Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays

Abstract

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0-742 mg/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539-758 mg/L for the APTT and between 329 and 2505 mg/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russell's viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 mg/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.

Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory

“…Van Blerk et al, in a multicenter study performed in 192 laboratories in Belgium, reported a mean factitious elevation of AT activity of ±15%‐20% at 250 ng/mL of dabigatran with the Berichrom ® ATIII and the Stachrom ® ATIII, respectively 13 . An overestimation of 25%–45% of AT levels was observed in presence of 290 ng/mL of rivaroxaban with HemosIL ® Liquid‐Antithrombin, Coamatic ® Antithrombin or Innovance ® Antithrombin and several studies reported similar results for apixaban and edoxaban with an estimated increase of 10% per 100 ng/mL 1,6,8‐10,12‐15,20,29‐31 …”

The Interactions of Nintedanib and Oral Anticoagulants—Molecular Mechanisms and Clinical Implications

“…The best way to accurately monitor the anticoagulant activity of rivaroxaban is to measure anti-Xa activity. At present work is underway to standardize and validate the test for this indication [92,93].…”

Clinical use and laboratory testing of oral anticoagulation therapy: experience from Finland

“…Monitoring of DOAC anticoagulation effect is not recommended for routine use, while liver or kidney dysfunction, thrombosis or bleeding breakthrough during treatment, extremes in body weight, suspicion of noncompliance or overdose are situations where measurement is useful. Routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (APTT) are unreliable in assessment of DOAC effect, and their sensitivity depends on laboratory and reagents used (13)(14)(15)(16). However, the baseline assessment of PT and APTT are valuable screening tests to obtain an understanding of the 1400 1200 1000 800 600 400 200 0 Handled All liver function prior to initiation of DOACs.…”

“…Owren type PT/INR, as used in the Nordic countries, is insensitive to DOACs and FV deficiency (impaired liver function), and this is still a matter of education for our clinicians (16). APTT may show an effect of dabigatran, whereas FXaIs affect the APTT less, or do not affect the APTT (15,16,(67)(68)(69). More specific assays were quickly needed, and HUSLAB laboratory services was the first laboratory in Finland to set up the specific assays for dabigatran, rivaroxaban and apixaban, and offer them 24/7 for clinical use (since May 2017).…”