Baugh1998 - Regulation of coagulation factor Xa by TFPI

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Basic mathematical model of the formation of coagulation factor Xa involving TF:VIIa and its inhibition by TFPI.
Related Publication
  • Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor.
  • Baugh RJ, Broze GJ Jr, Krishnaswamy S
  • The Journal of Biological Chemistry , 2/ 1998 , Volume 273 , Issue 8 , pages: 4378-4386 , PubMed ID: 9468488
  • Department of Medicine, Division of Hematology/Oncology, Emory University, Atlanta, Georgia 30322, USA.
  • Tissue factor (TF) pathway inhibitor (TFPI) regulates factor X activation through the sequential inhibition of factor Xa and the VIIa.TF complex. Factor Xa formation was studied in a purified, reconstituted system, at plasma concentrations of factor X and TFPI, saturating concentrations of factor VIIa, and increasing concentrations of TF reconstituted into phosphatidylcholine:phosphatidylserine membranes (TF/PCPS) or PC membranes (TF/PC). The initial rate of factor Xa formation was equivalent in the presence or absence of 2.4 nM TFPI. However, reaction extent was small (<20%) relative to that observed in the absence of TFPI, implying the rapid inhibition of VIIa.TF during factor X activation. Initiation of factor Xa formation using increasing concentrations of TF/PCPS or TF/PC in the presence of TFPI yielded families of progress curves where both initial rate and reaction extent were linearly proportional to the concentration of VIIa.TF. These observations were consistent with a kinetic model in which the rate-limiting step represents the initial inhibition of newly formed factor Xa. Numerical analyses of progress curves yielded a rate constant for inhibition of VIIa.TF by Xa.TFPI (>10(8) M-1.s-1) that was substantially greater than the value (7.34 +/- 0.8 x 10(6) M-1.s-1) directly measured. Thus, VIIa.TF is inhibited at near diffusion-limited rates by Xa.TFPI formed during catalysis which cannot be explained by studies of the isolated reaction. We propose that the predominant inhibitory pathway during factor X activation may involve the initial inhibition of factor Xa either bound to or in the near vicinity of VIIa.TF on the membrane surface. As a result, VIIa.TF inhibition is unexpectedly rapid, and the concentration of active factor Xa that escapes regulation is linearly dependent on the availability of TF.
Submitter of the first revision: Matthew Roberts
Submitter of this revision: Matthew Roberts
Modellers: Matthew Roberts

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isDescribedBy (1 statement)
PubMed 9468488

isVersionOf (1 statement)
Gene Ontology blood coagulation

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Baugh1998.xml SBML L2V4 representation of Baugh1998 - Regulation of coagulation factor Xa by TFPI 13.81 KB Preview | Download

Additional files

Baugh1998.cps Model COPASI file for Scheme 1. Attempt at reproducing figure 3 - quantity P (Xa) for 900 seconds. Only the equilibrium constant was given for the reversible reaction involving factor X and TF:VIIa and the unit was in nM (Model used uM). Initial conditions given in figure description. Note: parameters 'k-,Xa' and 'k-,VIIa:TF' are expressed in units of 1e4 seconds. 43.69 KB Preview | Download

  • Model originally submitted by : Matthew Roberts
  • Submitted: Jul 18, 2018 9:18:28 AM
  • Last Modified: Jul 18, 2018 9:18:28 AM
  • Version: 2 public model Download this version
    • Submitted on: Jul 18, 2018 9:18:28 AM
    • Submitted by: Matthew Roberts
    • With comment: Edited model metadata online.