Mouse models in coagulation.

In the past six years, analysis of numerous murine models, enabled by investigator-designed manipulation of the mouse genome, has gene-rated 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). In-formation 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 simpli-fied 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 forma-tion 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 anti-thrombin III (ATIII) serves as an anti-angiogenic factor. Moreover, as shown remarkably by the analysis of these mouse models, many of these proteins also have a critical role in normal embryonic develop-ment (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 con-text, 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 thrombin. Thrombin catalyzes multiple events in coagulation by acti-vating the platelet integrin IIb3, which mediates fibrinogen- and von Willebrand factor (vWF)-dependent platelet interactions, and by trans-forming soluble fibrinogen molecules into a fibrin fiber matrix. Thrombin further amplifies its own generation by activating factors (FXI, FX, FIX) and cofactors (FV and FVIII) that promote TF-inde-pendent production of the active protease FXa. Anticoagulation is achieved through the inhibition of the various steps of thrombin gene-ration. TFPI forms a complex with TF, FVIIa and FXa to terminate the initiating step. Protein Z forms a complex with FXa and serves as a cofactor in the inhibition of FXa activity. Thrombomodulin (TM), an endothelial cell surface-bound protein, and thrombin complex to activate protein C (PC). With its cofactor protein S (PS), activated protein C (APC) degrades FVa and FVIIIa and thus limits generation of thrombin. The serpin, ATIII, forms complexes with FXa and thrombin to directly inhibit these proteases.