APTT therapeutic range for monitoring unfractionated heparin therapy. Significant impact of the anti‐Xa reagent used for correlation

Abstract

Introduction: Unfractionated heparin (UFH) therapy is monitored by using the anti-activated factor X (anti-Xa) activity, or the activated partial thromboplastin time (APTT), which remains the most widely used assay. One of the main advantages of anti-Xa relies on its hypothesized standardization, with a unique therapeutic range (0.30-0.70 IU/ml) for all reagents, whereas APTT is influenced by numerous preanalytical and analytical parameters not related to the anticoagulant activity of UFH. Methods:The aim of this study was to compare the anti-Xa-correlated APTT therapeutic ranges calculated using different combinations of APTT (n = 4) and anti-Xa reagents (n = 4) in frozen citrated plasmas from 87 inpatients on UFH. Results:The median APTT ratio ranged from 2.19 for the less sensitive to 3.23 for the most sensitive reagent, whereas the median anti-Xa activity was between 0.37 IU/ml and 0.57 IU/ml. The APTT therapeutic ranges calculated to correlate with anti-Xa activities between 0.30 and 0.70 IU/ml were found to be highly different from one combination of APTT reagent and analyzer to another. The same applied to the therapeutic range of a single APTT reagent calculated using different anti-Xa assays performed on the same analyzer, leading to a lack of agreement as to whether a sample was classified as subtherapeutic, therapeutic or supratherapeutic in 8.0% to 23.0% of the patients, with kappa coefficients between 0.908 and 0.753. Conclusions:These results suggest that the APTT therapeutic range calculated to correlate with anti-Xa activities between 0.30 and 0.70 IU/ml is influenced not only by the APTT reagent, but also by the anti-Xa reagent used for calculation.

APTT therapeutic range for monitoring unfractionated heparin therapy. Significant impact of the anti‐Xa reagent used for correlation: Response from original authors Toulon et al.

“…We thank Kovacs et al for their valuable comments on our manuscript entitled "APTT therapeutic range for monitoring unfractionated heparin therapy. Significant impact of the anti-Xa reagent used for correlation" 1 and for sharing their experience on that topic. 2 By testing plasma samples from patients on unfractionated heparin (UFH) and low molecular weight heparin (LMWH), they reported, in the late 1990s, that different chromogenic methods for anti-Xa activity did not give equivalent test results and that the analyzer could play a role in the reported discrepancy.…”

“…2 As it is not usually recommended to monitor treatments with LMWH, 3 unlike Kovacs et al 2 and others, 4 we focused our study on the use of this assay in monitoring treatments with UFH. 1,5 For this purpose, we measured anti-Xa activities using four among the most widely used commercially available assays in the plasmas from patients on UFH, and clearly demonstrated that this assay was far from being standardized, as it was commonly believed to be. 3 The median anti-Xa activity was found to be in the range from 0.37 international units (IU)/ml when evaluated using one reagent (Stago) to 0.57 IU/ml using another (HYPHEN BioMed), with in-between results (0.44 IU/ml) obtained using the two other reagents from Siemens and Werfen/Instrumentation Laboratory.…”

“…5 However, it is difficult to agree when Kovacs et al stated in their last sentence that anti-Xa assays are of limited value for monitoring | 2091 LETTERS TO THE EDITOR and 0.70 IU/ml 3,7,8 was found to be influenced not only by the combination of APTT reagent and analyzer, 1,3,10 but also by the anti-Xa reagent used for calculation. 1 In conclusion, taken together, our results 1,5 and the data reported by Kovacs et al 2 clearly highlight the urgent need for a better standardization of the anti-Xa assay and particularly the development of better standardized calibration materials.…”

Optimization of Heparin Monitoring with Anti-FXa Assays and the Impact of Dextran Sulfate for Measuring All Drug Activity

“…Despite the many efforts for anti-FXa assay standardization, many differences are still observed for heparin measurements when the various branded chromogenic methods are used [ 55 , 56 , 57 , 58 ]. This is illustrated by the external quality assessment programs, such as ECAT, showing a significant reagent-to-reagent and laboratory-to-laboratory variability, especially for UFH in the low range [ 57 ].…”

APTT therapeutic range for monitoring unfractionated heparin therapy. Significant impact of the anti‐Xa reagent used for correlation: COMMENT

“…We read with interest the article of Toulon et al, 1 demonstrating that the therapeutic range for activated partial thromboplastin time monitoring of unfractionated heparin therapy is significantly impacted by the choice of anti-Xa reagents used. They had similar findings showing a lack of standardization of anti-Xa reagents for monitoring of unfractionated heparin levels in an earlier paper.…”