Influence of dabigatran and rivaroxaban on routine coagulation assays

Blerk, Marjan Van; Bailleul, Els; Châtelain, Bernard; Demulder, Anne; Devreese, Katrien; Douxfils, Jonathan; Jochmans, Kristin; Mullier, François; Wijns, Walter; Soumali, Mohamed Rida; Coucke, Wim; Vernelen, Kris; Walle, P. Van de

doi:10.1160/th14-02-0161

Cited by 72 publications

(12 citation statements)

References 39 publications

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“…However, we employed a sensitive thromboplastin reagent (RecombiPlasTin 2G®) for the assay [ 39 ]. A nationwide Belgian survey has previously highlighted a wide variation in response to rivaroxaban according to the reagent used [ 40 ]. Commercial specific assays are currently available for all DOACs [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Sennesael

Larock²,

Douxfils

et al. 2018

Thrombosis J

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BackgroundSerious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.MethodsThis analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.ResultsRivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).ConclusionsRivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.

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Section: Discussionmentioning

confidence: 99%

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Sennesael

Larock²,

Douxfils

et al. 2018

Thrombosis J

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“…The non-linear dose–response relationship as observed for rivaroxaban with mPT but also with standard PT reagents, is usually much less prominent for apixaban and dabigatran. Another issue of importance is standardization, given the high variability in NOAC response between different thromboplastin reagents (Table 2 [61,64-66,70,88,90,91]), an essential aspect when applying the PT test to NOAC monitoring. For VKA anticoagulation, it is general practice to normalize PT outcome to INR using an international sensitivity index (ISI) supplied by the manufacturer of the used thromboplastin reagent.…”

Section: Introductionmentioning

confidence: 99%

Global assays and the management of oral anticoagulation

Brinkman

2015

Thrombosis J

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Coagulation tests range from global or overall tests to assays specific to individual clotting factors and their inhibitors. Whether a particular test is influenced by an oral anticoagulant depends on the principle of the test and the type of oral anticoagulant. Knowledge on coagulation tests applicable in monitoring status and reversal of oral anticoagulation is a prerequisite when studying potential reversal agents or when managing anticoagulation in a clinical setting. Specialty tests based on the measurement of residual activated factor X (Xa) or thrombin activity, e.g., are highly effective for determining the concentration of the new generation direct factor Xa- and thrombin inhibitors, but these tests are unsuitable for the assessment of anticoagulation reversal by non-specific prohemostatic agents like prothrombin complex concentrate (PCC) and recombinant factor VIIa (FVIIa). Global coagulation assays, in this respect, seem more appropriate. This review evaluates the current status on the applicability of the global coagulation assays PT, APTT, thrombin generation and thromboelastography in the management of oral anticoagulation by vitamin K antagonists and the direct factor Xa and thrombin inhibitors. Although all global tests are influenced by both types of anticoagulants, not all tests are useful for monitoring anticoagulation and reversal thereof. Many (pre)analytical conditions are of influence on the assay readout, including the oral anticoagulant itself, the concentration of assay reagents and the presence of other elements like platelets and blood cells. Assay standardization, therefore, remains an issue of importance.

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“…In contrast, a dabigatran-calibrated diluted thrombin time is reliable but not readily available in every laboratory. The better correlation of the thrombin time over aPTT with dabigatran plasma levels was described by various investigators [21][22][23][24], which also might be explained by the fact that the aPTT results are highly dependent on the test reagent used [24,25].…”

Section: Measurement Of Dabigatran With Aptt Thrombin Time and Dabimentioning

confidence: 87%

In vitro and ex vivo Measurement of Prophylactic Dabigatran Concentrations with a New Ecarin-Based Thromboelastometry Test

Körber

Langer

Köhr

et al. 2017

Transfus Med Hemother

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Background: An increasing number of oral anticoagulants has been approved, including dabigatran etexilate (DE). DE is a direct thrombin inhibitor that requires no routine monitoring, but, if necessary (e.g. urgent surgery etc.), the diluted thrombin time measured with Hemoclot® has shown reliable results. So far, no point-of-care (PoC) assay is available to measure DE effects. The EcaTEM assay uses ecarin to initiate the coagulation cascade at the step of thrombin generation and measures the clotting time (CT) by thromboelastometry. Methods: This study investigated the correlation of the EcaTEM with standard laboratory assays in dabigatran-treated patients. Ten patients undergoing total hip or knee arthroplasty were included in the study. DE for thromboprophylaxis was started 4 h after surgery. Blood samples were taken before surgery as well as 2, 6 and 12 h after ingestion on the 3rd postoperative day. Dabigatran concentration (Hemoclot), activated partial thromboplastin time, thrombin time and CT EcaTEM were measured. Results: Only CT EcaTEM and Hemoclot showed a correlation > 0.75 for all measurements. Conclusion: CT EcaTEM appears a valid PoC method parameter to detect thrombin inhibition and thus the presence of dabigatran beside diluted thrombin time at different concentration levels. This may represent an opportunity to identify the presence of dabigatran, e.g., in emergency situations.

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Influence of dabigatran and rivaroxaban on routine coagulation assays

Cited by 72 publications

References 39 publications

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

Global assays and the management of oral anticoagulation

In vitro and ex vivo Measurement of Prophylactic Dabigatran Concentrations with a New Ecarin-Based Thromboelastometry Test

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