Figure 1.
Schematic of the Extrinsic Coagulation Cascade
(A) Upstream coagulation factors are activated by substances exposed by vessel injury; chief among these factors is TF. Activated upstream coagulation factors initiate a cascade of events that culminate in the activation of platelets and the key protease FIIa. Thrombin forms an amplification loop by activating itself and other coagulations factors as well as platelets.
(B) Activated platelets then aggregate to form platelet plugs, which serve as scaffolds for fibrin clots.
Table 1.
Reactions and Parameter Values Used in the Extrinsic Coagulation Model
Figure 2.
Model Validation Using Published In Vitro Datasets
(A) Thrombin concentration versus time as a function of TFPI concentration following the addition of 1.25pMTF–FVIIa to synthetic plasma.
(B) Thrombin concentration versus time for different combinations of TFPI and ATIII following the addition of 1.25pM TF–FVIIa to synthetic plasma.
(C) APC concentration versus time as a function of TM concentration following the addition of 1.25pM TF–FVIIa to synthetic plasma.
(D) Thrombin concentration as a function of time as a function of TM concentration following the addition of 1.25pM TF–FVIIa to synthetic plasma.
(E) Thrombin concentration versus time as a function of TF–FVIIa initiation strength in synthetic plasma.
(F) Fraction of activated platelets and thrombin concentration as a function of time in the cell-based assay.
The synthetic plasma assay cases were reproduced from Mann and coworkers [31,41], while the platelet activation data in (F) were reproduced from Roberts et al. [40]. The GraphClick software (Arizona Software, http://www.arizona-software.ch) was used for data extraction where a coefficient of variation (CV) of ±10% was added to the data to account for extraction and experimental error. Initial conditions for all simulations are given in Protocol S1.
Table 2.
Quantification of Model Error
Table 3.
The 25 Most Fragile Coagulation Mechanisms in the Absence of Inhibitors
Figure 3.
Sensitivity Analysis of the Coagulation Cascade
OSSC values were calculated using randomly generated parameter sets constructed by perturbing the nominal parameter set by up to ±50% for each parameter (N = 100).
(A–C) The x-axis denotes the trial index (index of the random parameter set), while the y-axis denotes the fragility index. The fragility index is calculated by determining the parameter index of the rank-ordered the OSSC values (the parameter index corresponding to the most fragile parameter has fragility index of 1; the next fragile is 2, while the most robust parameter has a fragility index of 148). The fragility index shows the robustness of a parameter; the smaller the fragility index, the more fragile the parameter. The parameter types are color-coded (shown in the color bar) and organized by biological function: 1–16, subendothelium interactions; 17–40, plasma interactions; 41–62, platelet surface binding; 63–77, platelet activation; 78–107, reactions on platelet surface; and 108–148, inhibitory reactions.
(D–F) The OSSC values from the TFPI, ATIII, and TFPI + ATIII cases versus the control.
Table 4.
Treatment Cases Considered in the Sensitivity Analysis
Table 5.
Ten Example Clinical Trials for FXa and Direct Thrombin Inhibitors