A characteristic clinical feature of COVID-19 is the frequent occurrence of thrombotic events. Furthermore, many cases of multiorgan failure have been found to be thrombotic in nature. Since the outbreak of COVID-19, D-dimer testing has been used extensively to evaluate COVID-19-associated thrombosis, but does not provide a complete view of the disease because it probes blood coagulation, but not platelet activity. Due to this limitation, D-dimer testing fails to account for thrombotic events which occur despite low D-dimer levels, such as sudden stroke in young patients and autopsy-identified widespread microthrombi in multiple organs. Here we demonstrate large-scale image-based profiling and temporal monitoring of circulating platelet aggregates in the blood of patients with COVID-19 (n = 110) at single-cell resolution. Surprisingly, our analysis shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients, including those who were not clinically diagnosed with thrombosis and those with low D-dimer levels (≤1 µg/mL). Additionally, results indicate a strong link between the concentration of platelet aggregates and the severity and mortality of COVID-19. Finally, high-dimensional analysis reveals that COVID-19 is a highly unique systemic disease having the properties and synergistic interaction of infectious and thrombotic complications.