Simulating blood coagulation: the contribution of α2‐macroglobulin and α1‐antitrypsin

Abstract

Our current numerical model of the tissue factor (TF) triggered process of blood coagulation includes two stoichiometric inhibitors found in blood, antithrombin III (ATIII) and tissue factor pathway inhibitor (Hockin et al. J. Biol. Chem. 2002; 277:18322). This model has been validated by its predictions of the behavior of synthetic reconstructions (using purified proteins) of the components thought to represent the TF pathway. However, neither synthetic nor numerical models adequately describe the response of whole blood to a TF challenge. The figure presents a comparison of the predicted time course of thrombin generation, shown as thrombin-ATIII (TAT) complex formation, with TAT data collected from TF triggered human whole blood (35 individuals (mean±SD); CT=clot time). While the current model achieves an adequate representation of the initiation phase (0–4 min), the predicted propagation phase is discrepant in the rate of TAT production (3 fold higher) and the final level of TAT (2 fold higher). Although ATIII is recognized as the major inhibitor of thrombin in vivo, other plasma protease inhibitors display significant reactivity in vitro toward thrombin and factor Xa, suggesting a modulatory role. Inclusion of the stoichiometric inhibitors α2-macroglobulin and α1-antitrypsin into the synthetic and numerical models significantly decreased the rate of TAT formation and yielded final TAT levels within 10% of whole blood data. These data emphasize the potential of low efficiency plasma protease inhibitors to regulate blood coagulation. Supported by Vermont EPSCoR grant (TO and KBZ) and NIH HL 46703(KGM).