Schematic representation of coagulation initiation and amplification. (A) In the current paradigm, activation of the FVIII and FV cofactors is considered to be primarily a thrombin-mediated feedback reaction, although a key role of FXa in relation to thrombin has been demonstrated for FV activation. (B) The coagulation scheme supported by the present studies highlights in addition the newly identified selective activation of FVIII by nascent FXa within the extrinsic TF-FVIIa-FXa initiation complex prior to inhibition by TFPI. By concurrently activating FIX, the extrinsic TF-FVIIa complex can initiate directly the FVIIIa-FIXa antihemophilic pathway. The 2 depicted mechanisms of coagulation activation may be variably integrated in response to different stimuli.