Background: Our previous mathematical study suggested that low-normal levels of FV can rescue thrombin generation in hemophilia A. Recent experiments suggest TFPI can inhibit partially activated FV (FVa^short) and affect thrombin generation.

Aims: The objective was to embed TFPI-FVa^short interactions into a mathematical model of flow-mediated coagulation, and use it to determine the effect of platelet-surface-mediated TFPI inhibition on thrombin generation for both normal and hemophilia A blood.

Methods: We extended a mathematical model of coagulation kinetics to include production of FVa^short via platelet secretion and activation by FXa, TFPI binding to FVa^short and platelet-bound FXa, and all the possible interactions leading to the formation of a ternary complex between FXa, FVa^short, and TFPI.

Results: Addition of the new TFPI-mediated inhibitory mechanisms increased the critical TF level necessary to produce a strong thrombin response. For physiologic levels of TFPI and fixed flow rate and TF density, the maximum thrombin generated is similar under all types of TFPI inhibition but occurs after different lag times, particularly at low TF levels. Previous version of this model only included TFPI inhibition of plasma-FXa and subendothelial TF:VIIa, and showed little sensitivity to different TFPI levels under the flow. With the new TFPI inhibitory mechanisms, the model displays remarkably different thrombin dynamics under variation of TFPI levels. Under a hemophilic condition (1% FVIII) and low TF, where little to no thrombin generation would occur, reducing TFPI to 50% enables substantial thrombin generation albeit with a long lag. A reduction of TFPI to 10% leads to a substantial reduction in this lag time.

Conclusions: Platelet-surface-mediated TFPI inhibition may play an important inhibitory role in thrombin generation under normal and hemophilic conditions. Such results suggest that blocking or reducing these inhibitory mechanisms may be beneficial to enhance thrombin generation.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/exploration-of-tfpi-mediated-inhibitory-mechanisms-in-coagulation-flow-model/