Updated project metadata. Platelets, the smallest cells in human blood known for their role in primary haemostasis, are also able to interact with pathogens and play a crucial role in the immune response. In severe coronavirus disease 2019 (COVID-19) cases, platelets become over-activated, resulting in the release of granules, exacerbating inflammation and contributing to the cytokine storm. Here we utilize label-free shotgun proteomics approach to further elucidate the role of platelets in COVID-19 progression and to identify predictive biomarkers for disease outcome. Platelet proteome of the severely ill COVID-19 patients varied significantly from to healthy controls. Significant changes in the levels of proteins associated with protein folding were detected. In addition, a number of proteins with isomerase activity were found in the patient samples, which appear to exert an influence on platelet activity via non-genomic properties of glucocorticoid receptor (GR) and nuclear factor κ-light-chain-enhancer of activated B cells (NFkB). We also performed a comparison of proteins found exclusively in controls, survivors and non-survivors. CRP, CA-1, SAA2 and SEPPINA3 were found to be biomarker candidates in platelets, showing a significant increase in ICU patients.