Integration of EC and platelet RNA sequencing revealed that platelet-released factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. We identified
S100A8 and
S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2. Consistent with increased gene expression, the heterodimer protein product of
S100A8/
A9, myeloid-related protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls.
....
As COVID-19 patients remain at increased risk for thrombosis, critical illness, and death with and without anticoagulant therapy (
3), we investigated the effect of antiplatelet therapy on platelet
S100A8 and
S100A9 mRNA and platelet-induced EC activation. A cohort of healthy controls received aspirin (
n = 63) daily or ticagrelor (
n = 49) twice daily for 4 weeks (table S7). Blood was collected and platelet RNA was extracted at baseline and following 4 weeks of therapy. While aspirin had no significant effect (
Fig. 6A), ticagrelor led to a significant reduction in both expression of platelet
S100A8 and
S100A9 mRNA (
P < 0.0001;
Fig. 6, B and C). To assess whether antiplatelet therapy could suppress the platelet-mediated proinflammatory effects on ECs, isolated platelets were incubated with aspirin, a P2Y[SUB]12[/SUB] antagonist (AZD1283), or a glycoprotein IIb/IIIa inhibitor (eptifibatide). Incubation of platelet releasate generated in the presence of different antiplatelet drugs found that the P2Y[SUB]12[/SUB] antagonist had the greatest reduction in proinflammatory EC gene expression (29% reduction in
IL6, 51% reduction in
IL8, and 32% reduction in
CCL20;
Fig. 6D).
