Abstract Number: PB0115
Meeting: ISTH 2021 Congress
Background: Factor XI (FXI) is a procoagulant enzyme that interacts with multiple substrates to promote thrombin generation. This is achieved directly through activation of coagulation factors and indirectly through inactivation of anticoagulants, including tissue factor pathway inhibitor (TFPI). Current computational models of coagulation do not incorporate functions of FXIa other than FXIa activation of factor IX.
Aims: To study the effect of TFPI inactivation by FXIa on thrombin generation using a mathematical model of thrombin generation.
Methods: We expanded the ordinary differential equations model of thrombin generation in plasma to include TFPI inactivation by FXIa. In simulations, we recorded time to generate 2 nM thrombin, maximum thrombin concentration (peak thrombin) and time to reach peak thrombin concentration. Simulations were initiated with tissue factor (TF, 1-10 pM). In select simulations, TFPI inactivation by FXIa was included by adjusting this reaction rate constant to ≥0, while the rate of feedback activation of FXI by thrombin was accelerated by the presence of polyphosphate.
Results: Including inactivation of TFPI by FXIa increased maximum thrombin concentration and decreased time to reach maximum thrombin concentration. However, our model predicted that time to initially generate 2 nM of thrombin by TF was insensitive to TFPI inactivation by FXIa. Inactivation of TFPI by FXIa led to a decrease in time to generate 2 nM of thrombin and time to reach peak thrombin as a function of the rate of FXIa generation by thrombin, while peak thrombin generation was unaffected. In all scenarios, the kinetics of thrombin generation was sensitive to the initial TF concentration.
Conclusions: Numerical simulations suggest that inactivation of TFPI by FXIa increases the initial rate and extent of thrombin generation. The rate of thrombin generation is amplified and is sensitive to inactivation of TFPI by FXIa when feedback activation of FXI by thrombin is accelerated by polyphosphate.
To cite this abstract in AMA style:Lakshmanan HHS, Estonilo A, Puy C, Zheng TJ, Maddala J, Gailani D, Shatzel JJ, Gruber A, Jurney PL, McCarty OJT. Refining and Validating a Model of FXI Activation and Activity in Thrombin Generation and Blood Coagulation [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/refining-and-validating-a-model-of-fxi-activation-and-activity-in-thrombin-generation-and-blood-coagulation/. Accessed May 20, 2022.
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