The contact system at the crossroads of various key patho- physiological functions: Update on present understanding, laboratory exploration and future perspectives.

The contact system initiates the intrinsic pathway of coagulation and is started by Factor XII activation, which then activates prekallicrein to kallicrein and Factor XI to Factor XIa and, in the presence of high molecular weight kininogen, forms a "contact phase activation loop", that amplifies Factor XII activation. FXII deficiency is not associated with bleeding tendencies, but when the blood clots, the thrombus is less dense, thus favoring antithrombotic protection. Activated Factor XII inhibition emerges as an efficient target for preventing thrombo-embolic diseases without inducing a hemorrhagic risk. Activated Factor XII exhibits other activities, in that it can activate complement and provoke inflammation, contributing to innate immunity. It also stimulates fibrinolysis through uPA activation from scu-PA. Among the other components of the contact phase, Factor XI has a more important role in coagulation pathways and can directly activate FX, FVIII and FV, in a FIX independent pathway. Its deficiency is associated with a mild bleeding diathesis ("pseudo-hemophilia" or hemophilia C), with a variable incidence among kindreds. Recently, the occurrence of thrombotic events the same day following infusion of immunoglobulin concentrates has been demonstrated to be caused by the presence of trace amounts of activated Factor XI, pointing out the key role of this factor for thrombogenicity. Prekallicrein can be activated at the endothelial surface in the presence of high molecular weight kininogen, whose cleavage generates bradykinins and contributes to vessel tonicity and inflammation. The contact phase, through its activation loop, is then an important physiological system, which can initiate and regulate various biological functions and is at the crossroads of various biological activities. Many of the body's physiological functions are intimately linked between them, making the global approach of special usefulness for understanding the interactions which can result from any abnormality of one of them. New pharmaceutical drugs targeting a defined activity need to be investigated for all the possible interferences or side effects. In this article we aim to present and summarize the present understanding of contact phase system activation and regulation, its involvement in various physiological functions, and the laboratory tools for its exploration.