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.
Highlights
The management of anticoagulant therapy has relied on clotbased assays such as the prothrombin time (PT) assay
In the case of warfarin therapy, it has been established in clinical studies that a prolonged clot time in the PT assay, after normalization to account for reagent variability in the 2 to 3-fold range indicates a sufficient level of anticoagulation in many patients [1]
We have previously shown that contact pathway inhibited blood samples from individuals with similar levels of warfarin anticoagulation (INR 1.9–2.5) and no reported bleeding pathology exhibit significant variability in their tissue factor (Tf)-initiated coagulation response [15]
Summary
The management of anticoagulant therapy has relied on clotbased assays such as the prothrombin time (PT) assay. In the case of warfarin therapy, it has been established in clinical studies that a prolonged clot time in the PT assay, after normalization to account for reagent variability (expressed as the International Normalized Ratio, INR) in the 2 to 3-fold range indicates a sufficient level of anticoagulation in many patients [1]. A generally applicable method to evaluate all classes of anticoagulants is lacking. A limitation of clot based assays is that more than 95% of thrombin generation occurs after clot formation, whether studied in plasma [4] or whole blood [5] or in reconstructions of the coagulation proteome using purified proteins [6]. Post-clot thrombin generation (i.e. propagation phase) is often characterized in terms of parameters describing features of its dynamics, e.g
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