Anticoagulants and the Propagation Phase of Thrombin Generation
Open Access
- 18 November 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (11), e27852
- https://doi.org/10.1371/journal.pone.0027852
Abstract
The view that clot time-based assays do not provide a sufficient assessment of an individual's hemostatic competence, especially in the context of anticoagulant therapy, has provoked a search for new metrics, with significant focus directed at techniques that define the propagation phase of thrombin generation. Here we use our deterministic mathematical model of tissue-factor initiated thrombin generation in combination with reconstructions using purified protein components to characterize how the interplay between anticoagulant mechanisms and variable composition of the coagulation proteome result in differential regulation of the propagation phase of thrombin generation. Thrombin parameters were extracted from computationally derived thrombin generation profiles generated using coagulation proteome factor data from warfarin-treated individuals (N = 54) and matching groups of control individuals (N = 37). A computational clot time prolongation value (cINR) was devised that correlated with their actual International Normalized Ratio (INR) values, with differences between individual INR and cINR values shown to derive from the insensitivity of the INR to tissue factor pathway inhibitor (TFPI). The analysis suggests that normal range variation in TFPI levels could be an important contributor to the failure of the INR to adequately reflect the anticoagulated state in some individuals. Warfarin-induced changes in thrombin propagation phase parameters were then compared to those induced by unfractionated heparin, fondaparinux, rivaroxaban, and a reversible thrombin inhibitor. Anticoagulants were assessed at concentrations yielding equivalent cINR values, with each anticoagulant evaluated using 32 unique coagulation proteome compositions. The analyses showed that no anticoagulant recapitulated all features of warfarin propagation phase dynamics; differences in propagation phase effects suggest that anticoagulants that selectively target fXa or thrombin may provoke fewer bleeding episodes. More generally, the study shows that computational modeling of the response of core elements of the coagulation proteome to a physiologically relevant tissue factor stimulus may improve the monitoring of a broad range of anticoagulants.Keywords
This publication has 53 references indexed in Scilit:
- Anticoagulation by factor Xa inhibitorsJournal of Thrombosis and Haemostasis, 2010
- Thrombin generation in rheumatoid arthritis: Dependence on plasma factor compositionThrombosis and Haemostasis, 2010
- Empirical and theoretical phenotypic discriminationJournal of Thrombosis and Haemostasis, 2009
- The impact of uncertainty in a blood coagulation modelMathematical Medicine and Biology: A Journal of the IMA, 2009
- Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs?Pharmacological Research, 2009
- The Nature of the Stable Blood Clot Procoagulant ActivitiesPublished by Elsevier ,2008
- Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor compositionJournal of Thrombosis and Haemostasis, 2008
- Argatroban: UpdateAmerican Heart Journal, 2006
- Fondaparinux Sodium Mechanism of ActionClinical Pharmacokinetics, 2002
- Functional Characterization of Recombinant Human Meizothrombin and Meizothrombin(desF1)Journal of Biological Chemistry, 1997