The scientific community's quest to identify optimal targets for anticoagulant pharmacotherapy.

The scientific community’s quest to identify optimal targets for anticoagulant pharmacotherapy must be soundly based on fundamental constructs of vascular biology and coagulation. Although this tenet, which has served as a platform for drug development during the past 50 years, is incontrovertible, one should also ask, “What experimental model of coagulation is most applicable and directly translatable to mammalian coagulation in general and to human thrombotic disorders in particular?” Is it the “waterfall-cascade” or “autoprothrombin model” of blood coagulation first described by Macfarlane1 and Davie and Ratnoff2 that so elegantly described inactive precursors being converted to active proteases in a sequential series of bioamplification steps? Or is it a cell-based model of coagulation3,4 that portrays an integrated and functional representation of complex biochemical events occurring on cellular surfaces in lieu of functionally independent cascades that principally reflect clot formation in static fluid systems rather than the dynamic interplay of tissue factor (TF)-bearing cells, platelets, and their respective protein intermediaries? Or is it a cumulative 4-component model based on numerical approximations of TF-mediated thrombin generation, TF activation of the blood coagulation proteome, TF-activated and contact pathway–inhibited whole blood in vitro, and blood shed from standardized microvascular wounds in vivo as an interactive paradigm of real-time events?5 Clearly, each model honestly represents, with increasing biochemical rigor, authenticity, and translatable convergence, blood coagulation under normal and pathological conditions. The remaining step, which provides a personalized stamp toward translating experimental models to human biology with concerted effort and safe, effective, and patientand disease-specific care, is applied genomics, wherein gene expression profiles and pharmacogenomics identify, through predictive models, individuals at risk for thrombosis and those likely to experience treatment failure and/or complications from anticoagulant pharmacotherapy.6 On the basis of a contemporary understanding of vascular biology and hemostasis as they apply to thrombotic disorders and on previously summarized models depicting the inherently dynamic properties of coagulation, we will consider the merits of factor Xa as a target for anticoagulant pharmacotherapy.