Carboxyheme and metheme states modulate hemostasis in humans and other species. Further, carbon monoxide and/or nitric oxide production increase in inflammatory disorders involving the gastrointestinal tract, with associated hypercoagulability or hypocoagulability. In particular, the horse suffers both thrombotic or coagulopathic complications during acute gastrointestinal disease. This investigation characterized the thrombelastographic response to carboxyheme (via CORM-2) or metheme (via phenylhydroxylamine, PHA) states without/with addition of tissue type plasminogen activator. Citrated plasma was obtained from 14 normal mares and three horses with enteritis. In normal horses, a carboxyheme state did not enhance the velocity of clot growth and minimally enhanced clot strength (9%). In contrast, a metheme state was associated with a decrease in the velocity of clot formation (54%) and clot strength (47%). During fibrinolysis, a carboxyheme state significantly decreased the onset (113%) and velocity (27%) of fibrinolysis; however, in contrast, a metheme state more markedly increased the onset (84%) and velocity (133%) of fibrinolysis. These data support a carbon monoxide-dominant modulation of hemostasis in normal horses. In contrast, an increase in the severity of acute gastrointestinal disease was associated with a likely nitric oxide-mediated, metheme state-induced hypocoagulable/hyperfibrinolytic state. Additional investigation is warranted to determine the role played by carbon monoxide and nitric oxide in equine thrombotic and coagulopathic disease.