The aim of the article was to systematically describe relevant features (clinical phenotype, pathophysiology and management) in patients with severe COVID-19 infection. These data suggest that severe COVID-19 infections could be considered through the prism of a TMA. Functional complement assays to select patients that would benefit from complement inhibition need to be further explored in patients meeting clinical criteria. Both C3 and C5 inhibitors have shown early promising results. Importantly, there is an unmet clinical need of larger prospective trials using complement inhibitors in patients with severe COVID-19 infections. Results from clinical studies are eagerly expected to address this unprecedented morbidity and mortality rate with detrimental effects on every aspect of the global future.