Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays

Abstract

To cite this article: Hillarp A, Baghaei F, Fagerberg Blixter I, Gustafsson KM, Stigendal L, Sten-Linder M, Strandberg K, Lindahl TL. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9: 133-9.Summary. Introduction: Rivaroxaban is an oral direct factor Xa inhibitor developed for prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary but the dose-dependent effects on common reagents and assay procedures are largely unknown. Objectives: To investigate the effect of rivaroxaban on commonly used coagulation assays. Materials and Methods: Rivaroxaban was added to plasma from healthy subjects in the concentration range 0-1000 lg L )1 and analyzed using different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, fibrinogen and activated protein C (APC) resistance assays. Results: At an expected peak concentration of rivaroxaban in clinical use, the APTTs were almost invariably prolonged but at lower concentrations the effect was weak. The concentration needed to double the APTT varied between 389 ± 106 and 617 ± 149 lg L )1 for different reagents. The PT assays showed a marked degree of difference. In general, the Quick PT type assays were more sensitive compared with the Owren type PT assays. The results from antithrombin assays were dependent on the type of reagent, with the Xa-based assay being sensitive for rivaroxaban with an estimated increase of 0.09 IU mL )1 per 100 lg L )1 rivaroxaban. There were only minor effects on fibrinogen assays based on thrombin reagents. The APTT-based assay for APC resistance is affected in a dose-dependent manner whereas an assay based on the activation of coagulation at the prothrombinase level was unaffected. Conclusions: Different assays, and even different reagents within an assay group, display variable effects by therapeutic concentrations of rivaroxaban.

Measurement of coagulation factors during rivaroxaban and apixaban treatment: Results from two crossover trials

“…In addition, both VWF:Ag as well as VWF activity measurements were not affected in an in vitro study with drug enriched samples of rivaroxaban and apixaban 19. In other studies in which factor Xa inhibitors were added to human plasma ex vivo, fibrinogen measurements were reported not to be affected 17, 18, 19. Our study confirm these findings in healthy men on therapeutic doses of rivaroxaban/apixaban and by comparing coagulation factor levels before and after intake.…”

“…In contrast, FVIII levels are non‐vitamin K dependent and seem only marginally influenced by VKAs, but may be affected by DOACs11, 12, 13 which are now suggested as first treatment of choice for venous thromboembolism 14. Several previous studies that investigated the effect of DOACs on the measurement of coagulation factors investigated spiked ex vivo samples and found varying results according to the combinations of reagents and drugs 15, 16, 17, 18, 19. For instance, FVIII:C levels seem to be effected by concurrent DOAC use, while d ‐dimer, fibrinogen, and VWF:Ag may not 18, 19.…”

Factor VLeiden

“…However, direct thrombin inhibitors such as dabigatran, argatroban, and bivalirudin [50][51][52]. as well as rivaroxaban, a factor Xa-inhibitor [53], can cause discrepancies with FV Leiden DNA results by causing falsely normal APC resistance test results.…”

The laboratory and the direct oral anticoagulants

“…23 The degree of underestimation is reagent dependent and is likely due to different types or concentrations of thrombin used for testing. c Tests for activated protein C resistance may be affected by DOAC when testing is based on paired APTT with or without activated protein C. 23,24 Because of this effect, plasmas from heterozygous FV Leiden carriers might resemble wild-types when patients are treated with DOAC.…”