In the past six years, analysis of numerous murine models, enabled by investigator-designed manipulation of the mouse genome, has generated an explosion of new, and sometimes confounding, data. Mice with complete deficiencies in virtually all the known factors involved in hemostasis have been produced by targeted modification of the genes that encode the proteins that generate and regulate coagulation. Mice with altered factors or altered expression of normal factors have also been produced by transgenic techniques. In this review, we summarize the analyses of these mouse models and compare these results to those obtained from people with deficiencies in the same genes (Table 1). Information is available for all the models, but we will focus on those more completely characterized. We present the models in groups (Fig. 1), which places each factor into a single position within a simplified model of hemostasis. The phenotypes of these genetically modified mice reflect a compilation of functions, some of which do not fit within this simplified model of hemostasis. For example, Factor X (FX) not only acts in concert with factor V (FV) to foster clot formation but also acts in concert with tissue factor pathway inhibitor (TFPI) to limit clot formation. Additionally, we know that many factors have functions outside hemostasis; for example, a cleaved fragment of antithrombin III (ATIII) serves as an anti-angiogenic factor (1). Moreover, as shown remarkably by the analysis of these mouse models, many of these proteins also have a critical role in normal embryonic development (Fig. 2). Finally, genetic background significantly influenced the phenotype of some models, and we specify when this variable was examined.

To provide a structure to consider analysis of these mice, we divided the hemostasis proteins into three categories: those that promote the generation of thrombin, those that participate in clot formation, those that curtail the generation of thrombin. To place these proteins in context, we begin with a brief overview of coagulation. Coagulation is initiated when injury to the blood vessel exposes tissue factor (TF) to circulating factor VII (FVII), resulting in the formation of TF/VII complexes. This complex activates factor X (FX), either directly or indirectly though FIX. Activated FX (FXa) converts prothrombin to