The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

Claire Whyte; Megan Simpson; Gael B Morrow; Carol Wallace; Alexander J  Mentzer; Julian C. Knight; Susan  Shapiro; Nicola  Curry; Catherine N  Bagot; Catherine N  Bagot; Henry Watson; James Cooper; Nicola Mutch

doi:10.1111/jth.15806

The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

Claire Whyte, Megan Simpson, Gael B Morrow, Carol Wallace, Alexander J Mentzer, Julian C. Knight, Susan Shapiro, Nicola Curry, Catherine N Bagot, Catherine N Bagot, Henry Watson, James Cooper, Nicola Mutch^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background
Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. Here, we investigate whether the haemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system.

Methods
This prospective study analysed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella™ system or ELISA, clot lysis by turbidimetric assay, and PAI-1/plasmin activity using chromogenic substrates. Clot structure was visualised by confocal microscopy.

Results
PAI-1 and its cofactor, vitronectin, are significantly elevated in COVID-19 disease compared to non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in COVID-19 disease relative to healthy controls. PAI-1 and tPA were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fibre length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant tPA variant, Tenecteplase, over Alteplase lysis.

Discussion
We demonstrate that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1 which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the potential to utilise pre-existing drugs, such as Tenecteplase to treat COVID-19 disease and potentially other respiratory diseases.

Original language	English
Journal	Journal of Thrombosis and Haemostasis
Volume	20
Issue number	10
Early online date	3 Jul 2022
DOIs	https://doi.org/10.1111/jth.15806
Publication status	Published - 19 Sep 2022

Keywords

COVID-19
Fibrin
Fibrinolysis
PAI-1
Vitronectin

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Whyte_etal_The_suboptimal_fibrinolytic_VOR
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ © 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.
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Cite this

@article{df006573778741eb97b5e62ba7011f9b,

title = "The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1",

abstract = "BackgroundSevere COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. Here, we investigate whether the haemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system.MethodsThis prospective study analysed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella{\texttrademark} system or ELISA, clot lysis by turbidimetric assay, and PAI-1/plasmin activity using chromogenic substrates. Clot structure was visualised by confocal microscopy.ResultsPAI-1 and its cofactor, vitronectin, are significantly elevated in COVID-19 disease compared to non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in COVID-19 disease relative to healthy controls. PAI-1 and tPA were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fibre length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant tPA variant, Tenecteplase, over Alteplase lysis.DiscussionWe demonstrate that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1 which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the potential to utilise pre-existing drugs, such as Tenecteplase to treat COVID-19 disease and potentially other respiratory diseases.",

keywords = "COVID-19, Fibrin, Fibrinolysis, PAI-1, Vitronectin",

author = "Claire Whyte and Megan Simpson and Morrow, {Gael B} and Carol Wallace and Mentzer, {Alexander J} and Knight, {Julian C.} and Susan Shapiro and Nicola Curry and Bagot, {Catherine N} and Bagot, {Catherine N} and Henry Watson and James Cooper and Nicola Mutch",

note = "Acknowledgements The authors would like to thank all the patients who consented to be part of this study, and all the staff at the Emergency Department of Aberdeen Royal Infirmary NHS Foundation Trust who looked after these patients, and the patients who consented. We thank the NHS Grampian Biorepository staff, Kristine Nellany, Nadine Hay and Joan Wilson for sample collection, processing and anonymisation and collation of clinical data. We acknowledge the Microscopy and Histology Core Facility and Dr Neil Scott from the Institute of Applied Health Sciences at the University of Aberdeen for excellent advice and use of the facilities. Funding This research was supported by NHS Grampian Endowment (COV19-004 and 20/021), Medical Research Scotland (CVG-1721-20), The University of Aberdeen Development Trust (RG15537), Friends of Anchor (RS 2019 003) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. CSW and NJM are supported by the British Heart Foundation (PG/15/82/31721; PG/20/17/35050). JGC is supported by NHS Research Scotland. SS receives funding support from the Medical Research Council (MR/T024054/1).",

year = "2022",

month = sep,

day = "19",

doi = "10.1111/jth.15806",

language = "English",

volume = "20",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Wiley-Blackwell ",

number = "10",

}

TY - JOUR

T1 - The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

AU - Whyte, Claire

AU - Simpson, Megan

AU - Morrow, Gael B

AU - Wallace, Carol

AU - Mentzer, Alexander J

AU - Knight, Julian C.

AU - Shapiro, Susan

AU - Curry, Nicola

AU - Bagot, Catherine N

AU - Watson, Henry

AU - Cooper, James

AU - Mutch, Nicola

N1 - Acknowledgements The authors would like to thank all the patients who consented to be part of this study, and all the staff at the Emergency Department of Aberdeen Royal Infirmary NHS Foundation Trust who looked after these patients, and the patients who consented. We thank the NHS Grampian Biorepository staff, Kristine Nellany, Nadine Hay and Joan Wilson for sample collection, processing and anonymisation and collation of clinical data. We acknowledge the Microscopy and Histology Core Facility and Dr Neil Scott from the Institute of Applied Health Sciences at the University of Aberdeen for excellent advice and use of the facilities. Funding This research was supported by NHS Grampian Endowment (COV19-004 and 20/021), Medical Research Scotland (CVG-1721-20), The University of Aberdeen Development Trust (RG15537), Friends of Anchor (RS 2019 003) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. CSW and NJM are supported by the British Heart Foundation (PG/15/82/31721; PG/20/17/35050). JGC is supported by NHS Research Scotland. SS receives funding support from the Medical Research Council (MR/T024054/1).

PY - 2022/9/19

Y1 - 2022/9/19

N2 - BackgroundSevere COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. Here, we investigate whether the haemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system.MethodsThis prospective study analysed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella™ system or ELISA, clot lysis by turbidimetric assay, and PAI-1/plasmin activity using chromogenic substrates. Clot structure was visualised by confocal microscopy.ResultsPAI-1 and its cofactor, vitronectin, are significantly elevated in COVID-19 disease compared to non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in COVID-19 disease relative to healthy controls. PAI-1 and tPA were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fibre length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant tPA variant, Tenecteplase, over Alteplase lysis.DiscussionWe demonstrate that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1 which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the potential to utilise pre-existing drugs, such as Tenecteplase to treat COVID-19 disease and potentially other respiratory diseases.

AB - BackgroundSevere COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. Here, we investigate whether the haemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system.MethodsThis prospective study analysed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella™ system or ELISA, clot lysis by turbidimetric assay, and PAI-1/plasmin activity using chromogenic substrates. Clot structure was visualised by confocal microscopy.ResultsPAI-1 and its cofactor, vitronectin, are significantly elevated in COVID-19 disease compared to non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in COVID-19 disease relative to healthy controls. PAI-1 and tPA were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fibre length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant tPA variant, Tenecteplase, over Alteplase lysis.DiscussionWe demonstrate that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1 which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the potential to utilise pre-existing drugs, such as Tenecteplase to treat COVID-19 disease and potentially other respiratory diseases.

KW - COVID-19

KW - Fibrin

KW - Fibrinolysis

KW - PAI-1

KW - Vitronectin

U2 - 10.1111/jth.15806

DO - 10.1111/jth.15806

M3 - Article

C2 - 35780481

VL - 20

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 10

ER -

The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

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