Fibrin stabilizing factor (factor XIII or FXIII) plays a critical role in the generation of a viable hemostatic plug. Following exposure to thrombin and calcium, the zymogen is activated to FXIIIa that, in turn, catalyzes the formation of N epsilon(gamma-glutamyl)lysine protein-to-protein side chain bridges within the clot network. Introduction of these covalent crosslinks greatly augments the viscoelastic storage modulus of the structure and its resistance to fibrinolytic enzymes. Analysis of the individual reaction steps and regulatory control mechanisms involved in clot stabilization enabled us to reconstruct the entire physiological process. This also serves as a guide for the differential diagnosis of the variety of molecular defects of fibrin stabilization.