Simplified diagram of protease activation driving the coagulation cascade. Tissue factor (TF) is a transmembrane protein receptor expressed by extravascular cells and is a cofactor for factor VII (FVII). Once bound to TF, the proenzyme FVII is activated to the enzyme FVIIa. The TF-FVIIa complex (extrinsic tenase) activates FX to FXa. The TF-FVIIa complex can also activate FIX to FIXa. FVIII and von Willebrand factor (vWF) circulate in plasma as a noncovalent bimolecular complex. Upon activation by thrombin, FVIIIa dissociates from the FVIII-vWF complex to interact with FIXa. FIXa on platelets and TF-bearing cells binds with FVIIIa, assembling the FIXa-FVIIIa complex (intrinsic tenase). The FIXa-FVIIIa complex activates FX to FXa. FV is principally synthesized in the liver and is activated to FVa by FXa and thrombin. FXa associates with its cofactor FVa to form prothrombinase complexes that activate FII (prothrombin) to FIIa (thrombin). Thrombin activates FXIII to FXIIIa and also cleaves FI (fibrinogen) to soluble fibrin (FIa), which is then cross-linked by FXIIIa to form insoluble fibrin.