Factor XII: form determines function

Factor XII is a mysterious plasma protein without a clear physiologic function. It was identified as a clotting factor, but has no clear role in hemostasis. However, FXII also contributes to the production of bradykinin, a short-lived inflammatory peptide. A growing body of mechanistic research from animal models indicates that FXII contributes to thrombotic disease by triggering excessive coagulation. FXII is evolutionarily conserved, suggesting that this molecule does have a physiologic function. This leads to intriguing questions: What does FXII really do? Is it even a real clotting factor at all? Before the groundbreaking discovery of a role for FXII in thrombotic disease, many studies investigated the biochemical properties of FXII and its activators. In this review, we highlight several biochemical studies that reveal much about the natural behavior of FXII. On the basis of these findings, it is possible to draft a conceptual model to explain how FXII reacts to surface materials. We then discuss how this model applies to the activities of FXII in its natural environment. There are two tentative physiologic functions of FXII that can operate exclusively: (i) maintenance of thrombus stability; (ii) local regulation of vascular permeability. Either, or both, of these natural functions may explain the evolutionary development and maintenance of FXII.