Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Direct oral anticoagulants (DOACs) have emerged as an alternative to vitamin K antagonists for many indications, including atrial fibrillation and venous thromboembolism. The anticoagulant effect of DOACs is usually directly proportional to its plasma concentration. Routine monitoring of DOACs in the laboratory is, therefore, not recommended. However, there are some clinical situations in which measuring the anticoagulant effect of DOACs is desirable, such as acute renal impairment, thrombosis despite a correct DOAC intake or immediate DOAC reversion requirement. Liquid chromatography/coupled tandem mass spectrometry is the most accurate assay to evaluate DOAC plasma concentration. This procedure is not available in the majority of clinical laboratories, though. Here, the main feasible analysis in the urgent and routine clinical laboratory, in addition to the assay of choice depending on the DOAC, is described. This review also focuses on how to optimally reverse DOAC activity and describes strategies to minimize interferences in DOAC monitoring.
University General Hospital Dr. Balmis, Alicante, Spain
Thrombosis and Hemostasis Department, Hematology Service, Biomedical Research Institute, Alicante, Spain
*Address all correspondence to: marco_anaric@gva.es
1. Introduction
The development of direct oral anticoagulants (DOACs) has changed the paradigm of anticoagulation in the last few years. DOACs have emerged as the first-line anticoagulant treatment for many indications, in particular for stroke prevention in atrial fibrillation and prevention and treatment of venous thromboembolism (VT) [1]. Four DOACs have been approved for these indications: dabigatran, which directly inhibits factor IIa, and three direct agents with anti-factor Xa activity, including rivaroxaban, apixaban, and edoxaban. In general, DOACs have a more favorable efficacy compared to vitamin K antagonists (VKA) and are safer, especially when it comes to serious bleeding, according to clinical trials [2].
The anticoagulant effect of DOAC is generally directly proportional to its plasma concentration [3]. Liquid chromatography/coupled tandem mass spectrometry is the most accurate way to determine drug concentration. Unfortunately, this technique is not available in the majority of clinical laboratories, and it is time-consuming and requires personnel with expertise. The optimal concentration range to reach the appropriate therapeutic anticoagulant effect is still not well defined, although some publications included data on pharmacokinetics analysis (Table 1) [4].
DOAC type
Dose
Peak (ng/ml)
Trough (ng/ml)
Dabigatran
150 mg /12 h
68-443
31-225
Rivaroxaban
20 mg/24 h
189-419
6-87
Apixaban
5 mg/12 h
91-321
41-230
Edoxaban
60 mg/24 h
120-250
10-40
Table 1.
Expected peak and trough levels of DOAC.
A fixed-dose (once daily for rivaroxaban and edoxaban and twice daily for apixaban and dabigatran) and no requirement of routine monitoring for dose adjustment due to the lineal pharmacokinetics are potential advantages over VKA [3, 4]. However, in certain medical settings, laboratory monitoring of DOAC can be beneficial. These scenarios include urgent situations such as acute bleeding events and DOAC anticoagulant measurement prior to critical surgery and reversal strategies, if necessary. Additionally, in nonurgent situations, including acute renal failure, evaluation of DOAC adherence, drug interactions, or extreme body weight patients, DOAC monitoring can also be helpful [5]. In 2018, the International Council for Standardization in Hematology (ICSH) published a consensus document for laboratory measurement of DOAC [6]. Since then, different breakthroughs related to DOAC have been reported, including DOAC (apixaban and rivaroxaban) reversal with andexanet alfa and betrixaban approval by the Food and Drug Administration (FDA) [7]. Betrixaban is the fourth direct anti-Xa agent with a potential initial indication in extended VT prevention in acute medically ill patients with thrombotic risk factors but has since been discontinued by the manufacturer [8]. The ICSH recommendations have been updated in 2021 [7].
Next, the main affordable assays in the emergency department (ED) and in nonurgent settings for monitoring DOAC are described. Additionally, an optimal treatment approach depending on the clinical data and laboratory results is reported.
DOAC measurement in urgent situations basically includes acute bleeding events and prior to critical surgery or invasive procedure [7]. Reversal strategies are necessary if clinical and laboratory data suggest anticoagulant effect [9].
Measuring the anticoagulant effect of DOAC could be beneficial to determine their input to bleeding and help the clinician guide about the safety of the urgent intervention. However, the ICSH suggested that there are not enough data to dose adjustment of DOAC based only on laboratory findings, encouraging to carefully consider both clinical and laboratory results for an optimal DOAC management [6]. Regarding clinical information, the key factors to estimate DOAC effect are: (1) DOAC type, (2) recent renal and hepatic function, (3) timing from the last DOAC intake, (4) potential bleeding risk of the intervention, and (5) other medical relevant records [9].
As previously mentioned, in the majority of the emergency laboratories, the specific techniques for an accurate drug concentration measurement are not accessible.
Next, basic hemostatic parameters changes depending on the DOAC type are described.
2.1 Dabigatran
Dabigatran is administered as the etexilate ester prodrug. Following absorption, the prodrug is converted by nonspecific esterases to a potent direct thrombin inhibitor. The bioavailability is 6.5%, the half-life is 12-14 hours, and the elimination is mainly via kidney (up to 80%) [10].
Activated partial thromboplastin clotting time (APTT): Dabigatran prolongs the APTT. However, a poor correlation between APTT prolongation and the anticoagulant dabigatran activity, especially at higher APTT results (>200 ng/ml), has been described [11].
Prothrombin time (PT): Dabigatran prolongs the PT. Nevertheless, the sensitivity of PT is low for dabigatran detection in plasma, in particular within and below the therapeutic range. PT often exceeds the upper limits of the assay at dabigatran concentration above the therapeutic range [4].
Thrombin time (TT): TT is very sensitive to low dabigatran concentrations. A normal TT can exclude the presence of dabigatran [4].
Fibrinogen: Fibrinogen is not usually affected in the presence of dabigatran in plasma [12].
2.2 Rivaroxaban
Rivaroxaban inhibits clot-based factor Xa. Similar to dabigatran and the other anti-Xa DOAC, the peak levels are reached between 2 and 4 hours following DOAC intake. Rivaroxaban is eliminated partially by the kidneys (36%) and has a half-life between 6 and 13 hours.
APTT: Rivaroxaban can prolong the APTT in a dose-dependent pattern. However, this is a nonlinear association. Variability depending on the reagent and between laboratories has been reported. The nonlinear relationship between APTT and rivaroxaban concentration makes APTT not suitable for measuring rivaroxaban anticoagulant activity [13].
PT: Rivaroxaban prolongs the PT linearly to its anticoagulant activity, although this correlation can be weak. Variability can be significant depending on the reagent and the laboratory. Conversion of PT to international normalized ratio (INR) reduces sensitivity and increases variability, so INR is not useful for measuring rivaroxaban activity. As some PT assays have a low sensitivity, a normal PT does not exclude relevant rivaroxaban concentration in plasma. Nevertheless, a prolonged PT indicates drug activity [13].
Fibrinogen is not affected by rivaroxaban intake [14].
2.3 Apixaban
Apixaban inhibits clot-based factor Xa. The peak plasma concentration is achieved 3 hours after ingestion, is not affected by food intake, and is highly protein bounded in plasma. Apixaban metabolism occurs in different routes; therefore, it is less dependent on acute renal failure than the other DOAC. The half-life is approximately 12 hours.
APTT: A weak correlation between APTT and apixaban concentration has been observed. The sensitivity of APTT is low. Normal APTT results have been reported at apixaban concentrations of 100 ng/ml [4].
PT: PT is inadequately sensitive to apixaban, not only below but also >50 ng/ml [4]. Blerk et al. described that at 225 ng/ml of apixaban, PT and APTT were only 1.15 times longer than an apixaban concentration of 0 ng/ml [15].
Fibrinogen results are unaffected by the presence of apixaban [14, 15].
2.4 Edoxaban
Edoxaban is a direct factor Xa inhibitor. The peak plasma concentration is usually achieved 1-2 hours after the drug intake and has a half-life between 10 and 14 hours. Renal excretion remains approximately one-half of the total clearance of edoxaban.
APTT: Edoxaban prolongs APTT in a dose-dependent pattern. In general, APTT is less sensitive to edoxaban than PT.
PT: Similar to APTT, edoxaban prolongs PT linearly. Therefore, a prolonged PT indicates drug presence. However, the assays were insufficiently sensitive at low therapeutic levels [4]. A normal PT does not exclude therapeutic edoxaban concentrations. In addition, the sensitivity may vary depending on the reagent [4].
In Table 2, the main changes in the basic hemostatic parameters are summarized.
Coagulation assay
Relationship to expected “on therapy” range
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
APTT
Below
Normal or prolonged
Normal
Normal
Normal
Within
Prolonged
Normal or prolonged
Normal or prolonged
Normal
Above
Prolonged
Normal or prolonged
Prolonged
Normal or prolonged
PT
Below
Normal
Normal
Normal
Normal
Within
Normal or prolonged
Normal or prolonged
Normal or prolonged
Normal or prolonged
Above
Normal or prolonged
Normal or prolonged
Normal or prolonged
Normal or prolonged
TT
Below
Prolonged
Normal
Normal
Normal
Within
Prolonged
Normal
Normal
Normal
Above
Prolonged
Normal
Normal
Normal
Table 2.
Changes in the basic hemostatic parameters.
In Figure 1, a practical algorithm about DOAC management, including laboratory (if available) and clinical data before urgent surgery or procedure, is shown [16, 17].
Figure 1.
Practical algorithm before urgent surgery or procedure.
There are nonurgent situations and specific populations, including acute renal failure, evaluation of DOAC adherence, drug interactions, or extreme body weight patients, in which DOAC monitoring can be beneficial for an optimal patient management [17]. Liquid chromatography-coupled tandem mass spectrometry directly quantifies the drug concentration and is the gold standard for DOAC measurement in the clinical laboratory [18].
Next, the main feasible assays available in the laboratories in thrombosis and hemostasis to monitor DOAC are as follows:
3.1 Dabigatran
Dilute thrombin time (DTT): DTT is a clot-based assay on thrombin time in which patient plasma is diluted. DTT shows a strong and linear correlation with dabigatran concentrations in the therapeutic range. Even so, the correlation was weaker at low (<50 ng/ml) and high (>500 ng/ml) dabigatran concentrations [4].
Ecarin-based assays: Ecarin is a metalloprotease that cleaves prothrombin to meizothrombin, an active intermediate, which is inhibited by dabigatran. Ecarin clotting time (ECT) and ecarin chromogenic assay (ECA) have a linear dose–response relationship directly proportional to dabigatran concentrations. ECT is a clot-based assay, while ECA is based on color generation. Both ECT and ECA show a strong correlation with mass spectrometry at low range and high dabigatran concentrations, although this correlation may somewhat decrease at extreme concentrations (>500 ng/ml) [4, 18].
Other assays: Few data have been published in this area.
Thrombin generation: This assay describes the overall balance between procoagulant and anticoagulant activity. The thrombin generation curve is characterized by an initiation phase (lag time), following by the formation of thrombin (endogenous thrombin potential, ETP), reaching a peak of thrombin concentration, and final inhibition of thrombin by the natural anticoagulants. Dabigatran suppressed thrombin generation in a concentration-dependent pattern [19]. The authors enhanced that further studies are required in this area.
Other techniques, including dilute prothrombin time, prothrombinase-induced clotting time, dilute Russell viper venom time (DRVVT), and thromboelastography, have no enough sensitivity to be included in the routine laboratory either for excluding or confirming dabigatran anticoagulant activity [4].
3.2 Rivaroxaban
Anti-Xa activity: In general, rivaroxaban-calibrated chromogenic anti-Xa activity assays have shown a linear concentration-dependent correlation (r = 0.95) in a wide range of rivaroxaban concentrations (0-755 ng/ml) [4].
Other assays:
Thrombin generation: Rivaroxaban produces dose-dependent effects in all thrombin generation parameters. ETP has lower response to rivaroxaban concentrations than the other parameters [20, 21].
Similar to dabigatran, other techniques, including DRVVT, dilute prothrombin time, and thromboelastography, require further studies to be included in the routine laboratory for excluding or confirming rivaroxaban anticoagulant activity [4].
3.3 Apixaban
Anti-Xa activity: Similar to rivaroxaban, the anti-Xa activity assay shows a linear correlation with apixaban concentration. However, one study showed that this correlation is weaker at low apixaban concentrations (15-30 ng/ml) [22].
Other assays:
Thrombin generation: Apixaban modifies all thrombin generation parameters in a dose-dependent pattern, although sensitivity can vary [4].
Some studies have described promised results with thromboelastography in their ability to detect apixaban activity. Nevertheless, further studies are recommended to confirm these results [23, 24].
3.4 Edoxaban
Anti-Xa activity: A dose-dependent fashion with edoxaban concentrations has been reported, even at low doses of edoxaban. However, precision was lower at high edoxaban concentrations (>200 ng/ml) [25].
Other assays:
Thrombin generation: Edoxaban affects all thrombin generation parameters; peak of thrombin and mean rate are the most sensitive parameters [4].
Other assays, including DRVVT, dilute thrombin time, or thromboelastography, have not revealed adequate sensitivity to support their use to determine edoxaban activity in the routine laboratory [4].
In Table 3, a summary, including how specific assays are modified depending on the DOAC anticoagulant activity, is reported.
Relationship between the available coagulation assays in the routine laboratory and expected DOAC concentration.
Highest sensitivity in range of 50-500 ng/ml.
High sensitivity for the presence of dabigatran below, within and above concentrations. Weaker sensitivity at extreme concentrations (<40 or > 940 ng/ml).
Abbreviations: APTT: activated partial thromboplastin clotting time, PT: prothrombin time; TT: thrombin time, ECT: ecarin thrombin time.
To summarize, in agreement with the published data, the recommended assays to measure the DOAC anticoagulant activity are as follows:
Dabigatran: The DTT and ecarin-based clotting assays show the best correlation with plasma concentrations. In the emergency laboratory, a normal thrombin time excludes dabigatran anticoagulant activity. APTT is usually prolonged by the dabigatran presence.
Rivaroxaban: Anti-Xa assay provides the best correlation with rivaroxaban plasma concentration. In the emergency laboratory, a prolonged PT indicates rivaroxaban activity.
Apixaban: Anti-Xa assay affords the best correlation with apixaban plasma concentration. In the emergency laboratory, APTT, PT, and TT assays are not useful to determine apixaban activity.
Edoxaban: Anti-Xa assay offers the best correlation with edoxaban plasma concentration. In the emergency laboratory, PT is more sensitive than APTT, and it could support edoxaban activity.
In general, there is no consensus in using global hemostatic assays to monitor DOAC activity.
DOAC intake can interfere with clot-based assays [26].
The basic hemostasis parameters (APTT, TP, TT) can be affected differently depending on the DOAC (see above). Fibrinogen activity seems to be unaffected by DOAC, in particular the Clauss fibrinogen assay. However, a false fibrinogen decrease has been reported at very high dabigatran plasma concentrations (385 and 744 ng/ml) in an external quality assessment program [27]. D-dimer is usually measured by enzyme-linked immunoassay (ELISA) or latex-immunoassays; these techniques are not influenced by DOAC presence [28].
Regarding the specialized hemostasis parameters, those evaluating risk factors are influenced by DOAC, as many of them are clot-based assays. Lupus anticoagulant (LA) is potentially affected by DOAC, even at low concentrations. The DRVVT and APTT-LA assays can show false positive LA results as they all inhibit factor Xa. Other clot-based hemostasis assays, such as coagulant protein C and protein S, antithrombin activity, and activated protein C resistance ratio, describe false increased results, which may misdiagnose patients with a real deficit [28].
Non-coagulation assays are, in general, not potentially influenced by DOAC intake. Using a chromogenic protein C assay or measuring free and total protein S antigens may offer an appropriate alternative not affected by DOAC intake. Hemostasis assays based on DNA-based assays, ELISA, or immunoassays are not influenced by DOAC. For instance, antiphospholipid antibodies or von Willebrand factor antigen and activity can be measured at any time, independently of DOAC intake [28].
5. Strategies to minimize DOAC interference on the hemostasis laboratory results
It is recommended to ensure that there is no DOAC activity to get a reliable result (or at least minimize DOAC anticoagulant activity), mainly when using a clot-based assay, to avoid false positive results.
For this purpose, an option could be to discontinue the DOAC 2-4 days before the analysis, depending on the renal function. However, in high-risk thrombotic patients, this is not always feasible. In these cases, the bridging therapy with heparin can minimize thrombotic risk. Low molecular weight heparin (LMWH) is of choice, instead of unfractionated heparin, due to its subcutaneous administration. Patients with heparin bridging dabigatran, only the anti-Xa activity of the LMWH is suitable as APTT and TT are affected by both drugs. For patients with an anti-Xa DOAC, this is still a challenge as APTT and anti-Xa activity can be prolonged by both drugs, leading to supratherapeutic levels [7].
Testing at expected trough concentration is a potential solution, which means just before the following DOAC dose.
DOAC-stop® (Haematex, Hornsby, NSW, Australia) and DOAC-remove ® (5-Diagnostics, Quadratech, Switzerland) are other options, absorbing DOAC from plasma [29]. These agents are composed of activated charcoal-containing adsorbent compounds. This procedure can minimize false positive LA and reduces interferences with clot-based assays. However, complete DOAC activity reversal is not always feasible, and it can vary depending on the DOAC.
Idarucizumab (praxbind®) is a specific reversal agent for dabigatran approved in the United States and Europe. It can be administered in case of urgent surgery/procedure or in a life-threatening bleeding in patients on dabigatran. The total dose is 5 g, divided into 2 administrations of 2.5 g each, one after the other. DOAC monitoring in the laboratory (either in the emergent or routine laboratory, see above) is useful to determine the presence of dabigatran in plasma. In that case, clinicians can optimize patient’s management with idarucizumab. Ten-15 minutes after the infusion, if available, the neutralizing effect of idarucizumab is recommended to be checked. A rebound effect after 12-24 hours has been described, detecting dabigatran activity [7].
6.2 Andexanet alfa
Andexanet alfa (Andexxa®) was approved in the United States for reversing anticoagulant activity of rivaroxaban and apixaban, in case of a life-threatening or uncontrolled bleeding. Andexanet alfa has been approved by the Committee for Medicinal Products for Human Use in Europe for the same indication. There are two dosing strategies (low and high dose) as a bolus followed by a continuous infusion. The recommended dose in bolus depends on the dose of the DOAC the patient is taking at the moment of the reversal and time from the last intake and renal function. Measurement of baseline anti-Xa activity can be useful to support the reversal procedure. Additionally, a transient increase in prothrombin F1 + 2 fragments and D-dimer value following andexanet alfa administration have been described. An increase in thrombin generation has also been observed, which may be related to the concomitant tissue factor pathway inhibitor (TFPI) inhibition [7]. Unfortunately, these reversal agents may not be available, depending mainly on the country and the hospital. In that case, using three-or-four factor prothrombin complex concentrates (PCC) or activated PCC is an alternative. These nonspecific reversal agents can impact on coagulation screening test but not on the routine techniques previously described to measure DOAC anticoagulant activity. The optimal dose of PCC is based on the expected residual DOAC concentration in plasma. For that purpose, it can be useful to collect data about recent renal function, the last DOAC intake, and type of DOAC, as well as to assess possible pharmacological interactions [7].
International Council for Standardization in Hematology
INR
international normalized ratio
LA
lupus anticoagulant
LMWH
low molecular weight heparin
PCC
prothrombin complex concentrates
PT
prothrombin time
TFPI
tissue factor pathway inhibitor
TT
thrombin time
VKA
vitamin K antagonists
References
1.Ansell JE. Management of venous thromboembolism: Clinical guidance from the anticoagulation forum. Journal of Thrombosis and Thrombolysis. 2016;41:1-2
2.Chen A, Stecker E, Warden BA. Direct oral anticoagulant use: A practical guide to common clinical challenges. Journal of the American Heart Association. 2020;9:e017559
3.Rose DK, Bar B. Direct oral anticoagulant agents: Pharmacologic profile, indications, coagulation monitoring and reversal agents. Journal of Stroke and Cerebrovascular Diseases. 2018;27:2049-2058
4.Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants. Chest. 2017;151:127-138
5.Douxfils J, Ageno W, Samama CM, Lessire S, Ten Cate H, Verhamme P, et al. Laboratory testing in patients treated with direct oral anticoagulants: A practical guide for clinicians. Journal of Thrombosis and Haemostasis : JTH. 2018;16:209-219
6.Gosselin RC, Adcock DM, Bates SM, Douxfils J, Favaloro EJ, Gouin-Thibault I, et al. International Council for Standardization in Hematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thrombosis and Haemostasis. 2018;118:437-450
7.Douxfils J, Adcock DM, Bates SM, Favaloro EJ, Gouin-Thibault I, Guillermo C, et al. 2021 update of the International Council for Standardization for laboratory measurement of direct oral anticoagulants. Thrombosis and Haemostasis. 2021;121:1008-1020
8.Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. The New England Journal of Medicine. 2016;375:534-544
9.Burnett AE, Mahan CE, Vazquez S, Oertel LB, García DA, Ansell J. Guidance for the practical management of direct oral anticoagulants (DOAC) in VTE treatment. Journal of Thrombosis and Thrombolysis. 2016;41:206-232
10.Ganetsky M, Babu KM, Salhanick SD, Brown RS, Boyer EW. Dabigatran: Review of pharmacology and management of bleeding complications of this novel oral anticoagulant. Journal of Medical Toxicology. 2011;7:281-287
11.Hanket GJ, Eikelboom JW. Dabigatran etexilate: A new oral thrombin inhibitor. Circulation. 2011;123:1436-1450
12.Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogne JM. Impact of dabigatran on a large panel of routine and or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thrombosis and Haemostasis. 2012;107:985-997
13.Siegal DM, Konkle BA. What is the effect of rivaroxaban on routine coagulation tests? Hematology: the American Society of Hematology Education Program. 2014;1:334-336
14.Scheres LJ, Lijfering WM, Middeldorp S, Cheung YW, Barco S, Cannegieter SC, et al. Measurement of coagulation factors during rivaroxaban and apixaban treatment: Results from two crossover trials. Research and Practice in Thrombosis and Haemostasis. 2018;2:689-695
15.Blerk MV, Bailleul E, Chatelain B, Demulder A, Devreese K, Douxfils J, et al. Influence of apixaban on commonly used coagulation assays: Results from the Belgium National External Quality Assessment Scheme. International Journal of Laboratory Hematology. 2017;39:402-408
16.Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Van Cott EM, et al. Reversal of direct oral anticoagulants: Guidance from the anticoagulation forum. American Journal of Hematology. 2019;94:697-709
17.Douketis JD, Spyropoulus AC, Duncan A, Carrier M, Le Gal G, Tafuer AJ, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Internal Medicine. 2019;179:1469-1478
18.Toorop MMA, Lijfering WM, Scheres LJJ. The relationship between DOAC levels and clinical outcomes: The measures tell the tale. Journal of Thrombosis and Haemostasis. 2020;18:3163-3168
19.Zhang C, Zhang P, Li H, Han L, Zhang L, Zhang L, et al. The effect of dabigatran on thrombin generation and coagulation assays in rabbit and human plasma. Thrombosis Research. 2018;165:38-43
20.Molenaar PJ, Dinkelaar J, Leyte A. Measuring rivaroxaban in a clinical laboratory setting, using common coagulation assays, Xa inhibition and thrombin generation. Clinical Chemistry and Laboratory Medicine. 2012;50:1799-1807
21.Samama MM, Martinoli JL, Le Flem L, Guinet C, Plu-Bureau G, Depasse F, et al. Assessment of laboratory assays to measure rivaroxaban, an oral, direct factor Xa inhibitor. Thrombosis and Haemostasis. 2010;103:815-825
22.Skeppholm M, Al-Aieshy F, Berndtsson M, Al-Khalili F, Ronquist-Nii Y, Soderblom L. Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation. Thrombosis Research. 2015;136:148-153
23.Dias JD, Norem K, Doorneweerd DD, Thurer RL, Popovsky MA, Omert LA. Use of thromboelastography (TEG) for detection of new oral anticoagulants. Archives of Pathology & Laboratory Medicine. 2015;139:665-673
24.Adelmann D, Wiegele M, Wohlgemuth RK, Koch S, Frantal S, Quehenberger P, et al. Measuring the activity of apixaban and rivaroxaban with rotational thromboelastometry. Thrombosis Research. 2014;134:918-923
25.Wolzt M, Samama MM, Kapiotis S, Ogata K, Mendell J, Kunitade S. Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux. Thrombosis and Haemostasis. 2011;105:1080-1090
26.Siriez R, Dogne JM, Gosselin R, Laloy J, Mullier F, Douxfils J. Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory. International Journal of Laboratory Hematology. 2021;45:7-20
27.Bonar R, Favaloro EJ, Mohammed S, Pasalic C, Sloufi J, Marsden K. The effect of dabigatran on hemostasis tests: A comprehensive assessment using in vitro and ex vivo samples. Pathology. 2015;47:355-364
28.Moser KA, Smock K. Direct oral anticoagulant (DOAC) interference in hemostasis assays. Hematology. American Society of Hematology. Education Program. 2021;1:129-133. DOI: 10.1182/hematology.2021000241
29.Arachchillage DR, Mackie IJ, Efthymiou M, Isenberg DA, Machin SJ, Cohen H. Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome. Journal of Thrombosis and Haemostasis. 2015;13:1264-1273
Written By
Ana Marco-Rico
Submitted: 15 May 2023Reviewed: 03 June 2023Published: 07 December 2023
Open access peer-reviewed chapter
