Na+ binding to thrombin enhances the procoagulant and prothrombotic functions of the enzyme and obeys a mechanism that produces two kinetic phases: one fast (in the microsecond time scale) due to Na+ binding to the low activity form E to produce the high activity form E:Na+ and another considerably slower (in the millisecond time scale) that reflects a pre-equilibrium between E and the inactive form E*. In this study, we demonstrate that this mechanism also exists in other Na+-activated clotting proteases like factor Xa and activated protein C. These findings, along with recent structural data, suggest that the E*-E equilibrium is a general feature of the trypsin fold.