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Potential pharmacological applications of the antithrombotic molecule high molecular weight kininogen.

During the past 20 years, the proteins of the "contact system", namely high molecular weight kininogen (HK), kallikrein and Factor XII have been shown to have very little direct impact on hemostasis despite their initial description as initiators of the "intrinsic system". In fact these proteins have rather anticoagulant and profibrinolytic properties. The focus of this review is to summarize the known antithrombotic properties of HK demonstrating its potential application for the novel therapeutic interventions against thromboembolic complications. In particular, HK can inhibit platelet aggregation, as (i) its domain 5 interferes with ligand binding of alphaIIbbeta3-integrins, (ii) its domain 3 blocks thrombin-dependent platelet aggregation by interfering with thrombin binding to the glycoprotein Ib-IX-V complex on platelets, (iii) bradykinin, which is derived upon cleavage of HK, blocks thrombin-induced platelet aggregation, and (iv) HK domain 2 can inhibit the function of platelet calpain. Moreover, HK may have profibrinolytic actions as it can (i) inhibit plasminogen activator inhibitor-1 function and (ii) potentiate prourokinase activation with subsequent pericellular plasmin formation. Indeed, patients lacking circulating HK are at increased risk for thrombosis, and a prothrombotic phenotype was reported for kininogen-deficient rats. All these observations render kininogen antithrombotic, rather than prothrombotic, and the ongoing research aims to develop novel kininogen-related antithrombotic therapies.