Transcriptional landscape of circulating platelets from patients with COVID-19 reveals key subnetworks and regulators underlying SARS-CoV-2 infection: implications for immunothrombosis

Abstract

Background Thrombosis and coagulopathy are pervasive pathological features of coronavirus disease 2019 (COVID-19), and thrombotic complications are a sign of severe COVID-19 disease and are associated with multiple organ failure and increased mortality. Platelets are essential cells that regulate hemostasis, thrombus formation and inflammation; however, the mechanism underlying the interaction between platelets and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. Results The present study performed RNA sequencing on the RNA isolated from platelets obtained from 10 COVID-19 patients and eight healthy donors, and discovered that SARS-CoV-2 not only significantly altered the coding and non-coding transcriptional landscape, but also altered the function of the platelets, promoted thrombus formation and affected energy metabolism of platelets. Integrative network biology analysis identified four key subnetworks and 16 risk regulators underlying SARS-CoV-2 infection, involved in coronavirus disease-COVID-19, platelet activation and immune response pathways. Furthermore, four risk genes (upstream binding transcription factor, RNA polymerase II, I and III subunit L, Y-box binding protein 1 and yippee like 2) were found to be associated with COVID-19 severity. Finally, a significant alteration in the von Willebrand factor/glycoprotein Ib-IX-V axis was revealed to be strongly associated with platelet aggregation and immunothrombosis. Conclusions The transcriptional landscape and the identification of critical subnetworks and risk genes of platelets provided novel insights into the molecular mechanisms of immunothrombosis in COVID-19 progression, which may pave the way for the development of novel therapeutic strategies for preventing COVID-19-associated thrombosis and improving the clinical outcome of COVID-19 patients.

Transcriptional Profiles Analysis of COVID-19 and Malaria Patients Reveals Potential Biomarkers in Children

“…RNF187 gene (E3 ubiquitin-protein ligase RNF187) is involved in transfer of ubiquitin and innate immune response. This gene has been reported to be expressed in platelets from COVID-19 patients [77,78] as observed in the present study. We also noticed that among the shared genes, the hemoglobin complexes and lipid mediators are differentially expressed between the COVID-19 samples and malaria samples (Fig.…”

COVID‐19 immunopathology: From acute diseases to chronic sequelae

“… 39 Transcriptomic analysis of platelets from COVID‐19 patients revealed enrichment of pathways including IL‐6, tumor necrosis factor (TNF)‐α, blood coagulation, and hemostasis, suggesting the role of platelet activation in the development of thrombosis. 40 , 41 Postmortem examination of lungs also revealed microvascular thrombi in association with neutrophil extracellular traps (NETs) and platelets, suggesting NET‐triggered thrombosis. 42 As the development of thrombosis has been associated with poor prognosis in hospitalized COVID‐19 patients, early prediction of thrombosis and thromboprophylaxis may improve the clinical outcome.…”

“…Upon stimulation, the platelets secrete coagulation factors, resulting in the formation of leukocyte–platelet aggregates 39 . Transcriptomic analysis of platelets from COVID‐19 patients revealed enrichment of pathways including IL‐6, tumor necrosis factor (TNF)‐α, blood coagulation, and hemostasis, suggesting the role of platelet activation in the development of thrombosis 40,41 . Postmortem examination of lungs also revealed microvascular thrombi in association with neutrophil extracellular traps (NETs) and platelets, suggesting NET‐triggered thrombosis 42 .…”

The amazing genetic complexity of anucleated platelets

“…[22][23][24] Distinctive changes in the gene-expression profile of circulating platelets of COVID-19 patients have been shown involving the pathways associated with protein ubiquitination, antigen presentation, and mitochondrial dysfunction, 24 suggesting a drastic change in the redox balance and in platelet metabolism leading to platelet activation and to the high thrombotic risk of COVID-19 patients. Another study similarly found in platelets from COVID-19 patients differentially expressed lncRNAs involved in the regulation of hemostasis, platelet activation and the immune response, 25 further confirming that platelet hyperactivation and immune-thrombosis are major players in COVID-19 complications.…”