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Exploring the efficiency of thrombin inhibitors with a quantitative model of the coagulation cascade
Author(s) -
Zavyalova Elena G.,
Ustinov Nikita B.,
Kopylov Alexey M.
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13684
Subject(s) - thrombin , coagulation , coagulation cascade , cascade , thrombin generation , chemistry , discovery and development of direct thrombin inhibitors , combinatorial chemistry , biochemistry , pharmacology , biophysics , chromatography , biology , platelet , medicine , immunology
A detailed mathematical description of the coagulation cascade is a challenging task due to a huge set of protein–protein interactions. Simplified models do not permit quantitative description of anticoagulants. The detailed mathematical model presented here was constructed with 98 reactions between 70 species. The model was verified using experimental data on thrombin generation. Four thrombin inhibitors, which have different inhibitory mechanisms, were incorporated into the model. All four thrombin inhibitors delayed prothrombin conversion into thrombin, but did not preclude it. At high inhibitor concentration, thrombin‐mediated positive feedback loops were strongly inhibited and the proportion of prothrombin, converted with factor Xa only, was considerably increased. The most potent inhibitor of prothrombin conversion was aptamer NU172, which also binds prothrombin and inhibits its conversion.