devine
- Centre for Innovation, Canadian Blood Services, University of British Columbia, Vancouver, British Columbia, Canada
| | - Peter Schubert
- Centre for Innovation, Canadian Blood Services, University of British Columbia, Vancouver, British Columbia, Canada
| | - Lacey Johnson
- Research & Development, Australian Red Cross Lifeblood, Alexandria, New South Wales, Australia
| | - Denese C Marks
- Research & Development, Australian Red Cross Lifeblood, Alexandria, New South Wales, Australia
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21
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van Baarle FLF, de Bruin S, Bulle EB, van Mourik N, Lim EHT, Tuip-de Boer AM, Bongers A, de Wissel MB, van Bruggen R, de Korte D, Vermeulen C, Tan KW, Jonkers RE, Bonta PI, Lutter R, Dekker T, Dierdorp BS, Peters AL, Biemond BJ, Vlaar APJ. Aged versus fresh autologous platelet transfusion in a two-hit healthy volunteer model of transfusion-related acute lung injury. Transfusion 2022; 62:2490-2501. [PMID: 36300793 PMCID: PMC10092071 DOI: 10.1111/trf.17157] [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: 07/20/2022] [Revised: 09/13/2022] [Accepted: 09/16/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Transfusion-related acute lung injury (TRALI) is a severe complication of blood transfusion that is thought of as a two-hit event: first the underlying patient condition (e.g., sepsis), and then the transfusion. Transfusion factors include human leukocyte antigen antibodies or biologic response modifiers (BRMs) accumulating during storage. Preclinical studies show an increased TRALI risk with longer stored platelets, clinical studies are conflicting. We aim to discover whether longer platelet concentrate (PC) storage time increases TRALI risk in a controlled human experiment. STUDY DESIGN AND METHODS In a randomized controlled trial, 18 healthy male volunteers received a first hit of experimental endotoxemia (2 ng/kg lipopolysaccharide), and a second hit of fresh (2-day old) or aged (7-day old) autologous PC, or physiological saline. After 6 h, changes in TRALI pathways were determined using spirometry, chest X-ray, and bronchoalveolar lavage (BAL). RESULTS All subjects reacted adequately to lipopolysaccharide infusion and satisfied SIRS criteria (increased pulse [>90/min] and temperature [>38°C]). There were no differences between the saline, fresh, and aged PC groups in BAL-fluid protein (95 ± 33 μg/ml; 83 ± 21 μg/ml and 104 ± 29 μg/ml, respectively) and relative neutrophil count (1.5 ± 0.5%; 1.9 ± 0.8% and 1.3 ± 0.8%, respectively), nor in inflammatory BAL-fluid BRMs (Interleukin-6, CXCL8, TNFα , and myeloperoxidase), clinical respiratory parameters, and spirometry results. All chest X-rays were normal. CONCLUSIONS In a human endotoxemia model of autologous platelet transfusion, with an adequate first hit and platelet storage lesion, transfusion of 7-day-old PC does not increase pulmonary inflammation compared with 2-day-old PC.
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Affiliation(s)
- Floor L F van Baarle
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Sanne de Bruin
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Esther B Bulle
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Niels van Mourik
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Endry H T Lim
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Anita M Tuip-de Boer
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Annabel Bongers
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Marit B de Wissel
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Robin van Bruggen
- Department of Blood Cell Research, Sanquin Blood Supply, Amsterdam, The Netherlands
| | - Dirk de Korte
- Department of Blood Cell Research, Sanquin Blood Supply, Amsterdam, The Netherlands.,Department of Product and Process Development, Sanquin Blood Supply, Amsterdam, The Netherlands
| | - Christie Vermeulen
- Department of Product and Process Development, Sanquin Blood Supply, Amsterdam, The Netherlands
| | - Khik Wie Tan
- Sanquin Blood Bank Location Leiden, Sanquin Blood Supply, Amsterdam, The Netherlands
| | - René E Jonkers
- Department of Respiratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Peter I Bonta
- Department of Respiratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - René Lutter
- Department of Respiratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Amsterdam Institute for Infection and Immunity, Inflammatory Diseases, Amsterdam, The Netherlands
| | - Tamara Dekker
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Barbara S Dierdorp
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Anna L Peters
- Department of Anesthesiology, UMC Utrecht, Utrecht, The Netherlands
| | - Bart J Biemond
- Department of Hematology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Alexander P J Vlaar
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
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22
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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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23
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Jiang SZ, To JL, Hughes MR, McNagny KM, Kim H. Platelet signaling at the nexus of innate immunity and rheumatoid arthritis. Front Immunol 2022; 13:977828. [PMID: 36505402 PMCID: PMC9732516 DOI: 10.3389/fimmu.2022.977828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/03/2022] [Indexed: 11/26/2022] Open
Abstract
Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by chronic inflammation of the synovial tissues and progressive destruction of bone and cartilage. The inflammatory response and subsequent tissue degradation are orchestrated by complex signaling networks between immune cells and their products in the blood, vascular endothelia and the connective tissue cells residing in the joints. Platelets are recognized as immune-competent cells with an important role in chronic inflammatory diseases such as RA. Here we review the specific aspects of platelet function relevant to arthritic disease, including current knowledge of the molecular crosstalk between platelets and other innate immune cells that modulate RA pathogenesis.
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Affiliation(s)
- Steven Z. Jiang
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
| | - Jeffrey L. To
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
| | - Michael R. Hughes
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Kelly M. McNagny
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Hugh Kim
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
- Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada
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24
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Abstract
Platelet transfusions are commonly administered for the prevention or treatment of bleeding in patients with acquired thrombocytopenia across a range of clinical contexts. Recent data, including randomized trials, have highlighted uncertainties in the risk-benefit balance of this therapy, which is the subject of this review. Hemovigilance systems report that platelets are the most frequently implicated component in transfusion reactions. There is considerable variation in platelet count increment after platelet transfusion, and limited evidence of efficacy for clinical outcomes, including prevention of bleeding. Bleeding events commonly occur despite the different policies for platelet transfusion prophylaxis. The underlying mechanisms of harm reported in randomized trials may be related to the role of platelets beyond hemostasis, including mediating inflammation. Research supports the implementation of a restrictive platelet transfusion policy. Research is needed to better understand the impact of platelet donation characteristics on outcomes, and to determine the optimal thresholds for platelet transfusion before invasive procedures or major surgery (eg, laparotomy). Platelet transfusion policies should move toward a risk-adapted approach that does not focus solely on platelet count.
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25
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Human neutrophil antigen 3 genotype impacts neutrophil-mediated endothelial cell cytotoxicity in a two-event model of TRALI. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2022; 20:465-474. [PMID: 35848624 PMCID: PMC9726621 DOI: 10.2450/2022.0013-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 04/08/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Antibodies against human neutrophil antigen (HNA)-3a are associated with severe cases of transfusion-related acute lung injury (TRALI). The HNA-3 system is located on choline transporter-like 2 (CTL-2) protein. CTL-2 is encoded by the gene SLC44A2 and a single-nucleotide polymorphism c.461G>A results in two antigens: HNA-3a and HNA-3b. Three HNA-3 genotypes/ phenotypes exist: HNA-3aa, HNA-3bb, and HNA-3ab. Two different pathways of anti-HNA-3a TRALI have been described: a two-hit neutrophil-dependent pathway and a one-hit neutrophil-independent pathway. However, it is not clear whether HNA-3ab heterozygous patients have a lower risk of anti-HNA-3a-mediated TRALI compared to HNA-3aa homozygous patients. MATERIALS AND METHODS Healthy volunteers were genotyped for HNA-3 by real-time polymerase chain reaction, and phenotyped for HNA-3a by granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT) against two donor sera containing anti-HNA-3a antibodies. The two sera were also used in in vitro models of human pulmonary microvascular endothelial cell (HLMVEC) cytotoxicity to investigate pathways of TRALI development. RESULTS For both anti-HNA-3a sera, GIFT results matched the genotype, with a lower GIFT ratio for HNA-3ab neutrophils compared to HNA-3aa neutrophils, whereas GAT results showed no difference in agglutination. HLMVEC cytotoxicity was not observed in a one-hit neutrophil-independent model but was observed in a two-hit neutrophil-dependent model. Differences in cytotoxicity were observed between the two anti-HNA-3a sera used. Consistent with reduced HNA-3a antigen density as measured by GIFT, HNA-3ab neutrophils mediated less HLMVEC cytotoxicity than HNA-3aa neutrophils. CONCLUSION HNA-3 genotype and HNA-3a antigen expression impacted the severity of anti-HNA-3a-mediated HLMVEC cytotoxicity in a two-hit neutrophil-dependent model of TRALI. Different HNA-3a antibodies might also impact the magnitude of HLMVEC cytotoxicity.
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26
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Characterization of Platelet Biologic Markers in the Early Pathogenesis of Postoperative Acute Respiratory Distress Syndrome. Crit Care Explor 2022; 4:e0728. [PMID: 36818750 PMCID: PMC9937690 DOI: 10.1097/cce.0000000000000728] [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] [Indexed: 11/26/2022] Open
Abstract
Animal models and limited human studies have suggested a plausible role for platelets in the pathogenesis and resolution of acute respiratory distress syndrome (ARDS). However, there are little data regarding the role of platelets in ARDS development. OBJECTIVES The objective of this study was to characterize the role of platelets in a postoperative ARDS model through an analysis of two platelet-specific biologic markers: thromboxane A2 (TxA2) and soluble CD-40-ligand (sCD40L). DESIGN SETTING AND PARTICIPANTS This was a nested case-control study of ARDS cases matched to non-ARDS controls. Blood samples were collected from a cohort of 500 patients undergoing thoracic, aortic vascular, or cardiac surgery that placed them at high-risk of developing postoperative ARDS. MAIN OUTCOMES AND MEASURES TxA2 and sCD40L were analyzed at baseline (prior to surgical incision) as well as 2 hours and 6 hours after the key intraoperative events believed to be associated with increased risk of postoperative ARDS. RESULTS Of 500 patients enrolled, 20 ARDS cases were matched 1:2 to non-ARDS controls based on age, sex, surgical procedure, and surgical lung injury prediction score. Those who developed ARDS had longer surgeries, greater fluid administration, and higher peak inspiratory pressures. There were no significant differences in levels of TxA2 or sCD40L at baseline, at 2 hours, or at 6 hours. There was also no difference in the change in biomarker concentration between baseline and 2 hours or baseline and 6 hours. CONCLUSIONS Two novel platelet-associated biologic markers (TxA2 and sCD40L) were not elevated in patients who developed ARDS in a postoperative ARDS model. Although limited by the relatively small study size, these results do not support a clear role for platelets in the early pathogenesis of postoperative ARDS.
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27
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Platelet CD40L Expression Response to Mixing of pRBCs and Washed Platelets but no Causality Association between Platelet ROS Generation and CD40L Expression: An In Vitro Study. Antioxidants (Basel) 2022; 11:antiox11061108. [PMID: 35740005 PMCID: PMC9219937 DOI: 10.3390/antiox11061108] [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: 04/16/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 11/21/2022] Open
Abstract
Platelets play a role in transfusion reaction via reactive oxygen species (ROS) generation and CD40 ligand (CD40L) expression. In this study, we aimed to test the hypothesis that the mixing of packed red blood cells (pRBCs) and washed platelets has a causal effect on platelet ROS generation and CD40L expression. Thus, a better understanding of this causality relationship may help interrupt the chain of events and avoid an uncontrollable transfusion reaction. We simulated transfusion in vitro by mixing pRBCs and washed platelets. Donor cross-matched stored pRBCs) from our blood bank and recipient whole blood from patients undergoing coronary artery bypass graft surgery prepared into washed platelets were used. Briefly, donor pRBCs were added to washed recipient platelets to form 1%, 5%, or 10% (v/v) mixtures. The mixed blood sample was used to determine platelet ROS generation (dichlorofluorescein fluorescence levels) and CD40L expression. The effect of antioxidants (20 mM glutamine and 20 mM dipeptiven) on ROS generation and CD40L expression was also evaluated. Platelet ROS generation was not significantly associated with the mixing of pRBCs and washed platelets (p = 0.755), glutamine treatment (p = 0.800), or dipeptiven treatment (p = 0.711). The expression of CD40L by platelets increased significantly (p < 0.001), and no significant difference was noted after treatment with glutamine (p = 0.560) or dipeptiven (p = 0.618). We observed that the mixing pRBCs and washed platelets had no effect via ROS, whereas CD40L could directly induce transfusion reactions. Furthermore, platelets did not causally express ROS or CD40L after being mixed with pRBCs. Although antioxidants are more accessible than anti-CD40L antibodies, platelet ROS may not serve as a therapeutic target for antioxidants. Nevertheless, CD40L expression may be a valuable therapeutic target for managing transfusion reactions.
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28
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Hwang W, Shimizu M, Lee JW. Role of extracellular vesicles in severe pneumonia and sepsis. Expert Opin Biol Ther 2022; 22:747-762. [PMID: 35418256 PMCID: PMC9971738 DOI: 10.1080/14712598.2022.2066470] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Extracellular vesicles (EV) released constitutively or following external stimuli from structural and immune cells are now recognized as important mediators of cell-to-cell communication. They are involved in the pathogenesis of pneumonia and sepsis, leading causes of acute respiratory distress syndrome (ARDS) where mortality rates remain up to 40%. Multiple investigators have demonstrated that one of the underlying mechanisms of the effects of EVs is through the transfer of EV content to host cells, resulting in apoptosis, inflammation, and permeability in target organs. AREAS COVERED The current review focuses on preclinical research examining the role of EVs released into the plasma and injured alveolus during pneumonia and sepsis. EXPERT OPINION Inflammation is associated with elevated levels of circulating EVs that are released by activated structural and immune cells and can have significant proinflammatory, procoagulant, and pro-permeability effects in critically ill patients with pneumonia and/or sepsis. However, clinical translation of the use of EVs as biomarkers or potential therapeutic targets may be limited by current methodologies used to identify and quantify EVs accurately (whether from host cells or infecting organisms) and lack of understanding of the role of EVs in the reparative phase during recovery from pneumonia and/or sepsis.
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Affiliation(s)
- Wonjung Hwang
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s hospital, Catholic College of Medicine, The Catholic University of Korea, Republic of Korea
| | - Masaru Shimizu
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
| | - Jae-Woo Lee
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California.,Jae-Woo Lee, MD, Professor, University of California San Francisco, Department of Anesthesiology, 505 Parnassus Ave., Box 0648, San Francisco, CA 94143, Telephone: (415) 476-0452, Fax: (415) 514-2999,
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29
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Abstract
Platelets are at the crossroads between thrombosis and inflammation. When activated, platelets can shed bioactive extracellular vesicles [pEVs] that share the hemostatic potential of their parent cells and act as bioactive shuttles of their granular contents. In a viral infection, platelets are activated, and pEVs are generated with occasional virion integration. Both platelets and pEVs are engaged in a bidirectional interaction with neutrophils and other cells of the immune system and the hemostatic pathways. Severe COVID-19 infection is characterized by a stormy thromboinflammatory response with platelets and their EVs at the center stage of this reaction. This review sheds light on the interactions of platelets, pEVS and SARS-CoV-2 infection and prognostic and potential therapeutic role of pEVs. The review also describes the role of pEVs in the rare adenovirus-based COVID-19 vaccine-induced thrombosis thrombocytopenia.
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30
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Arnason NA, Johannsson F, Landrö R, Hardarsson B, Gudmundsson S, Lian AM, Reseland J, Rolfsson O, Sigurjonsson OE. Protein Concentrations in Stored Pooled Platelet Concentrates Treated with Pathogen Inactivation by Amotosalen Plus Ultraviolet a Illumination. Pathogens 2022; 11:pathogens11030350. [PMID: 35335674 PMCID: PMC8954553 DOI: 10.3390/pathogens11030350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/04/2023] Open
Abstract
Platelet granules contain a diverse group of proteins. Upon activation and during storage, platelets release a number of proteins into the circulation or supernatant of stored platelet concentrate (PC). The aim of this work was to investigate the effect of pathogen inactivation (PI) on a selection of proteins released in stored platelets. Materials and Methods: PCs in platelet additive solution (PAS) were produced from whole blood donations using the buffy coat (BC) method. PCs in the treatment arm were pathogen inactivated with amotosalen and UVA, while PCs in the second arm were used as an untreated platelet control. Concentrations of 36 proteins were monitored in the PCs during storage. Results: The majority of proteins increased in concentration over the storage period. In addition, 10 of the 29 proteins that showed change had significantly different concentrations between the PI treatment and the control at one or more timepoints. A subset of six proteins displayed a PI-related drop in concentration. Conclusions: PI has limited effect on protein concentration stored PC supernatant. The protein’s changes related to PI treatment with elevated concentration implicate accelerated Platelet storage lesion (PSL); in contrast, there are potential novel benefits to PI related decrease in protein concentration that need further investigation.
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Affiliation(s)
- Niels Arni Arnason
- The Blood Bank, Landspitali-The National University Hospital of Iceland, 105 Reykjavik, Iceland; (N.A.A.); (R.L.); (B.H.); (S.G.)
- School of Engineering, Reykjavik University, 105 Reykjavik, Iceland
| | - Freyr Johannsson
- Department of Medicine, University of Iceland, 105 Reykjavik, Iceland; (F.J.); (O.R.)
| | - Ragna Landrö
- The Blood Bank, Landspitali-The National University Hospital of Iceland, 105 Reykjavik, Iceland; (N.A.A.); (R.L.); (B.H.); (S.G.)
| | - Björn Hardarsson
- The Blood Bank, Landspitali-The National University Hospital of Iceland, 105 Reykjavik, Iceland; (N.A.A.); (R.L.); (B.H.); (S.G.)
| | - Sveinn Gudmundsson
- The Blood Bank, Landspitali-The National University Hospital of Iceland, 105 Reykjavik, Iceland; (N.A.A.); (R.L.); (B.H.); (S.G.)
| | - Aina-Mari Lian
- Institute of Clinical Dentistry, Faculty of Dentistry, University of Oslo, 0317 Oslo, Norway; (A.-M.L.); (J.R.)
| | - Janne Reseland
- Institute of Clinical Dentistry, Faculty of Dentistry, University of Oslo, 0317 Oslo, Norway; (A.-M.L.); (J.R.)
| | - Ottar Rolfsson
- Department of Medicine, University of Iceland, 105 Reykjavik, Iceland; (F.J.); (O.R.)
| | - Olafur E. Sigurjonsson
- The Blood Bank, Landspitali-The National University Hospital of Iceland, 105 Reykjavik, Iceland; (N.A.A.); (R.L.); (B.H.); (S.G.)
- School of Engineering, Reykjavik University, 105 Reykjavik, Iceland
- Correspondence: ; Tel.: +354-543-5523 or +354-694-9427; Fax: +354-543-5532
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31
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Al-Tamimi AO, Yusuf AM, Jayakumar MN, Ansari AW, Elhassan M, AbdulKarim F, Kannan M, Halwani R, Ahmad F. SARS-CoV-2 infection induces soluble platelet activation markers and PAI-1 in the early moderate stage of COVID-19. Int J Lab Hematol 2022; 44:712-721. [PMID: 35266284 PMCID: PMC9111479 DOI: 10.1111/ijlh.13829] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/29/2022] [Accepted: 03/02/2022] [Indexed: 01/08/2023]
Abstract
Introduction Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID‐19. However, it is unclear when particularly platelet activation markers and coagulation factors dysregulated during the pathogenesis of COVID‐19. Here, we sought to assess the levels of coagulation and platelet activation markers at moderate and severe stages of COVID‐19 to understand the pathogenesis. Methods To understand this, hospitalized COVID‐19 patients with (severe cases that required intensive care) or without pneumonia (moderate cases) were recruited. Phenotypic and molecular characterizations were performed employing basic coagulation tests including prothrombin time (PT), activated partial thromboplastin time (APTT), D‐Dimer, and tissue factor pathway inhibitor (TFPI). The flow cytometry‐based multiplex assays were performed to assess FXI, anti‐thrombin, prothrombin, fibrinogen, FXIII, P‐selectin, sCD40L, plasminogen, tissue plasminogen activator (tPA), plasminogen activator inhibitor‐1 (PAI‐1), and D‐Dimer. Results The investigations revealed induction of plasma P‐selectin and CD40 ligand (sCD40L) in moderate COVID‐19 cases, which were significantly abolished with the progression of COVID‐19 severity. Moreover, a profound reduction in plasma tissue factor pathway inhibitor (TFPI) and FXIII were identified particularly in the severe COVID‐19. Further analysis revealed fibrinogen induction in both moderate and severe patients. Interestingly, an elevated PAI‐1 more prominently in moderate, and tPA particularly in severe COVID‐19 cases were observed. Particularly, the levels of fibrinogen and tPA directly correlated with the severity of the disease. Conclusions In summary, induction of soluble P‐selectin, sCD40L, fibrinogen, and PAI‐1 suggests the activation of platelets and coagulation system at the moderate stage before COVID‐19 patients require intensive care. These findings would help in designing better thromboprophylaxis to limit the COVID‐19 severity.
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Affiliation(s)
- Abaher O Al-Tamimi
- Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
| | - Ayesha M Yusuf
- Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
| | - Manju N Jayakumar
- Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
| | - Abdul W Ansari
- Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.,Dermatology Institute, Translational Research Institute, Academic Health Systems, Hamad Medical Corporation, Doha, Qatar
| | - Mona Elhassan
- Department of Internal Medicine, Rashid Hospital, Dubai, UAE
| | | | - Meganathan Kannan
- Blood and Vascular Biology Research Lab, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
| | - Rabih Halwani
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE
| | - Firdos Ahmad
- Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE
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Bojanić I, Lukić M, Plenković F, Raos M, Medenjak M, Ćepulić BG. Changes in the incidence of transfusion reactions in hematological patients over the past 30 years. Transfusion 2022; 62:600-611. [PMID: 35149994 DOI: 10.1111/trf.16816] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Patients with hematological diseases are polytransfused and often immunocompromised, therefore susceptible to transfusion reactions (TR). This study aims to document the incidence of TRs in adult hematological patients and assess the effect of changes in the production of blood components and transfusion practice on their occurrence. STUDY DESIGN AND METHODS Retrospective observational analysis of TRs reported from 1993 to 2019 was performed. For the analysis of the effect of changes on the incidence of TRs, the evaluated time was divided into two periods: the 1st period before the introduction of changes in production, when leukoreduced blood components were used only selectively, and the 2nd period, when semi-automated method of production and universal leukoreduction was introduced. RESULTS The decrease in the incidence of TRs was observed for both red blood cell (RBC) and platelet concentrate (PC) transfusions in the 2nd period. Since platelet additive solution has been used, a further decrease in the incidence was reported. The decrease in incidence was also observed for delayed hemolytic/serological transfusion reactions and for transfusion-transmitted bacterial infections. Four cases of incorrect blood transfusions were uniquely related to the hematological patients, caused by antigen loss and transfusion ordering after ABO-incompatible hematopoietic stem cell transplantation. DISCUSSION Our results provided evidence that the introduction of tools offered by modern transfusion medicine: universal leukodepletion, plasma replacement with additive solutions, sensitive laboratory techniques, prophylactic antigen matching policy, informatization, and automatization, decreased the incidence of TRs and improved transfusion safety.
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Affiliation(s)
- Ines Bojanić
- Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Zagreb, Croatia.,University of Zagreb, School of Medicine, Zagreb, Croatia.,University of Applied Health Sciences Zagreb, Zagreb, Croatia
| | - Marija Lukić
- Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Fini Plenković
- Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Mirela Raos
- Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Zagreb, Croatia.,University of Zagreb, School of Medicine, Zagreb, Croatia.,University of Applied Health Sciences Zagreb, Zagreb, Croatia
| | - Marta Medenjak
- University of Applied Health Sciences Zagreb, Zagreb, Croatia
| | - Branka Golubic Ćepulić
- Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Zagreb, Croatia.,University of Zagreb, School of Medicine, Zagreb, Croatia.,University of Applied Health Sciences Zagreb, Zagreb, Croatia
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Wang R, Wang S, Zhang J, He M, Xu J. Serum Lactate Level in Early Stage Is Associated With Acute Kidney Injury in Traumatic Brain Injury Patients. Front Surg 2022; 8:761166. [PMID: 35174203 PMCID: PMC8841417 DOI: 10.3389/fsurg.2021.761166] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/24/2021] [Indexed: 01/27/2023] Open
Abstract
Background Acute kidney injury (AKI) is a common complication in the clinical practice of managing patients with traumatic brain injury (TBI). Avoiding the development of AKI is beneficial for the prognosis of patients with TBI. We designed this study to testify whether serum lactate could be used as a predictive marker of AKI in patients with TBI. Materials and Methods In total, 243 patients with TBI admitted to our hospital were included in this study. Univariate and multivariate logistic regression analyses were utilized to analyze the association between lactate and AKI. The receiver operating characteristic (ROC) curves were drawn to verify the predictive value of lactate and the logistic model. Results Acute kidney injury group had higher age (p = 0.016), serum creatinine (p < 0.001), lactate (p < 0.001), and lower Glasgow Coma Scale (GCS; p = 0.021) than non-AKI group. Multivariate logistic regression showed that age [odds ratio (OR) = 1.026, p = 0.022], serum creatinine (OR = 1.020, p = 0.010), lactate (OR = 1.227, p = 0.031), fresh frozen plasma (FFP) transfusion (OR = 2.421, p = 0.045), and platelet transfusion (OR = 5.502, p = 0.044) were risk factors of AKI in patients with TBI. The area under the ROC curve (AUC) values of single lactate and predictive model were 0.740 and 0.807, respectively. Conclusion Serum lactate level in the early phase is associated with AKI in patients with TBI. Lactate is valuable for clinicians to evaluate the probability of AKI in patients with TBI.
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Affiliation(s)
- Ruoran Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Shaobo Wang
- Department of Infectious Diseases, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Jing Zhang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Min He
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Min He
| | - Jianguo Xu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
- Jianguo Xu
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OUP accepted manuscript. Lab Med 2022; 53:405-411. [DOI: 10.1093/labmed/lmac012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Tung JP, Chiaretti S, Dean MM, Sultana AJ, Reade MC, Fung YL. Transfusion-related acute lung injury (TRALI): Potential pathways of development, strategies for prevention and treatment, and future research directions. Blood Rev 2022; 53:100926. [DOI: 10.1016/j.blre.2021.100926] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/01/2021] [Accepted: 12/30/2021] [Indexed: 02/08/2023]
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Transfusion of target antigens to preimmunized recipients: a new mechanism in transfusion-related acute lung injury. Blood Adv 2021; 5:3975-3985. [PMID: 34438443 PMCID: PMC8945619 DOI: 10.1182/bloodadvances.2020003843] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 09/04/2021] [Indexed: 01/13/2023] Open
Abstract
The recipients’ preformed alloantibodies may initiate TRALI reaction in recipients transfused with soluble antigen. The antibody interaction with absorbed antigen on ECs leads to endothelial barrier dysfunction and lung injury. Transfusion-related lung injury (TRALI) is a serious side effect of blood transfusion. Exclusion of antibody carriers from the donor pool has significantly decreased the number of cases, but TRALI remains the leading cause of transfusion-related morbidity and mortality in industrialized countries. Here, we show that proteins released from donor cells during processing of blood components are capable of inducing a new type of reverse TRALI when transfused to preimmunized recipients. First, we show that soluble neutrophil surface protein CD177 in complex with proteinase 3 (sCD177/PR3) is not only present in human plasma but also in packed red blood cell (PRBC) supernatant. Filtration or storage enhances the concentration of sCD177/PR3 in PRBCs. Second, we show that sCD177/PR3 specifically binds to PECAM-1 on stimulated (but not on unstimulated) endothelial cells (ECs). Third, we provide evidence that the sCD177/PR3/PECAM-1 complex is functional. In the presence of monoclonal or human antibodies against CD177 or PR3, ECs produce reactive oxygen species and become apoptotic. Albumin flux through an EC monolayer increases significantly whenever antibodies and the cognate antigens are present. Finally, we describe a clinical case in which anti-CD177 present in a transfusion recipient precipitated TRALI after the transfusion of CD177-positive, but not CD177-negative, PRBCs. In conclusion, we introduce a new TRALI mechanism based on the specific binding of transfused, soluble antigens to activated ECs in preimmunized recipients. We suggest that further studies and clinical work-up of TRALI should also include antibody investigation of the recipient.
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Huang J, Khademi M, Lindhe Ö, Jönsson G, Piehl F, Olsson T, Kockum I. Assessing the Preanalytical Variability of Plasma and Cerebrospinal Fluid Processing and Its Effects on Inflammation-Related Protein Biomarkers. Mol Cell Proteomics 2021; 20:100157. [PMID: 34597789 PMCID: PMC8554621 DOI: 10.1016/j.mcpro.2021.100157] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 01/01/2023] Open
Abstract
Proteomics studies are important for the discovery of new biomarkers as clinical tools for diagnosis and disease monitoring. However, preanalytical variations caused by differences in sample handling protocol pose challenges for assessing biomarker reliability and comparability between studies. The purpose of this study was to examine the effects of delayed centrifuging on measured protein levels in plasma and cerebrospinal fluid (CSF). Blood from healthy individuals and patients with multiple sclerosis along with CSF from patients with suspected neurological disorders were left at room temperature for different periods (blood: 1, 24, 48, 72 h; CSF: 1 and 6 h) prior to centrifuging. Ninety-one inflammation-related proteins were analyzed using a proximity extension assay, a high-sensitivity multiplex immunoassay. Additional metabolic and neurology-related markers were also investigated in CSF. In summary, many proteins, particularly in plasma, had increased levels with longer delays in processing likely due in part to intracellular leakage. Levels of caspase 8, interleukin 8, interleukin 18, sirtuin 2, and sulfotransferase 1A1 increased 2-fold to 10-fold in plasma after 24 h at room temperature. Similarly, levels of cathepsin H, ectonucleoside triphosphate diphosphohydrolase 5, and WW domain containing E3 ubiquitin protein ligase 2 differentiated in CSF with <6 h delay in processing. However, the rate of change for many proteins was relatively consistent; therefore, we were able to characterize biomarkers for detecting sample handling variability. Our findings highlight the importance of timely and consistent sample collection and the need for increased awareness of protein susceptibility to sample handling bias. In addition, suggested biomarkers may be used in certain situations to detect and correct for preanalytical variation in future studies.
Several blood and cerebrospinal fluid proteins are affected by sample handling. Plasma protein levels increased with longer centrifugation delay from hemolysis. Certain proteins may assess sample handling variability and predict delay time.
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Affiliation(s)
- Jesse Huang
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Mohsen Khademi
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Örjan Lindhe
- Olink Proteomics AB, Uppsala Science Park, Uppsala, Sweden
| | - Gunn Jönsson
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Fredrik Piehl
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Tomas Olsson
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Ingrid Kockum
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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França TT, Al-Sbiei A, Bashir G, Mohamed YA, Salgado RC, Barreiros LA, Maria da Silva Napoleão S, Weber CW, Fernandes Severo Ferreira J, Aranda CS, Prando C, de Barros Dorna MB, Jurisica I, Fernandez-Cabezudo MJ, Ochs HD, Condino-Neto A, Al-Ramadi BK, Cabral-Marques O. CD40L modulates transcriptional signatures of neutrophils in the bone marrow associated with development and trafficking. JCI Insight 2021; 6:e148652. [PMID: 34255742 PMCID: PMC8410015 DOI: 10.1172/jci.insight.148652] [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] [Indexed: 11/17/2022] Open
Abstract
Neutrophils are produced in the BM in a process called granulopoiesis, in which progenitor cells sequentially develop into mature neutrophils. During the developmental process, which is finely regulated by distinct transcription factors, neutrophils acquire the ability to exit the BM, properly distribute throughout the body, and migrate to infection sites. Previous studies have demonstrated that CD40 ligand (CD40L) influences hematopoiesis and granulopoiesis. Here, we investigate the effect of CD40L on neutrophil development and trafficking by performing functional and transcriptome analyses. We found that CD40L signaling plays an essential role in the early stages of neutrophil generation and development in the BM. Moreover, CD40L modulates transcriptional signatures, indicating that this molecule enables neutrophils to traffic throughout the body and to migrate in response to inflammatory signals. Thus, our study provides insights into the complex relationships between CD40L signaling and granulopoiesis, and it suggests a potentially novel and nonredundant role of CD40L signaling in neutrophil development and function.
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Affiliation(s)
- Tábata Takahashi França
- Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Ashraf Al-Sbiei
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates (UAE) University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Ghada Bashir
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates (UAE) University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Yassir Awad Mohamed
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates (UAE) University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Ranieri Coelho Salgado
- Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Lucila Akune Barreiros
- Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil
| | | | - Cristina Worm Weber
- Pediatric Allergy & Immunology Clinic, Caxias do Sul, Rio Grande do Sul, Brazil
| | | | - Carolina Sanchez Aranda
- Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Federal University of São Paulo, São Paulo, São Paulo, Brazil
| | - Carolina Prando
- Faculdades Pequeno Príncipe, Pelé Pequeno Principe Research Intitute, Curitiba, Paraná, Brazil.,Hospital Pequeno Príncipe, Curitiba, Paraná, Brazil
| | - Mayra B de Barros Dorna
- Division of Allergy and Immunology, Department of Pediatrics, Children's Institute, Hospital das Clínicas, São Paulo, São Paulo, Brazil
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Krembil Research Institute, University Health Network, Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Ontaro, Canada.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maria J Fernandez-Cabezudo
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Hans D Ochs
- Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Washington, USA
| | - Antonio Condino-Neto
- Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Basel K Al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates (UAE) University, Al Ain, Abu Dhabi, United Arab Emirates.,Zayed Center for Health Sciences, UAE University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Otavio Cabral-Marques
- Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil.,Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.,Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), São Paulo, São Paulo, Brazil
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Platelet and Red Blood Cell Transfusions and Risk of Acute Graft-versus-Host Disease after Myeloablative Allogeneic Hematopoietic Cell Transplantation. Transplant Cell Ther 2021; 27:866.e1-866.e9. [PMID: 34252580 DOI: 10.1016/j.jtct.2021.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/28/2021] [Accepted: 07/04/2021] [Indexed: 12/22/2022]
Abstract
Transfusion therapy is a critical part of supportive care early after allogeneic hematopoietic cell transplantation (allo-HCT). Platelet and RBC transfusions elicit immunomodulatory effects in the recipient, but if this impacts the risk of acute graft-versus-host disease (aGVHD) has only been scarcely investigated. We investigated if platelet and RBC transfusions were associated with the development of aGVHD following myeloablative allo-HCT in a cohort of 664 patients who underwent transplantation between 2000 and 2019. Data were further analyzed for the impact of blood donor age and sex and blood product storage time. Exploratory analyses were conducted to assess correlations between transfusion burden and plasma biomarkers of inflammation and endothelial activation and damage. Between day 0 and day +13, each patient received a median of 7 (IQR, 5 to 10) platelet transfusions and 3 (IQR, 2 to 6) RBC transfusions (Spearman's ρ = 0.49). The cumulative sums of platelet and RBC transfusions, respectively, received from day 0 to day +13 were associated with subsequent grade II-IV aGVHD in multivariable landmark Cox models (platelets: adjusted hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.06 to 1.51; RBCs: adjusted HR, 1.41; 95% CI, 1.09 to 1.82; both per 5 units; 184 events). For both platelet and RBC transfusions, we did not find support for a difference in the risk of aGVHD according to age or sex of the blood donor. Transfusion of RBCs with a storage time longer than the median of 8 days was inversely associated with aGVHD (HR per 5 units, 0.54; 95% CI, 0.30 to 0.96); however, when using an RBC storage time of ≥14 days as a cutoff, there was no longer evidence for an association with aGVHD (HR, 1.03 per 5 units; 95% CI, 0.53 to 2.00). For platelets, there was no clear association between storage time and the risk of aGVHD. The transfusion burdens of platelets and RBCs were positively correlated with plasma levels of TNF-α, IL-6, and soluble thrombomodulin at day +14. In conclusion, platelet and RBC transfusions in the first 2 weeks after myeloablative allo-HCT were associated with subsequent development of grade II-IV aGVHD. We did not find evidence of an impact of blood donor age or sex or blood product storage time on the risk of aGVHD. Our findings support restrictive transfusion strategies in allo-HCT recipients.
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Li CN, Ge YP, Liu H, Zhang CH, Zhong YL, Chen SW, Liu YM, Zheng J, Zhu JM, Sun LZ. Blood Transfusion and Acute Kidney Injury After Total Aortic Arch Replacement for Acute Stanford Type A Aortic Dissection. Heart Lung Circ 2021; 31:136-143. [PMID: 34120843 DOI: 10.1016/j.hlc.2021.05.087] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/28/2021] [Accepted: 05/06/2021] [Indexed: 12/26/2022]
Abstract
AIM To evaluate the effect of packed red blood cells (pRBCs), fresh frozen plasma (FFP), and platelet concentrate (PC) transfusions on acute kidney injury (AKI) in patients with acute Stanford type A aortic dissection (ATAAD) with total arch replacement (TAR). METHOD From December 2015 to October 2017, 421 consecutive patients with ATAAD undergoing TAR were included in the study. The clinical data of the patients and the amount of pRBCs, FFP, and PC were collected. Acute kidney injury was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Logistic regression was used to identify whether pRBCs, FFP, and platelet transfusions were risk factors for KDIGO AKI, stage 3 AKI, and AKI requiring renal replacement therapy (RRT). RESULTS The mean ± standard deviation age of the patients was 47.67±10.82 years; 77.7% were men; and the median time from aortic dissection onset to operation was 1 day (range, 0-2 days). The median transfusion amount was 8 units (range, 4-14 units) for pRBCs, 400 mL (range, 0-800 mL) for FFP, and no units (range, 0-2 units) for PC. Forty-one (41; 9.7%) patients did not receive any blood products. The rates of pRBC, PC, and FFP transfusions were 86.9%, 49.2%, and 72.9%, respectively. The incidence of AKI was 54.2%. Considering AKI as the endpoint, multivariate logistic regression showed that pRBCs (odds ratio [OR], 1.11; p<0.001) and PC transfusions (OR, 1.28; p=0.007) were independent risk factors. Considering KDIGO stage 3 AKI as the endpoint, multivariate logistic regression showed that pRBC transfusion (OR, 1.15; p<0.001), PC transfusion (OR, 1.28; p<0.001), a duration of cardiopulmonary bypass (CPB) ≥293 minutes (OR, 2.95; p=0.04), and a creatinine clearance rate of ≤85 mL/minute (OR, 2.12; p=0.01) were independent risk factors. Considering RRT as the endpoint, multivariate logistic regression showed that pRBC transfusion (OR, 1.12; p<0.001), PC transfusion (OR, 1.33; p=0.001), a duration of CPB ≥293 minutes (OR, 3.79; p=0.02), and a creatinine clearance rate of ≤85 mL/minute (OR, 3.34; p<0.001) were independent risk factors. CONCLUSIONS Kidney Disease: Improving Global Outcomes-defined stage AKI was common after TAR for ATAAD. Transfusions of pRBCs and PC increased the incidence of AKI, stage 3 AKI, and RRT. Fresh frozen plasma transfusion was not a risk factor for AKI.
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Affiliation(s)
- Cheng-Nan Li
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Yi-Peng Ge
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Hao Liu
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Chen-Han Zhang
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Yong-Liang Zhong
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Su-Wei Chen
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Yong-Min Liu
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Jun Zheng
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Jun-Ming Zhu
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Li-Zhong Sun
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Aortic Disease Center, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
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Hu L, Wang B, Jiang Y, Zhu B, Wang C, Yu Q, Hou W, Xia Z, Wu G, Sun Y. Risk Factors for Transfusion-Related Acute Lung Injury. Respir Care 2021; 66:1029-1038. [PMID: 33774597 DOI: 10.4187/respcare.08829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Until now, transfusion-related acute lung injury (TRALI) has been considered the leading cause of blood transfusion-related diseases and death. In addition, there is no clinically effective treatment plan for TRALI. The aim of this study was to systematically summarize the literature on risk factors for TRALI in critical patients. METHODS Electronic searches (up to March 2020) were performed in the Cochrane Library, Web of Knowledge, Embase, and PubMed databases. We included studies reporting on the risk factors of TRALI for critical patients and extracted risk factors. A total of 13 studies met the inclusion criteria. RESULTS We summarized and analyzed the potential risk factors of TRALI for critical patients in 13 existing studies. Host-related factors were age (odds ratio [OR] 1.16 [95% CI 1.08-1.24]), female sex (OR 1.26 [95% CI 1.16-1.38]), tobacco use status (OR 3.82 [95% CI 1.91-7.65]), chronic alcohol abuse (OR 3.82 [95% CI 2.97-26.83]), positive fluid balance (OR 1.24 [95% CI 1.08-1.42]), shock before transfusion (OR 4.41 [95% CI 2.38-8.20]), and American Society of Anesthesiologists (ASA) score of the recipients (OR 2.72 [95% CI 1.43-5.16]). The transfusion-related factors were the number of transfusions (OR 1.40 [95% CI 1.14-1.72]) and units of fresh frozen plasma (OR 1.21 [95% CI 1.01-1.46]). The device-related factor was mechanical ventilation (OR 4.13 [95% CI 2.20-7.76]). CONCLUSIONS The risk factors that were positively correlated with TRALI in this study included number of transfusions and units of fresh frozen plasma. Age, female sex, tobacco use, chronic alcohol abuse, positive fluid balance, shock before transfusion, ASA score, and mechanical ventilation may be potential risk factors for TRALI. Our results suggest that host-related risk factors may play a more important role in the occurrence and development of TRALI than risk factors related to blood transfusions.
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Affiliation(s)
- Lunyang Hu
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China
| | - Baoli Wang
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China
| | - Yong Jiang
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China
| | - Banghui Zhu
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China
| | - Chen Wang
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China
| | - Qing Yu
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China
| | - Wenjia Hou
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China
| | - Zhaofan Xia
- Burn and Trauma Center, Changhai Hospital, Shanghai, People's Republic of China.
| | - Guosheng Wu
- Burn and Trauma Center, Changhai Hospital, Shanghai, People's Republic of China
| | - Yu Sun
- Burn and Trauma Center, Changhai Hospital, Shanghai, People's Republic of China
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Savage AK, Gutschow MV, Chiang T, Henderson K, Green R, Chaudhari M, Swanson E, Heubeck AT, Kondza N, Burley KC, Genge PC, Lord C, Smith T, Thomson Z, Beaubien A, Johnson E, Goldy J, Bolouri H, Buckner JH, Meijer P, Coffey EM, Skene PJ, Torgerson TR, Li XJ, Bumol TF. Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing. iScience 2021; 24:102404. [PMID: 34113805 PMCID: PMC8169801 DOI: 10.1016/j.isci.2021.102404] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/28/2021] [Accepted: 04/06/2021] [Indexed: 12/04/2022] Open
Abstract
Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMC up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.
Studies of human blood cells and plasma are highly sensitive to process variability Time variability distorts biology in cutting-edge single-cell and multiplex assays Longitudinal, multi-modal, and aligned data enable data qualification and exploration Dataset holds potential novel, multi-modal biological correlations and hypotheses
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Affiliation(s)
- Adam K Savage
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | | | - Tony Chiang
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | | | - Richard Green
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | | | | | | | - Nina Kondza
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | | | - Palak C Genge
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | - Cara Lord
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | - Tanja Smith
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | | | | | - Ed Johnson
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | - Jeff Goldy
- Allen Institute for Brain Science, Seattle, WA 98109, USA
| | - Hamid Bolouri
- Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
| | - Jane H Buckner
- Center for Translational Research, Benaroya Research Institute, Seattle, WA 98101, USA
| | - Paul Meijer
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | | | - Peter J Skene
- Allen Institute for Immunology, Seattle, WA 98109, USA
| | | | - Xiao-Jun Li
- Allen Institute for Immunology, Seattle, WA 98109, USA
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Lv Y, Xiang Q, Lin J, Jin YZ, Fang Y, Cai HM, Wei QD, Wang H, Wang C, Chen J, Ye J, Xie C, Li TL, Wu YJ. There is no dose-response relationship between allogeneic blood transfusion and healthcare-associated infection: a retrospective cohort study. Antimicrob Resist Infect Control 2021; 10:62. [PMID: 33781329 PMCID: PMC8008558 DOI: 10.1186/s13756-021-00928-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/11/2021] [Indexed: 01/28/2023] Open
Abstract
Background The association between allogeneic blood transfusion and healthcare-associated infection (HAI) is considered dose-dependent. However, this association may be confounded by transfusion duration, as prolonged hospitalization stay increases the risk of HAI. Also, it is not clear whether specific blood products have different dose–response risks. Methods In this retrospective cohort study, a logistic regression was used to identify confounding factors, and the association between specific blood products and HAI were analyzed. Then Cox regression and restricted cubic spline regression was used to visualize the hazard of HAI per transfusion product. Results Of 215,338 inpatients observed, 4.16% were transfused with a single component blood product. With regard to these transfused patients, 480 patients (5.36%) developed a HAI during their hospitalization stay. Logistic regression showed that red blood cells (RBCs) transfusion, platelets transfusion and fresh-frozen plasmas (FFPs) transfusion were risk factors for HAI [odds ratio (OR) 1.893, 95% confidence interval (CI) 1.656–2.163; OR 8.903, 95% CI 6.646–11.926 and OR 1.494, 95% CI 1.146–1.949, respectively]. However, restricted cubic spline regression analysis showed that there was no statistically dose–response relationship between different transfusion products and the onset of HAI. Conclusions RBCs transfusion, platelets transfusion and FFPs transfusion were associated with HAI, but there was no dose–response relationship between them.
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Affiliation(s)
- Yu Lv
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China.
| | - Qian Xiang
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Jia Lin
- Blood Transfusion Department, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Ying Z Jin
- Healthcare-Associated Infections Control Center, Hospital (T.C.M) Affiliated to Southwest Medical University, LuZhou, Sichuan, People's Republic of China
| | - Ying Fang
- Department of Nursing, Jianyang People's Hospital, Jianyang, 641400, Sichuan, People's Republic of China
| | - Hong M Cai
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Qiong D Wei
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Hui Wang
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Chen Wang
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China.
| | - Jing Chen
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Jian Ye
- Nosocomial Infection Management Department, Affiliated Hospital of Sichuan Nursing Vocational College, Chengdu, 610000, Sichuan, People's Republic of China
| | - Caixia Xie
- Department of Nursing, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China
| | - Ting L Li
- Development Department, Chengdu Yiou Technology Co. LTD, Chengdu, 610000, Sichuan, People's Republic of China
| | - Yu J Wu
- Healthcare-Associated Infection Management Office, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, 610072, Sichuan, People's Republic of China.
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Guo K, Ma S. The Immune System in Transfusion-Related Acute Lung Injury Prevention and Therapy: Update and Perspective. Front Mol Biosci 2021; 8:639976. [PMID: 33842545 PMCID: PMC8024523 DOI: 10.3389/fmolb.2021.639976] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/05/2021] [Indexed: 12/14/2022] Open
Abstract
As an initiator of respiratory distress, transfusion-related acute lung injury (TRALI) is regarded as one of the rare complications associated with transfusion medicine. However, to date, the pathogenesis of TRALI is still unclear, and specific therapies are unavailable. Understanding the mechanisms of TRALI may promote the design of preventive and therapeutic strategies. The immune system plays vital roles in reproduction, development and homeostasis. Sterile tissue damage, such as physical trauma, ischemia, or reperfusion injury, induces an inflammatory reaction that results in wound healing and regenerative mechanisms. In other words, in addition to protecting against pathogens, the immune response may be strongly associated with TRALI prevention and treatment through a variety of immunomodulatory strategies to inhibit excessive immune system activation. Immunotherapy based on immune cells or immunological targets may eradicate complications. For example, IL-10 therapy is a promising therapeutic strategy to explore further. This review will focus on ultramodern advances in our understanding of the potential role of the immune system in TRALI prevention and treatment.
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Affiliation(s)
- Kai Guo
- Department of Transfusion Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Shuxuan Ma
- Department of Transfusion Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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Bedside Allogeneic Erythrocyte Washing with a Cell Saver to Remove Cytokines, Chemokines, and Cell-derived Microvesicles. Anesthesiology 2021; 134:395-404. [PMID: 33503656 DOI: 10.1097/aln.0000000000003689] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Removal of cytokines, chemokines, and microvesicles from the supernatant of allogeneic erythrocytes may help mitigate adverse transfusion reactions. Blood bank-based washing procedures present logistical difficulties; therefore, we tested the hypothesis that on-demand bedside washing of allogeneic erythrocyte units is capable of removing soluble factors and is feasible in a clinical setting. METHODS There were in vitro and prospective, observation cohort components to this a priori planned substudy evaluating bedside allogeneic erythrocyte washing, with a cell saver, during cardiac surgery. Laboratory data were collected from the first 75 washed units given to a subset of patients nested in the intervention arm of a parent clinical trial. Paired pre- and postwash samples from the blood unit bags were centrifuged. The supernatant was aspirated and frozen at -70°C, then batch-tested for cell-derived microvesicles, soluble CD40 ligand, chemokine ligand 5, and neutral lipids (all previously associated with transfusion reactions) and cell-free hemoglobin (possibly increased by washing). From the entire cohort randomized to the intervention arm of the trial, bedside washing was defined as feasible if at least 75% of prescribed units were washed per protocol. RESULTS Paired data were available for 74 units. Washing reduced soluble CD40 ligand (median [interquartile range]; from 143 [1 to 338] ng/ml to zero), chemokine ligand 5 (from 1,314 [715 to 2,551] to 305 [179 to 488] ng/ml), and microvesicle numbers (from 6.90 [4.10 to 20.0] to 0.83 [0.33 to 2.80] × 106), while cell-free hemoglobin concentration increased from 72.6 (53.6 to 171.6) mg/dl to 210.5 (126.6 to 479.6) mg/dl (P < 0.0001 for each). There was no effect on neutral lipids. Bedside washing was determined as feasible for 80 of 81 patients (99%); overall, 293 of 314 (93%) units were washed per protocol. CONCLUSIONS Bedside erythrocyte washing was clinically feasible and greatly reduced concentrations of soluble factors thought to be associated with transfusion-related adverse reactions, increasing concentrations of cell-free hemoglobin while maintaining acceptable (less than 0.8%) hemolysis. EDITOR’S PERSPECTIVE
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Abstract
Sepsis is a life-threatening syndrome with a high incidence and a weighty economic burden. The cytokines storm in the early stage and the state of immunosuppression in the late stage contribute to the mortality of sepsis. Immune checkpoints expressed on lymphocytes and APCs, including CD28, CTLA-4, CD80, CD86, PD-1 and PD-L1, CD40 and CD40L, OX40 and OX40L, 4-1BB and 4-1BBL, BTLA, TIM family, play significant roles in the pathogenesis of sepsis through regulating the immune disorder. The specific therapies targeting immune checkpoints exhibit great potentials in the animal and preclinical studies, and further clinical trials are planning to implement. Here, we review the current literature on the roles played by immune checkpoints in the pathogenesis and treatment of sepsis. We hope to provide further insights into this novel immunomodulatory strategy.
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Affiliation(s)
- Yan-Cun Liu
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Song-Tao Shou
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Yan-Fen Chai
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
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Wood B, Padula MP, Marks DC, Johnson L. The immune potential of ex vivo stored platelets: a review. Vox Sang 2020; 116:477-488. [PMID: 33326606 DOI: 10.1111/vox.13058] [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: 09/18/2020] [Revised: 11/14/2020] [Accepted: 12/02/2020] [Indexed: 11/30/2022]
Abstract
Platelets are now acknowledged as key regulators of the immune system, as they are capable of mediating inflammation, leucocyte recruitment and activation. This activity is facilitated through platelet activation, which induces significant changes in the surface receptor profile and triggers the release of a range of soluble biological response modifiers (BRMs). In the field of transfusion medicine, the immune function of platelets has gained considerable attention as this may be linked to the development of adverse transfusion reactions. Further, component manufacturing and storage methodologies may impact the immunoregulatory role of platelets, and an understanding of this impact is crucial and should be considered alongside their haemostatic characteristics. This review highlights the key interactions between platelets and traditional immune modulators. Further, the potential impact of current and novel component storage methodologies, such as refrigeration and cryopreservation, on this functional capacity is examined, highlighting why further knowledge in this area would be of benefit.
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Affiliation(s)
- Ben Wood
- Research & Development, Australian Red Cross Lifeblood, Alexandria, NSW, Australia.,School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia
| | - Matthew P Padula
- School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia
| | - Denese C Marks
- Research & Development, Australian Red Cross Lifeblood, Alexandria, NSW, Australia.,Sydney Medical School, The University of Sydney, Camperdown, NSW, Australia
| | - Lacey Johnson
- Research & Development, Australian Red Cross Lifeblood, Alexandria, NSW, Australia
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Maouia A, Rebetz J, Kapur R, Semple JW. The Immune Nature of Platelets Revisited. Transfus Med Rev 2020; 34:209-220. [PMID: 33051111 PMCID: PMC7501063 DOI: 10.1016/j.tmrv.2020.09.005] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 01/08/2023]
Abstract
Platelets are the primary cellular mediators of hemostasis and this function firmly acquaints them with a variety of inflammatory processes. For example, platelets can act as circulating sentinels by expressing Toll-like receptors (TLR) that bind pathogens and this allows platelets to effectively kill them or present them to cells of the immune system. Furthermore, activated platelets secrete and express many pro- and anti-inflammatory molecules that attract and capture circulating leukocytes and direct them to inflamed tissues. In addition, platelets can directly influence adaptive immune responses via secretion of, for example, CD40 and CD40L molecules. Platelets are also the source of most of the microvesicles in the circulation and these miniscule elements further enhance the platelet’s ability to communicate with the immune system. More recently, it has been demonstrated that platelets and their parent cells, the megakaryocytes (MK), can also uptake, process and present both foreign and self-antigens to CD8+ T-cells conferring on them the ability to directly alter adaptive immune responses. This review will highlight several of the non-hemostatic attributes of platelets that clearly and rightfully place them as integral players in immune reactions.
Platelets can act as circulating sentinels by expressing pathogen-associated molecular pattern receptors that bind pathogens and induce their killing and elimination. Activated platelets secrete and express a multitude of pro- and anti-inflammatory molecules that attract and capture circulating leukocytes and direct them to inflamed tissues. Platelets express and secrete many critical immunoregulatory molecules that significantly affect both innate and adaptive immune responses. Platelets are the primary source of microparticles in the circulation and these augment the platelet’s ability to communicate with the immune system. Platelets and megakaryocytes can act as antigen presenting cells and present both foreign- and self-peptides to T-cells.
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Affiliation(s)
- Amal Maouia
- Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden
| | - Johan Rebetz
- Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden
| | - Rick Kapur
- Sanquin Research, Department of Experimental Immunohematology, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - John W Semple
- Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden; Clinical Immunology and Transfusion Medicine, Office of Medical Services, Region Skåne, Lund, Sweden.
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Protective effects of plasma products on the endothelial-glycocalyx barrier following trauma-hemorrhagic shock: Is sphingosine-1 phosphate responsible? J Trauma Acute Care Surg 2020; 87:1061-1069. [PMID: 31453986 DOI: 10.1097/ta.0000000000002446] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Plasma is an important component of resuscitation after trauma and hemorrhagic shock (T/HS). The specific plasma proteins and the impact of storage conditions are uncertain. Utilizing a microfluidic device system, we studied the effect of various types of plasma on the endothelial barrier function following T/HS. METHODS Human umbilical vein endothelial cells (HUVEC) were cultured in microfluidic plates. The microfluidic plates were subjected to control or shock conditions (hypoxia/reoxygenation + epinephrine, 10 μM). Fresh plasma, 1 day thawed plasma, 5-day thawed plasma and lyophilized plasma were then added. Supplementation of sphingosine-1 phosphate (S-1P) was done in a subset of experiments. Effect on the endothelial glycocalyx was indexed by shedding of syndecan-1 and hyaluronic acid. Endothelial injury/activation was indexed by soluble thrombomodulin, tissue plasminogen activator, plasminogen activator inhibitor-1. Vascular permeability determined by the ratio of angiopoietin-2 to angiopoietin-1. Concentration of S-1P and adiponectin in the different plasma groups was measured. RESULTS Human umbilical vein endothelial cells exposed to shock conditions increased shedding of syndecan-1 and hyaluronic acid. Administration of the various types of plasma decreased shedding, except for 5-day thawed plasma. Shocked HUVEC cells demonstrated a profibrinolytic phenotype, this normalized with all plasma types except for 5-day thawed plasma. The concentration of S-1P was significantly less in the 5-day thawed plasma compared with the other plasma types. Addition of S-1P to 5-day thawed plasma returned the benefits lost with storage. CONCLUSION A biomimetic model of the microcirculation following T/HS demonstrated endothelial glycocalyx and endothelial cellular injury/activation as well as a profibrinolytic phenotype. These effects were abrogated by all plasma products except the 5-day thawed plasma. Plasma thawed longer than 5 days had diminished S1-P concentrations. Our data suggest that S1-P protein is critical to the protective effect of plasma products on the endothelial-glycocalyx barrier following T/HS.
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Page MJ, Pretorius E. A Champion of Host Defense: A Generic Large-Scale Cause for Platelet Dysfunction and Depletion in Infection. Semin Thromb Hemost 2020; 46:302-319. [PMID: 32279287 PMCID: PMC7339151 DOI: 10.1055/s-0040-1708827] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Thrombocytopenia is commonly associated with sepsis and infections, which in turn are characterized by a profound immune reaction to the invading pathogen. Platelets are one of the cellular entities that exert considerable immune, antibacterial, and antiviral actions, and are therefore active participants in the host response. Platelets are sensitive to surrounding inflammatory stimuli and contribute to the immune response by multiple mechanisms, including endowing the endothelium with a proinflammatory phenotype, enhancing and amplifying leukocyte recruitment and inflammation, promoting the effector functions of immune cells, and ensuring an optimal adaptive immune response. During infection, pathogens and their products influence the platelet response and can even be toxic. However, platelets are able to sense and engage bacteria and viruses to assist in their removal and destruction. Platelets greatly contribute to host defense by multiple mechanisms, including forming immune complexes and aggregates, shedding their granular content, and internalizing pathogens and subsequently being marked for removal. These processes, and the nature of platelet function in general, cause the platelet to be irreversibly consumed in the execution of its duty. An exaggerated systemic inflammatory response to infection can drive platelet dysfunction, where platelets are inappropriately activated and face immunological destruction. While thrombocytopenia may arise by condition-specific mechanisms that cause an imbalance between platelet production and removal, this review evaluates a generic large-scale mechanism for platelet depletion as a repercussion of its involvement at the nexus of responses to infection.
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Affiliation(s)
- Martin J Page
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Etheresia Pretorius
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
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