SARS-CoV-2 activates platelets in a plasma-dependent manner. Platelet responses to β-propiolactone–inactivated SARS-CoV-2 (CoV2, red) obtained from human A549 (ACE2) cell infection or conditioned media (C.Med, blue) solution (A549 [ACE2] cell culture supernatant obtained after 4 days of culture and treatment with β-propiolactone [1:1000 vol/vol]). (A) Platelets were stimulated with C.Med or CoV2 in the presence or absence of PFP (0.5%). Platelets were labeled and fixed after stimulation for 7.5, 15, 30, or 60 minutes, and platelet activation was determined by flow cytometry. N = 3. (B) Platelets were stimulated with C.Med or CoV2 (1:25 vol/vol) in the presence of PFP (0.5%) and injected into a microfluidics system. The images were taken after 15 minutes and show fluorescently-labeled platelets in the fibrinogen-coated channel. Representative images. N = 4. (C) Platelets were stimulated with C.Med or CoV2 in the presence of PFP (0.5%). N = 4. (D) Platelets were stimulated for 60 minutes with receptor-binding domain (RBD) peptide, S1 subunit of spike, full trimeric spike protein, or thrombin in the presence of platelet-free plasma (0.5%). N = 4. Data are represented as mean ± SD. Statistical analysis: (A, C, D) Ordinary two-way ANOVA followed by Sidak’s multiple comparison test. **P < .01, ***P < .001, and ****P < .0001. ns, not significant.