PB0605 - COVID-19 disease is associated with a hypofibrinolytic state driven by elevated plasminogen activator inhibitor-1 and its cofactor vitronectin

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Megan Simpson, MSci

PhD Student
University of Aberdeen
Aberdeen, Scotland, United Kingdom

Co-Author(s)

Claire S. Whyte, PhD

Research Fellow
Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen
Aberdeen, Scotland, United Kingdom
Gael B. Morrow, PhD

Postdoctoral Research Fellow
University of Oxford
Aberdeen, Scotland, United Kingdom
CW

Carol A. Wallace

Technician
University of Aberdeen
Aberdeen, Scotland, United Kingdom
AM

Alexander J. Mentzer

Clinical Research Fellow
University of Oxford
Oxford, England, United Kingdom
JK

Julian Knight

Professor of Genomic Medicine
University of Oxford
Oxford, England, United Kingdom
Susan Shapiro, MD, PhD

Consultant Hematologist
Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK
Oxford, England, United Kingdom
Nicola Curry, MD

Consultant Haematologist
Oxford University Hospitals NHS Foundation Trust
Oxford, England, United Kingdom
Catherine N. N. Bagot, Dr MBBS MD

MD, PhD
Department of Haematology, Glasgow Royal Infirmary, Glasgow, United Kingdom
Glasgow, Scotland, United Kingdom
HW

Henry Watson

Emeritus Professor
University of Aberdeen
Aberdeen, Scotland, United Kingdom
JC

Jamie Cooper

Consultant in Emergency Medicine
NHS Grampian
Aberdeen, Scotland, United Kingdom
Nicola J. J. Mutch, PhD

Professor
Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen
Aberdeen, Scotland, United Kingdom

Background: COVID-19 disease arises from infection with severe acute respiratory cornonavirus-2 (SARS-CoV-2). Severe disease is associated with a coagulopathy characterised by elevated D-dimer levels, fibrin deposition in the lung, and a thrombotic incidence of approximately 30%, indicating catastrophic derailment of the haemostatic system.

Aims: To investigate whether SARS-CoV-2-induced coagulopathy arises due to an imbalance in the fibrinolysis.

Methods: Citrated plasma was collected from 139 patients presenting with symptomatic COVID-19, 24 patients with non-COVID-19 respiratory infection and 30 healthy controls in a dual-centre study. Fibrinolytic biomarkers were evaluated including plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), plasminogen, vitronectin and thrombin activatable fibrinolysis inhibitor (TAFI). Furthermore, diagnostic biomarkers including, fibrinogen, C-reactive protein (CRP), D-dimer and inflammatory cytokines were quantified. Clot lysis was evaluated using turbidity assays, plasma clot structure visualised by confocal microscopy and plasmin generation quantified by chromogenic substrate.

Results: PAI-1 antigen, activity, and the cofactor for this serpin, vitronectin, were significantly elevated in patients with COVID-19 compared to healthy controls and non-COVID-19 respiratory infection. Patients with COVID-19 exhibit attenuated plasmin generation compared to healthy volunteers despite significant elevation in tPA. PAI-1 correlated with inflammatory cytokines (IL-1β, IL-8 and TNF-α). In line with this acute phase proteins, fibrinogen and CRP were high in patients with COVID-19 but only CRP was increased compared to non-COVID-19 respiratory infections. Levels of PAI-1 and vitronectin were associated with escalating oxygen support and a corresponding decrease in plasminogen. Importantly, patients with COVID-19 disease exhibit resistance to fibrinolytic degradation by Actilyse®, however, this could be overcome by the PAI-1 resistant form of tPA, Metalyse®.

Conclusion(s): We reveal that COVID-19 disease promotes a hypofibrinolytic state due to elevated PAI-1 and its stabilizing cofactor vitronectin. PAI-1 correlates with inflammatory cytokines and disease severity thereby highlighting its potential prognostic power in the development of severe COVID-19 disease.