Factors Influencing Anti-Xa Assays: A Multicenter Prospective Study in Critically Ill and Noncritically Ill Patients Receiving Unfractionated Heparin

Abstract

Background The presence of dextran sulfate (DS) in reagents and the type of blood collection tube (citrate/citrated-theophylline-adenosine-dipyridamole [CTAD]) can lead to discrepancies between unfractionated heparin (UFH) anti-Xa levels.

Objectives To evaluate the extent of the effect (1) of different reagents containing or not containing DS and (2) of the blood collection tubes, on UFH anti-Xa levels, in various clinical situations (NCT04700670).

Methods We prospectively included patients from eight centers: group (G)1, cardiopulmonary bypass (CPB) after heparin neutralization (n = 39); G2, cardiothoracic intensive care unit (ICU) after CPB (n = 35); G3, medical ICU (n = 53); G4, other medical inpatients (n = 38). Blood was collected into citrated and CTAD tubes. Chromogenic anti-Xa assays were centrally performed, using seven reagent/analyzer combinations including two without DS. The association between anti-Xa levels and covariates was tested using a linear mixed-effects model.

Results We analyzed 4,546 anti-Xa values from 165 patients. Median anti-Xa levels were systematically higher with reagents containing DS, whatever the patient group, with the greatest effect observed in G1 (0.32 vs. 0.05 IU/mL). Anti-Xa levels were slightly higher in CTAD than in citrate samples, irrespective of the assay. The model showed: (1) a significant dextran–patient group interaction (p < 0.0001), the effect of DS on anti-Xa levels varying from 30.9% in G4 to 296% in G1, and (2) a significant effect of CTAD, varying between patient groups (p = 0.0302).

Conclusion The variability of anti-Xa levels with a great overestimation of the values, using a reagent containing DS, can lead to different treatment decisions, especially after heparin neutralization by protamine. Clinical consequences of these differences remain to be demonstrated.

Keywords

heparin - neutralizing proteins - monitoring - anti-Xa inhibitors

^* Prof. Siguret and Dr. Gouin-Thibault contributed equally to this article.

Publikationsverlauf

Eingereicht: 23. Januar 2023

Angenommen: 15. Mai 2023

Artikel online veröffentlicht:
15. Juni 2023

• References

• 1 Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants. Chest 2012; 141 (2, Suppl): e24S-e43S
• 2 Finley A, Greenberg C. Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg 2013; 116 (06) 1210-1222
• 3 Baluwala I, Favaloro EJ, Pasalic L. Therapeutic monitoring of unfractionated heparin - trials and tribulations. Expert Rev Hematol 2017; 10 (07) 595-605
• 4 Arachchillage DRJ, Kamani F, Deplano S, Banya W, Laffan M. Should we abandon the APTT for monitoring unfractionated heparin?. Thromb Res 2017; 157: 157-161
• 5 Erdem-Eraslan L, Hens JJH, van Rossum AP, Frasa MAM, Keuren JFW. Inter-individual variability in phospholipid-dependent interference of C-reactive protein on activated partial thromboplastin time. Br J Haematol 2018; 183 (04) 681-683
• 6 Takemoto CM, Streiff MB, Shermock KM. et al. Activated partial thromboplastin time and anti-xa measurements in heparin monitoring: biochemical basis for discordance. Am J Clin Pathol 2013; 139 (04) 450-456
• 7 Hirsh J, Guyatt G, Albers GW, Harrington R, Schünemann HJ. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 110S-112S
• 8 Hollestelle MJ, van der Meer FJM, Meijer P. Quality performance for indirect Xa inhibitor monitoring in patients using international external quality data. Clin Chem Lab Med 2020; 58 (11) 1921-1930
• 9 Smahi M, De Pooter N, Hollestelle MJ, Toulon P. Monitoring unfractionated heparin therapy: lack of standardization of anti-Xa activity reagents. J Thromb Haemost 2020; 18 (10) 2613-2621
• 10 Amiral J, Amiral C, Dunois C. Optimization of heparin monitoring with anti-FXa assays and the impact of dextran sulfate for measuring all drug activity. Biomedicines 2021; 9 (06) 700
• 11 Lyon SG, Lasser EC, Stein R. Modification of an amidolytic heparin assay to express protein-bound heparin and to correct for the effect of antithrombin III concentration. Thromb Haemost 1987; 58 (03) 884-887
• 12 Kovacs MJ, Keeney M, MacKinnon K, Boyle E. Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin. Clin Lab Haematol 1999; 21 (01) 55-60
• 13 Mouton C, Calderon J, Janvier G, Vergnes MC. Dextran sulfate included in factor Xa assay reagent overestimates heparin activity in patients after heparin reversal by protamine. Thromb Res 2003; 111 (4–5): 273-279
• 14 Contant G, Gouault-Heilmann M, Martinoli JL. Heparin inactivation during blood storage: its prevention by blood collection in citric acid, theophylline, adenosine, dipyridamole-C.T.A.D. mixture. Thromb Res 1983; 31 (02) 365-374
• 15 van den Besselaar AM, Meeuwisse-Braun J, Jansen-Grüter R, Bertina RM. Monitoring heparin therapy by the activated partial thromboplastin time–the effect of pre-analytical conditions. Thromb Haemost 1987; 57 (02) 226-231
• 16 Funk DM. Collection, Transport, and Processing of Blood Specimens for Testing Plasma-Based Coagulation Assays and Molecular Hemostasis Assays: Approved Guideline. 5th ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2008
• 17 R Core Team. A language and environment for statistical computing. R Foundation for Statistical Computing. 2021. Accessed May 30, 2023 at: https://www.R-project.org/
• 18 Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw 2015; 67 (01) 1-48
• 19 Ignjatovic V, Summerhayes R, Gan A. et al. Monitoring unfractionated heparin (UFH) therapy: which anti-factor Xa assay is appropriate?. Thromb Res 2007; 120 (03) 347-351
• 20 Toulon P, Smahi M, De Pooter N. APTT therapeutic range for monitoring unfractionated heparin therapy. Significant impact of the anti-Xa reagent used for correlation. J Thromb Haemost 2021; 19 (08) 2002-2006
• 21 Boer C, Meesters MI, Veerhoek D, Vonk ABA. Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review. Br J Anaesth 2018; 120 (05) 914-927
• 22 Galeone A, Rotunno C, Guida P. et al. Monitoring incomplete heparin reversal and heparin rebound after cardiac surgery. J Cardiothorac Vasc Anesth 2013; 27 (05) 853-858
• 23 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3, Suppl): 188S-203S
• 24 Billoir P, Clavier T, Guilbert A. et al. Is citrate theophylline adenosine dipyridamole (CTAD) better than citrate to survey unfractionated heparin treatment? Has delayed centrifugation a real impact on this survey?. J Thromb Thrombolysis 2019; 48 (02) 277-283