Factor Xa Generation by Computational Modeling: An Additional Discriminator to Thrombin Generation Evaluation

Kathleen E Brummel-Ziedins,Matthew Gissel,Thomas Orfeo,Kenneth G Mann,Frits R Rosendaal,Pieter H Reitsma

doi:10.1371/journal.pone.0029178

Kathleen E Brummel-Ziedins, Matthew Gissel + Show 4 more

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https://doi.org/10.1371/journal.pone.0029178

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Journal: PloS one	Publication Date: Jan 11, 2012
Citations: 60	License type: CC BY 4.0

Affiliation: University of Vermont, Leiden University Medical Center

Abstract

Factor (f)Xa is a critical enzyme in blood coagulation that is responsible for the initiation and propagation of thrombin generation. Previously we have shown that analysis of computationally generated thrombin profiles is a tool to investigate hemostasis in various populations. In this study, we evaluate the potential of computationally derived time courses of fXa generation as another approach for investigating thrombotic risk. Utilizing the case (n = 473) and control (n = 426) population from the Leiden Thrombophilia Study and each individual's plasma protein factor composition for fII, fV, fVII, fVIII, fIX, fX, antithrombin and tissue factor pathway inhibitor, tissue factor-initiated total active fXa generation was assessed using a mathematical model. FXa generation was evaluated by the area under the curve (AUC), the maximum rate (MaxR) and level (MaxL) and the time to reach these, TMaxR and TMaxL, respectively. FXa generation was analyzed in the entire populations and in defined subgroups (by sex, age, body mass index, oral contraceptive use). The maximum rates and levels of fXa generation occur over a 10- to 12- fold range in both cases and controls. This variation is larger than that observed with thrombin (3–6 fold) in the same population. The greatest risk association was obtained using either MaxR or MaxL of fXa generation; with an ∼2.2 fold increased risk for individuals exceeding the 90th percentile. This risk was similar to that of thrombin generation(MaxR OR 2.6). Grouping defined by oral contraceptive (OC) use in the control population showed the biggest differences in fXa generation; a >60% increase in the MaxR upon OC use. FXa generation can distinguish between a subset of individuals characterized by overlapping thrombin generation profiles. Analysis of fXa generation is a phenotypic characteristic which may prove to be a more sensitive discriminator than thrombin generation among all individuals.

Highlights

The inventory of blood and vessel wall components associated with the blood coagulation system for hemorrhage control is extensive, and this inventory increases substantially with the inclusion of intermediate species that emerge in the individual processes leading to thrombin generation
We have reported differences in thrombin generation profiles between acute (ACS) and stable coronary artery disease (CAD) populations [22] and have determined that in the ACS population, the procoagulant phenotype seen with thrombin generation profiles appears to depend primarily on the influence of AT, fVIII and prothrombin
When we evaluated the influence of the ensemble of plasma composition on the fXa generation output, we determined that that the increased fXa generation in women on oral contraceptives was primarily driven by differences in the levels of fIX and tissue factor pathway inhibitor (TFPI) (Figure 6A)

Summary

Introduction

The inventory of blood and vessel wall components associated with the blood coagulation system for hemorrhage control is extensive, and this inventory increases substantially with the inclusion of intermediate species that emerge in the individual processes leading to thrombin generation. The limited amounts of fXa produced by the extrinsic tenase bind to available membrane sites and convert picomolar amounts of prothrombin to thrombin [4] This thrombin activates fVIII and fV allowing the initial formation of the intrinsic tenase and prothrombinase complexes. The intrinsic tenase complex activates fX at a 50- to 100- fold higher rate than the extrinsic tenase complex [5,6,7] This increased rate of fXa generation overcomes the suppressive action of fXa inhibitors such as tissue factor pathway inhibitor (TFPI) and antithrombin (AT) resulting in increasing levels of prothrombinase and the propagation of the procoagulant event. Many studies are currently underway to clinically evaluate antithrombotic agents that target fXa [10]

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