Fig 1.
Simplified model reaction network.
Factor Xa inhibitor target is shown in aqua brackets and common components in plasma and 4F-PCC formulations in yellow background. Physiological inhibitor reactions are depicted in red. a, activated; APC, activated protein C; AT, antithrombin; F, factor; Fbg, fibrinogen; Fbn, fibrin; FPA, fibrinopeptide A; FPB, fibrinopeptide B; mIIa, meizothrombin; PC, protein C; PS, protein S; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin.
Fig 2.
A comparison between the clinical trial prothrombin time test (PT) data (orange) and the simulated PT data (blue), shown are the mean with SD values.
4F-PCC, four-factor prothrombin complex concentrate; INR, international normalized ration; SD, standard deviation; VKA, vitamin K antagonist.
Fig 3.
Model results for all factors (A) and for factor IIa (B) using a TF concentration of 4 nM to trigger thrombin generation.
Table 1.
Clotting times for the simulations of the PT test.
Fig 4.
Simulation of the effect of rivaroxaban (A) and apixaban (B) using a TF concentration of 4 nM. BID, twice a day.
Fig 5.
Rivaroxaban reversal with 4F-PCC (50 IU/kg, 25 IU/kg, and 15 IU/kg), using a TF concentration of 4 nM.
The bars in each plot represent simulations of total IIa in the presence of rivaroxaban and 4F-PCC (all components), individual pro-coagulant components of 4F-PCC (FII, FVII, FIX, FX), and different combinations of two 4F-PCC components (FII and FVII, FII and FIX, FII and FX, FVII and FIX, FVII and FX, FIX and FX) compared with the base model total IIa results. The inhibitors PC and PS were included at the appropriate level in all the simulations. 4F-PCC, four-factor prothrombin complex concentrate; FII, factor II, FVII, factor VII; FIX, factor IX; FX, factor X; IU, international unit; PC, protein C; PS, protein S; TF, tissue factor.
Fig 6.
Apixaban reversal with 4F-PCC (50 IU/kg, 25 IU/kg, and 15 IU/kg) using a TF concentration of 4 nM.
The bars in each plot represent simulations of total IIa in the presence of apixaban and 4F-PCC (all components), individual pro-coagulant components of 4F-PCC (FII, FVII, FIX, FX), and different combinations of two 4F-PCC components (FII and FVII, FII and FIX, FII and FX, FVII and FIX, FVII and FX, FIX and FX) compared with the base model total IIa results. The inhibitors PC and PS were included at the appropriate level in all the simulations. 4F-PCC, four-factor prothrombin complex concentrate; FII, factor II, FVII, factor VII; FIX, factor IX; FX, factor X; IU, international unit; PC, protein C; PS, protein S; TF, tissue factor.