In this study, we demonstrated that (1) COVID-19 patients experience increased in vivo platelet activation, as evidenced by increased αIIbβ3 activation and P-selectin expression, and detectable virus RNA in the blood is associated with platelet hyperactivity; (2) platelets robustly express ACE2 and TMPRSS2; (3) SARS-CoV-2 and its Spike protein promote platelet function and thrombus formation via the MAPK pathway downstream of ACE2; and (4) recombinant human ACE2 protein and anti-Spike monoclonal antibody treatment may block SARS-CoV-2-induced platelet activation and thrombus formation. This evidence concerns the gene TMPRSS2 and COVID-19.