Histidine-rich glycoprotein, and alpha 2-glycoprotein in human plasma, has been shown to interact with heparin, with the high-affinity lysine- binding site of plasminogen, with divalent cations, and is associated with the rosette formation between erythrocytes and lymphocytes. A specific enzyme-linked immunosorbent assay for histidine-rich glycoprotein has been developed and used to demonstrate that histidine- rich glycoprotein is present in human platelets. Histidine-rich glycoprotein was detected and quantified in detergent extracts of washed human platelets, with a mean level of 371 ng/10(9) platelets. Plasma histidine-rich glycoprotein, either in the platelet suspending medium or on the surface of the platelets, accounted for less than 3.4% of the detectable platelet histidine-rich glycoprotein. Histidine-rich glycoprotein was also demonstrated in human bone marrow megakaryocytes by immunofluorescence. The extent of histidine-rich glycoprotein release from platelets was dependent on the thrombin dose and correlated directly with the extent of serotonin release. The platelet and plasma histidine-rich glycoprotein were similar by immunochemical analysis. Anti-histidine-rich glycoprotein IgG did not inhibit platelet aggregation. Histidine-rich glycoprotein released by platelets following thrombin stimulation may play a significant role in modulating inflammatory events in the microenvironment of the platelet plug.