These findings demonstrate the functionality of the PAR4 Ala120Thr variant in vivo and ex vivo, underscore the pathophysiologic importance of PAR4-mediated platelet activation to induce NETs in stroke, and suggest a different therapeutic approach for stroke management in patients homozygous for the common hyperactive PAR4 Thr120 allele. Here, F2RL3 is linked to stroke disorder.