Cathepsin G, a leukocyte protease, activates coagulation factor VIII

Neutrophils and monocytes express Cathepsin G and can also bind to activated platelets, thus they can be localized to the site of active coagulation. Previous studies have suggested that Cathepsin G inactivated coagulation Factor VIII (FVIII) and was thus anticoagulant. But Other studies have indicated procoagulant functions for Cathepsin G in activation of coagulation factor V or activation of platelets among Other possible mechanisms. Therefore, it remains unclear if Cathepsin G is anticoagulant or procoagulant. We investigated the effects of human neutrophil Cathepsin G on FVIII/VIIIa. Cathepsin G activates FVIII to a partially active form while having only a minor inactivating effect on thrombin-activated FVIIIa. This inactivation is mostly due to decreased stability of FVIIIa since a disulfide bond that prevents A2 subunit dissociation from FVIIIa prevents any loss of activity due to Cathepsin G proteolysis. FVIII that has been cleaved by Cathepsin G can still be activated by Thrombin if A2 subunit dissociation is prevented. Cathepsin G cleavages of FVIII are limited to a few specific sites that are mostly located near known activating and inactivating cleavage sites. Cathepsin G cleavage sites near to Thrombin cleavage sites likely contribute to the partial activation of FVIII. Therefore, it is possible that Cathepsin G from neutrophils and monocytes may provide some pro-coagulant effect by activating FVIII.