Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia

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.

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Publication Details

Journal
Blood Advances
Published
2025-03-14
DOI
https://doi.org/10.1182/bloodadvances.2024014165
Citations
8
Primary Topic
Platelet Disorders and Treatments
Type
article
Field-Weighted Citation Impact
14.16

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article

Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia

Jemma Fenwick, Mark Larance, Qizhen Shi, Lining Arnold Ju et al.
8 citations
Blood Advances
Platelet Disorders and Treatments
14.16
article

Endothelial cell activation enhances thromboinflammation in vaccine-induced immune thrombotic thrombocytopenia

Jemma Fenwick, Mark Larance, Qizhen Shi, Lining Arnold Ju, Alexander Dupuy, Mortimer Poncz, Vivien Chen, Paul Coleman, Jennifer R. Gamble, Yvonne Kong, Freda Passam, Jessica Tieng, Elizabeth E. Gardiner, José Perdomo, Bede Johnston, Huyen Tran, Yingqi Zhang, Xiaoming Liu, Miao Qi
article en
8 citations

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.

Blood AdvancesVol. 9(12)
Australian National University (AU), The University of Sydney (AU), Children's Hospital of Philadelphia (US), Australian Cancer Research Foundation (AU), Concord Repatriation General Hospital (AU), Centenary Institute (AU), The Heart Research Institute (AU), The Alfred Hospital (AU), Migration Institute of Australia (AU), Anzac Research Institute (AU), Sydney Orthopaedic Research Institute (AU), Monash University (AU), University of Pennsylvania (US)
Oklahoma Medical Research Foundation, Heart Research Institute, National Institutes of Health, Nano Institute, University of Sydney, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Good health and well-being
Openalex Percentile: Top 1%
Platelet Disorders and Treatments
14.16
DOIOpen Access PDFOpenAlex
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