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Introduction

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

Fibrinolysis
The fibrinolytic system interacts to regulate fibrin deposition and removal during healing. Plasmin is the key effector enzyme to fulfil this task (Fig. 11). Plasmin is derived from plasminogen, and is a highly unspecific protease, able to split several other plasma components. Fortunately, plasmin is mainly generated in the fibrin clot and cells are able to balance the secretion of activators and inhibitors so as to ensure a localised plasminogen activation. Circulating plasmin is rapidly inhibited by alpha-2-antiplasmin.

Fig. 11. The fibrinolytic system. Inhibitors and substances with inhibitory effects are shown in italics with a fork like symbol. The effect of streptokinase, when exogenously added, is also included. u-PA= urokinase type plasminogen activator. t-PA= tissue plasminogen activator. rt-PA = recombinantly produced PA. PAI-1= plasminogen activator inhibitor 1. AT=antithrombin. FDP= fibrinogen degradation products.

Even though C1-INH is a weak inhibitor of plasmin (224), plasmin/C1-INH complexes or inactive C1-INH could be formed in extreme situations (225,226). Fibrinolysis is increased in HAE during attacks or in remission (227-229). Since plasminogen is present in the highest concentration of all the C1-INH inhibitable enzymes, activation of plasminogen could theoretically consume substantial amounts of C1-INH (230). Such a situation is created during infusion of streptokinase, although opposing data as concerns the exhausting of C1-INH have been found (231-233). Plasmin can also activate C1s directly (234).
Streptokinase also activates the classical complement pathway (234,235), which can be an additional mechanism by which the C1-INH pool decline. Moreover, plasmin enhances the production of bradykinin from HK (236), a process already enhanced in HAE patients.

Tissue plasminogen activator (t-PA), normally inhibited by PAI-1, may during infusion of recombinant t-PA likewise overwhelm PAI and bind to C1-INH (237,238). About 8 % of the infused dose of recombinant t-PA (alteplase) was shown to be inhibited by C1- inhibitor at peak level (239). The concentration of C1-INH in plasma is normally more than 1000 fold higher than the peak t-PA level during therapeutical thrombolysis with rt-PA, but may diminish during a continuous infusion of t-PA over longer periods. According to the facts mentioned above, thrombolytic therapy with either streptokinase or rt-PA could represent a threat to patients with a marginal C1-INH pool.

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