Monitoring unfractionated heparin therapy: Lack of standardization of anti‐Xa activity reagents

Abstract

Introduction: One of the main advantages of using anti-Xa instead of activated partial thromboplastin time in monitoring of unfractionated heparin (UFH) therapy relies on its hypothesized standardization, with a unique therapeutic range defined to be 0.30 to 0.70 IU/mL. The aim of the present study was to compare the inter-reagent agreement of anti-Xa activity. Methods: Citrate tubes were obtained from 104 inpatients on UFH. Plasma samples were stored frozen in aliquots at −70°C before being shipped to three accredited coagulation laboratories to be evaluated for anti-Xa activity using their routine assay(s). Pooled normal plasmas spiked with dilutions of the 6th International Standard of UFH to achieve anti-Xa activities up to 1.0 IU/mL were evaluated using the same techniques. Results: In the plasmas from patients on UFH, the median anti-Xa activity ranged from 0.37 IU/mL with one reagent to 0.57 IU/mL with another; results were in between (0.45 IU/mL) using two other reagents. Comparisons of results obtained using the different reagents demonstrated unacceptable bias up to 0.24 IU/mL between some reagents (41% difference). The concordance as whether anti-Xa activities measured using different reagents were within or outside the therapeutic range was between 0.411 and 0.939 (kappa). Similar discrepancy was demonstrated for anti-Xa activities when evaluating normal plasma spiked with the International Standard. A discrepancy of the same order of magnitude was demonstrated in the 2017 External Quality Assessment Program provided by the External Quality Control in Assays and Tests exercises. Conclusions: The reported discrepancy between test results obtained using different anti-Xa assays clearly suggests a lack of standardization of that assay with potentially significant impact on the patients' anticoagulation.

Prevention of venous thromboembolism and haemostasis monitoring in patients with COVID-19: Updated proposals (April 2021)

“…Concerning unfractionated heparin (UFH) monitoring, the use of activated partial thromboplastin time (aPTT) may be inappropriate due to the hyper inflammatory status of the disease. Anti-Xa activity, although not fully standardised [45] , may be more suitable to monitor UFH, since it is less dependent on pre-analytical conditions and less vulnerable to laboratory interference [40] . Heparin resistance is frequently observed in critically ill COVID-19 patients [46] and is likely due to high factor VIII and fibrinogen levels [47] .…”

Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory

“…Unlike a 'global' test like APTT, the measurement of anti-Xa activity is insensitive to fluctuations in the underlying hemostatic state (for example, coagulation factor defect following hemorrhage or DIC), which should prompt an adjustment in therapeutic targets to the clinical context and the possible identification of such defects. Finally, significant variability in heparin sensitivity has been reported between the different commercial kits [153][154][155][156].…”

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

“…Recent reports and ECAT surveys have pointed out the variability of heparin measurements using various commercially available anti-FXa assays [ 55 , 56 , 57 ]. This debate has been reactivated with the extended use of heparin therapy in COVID-19 patients, with accumulation when drug clearance is decreased, or drug resistance when strong inflammation, NETs, and histones are present [ 14 , 15 , 17 , 66 ].…”

“…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 ].…”