Fig 1.
BK generation reaction network including surface-mediated reactions.
FXII: factor FXII, αFXIIa: two-chain activated factor FXII, βFXIIa: single-chain activated FXII, FXI: factor FXI, PK: prekallikrein, PKa: kallikrein, HK: high molecular weight kininogen, cHK: cleaved high molecular weight kininogen, BK: bradykinin, α2M: α2-macroglobulin, C1inh: C1 esterase inhibitor. Surface-bound species are indicated by subscript ‘s’.
Table 1.
List of biochemical reactions in the computational model of the kallikrein-kinin system.
Surface-bound species are indicated by subscript ‘s’, and solution-phase species are indicated by subscript ‘v’.
Fig 2.
Effect of DXS concentration on the rate of FXII activation.
Fig 3.
FXII activation versus DXS concentration via two alternative FXII activation mechanisms.
Comparison of the Røjkjær and Schousboe [44] experimental data with simulations using optimised kinetic parameters for FXII activation, via either a combination of FXII autoactivation (reaction 3) and FXII self-activation (reaction 4), or just FXII self-activation in the presence of background αFXIIa.
Fig 4.
Comparison of simulations of the activation of FXII, PK and cleavage of HK with the experimental data from Björkqvist et al [30].
a) [DXS] = 0.1 μg/ml, b) [DXS] = 1 μg/ml.
Fig 5.
The level of BK generated by addition of 100 μg/mL DXS to plasma; comparison between in vitro data and model output.
In the LC-MS/MS assay, the BK level was tested at 10 different time points. The error bars represent the standard deviation of the BK levels in four tested plasma samples.
Fig 6.
Model simulation comparison of BK generation in healthy and HAE plasma in the presence of 100 μg/ml DXS.
Fig 7.
Inhibition of BK generation via different KKS inhibitors.
a) Simulated data showing the proportion of CSL312-FXII complex to total FXII in plasma equilibrated with different concentrations of CSL312, b) normalised BK concentrations generated by DXS-mediated activation of healthy pooled plasma titrated with various KKS inhibitors, comparison of in vitro data with model output. Experimental data was adapted from Cao et al. [8].