Therapeutic Monitoring of Warfarin: the Appropriate Response Marker

Abstract

Warfarin is a 4-hydroxycoumarin anticoagulant drug used for the prevention and management of thromboembolic and vascular diseases. It acts through the inhibition of the vitamin K-dependent transcarboxylation reactions that convert precursors of clotting factors into their active form. Appropriate use of warfarin requires patient monitoring and dosage adjustments, to ensure its safety and efficacy. The aim of this work was to clarify the relationship between traditional (prothrombin time, usually expressed as the international normalized ratio; INR) and alternative (clotting factors II and X) warfarin response markers to establish their usefulness for therapeutic drug monitoring. Seventy adult outpatients, aged between 31 and 86 years old, were involved in the study. All subjects received warfarin in a monotherapy regimen and had been on a stable dosing schedule for at least two weeks to assure a steady-state condition. A total of 81 prothrombin times (expressed as INR), and factor II and factor X activity were simultaneously determined. Eleven patients presented repeated measurements at different time periods under the same dosing regimen. The results obtained from regression and cluster analysis showed a close relationship between factors II and X (r = 0.73), a weak correlation between INR and both factor II (r = -0.35) and factor X (r = -0.36), and a very slight dependency between warfarin and the response markers used. In addition, it seems that independent of the selected response marker, in long-term warfarin therapy, reproducible responses can be obtained over time if a steady-state condition is achieved. The coefficients of variation for factors II and X were greater (35.44 and 37.93%, respectively) than INR (14.50%), indicating that INR is a more precise measure than either factor II or factor X. In conclusion, INR appears to be the most appropriate warfarin response marker for therapeutic drug monitoring due to its universality, objectivity as a direct physiological effect measurement, and the available information regarding appropriate endpoints. However, when INR values are not in accordance with patient response therapy, factor II and factor X should be considered as an alternative to optimize warfarin therapy.

Thrombin generation and coagulation factor activities: evaluation and comparison with the international normalized ratio

“…Lind et al [14] found, in contrast, that coagulation factor II had a relative little influence on INR. Sarode et al [9] found that in INR above 5.0, only a sparse correlation existed between INR and coagulation factors II and X. Costa et al [10] confirmed this observation, also in patients with INR within therapeutic INR target range. This is in contrast to our findings, in which we found significant association between coagulation factor activities and INR.…”

“…Costa et al [10] have reported on a weak relationship between coagulation factors II and X versus the level of INR, and advocated that coagulation factors II and X could be used for optimizing monitoring. Furthermore, D 0 Angelo et al [4] have stated that the activity of coagulation factor II better reflects the antithrombotic effect than the INR.…”

“…In general, INR measurements are easy and sufficient regarding monitoring of OAT [3,4,10], although it may be speculated that recordings of CAT generation or the clotting activity of single coagulation factors perform better as predictors of complications of OAT. However, if CAT or single coagulation factor activities are closely associated with the INR, then it seems unlikely that these methods will contribute with additional information.…”

Single‐center determination of reference factor II and factor X activity level values for the monitoring of vitamin K antagonist therapy

“…was 12IU/dL [10][11][12][13][14] in the INR 2-3 group, 9IU/dL [8][9][10][11] in the INR>3-4.5group,and7IU/dL [6][7][8][9]intheINR>4.5group(Kruskal-Wallis test, P<0.0001; Figure 1C)…”

Determination of free and total warfarin concentrations in plasma using UPLC MS/MS and its application to a patient samples

“…Since adverse events are common during oral anticoagulation therapy (Linkins et al , ), maximizing time in a therapeutic range is essential to improve outcomes. In fact, the response to warfarin administration is highly variable and requires close monitoring to ensure its safety and efficacy (Costa et al , ; Wiedermann and Stockner, ).…”