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Unraveling The Pathophysiological Role of Angiostatin in COVID-19

A. Franczak1, M. Joyce2, B. Ritchie3, L. Tyrrel2, P. Jurasz4

1University of Alberta, Edmonton, AB, Canada, Edmonton, Alberta, Canada, 2Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, Edmonton, Alberta, Canada, 3Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, Edmonton, Alberta, Canada, 4Department of Pharmacology, Faculty of Medicine and Dentistry / Cardiovascular Research Centre / Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada

Abstract Number: VPB0613

Meeting: ISTH 2022 Congress

Theme: COVID and Coagulation » COVID and Coagulation, Basic Science

Background: Angiostatin is a break-down product of plasmin(ogen). Physiologically, angiostatin is generated by platelets in an urokinase (uPA)-dependent manner. During normoxia angiostatin has anti-angiogenic/anti-inflammatory effects and protects against lung injury, however during hypoxia/acidosis it is pro-apoptotic. In SARS-CoV infected mice, the uPA-plasminogen pathway was shown to be the most transcriptionally enriched regulating sublethal vs. lethal infection. Similarly, uPA has been shown to be transcriptionally upregulated in SARS-CoV-2; however, the role of angiostatin has not been investigated.

Aims: To assess role of angiostatin in COVID-19.

Methods: Plasma samples from COVID-negative controls and from hospitalized COVID-19 patients (n=30) were collected (day 1, 7, 14, 28, 70) via the COVID-19 Surveillance Collaboration study. WHO clinical progression scale was used to assess COVID-19 severity. Angiostatin and plasminogen were quantified by immunoblot. VeroE6 cells were infected with SARS-CoV-2 and treated with angiostatin (140 μg/ml) for 24h at pH 7.5 or 6.9. Cell death was quantified by both TUNEL and the percentage of detached cells. Immunofluorescent staining against the spike protein was used to confirm cellular infection.

Results: Plasma angiostatin level was elevated in COVID-19 patients compared to COVID-negative controls at baseline. Both angiostatin and plasminogen increased with time of hospitalization in patients with severe COVID-19, but not with mild-to-moderate disease (p=0.05; Fig.1). In preliminary cell culture experiments, at pH=7.5 angiostatin decreased the percentage of detached (26±8% vs 67±5%; p=0.0004) and TUNEL-positive VeroE6 (6±6 vs 11±7%; p=0.07) following infection. Conversely, at pH=6.9 angiostatin increased the percentage of detached cells following infection. Interestingly, angiostatin lowered the percentage of spike protein-positive Vero E6 at both pH (Fig.2).

Conclusion(s): Angiostatin concentrations increase with disease progression in severe COVID-19. This likely reflects angiostatin’s complex role in COVID-19 pathophysiology. Angiostatin promotes cell death in acidotic microenvironments (associated with severe Covid-19). Conversely, at physiological pH, angiostatin may have protective effects possibly by reducing viral entry and/or replication.

Figure 1

Plasma angiostatin concentration in Covid-19 patients with A- mild-to-moderate disease and B- severe disease over the time of hospitalization.

Figure 2

Fluorescent microscopy of SARS-CoV-2-infected VeroE6 cells with and without angiostatin treatment in pH 7.5 and pH 6.9.

To cite this abstract in AMA style:

Franczak A, Joyce M, Ritchie B, Tyrrel L, Jurasz P. Unraveling The Pathophysiological Role of Angiostatin in COVID-19 [abstract]. https://abstracts.isth.org/abstract/unraveling-the-pathophysiological-role-of-angiostatin-in-covid-19/. Accessed August 16, 2022.

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