Computational Modeling of Factor Xa Inhibition by Immobilized Tissue Factor Pathway Inhibitor

Abstract

Coating surfaces of implanted devices with anticoagulants can reduce thrombosis and studies using a recombinant form of endogenous tissue factor pathway inhibitor (rTFPI) are promising. The anticoagulant function of immobilized rTFPI is thought to occur primarily by its inhibition of plasma clotting factor Xa (FXa); however the kinetics of this reaction at a surface are as yet unknown. To better understand the surface inhibition reaction under flow conditions, a theoretical model was developed delineating the roles of mass transport and reaction kinetics for an in vitro parallel plate device used in prior experimental studies [Hall et al., J. Biomech. Eng. 120:484-490, 1998]. As a first approximation, the kinetics of inhibition of FXa by rTFPI reported for static, homogeneous systems was considered. The unsteady convection-diffusion equation was solved for different wall-shear rates and inlet concentrations of FXa using the computational fluid dynamics software CFD-ACE (ESI Software Group). The results show that the heterogeneous inhibition reaction is diffusion controlled prior to saturation of the rTFPI. The experimental results compare favorably with the model at the lower shear rates (100-400 s(-1)). At higher shear rates (>400 s(-1)) the theoretical results follow the same trend as the experimental results but show a greater inhibition of FXa, implying an effect of flow or shear on the inhibition reaction.

A Computational Analysis of an In Vitro Vessel Wall Injury Model

“…6a and 6b). Furthermore, unlike the earlier model of rTFPI inhibition, 16 FXa is generated at the upstream wall rather then delivered at a uniform concentration in the fluid-phase. Therefore, the lower the wall shear rate, the greater the effect of diffusion of FXa into the bulk and away from the downstream wall where the inhibition reaction occurs.…”

“…17 The theoretical model was developed using parameters published for the enzymatic conversion of FX to FX by TF:VIIa and for the homogeneous fluid phase reaction between FXa and TFPI. These mechanisms were implemented previously in separate computational models for the interaction of FXa and rTFPI 16 at shear rates of 200 and 400 s 21 , but deviated by 30-40% at a wall shear rate of 50 s 21 . The increased binding capacity of adsorbed rTFPI at lower shear rates may be the result of FXa binding to the C-terminal region of rTFPI or the K3 domain in addition to K2.…”

“…8 The second section of the reaction surface involved the inhibition of the FXa generated in the upstream section. Tummala and Hall 16 successfully employed the reaction mechanism and respective rate constants in an earlier model of FXa inhibition by surface bound rTFPI. 16 It was assumed that a one to one binding occurred between the FXa and the TFPI on the surface and the simulation was based on the reaction mechanism proposed by Huang et al 9 They concluded that the binding of TFPI to FXa in a static homogeneous fluid phase system takes place in two steps.…”