Figure 5.

Production of platelet-bound FIXa and timing of FVIIIa:FIXa formation in in silico experiments for (Left) TF^HFXIa⁻ ([TF]_d = 10 fmol/cm²and [E-FXIa]= 0) and (Right) TF^LFXIa⁺ ([TF]_d = 0.02 fmol/cm² and [E-FXIa]= 10 pM). The model includes 250 ‘shared’ binding sites per activated platelet for which FIX and FIXa compete and 250 ‘exclusive’ binding sites per activated platelet to which only FIXa can bind. (A) For TF^HFXIa⁻, the formation of platelet-bound FIXa for the first ≈ 400 sec occurs almost exclusively by fluid-phase FIXa binding to the exclusive sites. FXIa-mediated activation of platelet-bound FIX (red curve) contributes negligibly early in the simulation, but becomes dominant at later times. (B) For TF^LFXIa⁺, platelet-bound FIXa formation is dominated throughout the simulation by the activation of platelet-bound FIX (bound to the shared binding sites) by platelet-bound FXIa (red curve). Little platelet-bound FIXa is formed by plasma FIXa binding to either type of platelet binding site (green and blue curves). (C) For TF^HFXIa⁻, platelet-bound FVIIIa becomes available early (see Fig. 3A and 4A) because of activation by platelet-bound FXa originally produced by TF:FVIIa, and so [FVIIIa:FIXa] also rises early and involves FIXa bound to the exclusive binding sites (green curve). Compared to these results, in (D) we see that for TF^LFXIa⁺, platelet-bound FVIIIa becomes available later (see Fig. 3C and 4B), because of the bootstrap feedback process, and so [FVIIIa:FIXa] rises much later, and involves FIXa bound to the shared binding sites (red curve). The onset of the thrombin burst is indicated by the dashed lines which show when the plasma thrombin concentration reached 1 nM and 30 nM in the respective simulations. Platelet count 250,000/μL, shear rate 100/sec.