Table 1.
Patient characteristics.
Fig 1.
Thrombin generation in cirrhosis patients and healthy subjects.
(A) Mean thrombin generation curves in healthy subjects (○), Child-Pugh A patients (●), Child-Pugh B patients (Δ), and Child-Pugh C patients (▲) measured at 1 pM TF. (B) Lag time, (C) peak height, (D) endogenous thrombin potential, (E) time-to-peak and (F) velocity index were quantified from the TG curves. *p<0.05, **p<0.01, ***p<0.001 compared to healthy subject values.
Table 2.
Coagulation factor levels.
Fig 2.
Prothrombin conversion in cirrhosis patients and healthy subjects.
(A) Mean prothrombin conversion curves in healthy subjects (○), Child-Pugh A patients (●), Child-Pugh B patients (Δ), and Child-Pugh C patients (▲) triggered with 1 pM TF. (B) Total prothrombin conversion, (C) maximal rate of prothrombin conversion, (D) thrombin-antithrombin formation, (E) thrombin-α2-macroglobulin formation and (F) the percentage of thrombin inhibited by α2-macroglobulin were quantified from the TG curves. *p<0.05, **p<0.01, ***p<0.001 compared to healthy subject values.
Fig 3.
Thrombin inactivation capacity in cirrhosis patients and healthy subjects.
The thrombin decay capacity was calculated based on the antithrombin, α2-macroglobulin and fibrinogen level of the sample.*p<0.05, **p<0.01, ***p<0.001 compared to healthy subject values.
Fig 4.
APC sensitivity in cirrhosis patients and healthy subjects.
(A-B) Thrombin generation and prothrombin conversion curves measured at 1 pM TF in the absence (gray) or presence of 0.56 nM thrombomodulin (black) in healthy subjects (○), Child-Pugh A patients (●), Child-Pugh B patients (Δ), Child-Pugh C patients (▲). (C) (C-F) The percentage of the ETP, peak height, total prothrombin conversion and the maximum prothrombin conversion rate in plasma with thrombomodulin compared to plasma without thrombomodulin. *p<0.05, **p<0.01, ***p<0.001 compared to healthy subject values.
Fig 5.
The contribution of changes in prothrombin conversion, antithrombin levels and a2-macroglobulin levels to the altered thrombin generation profile in cirrhosis patients.
Prothrombin conversion (A-B), antithrombin levels (C-D) and α2-macroglobulin levels (E-F) were normalized in silico to the average level found in the healthy subjects group. Thrombin generation was simulated (black) in healthy subjects (○), Child-Pugh A patients (●), Child-Pugh B patients (Δ), Child-Pugh C patients (▲) and compared to the experimental values found in the same group of subjects (grey). The simulated and experimental TG curves in the healthy subject group are almost completely superimposed. The ratio of simulated and experimental ETP values were compared between patients and healthy subjects. *p<0.05, **p<0.01, ***p<0.001 compared to healthy subject values.
Fig 6.
The in silico effect prothrombin complex concentrates with or without co-supplementation of antithrombin in cirrhosis.
In silico experimentation was performed to predict the effect of prothrombin complex concentrate administration on thrombin generation in cirrhosis patients in the absence (A) or presence (B) of antithrombin supplementation. Prothrombin conversion curves were increased in silico to 110% (- -), 120% (- -), ad 130% (- ∙ -) with or without co-administration of 100%, 120%, or 130% AT. The effects of PCC with or without antithrombin were quantified by the ETP (C-D) and the peak height (E-F). Healthy subjects are shown in black, CP-A patients in red, CP-B patients in blue and CP-C patients in green. *p<0.05, **p<0.01, ***p<0.001 compared to healthy subject values.