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

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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.

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References

  1. Balasubramanian, V., et al. Residence-time dependent changes in fibrinogen adsorbed to polymeric biomaterials. J. Biomed. Mater. Res. 44(3):253–260, 1999.

    Article  PubMed  CAS  Google Scholar 

  2. Baugh R. J., Broze G. J. Jr., Krishnaswamy S. (1998) Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J. Biol. Chem. 273:4378–4386

    Article  PubMed  CAS  Google Scholar 

  3. Broze, G. J. Jr., et al. (1988) The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: Insight into its possible mechanism of action. Blood 71:335–343

    PubMed  CAS  Google Scholar 

  4. Broze, G. J. Jr. (1992) The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin. Hematol. 29:159–169

    PubMed  CAS  Google Scholar 

  5. Broze, G. J. Jr. (1995) Tissue factor pathway inhibitor and the revised theory of coagulation. Annu. Rev. Med. 46:103–112

    Article  PubMed  CAS  Google Scholar 

  6. Chandiwal, A., et al. Factor Xa Inhibition by immobilized recombinant tissue factor pathway inhibitor. J. Biomater. Sci. Polym. Ed. 17(9):1025–1037, 2006.

    Article  PubMed  CAS  Google Scholar 

  7. Cunningham A. C., et al. (2002) Structural and functional characterization of tissue factor pathway inhibitor following degradation by matrix metalloproteinase-8. Biochem. J. 367:451–458

    Article  PubMed  CAS  Google Scholar 

  8. Ettelaie, C., et al. (1999) The role of the C-terminal domain in the inhibitory functions of tissue factor pathway inhibitor. FEBS Lett. 463:341–344

    Article  PubMed  CAS  Google Scholar 

  9. Ferziger J. H., Peric M. (2003) Computational Methods for Fluid Dynamics. New York, Springer-Verlag, 71–89

    Google Scholar 

  10. Fletcher C. A. J. (1991) Computational Techniques for Fluid Dynamics. Berlin, Springer Verlag, 401

    Google Scholar 

  11. Gemmel C. H., Nemerson Y., Turitto V. T. (1990) The effects of shear rate on the enzymatic activity of the tissue factor-factor VIIa complex. Microvasc. Res. 40:327–340

    Article  Google Scholar 

  12. Hall, C. L., S. M. Slack, and V. T. Turitto. A computational analysis of FXa generation by the TF:VIIa complex on the surface of cultured rat vascular smooth muscle cells. Ann. Biomed. Eng. 26:28–36, 1998.

    Google Scholar 

  13. Hall C. L., et al. (1998) Factor Xa generation at the surface of cultured rat vascular smooth muscle cells in an in vitro flow system. J. Biomech. Eng. 120:484–490

    PubMed  CAS  Google Scholar 

  14. Huang Z. F., Wun T. C., Broze G. J. Jr. (1993) Kinetics of factor Xa inhibition by tissue factor pathway inhibitor. J. Biol. Chem. 268:26950–26955

    PubMed  CAS  Google Scholar 

  15. Lindhout T., et al. (1994) Kinetics of the inhibition of human factor Xa by full length and truncated recombinant tissue factor pathway inhibitor. Biochem. J. 297:131–136

    PubMed  CAS  Google Scholar 

  16. Nemerson, Y. Tissue factor pathway of coagulation. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice, edited by M.D. Colman, et al. Philadelphia: J. B. Lippincott Company, 1994, pp. 81–93.

  17. Oltrona L., et al. (1996) Efficacy of local inhibition of procoagulant activity associated with small-diameter prosthetic vascular grafts. J. Vasc. Surg. 24:624–631

    Article  PubMed  CAS  Google Scholar 

  18. Østerud B., Bajaj M. S., Bajaj S. P. (1995) Sites of tissue factor pathway inhibitor (TFPI) and tissue factor expression under physiologic and pathologic conditions. Thromb. Haemost. 73:873–875

    PubMed  Google Scholar 

  19. Probstein R. F. (1994) Physicochemical Hydrodynamics: An Introduction. New York, John Wiley and Sons Inc., 400

    Google Scholar 

  20. Raybagkar D. A., et al. (2004) In vitro flow evaluation of recombinant tissue factor pathway inhibitor immobilized on collagen-impregnated Dacron. ASAIO J. 50:301–305

    PubMed  CAS  Google Scholar 

  21. Rubin B. G., et al. (1996) Preincubation of Dacron grafts with recombinant tissue factor pathway inhibitor decreases their thrombogenicity in vivo. J. Vasc. Surg. 24:865–870

    Article  PubMed  CAS  Google Scholar 

  22. Sun L.-B., et al. (2001) Pretreatment of a Dacron graft with tissue factor pathway inhibitor decreases thrombogenicity and neointimal thickness: A preliminary animal study. ASAIO J. 47:325–328

    Article  PubMed  CAS  Google Scholar 

  23. Wilcox J., et al. (1989) Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc. Natl. Acad. Sci. USA 86:2839–2843

    Article  PubMed  CAS  Google Scholar 

  24. Zhang J., et al. (2003) Glycosyl phosphatidylinositol anchorage of tissue factor pathway inhibitor. Circulation 108:623–627

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was funded by a Research Grant from the Whitaker Foundation.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Illinois Institute of Technology, 10 W. 32nd Street, E1-116, Chicago, IL, 60616, USA

    Shanti R. Tummala & Connie L. Hall

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  1. Shanti R. Tummala
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  2. Connie L. Hall
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Correspondence to Connie L. Hall.

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Tummala, S.R., Hall, C.L. Computational Modeling of Factor Xa Inhibition by Immobilized Tissue Factor Pathway Inhibitor. Ann Biomed Eng 35, 408–418 (2007). https://doi.org/10.1007/s10439-006-9246-x

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  • DOI: https://doi.org/10.1007/s10439-006-9246-x

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