Factor VII-activating protease: coagulation, fibrinolysis, and atherothrombosis?

The mechanistic description of a biological process first involves the development of an inventory of constituents that are presumed essential for the expression of the function. Although initially based on pathology, more frequently this inventory is developed by in vitro tests on the biochemistry, cell biology, or molecular genetics of a process. Elaborate schemes describing physiological reaction systems are frequently developed on the basis of these in vitro– developed inventories; however, it is becoming commonplace knowledge that the ultimate test of biological relevance, ie, a clinical phenotype, does not exist. In the coagulation system, this is evident in descriptions of the “intrinsic pathway” of coagulation, which take the view that surface contact activation of factor XII is the initial process.1,2 However, defects in the contact pathway produce no hemorrhagic phenotype.3 More recently, the use of transgenic animal models has provided a powerful tool for pathological phenotype recognition.4,5