Abstract Number: PB0048
Meeting: ISTH 2021 Congress
Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors
Background: By including thrombin feedback activation of FXI and the antithrombin-I activities of fibrin, a previously developed reduced model of flowing whole blood clotting on collagen/tissue factor was able to predict the rate of fibrin generation and the thrombin flux from a growing clot in the presence and absence of fibrin.
Aims: To explore the sensitivity of a reduced extrinsic pathway model for clotting in a 15-micron thick platelet deposit.
Methods: We performed the local sensitivity analysis where each of 5 plasma zymogens and 2 fibrin binding sites for thrombin were varied ±50% from their published value. We conducted 10,000 Monte Carlo simulations where 7 variables were changed simultaneously and independently exploring variations in the main zymogens and thrombin binding sites of fibrin.
Results: A sensitivity analysis of zymogen concentrations indicated that FIX most influenced thrombin generation, a result expected from hemophilia A and B. Averaging all MC simulations confirmed both the mean and standard deviation of measured fibrin generation on 1 tissue factor (TF) molecule per µm2. Across all simulations, free diffusible thrombin in the layer ranged from 20 to 300 nM (mean: 50 nM). The top 2% of simulations that produced maximal fibrin were dominated by conditions with low fibrin antithrombin-I activity (decreased weak and strong sites) and high FIX concentration. In contrast, the bottom 2% of simulations that produced minimal fibrin were dominated by low FIX and FX. The percent reduction of fibrin by an ideal FXIa inhibitor (FXI=0) ranged from 71% fibrin reduction in the top 2% of MC simulations to only 34% fibrin reduction in the bottom 2% of MC simulations. Thus, the antithrombotic potency of FXIa inhibitors may vary depending on normal ranges of zymogen concentrations.
Conclusions: This approach identified key zymogens variations that enhanced or reduced fibrin production during coagulation under flow conditions.
To cite this abstract in AMA style:
Chen J, Diamond SL. Sensitivity Analysis of a Reduced Model of Thrombosis under Flow: Roles of Factor IX, Factor XI, and γ’-Fibrin [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/sensitivity-analysis-of-a-reduced-model-of-thrombosis-under-flow-roles-of-factor-ix-factor-xi-and-%ce%b3-fibrin/. Accessed April 17, 2024.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/sensitivity-analysis-of-a-reduced-model-of-thrombosis-under-flow-roles-of-factor-ix-factor-xi-and-%ce%b3-fibrin/