Mathematical model of serine protease inhibition in the tissue factor pathway to thrombin.
A mathematical model has been developed to simulate the generation of thrombin by the tissue factor pathway. The model gives reasonable predictions of published experimental results without the adjustment of any 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 indicate that for an inhibitor simultaneously potent against VIIa, IXa, and 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 small amounts of thrombin generated early in the reaction. This model is also useful for predicting the potency of compounds that inhibit thrombosis 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 coagulation.
Leipold
R J
RJ
DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
Bozarth
T A
TA
Racanelli
A L
AL
Dicker
I B
IB
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D003198:Computer Simulation; D015949:Factor IXa / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D051381:Rats; D015203:Reproducibility of Results; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013917:Thrombin / Q000096:biosynthesis*; D013925:Thromboplastin / Q000378:metabolism*
D000925:Anticoagulants; D015842:Serine Proteinase Inhibitors; D013925:Thromboplastin; D015949:Factor IXa; D013917:Thrombin; D015951:Factor Xa