Critical evaluation of kinetic schemes for coagulation

Abstract

Two well-established numerical representations of the coagulation cascade either initiated by the intrinsic system (Chatterjee et al., PLOS Computational Biology 2010) or the extrinsic system (Butenas et al., Journal of Biological Chemistry, 2004) were compared with thrombin generation assays under realistic pathological conditions. Biochemical modifications such as the omission of reactions not relevant to the case studied, the modification of reactions related to factor XI activation and auto-activation, the adaptation of initial conditions to the thrombin assay system, and the adjustment of some of the model parameters were necessary to align in vitro and in silico data. The modified models are able to reproduce thrombin generation for a range of factor XII, XI, and VIII deficiencies, with the coagulation cascade initiated either extrinsically or intrinsically. The results emphasize that when existing models are extrapolated to experimental parameters for which they have not been calibrated, careful adjustments are required.

Fig 1. Variables used for in vitro and in silico comparison: IIa_max (peak thrombin concentration), τ_max (time to peak), τ_lag (time to reach 10 nM of thrombin) and ETP (endogenous thrombin potential) for a thrombin formation curve in time.

Fig 2. Experimental thrombin formation (from thrombin generation assay) and simulated thrombin formation using the original Int model for FXII, FXI and FVIII at 100%, 15%, and 0%.

Fig 3. Evolution of the different parameters (%) for each factor concentration range (%) after contact activation.

GRAY BAR In silico Thrombin Generation obtained by Int original; RED BAR obtained by Int modified; BLUE BAR experimental results. In the 0% experimental case for FXII and FXI thrombin is produced since residual amounts of coagulation factors are still present in plasma.

Fig 4. Thrombin generation (TG) for FVIII concentration range after contact activation the solid line - is the in silico data obtained by Int original; the dashed line -- is obtained by Int modified, and • is the experimental data.

Fig 5. Thrombin formation in a physiological plasma sample.

The original Ext model shows a low and delayed thrombin generation.

Fig 6. Thrombin generation (TG) for FVIII concentration range after TF activation A: In silico TG obtained by the original Ext; B: Obtained by modified Ext; C: Experimental curves.

Fig 7. Evolution of the endogenous thrombin potential (ETP).

GRAY BAR In silico ETP obtained by the original Ext model with the initial concentration FVIIa-TF complex = 1pM; RED BAR obtained by modified Ext model; BLUE BAR experimental results.