Platelets administered 1-chloro-2,4-dinitrobenzene to deplete intracellular glutathione (GSH) and inhibit GSH-peroxidase responded with irreversible aggregation to low doses of arachidonic acid (AA) more rapidly than control cells. This increase in sensitivity was correlated to inhibition of GSH-peroxidase, and not with the depletion of GSH. Addition of hydrogen peroxide, 15-hydroperoxyeicosatetraenoic acid, or inhibition of the lipoxygenase metabolic pathway by 4,7,10,13-eicosatetraynoic acid also induced a hypersensitive aggregation response to AA. These results suggest that the three modes of treatment share a common mechanism of increasing AA metabolism to biologically active prostaglandins and thromboxane A2 through alterations in cyclooxygenase kinetics and available enzyme substrate.