PB0184 - Role of Fibrinogen and Plasminogen in the Disease Course of COVID-19

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Kadri Kangro, PhD

Postdoctoral Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States

Co-Author(s)

LG

Lisa E. Gralinski

Assistant professor
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
NA

Nisha Asok Kumar

Postdoctoral Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
KK

Katheryn N. Kapfer

Undergraduate student
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
FF

Francesca Ferraresso

Graduate student
Versiti Blood Research Institute
Milwaukee, Wisconsin, United States
Christian J. Kastrup

Senior Investigator
Versiti Blood Research Institute
Milwaukee, Wisconsin, United States
Alisa S. Wolberg, PhD

Professor
University of North Carolina
Chapel Hill, North Carolina, United States
Matthew Flick

Professor
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States

Background: COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has infected more than half a billion people. Severe COVID-19 is characterized by a dysregulation of coagulation and fibrinolysis, increased fibrinogen expression, fibrin deposition, inflammatory cell activation, and enhanced risk of thrombosis.

Aims: To define the contribution of fibrinogen and plasminogen to acute COVID-19 disease development and progression.

Methods: Female 10-week-old BALB/c mice were injected with lipid nanoparticle-encapsulated siRNA targeting the fibrinogen alpha-chain (siFga), plasminogen (siPlg), or luciferase (siLuc, control) 10 and 1 day before infection with SARS-CoV-2 mouse-adapted virus (MA10) or vehicle (mock infection). Mice were weighed daily, and lung function was determined 2- and 5-days post-infection. Liver and plasma samples for gene expression and plasma protein analyses, respectively, were collected 5 days post-infection.

Results: Similar to patients with COVID-19, MA10-infected siLuc-treated mice became very sick (i.e., 23% weight loss) by day 5, experienced poor lung function, had both increased fibrinogen gene expression and plasma fibrinogen. and highly elevated plasma thrombin generation and plasmin generation potential. Despite the loss of fibrinogen, the siFga-treated mice were not protected from severe disease, as they also had profound (21.5%) weight loss, poor lung function, and slightly elevated thrombin generation potential. Although the siPlg-treated mice also had profound weight loss (19.5%) and poor lung function, these mice displayed normal fibrinogen gene expression and plasma fibrinogen levels, and plasma thrombin generation potential was similar to mock-infected control mice.

Conclusion(s): MA10-infected BALB/c mice show similar characteristics/symptoms of human patients with severe COVID-19, including poor lung function, increased fibrinogen and elevated procoagulant and fibrinolytic activity. Loss of plasminogen, but not fibrinogen, dampens the host’s procoagulant response to infection. These findings suggest plasminogen contributes to the transition from mild to severe COVID-19.