Figure 4.

fV activation by thrombin and fVII activation by fXa are essential for clotting system recognition of the local TF concentration. A detailed mechanism-driven mathematical model was used. (A) General equations (F, factor; A, activator; I, inhibitor; t, time; x, spatial coordinate). (B) The ratio of total fibrin generated upon clotting activation by spotted TF to that generated upon stimulation with the same quantity of uniformly distributed TF in the models with and without feedback loops. (C) Dependence of the initiation time on the average surface TF density. Clotting was activated by uniformly distributed TF (gray lines) or by rectangular spots (dark gray lines) with a high TF density (60 × 15 μm size and 500 pmol/m² TF density) in a 3D region. To evaluate the role of feedback loops in clotting sensitivity to TF distribution, we individually switched off positive feedback loops for fV, fVII, fVIII, and fXI activation by setting the rates of these reactions to zero in our computer simulations (D). The average TF density for this series of simulations was 12.5 pmol/m².