Models of coagulation and hemophilia. (A) Coagulation is initiated when coagulation proteins and platelets come into contact with the extravasculature. Factor VII binds to tissue factor, is activated, and activates both factor IX and factor X. The factor Xa forms a complex with factor Va on the tissue factor-bearing cell and activates a small amount of thrombin. This thrombin acts to amplify the initial coagulation signal by activating platelets causing release of factor V, activating factor V, cleaving factor VIII and releasing it from VWF, and activating factor XI. In the propagation phase, factor IXa, formed by factor VIIa/tissue factor or generated on the platelet surface by factor XIa, forms a complex with factor VIIIa to activate factor X on the platelet surface where, in complex with factor Va and in the presence of prothrombin, it is protected from inhibition. Formation of the factor Xa/Va complex results in a burst of thrombin generation. (B) In hemophilia, the initiation and amplification phases proceed normally. The propagation phase is absent or significantly decreased because factor Xa cannot be generated on the platelet surface. High-dose factor VIIa acts to partially restore platelet surface factor Xa generation so that factor Xa/Va complex formation proceeds and the propagation phase is improved relative to the hemophilic state.