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SARS-CoV-2 Infection of K18-hACE2 Transgenic Mice Induces an Early Hyperactive Phenotype in Circulating Platelets

1Department of Medicine, Boston University, Boston, United States, 2Center for Network Systems Biology, Boston University, Boston, United States, 3National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, United States, 4Department of Microbiology, Boston University, Boston, United States, 5Department of Pathology and Laboratory Medicine, Boston University, Boston, United States, 6Department of Medicine,Boston University, Boston, United States, 7Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, United States

Abstract Number: OC 03.2

Meeting: ISTH 2021 Congress

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

Background: Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state and increased incidence of cardiovascular complications. Platelets are effectors of hemostasis and play a  major role in coordinating immune and inflammatory activities. Suitable animal models are needed to study COVID-19-associated coagulopathy and platelet effector functions in COVID-19, which are currently poorly understood.

Aims: We aimed to characterize alterations of platelets isolated from K18-hACE2 transgenic mice infected with SARS-CoV-2.

Methods: Heterozygous K18-hACE2 (human ACE2) and C57BL/6J mice were used to study SARS-CoV-2 infectivity. Lung infection, infiltration, and platelet aggregation were characterized with histology and immunohistochemistry. Platelet response to SARS-CoV-2 infection was quantified by mass spectrometry analysis of proteome.

Results: SARS-CoV-2 inoculated (106 PFU, i.n.) K18-hACE2 mice started to lose weight at 4 days post-infection(dpi) and showed 90% lethality at 7-dpi in association with viral neuroinvasion. SARS-CoV-2 RNA copies peaked at 4-dpi in K18-hACE2 mouse lungs, but not in C57BL/6J mice, confirming the need for human ACE2 receptor for viral entry. Histopathologic findings of infected K18-hACE2 mice included progressive lymphohistiocytic interstitial pneumonia with absence of diffuse alveolar damage. Lungs and kidneys of infected K18-hACE2 mice (2-/4-dpi) showed mild increase in CD61+ aggregates compared to sham mice, but no overt tissue thrombosis. Gene ontology and pathway analysis of platelet proteome revealed that SARS-CoV-2 infection significantly upregulates the complement-coagulation cascades (F2/12/13, Tfpi, C1ra, Cd55, C4bp) and platelet activation-adhesion-degranulation proteins (Vwf, Itgb3/5, Gp9, Selp, Pecam1) and chemokine (Pf4, Cxcl5/12, Ccl8) signaling at 2-dpi. However, interferon (Ddx58, Trim25, Mapk3) signaling was dominant at 4-dpi. Abundance of SARS-CoV-2 spike protein at 2-/4-dpi in the lungs, but not in the kidneys and platelets of K18-hACE2 mice, suggests that platelet re-programming towards activation-degranulation-aggregation is likely attributable to pneumonia-induced cytokine-driven response rather than direct platelet infection.

Conclusions: Circulating platelets in SARS-CoV-2 infected K18-hACE2 mice demonstrate a specific early hyperactive phenotype consistent with procoagulant platelets.

To cite this abstract in AMA style:

Subramaniam S, Hekman RM, Jayaraman A, O'Connell AK, Montanaro P, Ravid K, A Crossland N, Douam F, Emili A, Bosmann M. SARS-CoV-2 Infection of K18-hACE2 Transgenic Mice Induces an Early Hyperactive Phenotype in Circulating Platelets [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/sars-cov-2-infection-of-k18-hace2-transgenic-mice-induces-an-early-hyperactive-phenotype-in-circulating-platelets/. Accessed November 29, 2023.

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