Kinetics and mechanisms of surface-dependent coagulation factor XII activation

Abstract

Surface-induced activation of factor XII is critical part of the intrinsic pathway of blood coagulation. The mechanism of this process remains unclear: in particular, it is not known whether the initial amounts of factor XIIa, an active form of factor XII, are produced purely by factor XII contacting a surface or if traces of factor XIIa pre-exist. Furthermore, it is not known whether factor XII first has to bind to a surface before it can interact with the surface-bound factor XIIa in a two-dimensional process to become activated (“bound-substrate model”) or if surface-bound factor XIIa activates a fluid-delivered form of factor XII (“free-substrate model”). To investigate these possibilities, we used mathematical modeling to implement various hypotheses. Time courses of factor XII production were generated under different initial conditions and matched with experimental data. We established that only the “bound-substrate model” fits with the majority of experimental data, whereas the “free-substrate model” does not. We also addressed the question of spontaneous activation and found that measurable differences between the models with and without spontaneous activation appear only under limiting conditions (deficit or excess of surface). As there are insufficient data regarding the system׳s behavior upon such variations of surface concentration in the literature, we designed new experiments to answer this question.