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The COVID-19 outbreak, caused by the SARS-CoV-2 coronavirus, has threatened and taken many lives since the end of 2019. Given the importance of COVID-19 worldwide, since its spread, many research groups have been seeking blood markers that could help to understand the disease establishment and prognosis. Usually, those markers are proteins with a differential accumulation only during infection. Based on that, proteomic studies have played a crucial role in elucidating diseases. Mass spectrometry (MS) is a promising technique in COVID-19 studies, allowing the identification and quantification of proteins present in the plasma or serum of affected patients. It helps us to understand pathological mechanisms, predict clinical outcomes, and develop specific therapies. MS proteomics revealed biomarkers associated with infection, disease severity, and immune response. Plasma or blood serum is easy to collect and store; however, its composition and the higher concentration of proteins (e.g., albumins) shadow the identification of less abundant proteins, which usually are essential markers. So, clean-up approaches such as depletion strategies and fractionating are often required to analyze blood samples, allowing the identification of low-abundant proteins. This review will discuss many proteomic approaches to discovering new plasma biomarkers of COVID-19 employed in recently published studies. The challenges inherent to blood samples will also be discussed, such as sample preparation, data processing, and identifying reliable biomarkers.
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