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Abstract
Background: Adenoviral vector-based COVID19 vaccine-induced immune thrombotic thrombocytopaenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood.
Objectives: To explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT.
Methods: Twenty-two hospitalised VITT patients, 9 pre- and 21 post-ChAdOx1 vaccine controls were recruited across England, UK. Admission blood samples were analysed for cytokine profiles, cell death markers, including lactate dehydrogenase (LDH) and circulating histones, neutrophil extracellular traps (NETs), as well as coagulation parameters. Tissue specimens from deceased patients were analysed.
Results: There were strong immune responses, characterised by significant elevations in proinflammatory cytokines and T-helper-1 and -2 cell activation in VITT patients. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n=15/22) of patients met the ISTH criteria for disseminated intravascular coagulation (DIC) in spite of negligible changes in the prothrombin time. The increased NETs formation in conjunction with marked lymphopenia, elevated LDH and circulating histone levels indicate systemic immune cell injury or death.
Both lymphopenia and circulating histone levels independently predicted 28-day mortality in VITT patients.
Conclusions: The coupling of systemic cell damage and death with strong immune inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.
Objectives: To explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT.
Methods: Twenty-two hospitalised VITT patients, 9 pre- and 21 post-ChAdOx1 vaccine controls were recruited across England, UK. Admission blood samples were analysed for cytokine profiles, cell death markers, including lactate dehydrogenase (LDH) and circulating histones, neutrophil extracellular traps (NETs), as well as coagulation parameters. Tissue specimens from deceased patients were analysed.
Results: There were strong immune responses, characterised by significant elevations in proinflammatory cytokines and T-helper-1 and -2 cell activation in VITT patients. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n=15/22) of patients met the ISTH criteria for disseminated intravascular coagulation (DIC) in spite of negligible changes in the prothrombin time. The increased NETs formation in conjunction with marked lymphopenia, elevated LDH and circulating histone levels indicate systemic immune cell injury or death.
Both lymphopenia and circulating histone levels independently predicted 28-day mortality in VITT patients.
Conclusions: The coupling of systemic cell damage and death with strong immune inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.
Original language | English |
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Journal | Journal of Thrombosis and Haemostasis |
Early online date | 15 Dec 2023 |
DOIs | |
Publication status | E-pub ahead of print - 15 Dec 2023 |
Bibliographical note
AcknowledgmentsThe authors thank all the patients, their families, and staff involved in this study. We would also like to thank Samantha Montague and Steve Watson for their constructive discussions, along with Sarah Cross, Ines Ushiro-Lumb, and John Forsythe for access to VITT patient samples.
This study is funded by the Liverpool University Hospitals National Health Service (NHS) Foundation Trust and the Department of Health and Social Care and is supported by the National Institute for Health Research (NIHR135073). The views expressed are those of the authors and not necessarily those of the Liverpool University Hospitals NHS Foundation Trust, National Institute for Health Research, or the Department of Health and Social Care.
Keywords
- Vaccine-induced immune thrombocytopaenia and thrombosis (VITT)
- lactate dehydrogenase
- circulating histones
- neutrophil extracellular traps (NETs)
- disseminated intravascular coagulation (DIC).
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- 1 Finished
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Understanding Mechanisms of Thrombosis and Thrombocytopenia in COVID-19 and with SARS-CoV-2 Vaccines
1/07/21 → 28/02/23
Project: Other Government Departments