Thrombin is an enzyme that is generated in both vascular and avascular systems, and is best known for its role in the biochemical reactions leading to the formation of fibrin, the key structural component of a blood clot. A mathematical model of thrombin generation, incorporating all of the major pro- and anti-coagulant factors required to maintain the hemostatic balance in vivo is developed. This model consists of 77 nonlinear ordinary differential equations with 112 parameters, describing the rate of change of the concentrations of the various proteins and lipid involved in thrombin generation. Two significant novel aspects of the model are the inclusion of the lipid component, and the dynamic protein C pathway of inhibition. Simulations indicate that the thrombin generating system in plasma is highly lipid dependent, although the peak thrombin produced is lipid saturable at ≈300 nM vesicles.; Recently, the presence of most of the precursors involved in thrombin generation has been established in ovarian follicular fluid (FF). By adaptations of our model, omitting specific reactions corresponding to proteins not present in FF, we studied the production of thrombin in human ovarian FF, which is an avascular system. Simulations indicate that the peak level of plasma thrombin generation is more than 400 times that in FF. The absence of the amplification pathway factors VIII, IX, and XI, in FF is a major contributor to the reduction of thrombin production in FF, since the peak thrombin level in plasma without these factors is only 2.4 times higher than in FF. Simulations reveal that thrombomodulin could significantly modulate thrombin generation in FF, however its presence in the follicle has not been experimentally determined. A sustained low level of thrombin production can occur in FF. However, since the generation of fibrin is not a healthy event in follicles, the role of the thrombin generating system in the follicle may not be solely to produce thrombin, but rather to produce sustained low levels of other enzymes or complexes which are capable of mediating a variety of cellular effects. FF simulations result in sustained low levels of TF:VIIa:Xa, a complex known to induce cellular signalling, which supports this hypothesis.; Parameter sensitivity analysis of the model found that thrombin generation in plasma is most sensitive to the rates of prothrombin activation, while thrombin generation in FF is most sensitive to the rate of antithrombin inhibition. Through investigation of the variation of the thrombin sensitivity coefficients over time, the importance of each parameter at different stages within the sequence of reactions was quantified.
展开▼
