Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia
Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious complication of the ChAdOx1 nCOV-19 vaccine. In Australia, the diagnosis of VITT required the detection of antibodies against platelet factor 4 (PF4) in plasma using a PF4/polyanion enzyme-linked immunosorbent...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925001648 |
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| author | Alexander Dupuy Xiaoming Liu Yvonne Kong Miao Qi Jose Perdomo Jemma Fenwick Jessica Tieng Bede Johnston Qiyu Sara Shi Mark Larance Yingqi Zhang Lining Arnold Ju Paul Coleman Jennifer Gamble Elizabeth E. Gardiner Mortimer Poncz Huyen Tran Vivien Chen Freda H. Passam |
| author_facet | Alexander Dupuy Xiaoming Liu Yvonne Kong Miao Qi Jose Perdomo Jemma Fenwick Jessica Tieng Bede Johnston Qiyu Sara Shi Mark Larance Yingqi Zhang Lining Arnold Ju Paul Coleman Jennifer Gamble Elizabeth E. Gardiner Mortimer Poncz Huyen Tran Vivien Chen Freda H. Passam |
| author_sort | Alexander Dupuy |
| collection | DOAJ |
| description | Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious complication of the ChAdOx1 nCOV-19 vaccine. In Australia, the diagnosis of VITT required the detection of antibodies against platelet factor 4 (PF4) in plasma using a PF4/polyanion enzyme-linked immunosorbent assay (ELISA). Half of the patients who fulfilled the clinical criteria for VITT tested positive when using this ELISA and another third tested positive when using platelet activation assays, highlighting limitations in the assays used for VITT. Using a microfluidic device coated with endothelial cells, the Endo-chip, we measured the effects of serum and immunoglobulin G (IgG) from patients with clinical VITT on endothelial thromboinflammation. Our cohort comprised 40 patients (21 ELISA-positive and 19 ELISA-negative patients as measured by PF4/polyanion ELISA), 12 vaccinated patients with venous thromboembolism without VITT, and 17 individuals who received the ChAdOx1 vaccine without adverse events (vax controls). Treatment with VITT serum, plasma, or IgG increased endothelial tissue factor (TF) expression and activity. Perfusion of blood from healthy donors labelled with fluorescent antibodies against platelets, neutrophils, and fibrin through Endo-chips treated with VITT serum or IgG induced a twofold to threefold increase in platelet, neutrophil, and fibrin deposition. Thromboinflammation was enhanced with addition of PF4 and reduced with an inhibitory antibody against TF. We conclude that endothelial activation contributes to thromboinflammation in patients with clinical features of VITT. The Endo-chip offers a platform for the study of endothelial responses in immune thrombosis. |
| format | Article |
| id | doaj-art-d2ff106cd3a14dc28cac2ca655bf2974 |
| institution | DOAJ |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-d2ff106cd3a14dc28cac2ca655bf29742025-08-20T03:11:26ZengElsevierBlood Advances2473-95292025-06-019122891290610.1182/bloodadvances.2024014165Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopeniaAlexander Dupuy0Xiaoming Liu1Yvonne Kong2Miao Qi3Jose Perdomo4Jemma Fenwick5Jessica Tieng6Bede Johnston7Qiyu Sara Shi8Mark Larance9Yingqi Zhang10Lining Arnold Ju11Paul Coleman12Jennifer Gamble13Elizabeth E. Gardiner14Mortimer Poncz15Huyen Tran16Vivien Chen17Freda H. Passam18Haematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Heart Research Institute, Sydney, Australia; Sydney Nano Institute (Sydney Nano), The University of Sydney, Sydney, Australia; School of Biomedical Engineering, The University of Sydney, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Heart Research Institute, Sydney, Australia; Sydney Nano Institute (Sydney Nano), The University of Sydney, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Heart Research Institute, Sydney, Australia; Sydney Nano Institute (Sydney Nano), The University of Sydney, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Centenary Institute, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Heart Research Institute, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, AustraliaSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, AustraliaSydney Nano Institute (Sydney Nano), The University of Sydney, Sydney, Australia; School of Biomedical Engineering, The University of Sydney, Sydney, AustraliaHeart Research Institute, Sydney, Australia; Sydney Nano Institute (Sydney Nano), The University of Sydney, Sydney, Australia; School of Biomedical Engineering, The University of Sydney, Sydney, AustraliaCentenary Institute, Sydney, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, AustraliaCentenary Institute, Sydney, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, AustraliaDivision of Genome Science and Cancer, The John Curtin School of Medical Research, Australian National University Canberra, Canberra, AustraliaDepartment of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PADepartment of Clinical Haematology, The Alfred Hospital, Melbourne, Australia; Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, AustraliaDepartment of Haematology, Concord Repatriation General Hospital, Sydney, Australia; ANZAC Research Institute, The University of Sydney, Sydney, AustraliaHaematology Research Group, Charles Perkins Centre, The University of Sydney, Sydney, Australia; Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Heart Research Institute, Sydney, Australia; Sydney Nano Institute (Sydney Nano), The University of Sydney, Sydney, Australia; Correspondence: Freda H. Passam, Haematology Research Lab, Charles Perkins Centre, The University of Sydney, Room 3116, Level 3E, John Hopkins Dr, Camperdown, Sydney, NSW 2050, Australia;Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious complication of the ChAdOx1 nCOV-19 vaccine. In Australia, the diagnosis of VITT required the detection of antibodies against platelet factor 4 (PF4) in plasma using a PF4/polyanion enzyme-linked immunosorbent assay (ELISA). Half of the patients who fulfilled the clinical criteria for VITT tested positive when using this ELISA and another third tested positive when using platelet activation assays, highlighting limitations in the assays used for VITT. Using a microfluidic device coated with endothelial cells, the Endo-chip, we measured the effects of serum and immunoglobulin G (IgG) from patients with clinical VITT on endothelial thromboinflammation. Our cohort comprised 40 patients (21 ELISA-positive and 19 ELISA-negative patients as measured by PF4/polyanion ELISA), 12 vaccinated patients with venous thromboembolism without VITT, and 17 individuals who received the ChAdOx1 vaccine without adverse events (vax controls). Treatment with VITT serum, plasma, or IgG increased endothelial tissue factor (TF) expression and activity. Perfusion of blood from healthy donors labelled with fluorescent antibodies against platelets, neutrophils, and fibrin through Endo-chips treated with VITT serum or IgG induced a twofold to threefold increase in platelet, neutrophil, and fibrin deposition. Thromboinflammation was enhanced with addition of PF4 and reduced with an inhibitory antibody against TF. We conclude that endothelial activation contributes to thromboinflammation in patients with clinical features of VITT. The Endo-chip offers a platform for the study of endothelial responses in immune thrombosis.http://www.sciencedirect.com/science/article/pii/S2473952925001648 |
| spellingShingle | Alexander Dupuy Xiaoming Liu Yvonne Kong Miao Qi Jose Perdomo Jemma Fenwick Jessica Tieng Bede Johnston Qiyu Sara Shi Mark Larance Yingqi Zhang Lining Arnold Ju Paul Coleman Jennifer Gamble Elizabeth E. Gardiner Mortimer Poncz Huyen Tran Vivien Chen Freda H. Passam Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia Blood Advances |
| title | Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia |
| title_full | Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia |
| title_fullStr | Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia |
| title_full_unstemmed | Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia |
| title_short | Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia |
| title_sort | endothelial cell activation enhances thromboinflammation in vaccine induced immune thrombotic thrombocytopenia |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925001648 |
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