Damage-associated cellular markers in the clinical and pathogenic profile of Vaccine-induced Immune Thrombotic Thrombocytopenia

Simon Abrams; Min Du; Rebecca J. Shaw; Carla Johnson; Dagmara McGiuiness; Jeremy Schofield; Jun Yong; Lance Turtle; Pip Nicolson; Christopher Moxon; Guozheng Wang; Cheng-Hock Toh

doi:10.1016/j.jtha.2023.12.008

Damage-associated cellular markers in the clinical and pathogenic profile of Vaccine-induced Immune Thrombotic Thrombocytopenia

Simon Abrams, Min Du, Rebecca J. Shaw, Carla Johnson, Dagmara McGiuiness, Jeremy Schofield, Jun Yong, Lance Turtle, Pip Nicolson, Christopher Moxon, Guozheng Wang^*, Cheng-Hock Toh^*

^*Corresponding author for this work

Cardiovascular Sciences

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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.

Original language	English
Journal	Journal of Thrombosis and Haemostasis
Early online date	15 Dec 2023
DOIs	https://doi.org/10.1016/j.jtha.2023.12.008
Publication status	E-pub ahead of print - 15 Dec 2023

Bibliographical note

Acknowledgments
The 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).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Understanding Mechanisms of Thrombosis and Thrombocytopenia in COVID-19 and with SARS-CoV-2 Vaccines
Nicolson, P. & Watson, S.
NIHR
1/07/21 → 28/02/23
Project: Other Government Departments

Cite this

Abrams, S., Du, M., Shaw, R. J., Johnson, C., McGiuiness, D., Schofield, J., Yong, J., Turtle, L., Nicolson, P., Moxon, C., Wang, G., & Toh, C.-H. (2023). Damage-associated cellular markers in the clinical and pathogenic profile of Vaccine-induced Immune Thrombotic Thrombocytopenia. Journal of Thrombosis and Haemostasis. Advance online publication. https://doi.org/10.1016/j.jtha.2023.12.008

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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.",

keywords = "Vaccine-induced immune thrombocytopaenia and thrombosis (VITT), lactate dehydrogenase, circulating histones, neutrophil extracellular traps (NETs), disseminated intravascular coagulation (DIC).",

author = "Simon Abrams and Min Du and Shaw, {Rebecca J.} and Carla Johnson and Dagmara McGiuiness and Jeremy Schofield and Jun Yong and Lance Turtle and Pip Nicolson and Christopher Moxon and Guozheng Wang and Cheng-Hock Toh",

note = "Acknowledgments The 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.",

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T1 - Damage-associated cellular markers in the clinical and pathogenic profile of Vaccine-induced Immune Thrombotic Thrombocytopenia

AU - Abrams, Simon

AU - Du, Min

AU - Shaw, Rebecca J.

AU - Johnson, Carla

AU - McGiuiness, Dagmara

AU - Schofield, Jeremy

AU - Yong, Jun

AU - Turtle, Lance

AU - Nicolson, Pip

AU - Moxon, Christopher

AU - Wang, Guozheng

AU - Toh, Cheng-Hock

N1 - Acknowledgments The 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.

PY - 2023/12/15

Y1 - 2023/12/15

N2 - 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.

AB - 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.

KW - Vaccine-induced immune thrombocytopaenia and thrombosis (VITT)

KW - lactate dehydrogenase

KW - circulating histones

KW - neutrophil extracellular traps (NETs)

KW - disseminated intravascular coagulation (DIC).

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U2 - 10.1016/j.jtha.2023.12.008

DO - 10.1016/j.jtha.2023.12.008

M3 - Article

SN - 1538-7933

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

ER -

Damage-associated cellular markers in the clinical and pathogenic profile of Vaccine-induced Immune Thrombotic Thrombocytopenia

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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Projects

Understanding Mechanisms of Thrombosis and Thrombocytopenia in COVID-19 and with SARS-CoV-2 Vaccines

Cite this