Linearized model for the initiation of factor Va, and thrombin generation.

A simple model of the initiation of thrombin formation in plasma as a response to factor Xa generation was constructed. In this model factor Xa is considered as an input with a constant concentration. Substrate depletion and inactivation by activated protein C are neglected. The resulting linear model allows a closed form solution by standard methods. With values of the reaction rate constants, as determined in purified systems, this model predicts a highly explosive and complete activation of factor V and prothrombin as a response to any given (steady state) factor Xa concentration even in situations where prothrombinase and(/or) thrombin are rapidly inactivated. However, the time delay to rapid thrombin production becomes longer at lower factor Xa concentrations. Analysis of this time delay as a function of the factor Xa concentration indicates that the gain of the feedback loop of factor V activation by thrombin is so high that the contribution of factor V activation by factor Xa is relatively unimportant for factor Xa concentrations in the nanomolar range. It appears that the time lag is mainly determined by the gain of this feedback loop: similar proportional reductions of each of these reaction rates causes a similar effect. The effects of moderately enhanced inhibition rates of thrombin and prothrombinase on the time delay depend strongly on factor Xa concentration. Only a minor prolongation of the delay is predicted for factor Xa concentrations in the nanomolar range, but for factor Xa concentrations in the 1-10 pM range, the enhanced decay will cause considerable delays. Simultaneous reduction of the turnover rate of prothrombinase results in much larger delays for the entire range of factor Xa concentrations.