During gram-negative septicemia, interactions between platelets and neutrophils initiate a detrimental feedback loop that sustains neutrophil extracellular trap (NET) induction, disseminated intravascular coagulation, and inflammation. Understanding intracellular pathways that control platelet-neutrophil interactions is essential for identifying new therapeutic targets. Here, we found that thrombin signaling induced activation of the transcription factor NFAT in platelets. Using genetic and pharmacologic approaches, as well as iNFATuation, a newly developed mouse model in which NFAT activation can be abrogated in a cell-specific manner, we demonstrated that NFAT inhibition in activated murine and human platelets enhanced their activation and aggregation, as well as their interactions with neutrophils and NET induction. During gram-negative septicemia, NFAT inhibition in platelets promoted disease severity by increasing disseminated coagulation and NETosis. NFAT inhibition also partially restored coagulation ex vivo in patients with hypoactive platelets. Our results define non-transcriptional roles for NFAT that could be harnessed to address pressing clinical needs. [Display omitted] • Thrombin receptor signaling activates NFAT in human and mouse platelets • Inhibition of NFAT in platelets promotes aggregation and neutrophil interactions • NFAT inhibition potentiates coagulation in patients with hypoactive platelets • NFAT blockade in platelets boosts NETosis and inflammation in bacterial septicemia The pathways controlling platelet-neutrophils interactions remain unclear. Poli et al. demonstrate that the transcription factor NFAT regulates the hemostatic and inflammatory activities of platelets. NFAT inhibition in activated platelets increases dense granule release, platelet aggregation, and interactions with neutrophils. NFAT inhibition in platelets in vivo initiates a detrimental feedback loop that enhances disseminated coagulation and NETosis and aggravates bacterial septicemia. [ABSTRACT FROM AUTHOR]