Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation.

Endothelial thrombomodulin (TM) plays a critical role in hemostasis as a cofactor for thrombin-dependent formation of activated protein C, a potent anticoagulant. Chloramine T. H202, or hypochlorous acid generated fromH202 by myeloperoxidase rapidly destroy 75-90% ofTM cofactor activity. Activated PMN, the primary in vivo source of biological oxidants, also rapidly inactivateTM. Oxidation ofTM byPMN is inhibited by diphenylene iodonium, an inhibitor ofNADPH oxidase. Both Met291 and Met388 in the six epidermal growth factorlike repeat domain are oxidized; however, only substitutions of Met388 lead to TM analogues that resist oxidative inactivation. We suggest that in inflamed tissues activated PMN may inactivateTM and demonstrate further evidence ofthe interaction between the inflammatory process and induction of thrombotic potential. (J. Clin. Invest. 1992. 90:2565-2573.) Key words: diphenyleneiodonium * oxidants * leukocytes * thrombin * protein C