Activation and function of human Hageman factor. The role of high molecular weight kininogen and prekallikrein.

Abstract

A B S T R A C T The activation and function of surfacebound Hageman factor in human plasma are dependent upon both high molecular weight (HMW) kininogen and prekallikrein. HMW kininogen does not affect the binding of Hageman factor to surfaces, but it enhances the function of surface-bound Hageman factor as assessed by its ability to activate prekallikrein and Factor XI. The initial conversion of prekallikrein to kallikrein by the surface-bound Hageman factor in the presence of HMW kininogen is followed by a rapid enzymatic activation of Hageman factor by kallikrein. The latter interaction is also facilitated by HMW kininogen. Kallikrein therefore functions as an activator of Hageman factor by a positive feedback mechanism and generates most of the activated Hageman factor during brief exposure of plasma to activating surfaces. HMW kininogen is a cofactor in the enzymatic activation of Hageman factor by kallikrein and it also augments the function of the activated Hageman factor generated. The stoichiometry of the Hageman factor interaction with HMW kininogen suggests that it enhances the activity of the active site of Hageman factor. Since HMW kininogen and prekallikrein circulate as a complex, HMW kininogen may also place the prekallikrein in an optimal position for its reciprocal interaction with Hageman factor to proceed. The surface appears to play a passive role upon which bound Hageman factor and the prekallikrein-HMW kininogen complex can interact.H. L. Meier is a Predoctoral fellow,

Thrombin-mediated Feedback Activation of Factor XI on the Activated Platelet Surface Is Preferred over Contact Activation by Factor XIIa or Factor XIa

“…The primary structure of factor XI has been determined (9, 10), including the identification of four tandem repeat sequences, designated Apple (A1, A2, A3, and A4) domains in the heavy chain region of factor XI. Binding sites (11-15) for thrombin, the Kringle 2 domain of prothrombin, and HK are present in the A1 domain, whereas both heparin-and plateletbinding sites exist within the A3 domain (16 -18) and a binding site for factor XIIa is located in the A4 domain (19).Factor XI can participate in the contact phase of blood coagulation in a reaction that requires the presence of anionic surfaces for optimal activation in vitro by factor XIIa (6,[20][21][22]. However, deficiencies in factor XII, prekallikrein, and HK are not associated with hemostatic abnormalities, whereas a deficiency in factor XI produces abnormal bleeding complications (23-25).…”

“…Factor XI can participate in the contact phase of blood coagulation in a reaction that requires the presence of anionic surfaces for optimal activation in vitro by factor XIIa (6,[20][21][22]. However, deficiencies in factor XII, prekallikrein, and HK are not associated with hemostatic abnormalities, whereas a deficiency in factor XI produces abnormal bleeding complications (23-25).…”

Role of surface in surface-dependent activation of Hageman factor (blood coagulation Factor XII)

“…Hence, soluble kallikrein, which is potent in the cleavage of surfacebound HF, is rapidly generated and readily available in plasma during contact activation. Fifth, the correction of the coagulation defect of prekallikrein-deficient plasma requires the addition of enzymatically active kallikrein as well as kaolin (8,34,35). Thus, reciprocal proteolytic activation of HF and prekallikrein (20,21,32,35) probably represents the major mechanism responsible for contact activation of HF.…”

Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

“…Although epidemiologic studies suggest that reduced plasma factor XII levels are associated with myocardial infarction, mice severely deficient in factor XII are protected from thrombosis and plasma levels of factor XII of only 10% to 15% in humans are sufficient to have normal blood coagulation times. 30,36,37 Alternatively, in plasma from PRCP-deleted mice, there is a small but significant increase in contact activation-induced thrombin generation and a nonsignificant increase in tissue factor-induced thrombin generation. The exact mechanism for increased thrombin generation in plasma of PRCP gt/gt mice is not completely known, but it may be related to ROS and vascular dysfunction.…”