Prekallikreins

Factor Xlla is a serine protease that activates FXI to FXIa (Fig. 5). This system is not of physiologic relevance since patients with hereditary deficiencies of factor XII, prekallikrein, and high-molecular weight kininogen do not present with bleeding symptoms. 

The various interactions of the constituents required for the formation of bradykinin are shown in figure 2. The initiating step is a slow autoactivation of factor XII [10]. However, once this has occurred and prekallikrein is converted to kallikrein, there is... 

HK it can interact with surface-bound factor XII on an adjacent particle thereby disseminating the reaction [25, 28]. As a result the effective kallikrein/factor XII ratio is increased in the presence of HK [25], Finally, in plasma, HK can displace other adhesive glycoproteins such as fibrinogen from binding to the surface [29]. In this sense, HK, like factor XII and prekallikrein, is also a coagulation cofactor because it is required for the generation of kalUkrein (a factor XII activator) as well as the activation of factor XI. 

An alternative pathway for activating the cascade has recently been demonstrated in which factor XII is absent from the reaction mixture [42-45]. Two different groups have isolated two different proteins, each of which seems to activate the HK-prekallikrein complex. One is heat-shock protein 90 [46] and the other is a prolylcarboxypeptidase [47]. Neither protein is a direct prekallikrein activator as is factor Xlla or factor Xllf because each activator requires HK to be complexed to the prekallikrein. In addition, the reaction is stoichiometric, thus the amount of prekallikrein converted to kallikrein equals the molar input of heat-shock protein 90 (or prolylcarboxypeptidase). These proteins can be shown to contribute to factor Xll-independent prekallikrein activation and antisera to each protein have been shown to inhibit the process. When whole endothelial cells are incubated with normal plasma or factor Xll-deficient plasma, the rate of activation of the deficient plasma is very much slower than that of the normal plasma, the latter being factor Xll-dependent [45]. Under normal circumstances (with factor XII present), formation of any kallikrein will lead to factor Xlla formation even if the process were initiated by one of these cell-derived factors. 

Factor Xlla converts prekallikrein to kallikrein and kallikrein cleaves HK to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XII to activated factor XII, and the rate of this reaction is hundreds of times faster than the rate of autoactivation [11]. Therefore, much of the unactivated factor XII can be cleaved and activated by kallikrein. Cl inhibitor inhibits all functions of factor Xlla and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including the feedback activation of factor XII, the cleavage of HK, and the activation of plasma pro-urokinase [66] to lead to plasmin formation. Cl inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to a2-antiplasmin or a2-macroglobulin. 

Kaplan AP, Austen KF A pre-albumin activator of prekallikrein. J Immunol 1970 105 802-811. 

Mandle RJ, Kaplan A Hageman factor substrates. Human plasma prekallikrein mechanism of activation by Hageman factor and participation in Hageman factor-dependent fibrinolysis. J Biol Chem 1977 252 6097-6104. 

Mandle R, Colman R, Kaplan A Identification of prekallikrein and high-molecular-weight kininogen as a complex in human plasma. Proc Natl Acad Sci USA 1976 73 4179-4183. 

Thompson RE, Mandle R Jr, Kaplan AP Studies of 30 binding of prekallikrein and factor XI to high molecular weight kininogen and its light chain. Proc Natl Acad Sci USA 1979 76 4862-4866. 

Tail JF, Fujikawa K Primary structure requirements 31 for the binding of human high molecular weight kininogen to plasma prekallikrein and factor XI. J Biol Chem 1987 262 11651-11656. 

Wiggins RC. Bouma BN. Cochrane CG. Griffin JH Role of high-molecular-weight kininogen in surface-binding and activation of coagulation factor XI and prekallikrein. Proc Natl Acad Sci USA 1977 74 4636-4640. 

Motta G, Rojkjser R, Hasan AA, Cines DB, Schmaier AH High molecular weight kininogen regulates prekallikrein assembly and activation on endothe- 57 lial cells a novel mechanism for contact activation. 

Shariat-Madar Z, Mahdi F. Schmaier A Identification and characterization of prolylcarboxypepti-dase as an endothelial cell prekallikrein activator. J Biol Chem 2002 277 17962-17969. 

Kaplan AP, Austen KF A prealbumin activator of prekallikrein. II. Derivation of activators of prekal-likrein from active Hageman factor by digestion with plasmin. J Exp Med 1971 133 696-712. 

Figure 51-1. The pathways of blood coagulation. The intrinsic and extrinsic pathways are indicated. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. New observations (dotted arrow) include the finding that complexes of tissue factor and factor Vila activate not only factor X (in the classic extrinsic pathway) but also factor IX in the intrinsic pathway, in addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). (PK, prekallikrein HK, HMW kininogen PL, phospholipids.) (Reproduced, with permission, from Roberts HR, Lozier JN New perspectives on the coagulation cascade. Hosp Pract [Off Ed] 1992Jan 27 97.)...

The intrinsic pathway (Figure 51-1) involves factors XII, XI, IX, VIII, and X as well as prekallikrein, high-molecular-weight (HMW) kininogen, Ca, and platelet phospholipids. It results in the production of factor Xa (by convention, activated clotting factors are referred to by use of the suffix a). 

Additional protein constituents of the intrinsic cascade include prekallikrein, an 88 kDa protein zymogen of the protease kallikrein, and high molecular mass kininogen, a 150 kDa plasma glycoprotein that serves as an accessory factor. 

---