INITIATION OF CONTACT SYSTEM ACTIVATION IN PLASMA IS DEPENDENT ON FACTOR-XII AUTOACTIVATION AND NOT ON ENHANCED SUSCEPTIBILITY OF FACTOR-XII FOR KALLIKREIN CLEAVAGE

Various mechanisms have been hypothesized to explain the initiation of contact system activation in plasma. We investigated the capability o f dextran sulphate (DS) of different molecular weights to initiate con tact system activation in normal human plasma, and compared this with their capability to support factor XII autoactivation and to enhance f actor XII susceptibility for cleavage by Kallikrein. Dextran sulphate of M-r 500000 (DS500) and 50000 (DS50) was able to initiate contact sy stem activation in plasma (determined by measuring the amount of facto r XIIa-Cl-inhibitor, kallikrein-Cl-inhibitor and factor XIa-Cl-inhibit or complexes generated) as well as to support factor XII autoactivatio n and to enhance factor XII susceptibility for cleavage by kallikrein (as measured with amidolytic assays using purified proteins). In contr ast, dextran sulphate of M-r 15000 (DS15) and 5000 (DS5) neither induc ed contact system activation in plasma, nor supported autoactivation o f factor XII, although both of these DS species enhanced the rate of a ctivation of factor XII by kallikrein in the purified system. Based on these properties (i.e. binding of factor XII without inducing autoact ivation), DS15 and DS5 were predicted to be inhibitors of contact syst em activation induced in plasma by DS500, which indeed was observed. W e conclude that enhanced factor XII susceptibility for kallikrein acti vation and factor XII autoactivation are distinct phenomena, the latte r being necessary to support activation of the contact system in plasm a.