Rj. Leipold et al., MATHEMATICAL-MODEL OF SERINE-PROTEASE INHIBITION IN THE TISSUE FACTORPATHWAY TO THROMBIN, The Journal of biological chemistry, 270(43), 1995, pp. 25383-25387
A mathematical model has been developed to simulate the generation of
thrombin by the tissue factor pathway. The model gives reasonable pred
ictions of published experimental results without the adjustment of an
y parameter values. The model also accounts explicitly for the effects
of serine protease inhibitors on thrombin generation, Simulations to
define the optimum affinity profile of an inhibitor in this system ind
icate that for an inhibitor simultaneously potent against VIIa, IXa, a
nd Xa, inhibition of thrombin generation decreases dramatically as the
affinity for thrombin increases. Additional simulations show that the
reason for this behavior is the sequestration of the inhibitor by sma
ll amounts of thrombin generated early in the reaction. This model is
also useful for predicting the potency of compounds that inhibit throm
bosis in rats, We believe that this is the first mathematical model of
blood coagulation that considers the effects of exogenous inhibitors.
Such a model, or extensions thereof, should be useful for evaluating
targets for therapeutic intervention in the processes of blood coagula
tion.