Abstract Number: OC 03.2
Meeting: ISTH 2021 Congress
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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