OC 22.2 - Endothelial activation and von Willebrand Factor role in COVID-19-associated coagulopathy.

Sunday, June 25, 2023

15:00 – 15:15 ET

Room: 515

Session Available As: On-Demand

Presenting Author(s)

Roberto Aiolfi, PhD

Staff Scientist
The Scripps Research Institute
La Jolla, California, United States

Co-Author(s)

HD

Hiroshi Deguchi

Staff Scientist
The Scripps Research Institute
La Jolla, California, United States
JF

José A Fernández

MD Phd
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA
San Diego, California, United States
JA

Jeanine Ahmed

Technician
The Scripps Research Institute
La Jolla, California, United States
MH

Miriam Hauer-Jensen

Student
The Scripps Research Institute
La Jolla, California, United States
SK

Sachiko Kanaji

Staff Scientist
The Scripps Research Institute
La Jolla, California, United States
ZR

Zaverio Ruggeri

Emeritus Professor
The Scripps Research Institute
La Jolla, California, United States
Jd

Juan Carlos de la Torre

Professor
The Scripps Research Institute
La Jolla, California, United States
Laurent O. Mosnier, PhD

Professor
Scripps Research
La Jolla, California, United States

Background: COVID-19-associated coagulopathy (CAC), involving complex interactions between a hyperactive immune response, vascular endothelial cell dysfunction, and a state of hypercoagulability, is associated with thrombosis and death. SARS-CoV-2 infected lung tissue releases inflammatory cytokines including interleukin-8 and TNF-α that stimulate von Willebrand Factor (VWF) release from vascular endothelial cells, potentially contributing to hypercoagulability and CAC.

Aims: To characterize the role of VWF in the pathogenesis of SARS-CoV-2 infection in a mouse model of COVID-19.

Methods: Human angiotensin-converting enzyme 2 (hACE2) transgenic mice (K18-hACE2) and VWF-deficient K18-hACE2 mice were intranasally infected with 2.5 x 103 FFU of SARS-CoV-2 (USA WA1/2020 strain) and followed for general health outcome, mortality, and plasma biomarkers associated with severe disease in humans.

Results: SARS-CoV-2 infection of K18-hACE2 mice recapitulated many of the CAC-associated findings observed in human patients, including increased plasma concentration of D-Dimers, soluble thrombomodulin, and VWF. The low viral dose used in our study prolongs the symptomatic phase of the infection, highlighting an increased susceptibility of male mice to severe infection showing increased mortality associated with increased weight loss and reduced body temperature. Histological analysis of the lungs showed the presence of foci of fibrin deposition associated with areas of leukocyte infiltration. Heterozygous deletion of VWF in K18-hACE2 mice resulted in reduced severity of the disease in males bringing the mortality to the level observed in females (male: VWF+/- 35% vs. control 69%; female: VWF+/- 25% vs. control 22%). On the contrary, a complete VWF deletion worsened disease outcomes in both sexes (male: VWF-/- 70%; female: VWF-/- 79%) due to the appearance of secondary bacterial infections (VWF+/+ 3%, VWF+/- 23%, VWF-/- 49%).

Conclusion(s): During SARS-CoV-2 infection, VWF levels must be tightly balanced to ensure protection from opportunistic infections while avoiding the generation of a deleterious procoagulant microenvironment.

Learning Objectives:

Upon completion, the participant will be able to understand the multifactorial aspects of COVID-19-associated coagulopathy in K18-hACE2 transgenic mice.
Upon completion, the participant will be able to understand the pathophysiological role of von Willebrand Factor (VWF) and platelet GPIbα during severe respiratory infections.
Upon completion, the participant will be able to learn the molecular mechanisms responsible for the sex difference in disease severity upon SARS-CoV-2.