The factor IXa heparin-binding exosite is a cofactor interactive site: mechanism for antithrombin-independent inhibition of intrinsic tenase by heparin.

摘要: Therapeutic heparin concentrations selectively inhibit the intrinsic tenase complex in an antithrombin-independent manner. To define molecular target and mechanism for this inhibition, recombinant human factor IXa with alanine substituted solvent-exposed basic residues (H92, R170, R233, K241) protease domain was characterized regard to enzymatic activity, affinity, inhibition by low weight (LMWH). These mutations only had modest effects on chromogenic substrate hydrolysis kinetics of X activation IXa. Likewise, H92A K241A showed IXa−factor VIIIa affinity similar wild type (WT). In contrast, R170A demonstrated a 4-fold increase apparent dramatically increased coagulant activity relative WT. Factor R233A 2.5-fold decrease cofactor reduced ability stabilize half-life type,...