Hemostasis, the prompt cessation of bleeding at a site of vascular injury, is among the most fundamental physiologic and teleologically vital defense mechanisms in nature. Without a functionally intact hemostatic mechanism, death could ensue rapidly even after minor traumas associated with everyday life. In mammalian blood coagulation, regulated by a complex network of integrated biochemical events, five protease factors (f ) (fIIa [thrombin], fVIIa, fIXa, fXa, and protein C) interact with five cofactors (tissue factor, f VIIIa, fVa, thrombomodulin, and protein S) to regulate the generation of fibrin (Davidson et al., 2003). Although each component of the mammalian coagulation network has unique functional properties, available data based on gene organizations, protein structure, and sequence analysis suggest that it may have resulted from the reduplication and diversification of two gene structures over 400 million years ago. A vitamin K–dependent serine protease is composed of a γ-carboxylated glutamic acid (GLA) epidermal growth factor-like (EGF) 1–EGF 2-serine protease domain structure common to fVII, fIX, fX, and protein C, and the A1-A2-B-AB-C1-C2 domain structure common to fV and fVIII. Prothrombin is also a vitamin K–dependent serine protease; however, it contains kringle domains rather than EGF domains (suggesting a replacement during gene duplication and shuffling). Analyses of active site function amino acid residues reveal distinguishing characteristics of thrombin from other serine proteases, supporting its position as the ancestral blood enzyme (Krem and Cera, 2002; McLysaght et al., 2002). The rapid transformation of fluid blood to a gel-like substance (clot) has been a topic of great interest to scientists, physicians, and philosophers since the days of Plato and Aristotle ( Jewett, 1892; Lee, 1952). However, it was not until the beginning of the 18th century that blood clotting (coagulation) was appreciated as a means to stem blood loss from wounds (hemostasis) (Petit, 1731). As with other areas of science, the microscope played a pivotal role in the understanding of coagulation. In the mid-17th century, Marcello Malpighi separated the individual components of a blood clot into fibers, cells, and serum (Forester, 1956).