Previous: Introduction: Plasma cascade systems with emphasis on the role of C1-inhibitor-Kallikrein-kinin system

Introduction

Plasma cascade systems with emphasis on the role of C1-inhibitor

Coagulation
Clotting involves plasma, platelets and components in the vessel wall. Platelets act as vehicles to concentrate and enhance coagulation on the damaged vessel. Up until some years ago, coagulation was divided into the intrinsic pathway initiated by factor XII, and the extrinsic- or tissue-factor pathway. This concept has changed (Fig. 9). A deficiency of prekallikrein, FXII or HK does not result in a bleeding disorder. In fact, persons with FXII deficiency often suffer from thromboembolic disease, and the inclusion of FXII assays in routine thrombophilia screening has recently been encouraged (205). For this reason activation of blood coagulation via the contact activation system is now believed to be an in vitro artefact, further supported by a series of recent clinical and experimental observations (156,207,209,210). The early discovery by Bjarne Østerud of a direct activation of FIX by tissue factor and FVIIa also attenuated the theory of two separate activation pathways (211). It now appears that tissue factor, which is a protein lipid complex in the vessel wall, and FVII play a major role in both the initiating as well as the propagation of normal coagulation (212,213). Lately, a reciprocal activation of FVII, by FIX and to a lesser degree FX has been proposed (214).

Fig. 9. The main pathways of the current concept of the coagulation system

Patients lacking FXI, the remaining factor of the four contact system factors mentioned above, variably have a bleeding tendency. The recent observation of thrombin as an important activator of FXI, led to the suggestion that under certain conditions FXIa is needed for the maintenance of normal hemostasis (208). In this context, it is of some interest that the former belief of alpha-1-antitrypsin as the main inhibitor of FXI has recently been challenged. It was found that the majority of FXIa added to plasma formed complexes with C1-INH (215,216).

It has also been recognised that the activation of protein C by thrombin, when thrombin is bound to endothelial cells, is a powerful anticoagulant event, leading to cleavage of FV and FVIII. Protein S is cofactor for protein C, but can probably also inactivate FXa directly (217). Protein S is bound to C4BP, which also binds the split product C4b of the complement system, but only on distinct chains. It is believed that these bindings are independent of each other (218). HAE patients have a continuous breakdown of C4 and, theoretically, would be expected to load the C4BP with increased amounts of C4b correspondingly. Interestingly, case reports of functional protein S deficiency in HAE have recently been published, although the mechanism is unexplained (219,220). Coagulative mechanisms of special interest in HAE patients are included in Fig. 10.

Fig. 10. The coagulation system with particular emphasis on reactions of possible importance in HAE. This includes the protein C/S system with C4b binding protein which also binds protein S, and a possible direct activation of FVII by the unopposed FXIIa. Names in italic and the fork like symbol depicts inhibition.

C1-INH can be secreted from platelets and also expressed on their activated membranes. The cell membrane expression of C1 INH may be important to modulate the activity of the proteases of the complement and kallikrein kinin systems in the local inflammatory response (221). How platelets function in HAE is an interesting issue (222,223), and remains to be thoroughly explored.

FXIIa may activate FVII directly, but this pathway is probably of minor importance in normals. However, since FXIIa is inhibited by C1-INH, this pathway could be of some significance in HAE patients.

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