The lifespan of factor VIII. Factor VIII is synthesized by various tissues, including liver, kidney, and spleen, as an inactive single-chain protein. After extensive posttranslational processing, factor VIII is released into the circulation as a set of heterodimeric proteins. This heterogenous population of factor VIII molecules readily interacts with vWF, which is produced and secreted by vascular endothelial cells. Upon triggering of the coagulation cascade and subsequent generation of serine proteases, factor VIII is subject to multiple proteolytic cleavages. These cleavages are associated with dramatic changes of the molecular properties of factor VIII, including dissociation of vWF and development of biological activity. After conversion into its active conformation, and participation in the factor X activating complex, activated factor VIII rapidly looses its activity. This process is governed by both enzymatic degradation and subunit dissociation.