Surface-mediated defense reactions. The plasma contact activation system.

uring the past two decades, considerable evidence has accrued that many of the body defenses against injury, specifically, blood coagulation, the inflammatory response, classical complement pathway activation, and fibrinolysis, are initiated by a common mechanism. antecedent) have been shown to be the major proteins required to initiate, amplify, and propagate surface-mediated defense reactions by activating Cl, Factor VII, prorenin (PR), and plas-minogen, by stimulating neutrophils, and by releasing bradykinin (BK). Purification of each has allowed functional and immu-nochemical assays to be developed. by limited proteolysis into the active serine proteases XIIa, kal-likrein (K), and XIa. HMWK is a nonenzymatic cofactor. The molecular events occurring during in vitro contact activation have begun to be described, and the role of these pathways in certain diseases has been tentatively probed. Despite advances, new questions have been raised in tandem with the answers provided. Striking laboratory abnormalities occur in surface-activated coagulation in individuals deficient in contact protein who otherwise appear asymptomatic. However, the proteolytic pathways initiated and amplified by these proteins are obviously important in host defense. In this review, new information will be summarized, problems that exist outlined, and approaches to their solution considered. Initiation ofthe contact system (Fig. 1, left). The activation of the contact system is probably initiated by the binding of plasma XII to a negatively charged surface, where autoactivation Receivedfor publication 26 January 1984. (1) occurs; i. e., the inert zymogen XII, after a conformational change on the surface, is converted to the active serine protease, XIIa, by a small amount of XIIa. The origin of the trace XIIa remains controversial. The substrates of XIIa, the zymogens PK and XI, can bind directly to activating surfaces, but, in the absence of HMWK, activation does not occur (2). Rather, PK (3) and XI (4) exist in bimolecular complexes with the contact system procofactor, HMWK. In normal plasma, HMWK binds to negatively charged surfaces, but little binding occurs in plasma deficient in XII (5). This observation suggests a means by which the adsorption of HMWK could be coordinated with the association of XII with the surface. The mechanism ofinitial binding ofthe PK-HMWK complex to the activating surface requires investigation. However , most of the PK and XI are bound while complexed with cleaved or "activated high molecular weight kininogen" (HMWKa) (5). An alternate possibility is that a few molecules of HMWK are cleaved to HMWKa by XIIa, as in a recently …