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Keywords:

  • Direct oral anticoagulant;
  • coagulation assays;
  • dabigatran;
  • rivaroxaban;
  • apixaban

Summary

  1. Top of page
  2. Summary
  3. Case Presentation
  4. Direct Oral Anticoagulants
  5. Laboratory Assessment of Direct Oral Anticoagulants
  6. Coagulation Test Interference from DOACs
  7. Conclusions
  8. References

The introduction of several oral direct anticoagulants within the past 2–3 years has dramatically changed clinical practice and has also impacted on utilization and interpretation of coagulation laboratory testing. This article reviews the effects of the oral thrombin inhibitor, dabigatran, and the oral factor Xa inhibitors, rivaroxaban and apixaban, on screening and diagnostic coagulation tests, and describes methods for measuring the their anticoagulant activity in plasma. Currently, there are evidence gaps regarding the role of laboratory testing for surveillance and management of adverse events associated with these new anticoagulants which do not require routine therapeutic drug monitoring. This is a rapidly changing field, and coagulation laboratory experts have a major role in ensuring patients receive appropriate testing and accurate interpretations of results.


Case Presentation

  1. Top of page
  2. Summary
  3. Case Presentation
  4. Direct Oral Anticoagulants
  5. Laboratory Assessment of Direct Oral Anticoagulants
  6. Coagulation Test Interference from DOACs
  7. Conclusions
  8. References

An elderly woman was admitted to hospital from a skilled nursing facility with an exacerbation of congestive heart failure. Past medical history included atrial fibrillation, hypertension, diabetes, and coronary artery disease. A medication history did not accompany the patient, but, according to a family member, warfarin had been stopped and rivaroxaban started a few days before admission. There were no signs or symptoms of abnormal bleeding. After reviewing screening coagulation test results: Prothrombin time (PT) 54 s (reference range, 9–12) INR 4.9 (reference range, 0.9–1.2), activated Partial Thromboplastin Time (aPTT) 48 s (reference range, 24–36), the admitting resident requested information on the INR therapeutic range for rivaroxaban. The Hematology Laboratory medical director educated the resident about direct oral anticoagulant drugs, emphasizing it was inappropriate to use the INR to monitor them. The director suspected the prolonged PT/INR was due to a combination of residual vitamin K antagonism from warfarin and direct inhibition of factor Xa (FXa) by rivaroxaban. The following tests were performed on a new plasma sample collected 13 h after admission:

PT/INR 40 s/3.7; PT/INR 50 : 50 mix 19 s/1.8; Thrombin Time (TT) 21 s (reference range, 15–22).; aPTT 45 s, aPTT 50 : 50 mix 36 s, chromogenic anti-FXa 2.1 IU/mL (hybrid heparin calibration).

A normal thrombin time ruled out the presence of heparin in the plasma. With 50 : 50 mixing, the aPTT corrected completely, consistent with factor deficiencies. However, the PT remained slightly prolonged after mixing, suggesting inhibitor activity as well. The elevated anti-FXa activity in the absence of heparin was consistent with the presence of rivaroxaban in the plasma sample (see Figure 1), at a minimum of 18–24 h following the last dose, based on arrival time in the emergency room. During the hospitalization, the patient's estimated creatinine clearance rate ranged from 23 to 18 mL/min. In consultation with Hematology service, rivaroxaban was discontinued due to the patient's poor kidney function. The INR declined to 1.89 over 72 h, and warfarin was resumed with plans for outpatient therapeutic INR monitoring by the patient's primary care physician.

image

Figure 1. Correlation of in vitro rivaroxaban concentrations in normal pooled plasma to Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT), Thrombin Time (TT), and chromogenic anti-FXa. Performed with RecombiPlasTin (PT), SynthASil (aPTT), Thrombin Time (TT), and Heparin (anti-FXa) reagents on TOPS® automated coagulation instrument (Instrumentation Laboratory, Lexington, MA, USA).

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Direct Oral Anticoagulants

  1. Top of page
  2. Summary
  3. Case Presentation
  4. Direct Oral Anticoagulants
  5. Laboratory Assessment of Direct Oral Anticoagulants
  6. Coagulation Test Interference from DOACs
  7. Conclusions
  8. References

The emergence of oral direct thrombin inhibitors (DTI) and direct factor Xa inhibitors (DFXaI) as alternatives to vitamin K antagonists like warfarin and antithrombin cofactors like heparin, low molecular weight heparins (LMWH), and fondaparinux is a new direction in antithrombotic therapy with important consequences for coagulation testing utilization and interpretation. As a class, direct oral anticoagulants (DOACs) have the following characteristics:

  • Similar or enhanced efficacy and safety compared with warfarin or LMWH for prevention or treatment of selected arterial and venous thromboembolic events [1]
  • Rapid onset of anticoagulant activity (1–3 h), and short half-lives (9–17 h) [2]
  • Limited drug or food interactions [3]
  • Fixed dosing guide lines [1] adjusted for diminished creatinine clearance rates
  • No requirement for routine therapeutic drug monitoring [1]
  • Fixed dosing is effective and safe despite wide ranges for peak and trough drug concentrations (i.e., wide therapeutic ranges) [4, 5]
  • No companion test development for monitoring drug concentration or anticoagulant activity
  • No effective reversal agent or specific antidote.

As of January 1, 2013, the United States Food and Drug Administration (FDA) has approved three DOACs, dabigatran etextilate, rivaroxaban, and apixaban for prevention of strokes and systemic emboli in patients with nonvalvular atrial fibrillation and has approved rivaroxaban for treatment of pulmonary emboli (PE) and deep vein thrombosis (DVT) and for prevention of DVT after hip and knee replacement surgeries. In addition, clinical trials have been completed or are underway for several other DOACs [2]. Within a few years, it is likely that DOACs will be the dominant chronic anticoagulation therapy [6].

While clinical trial outcomes validate prescribing DOACs without therapeutic drug monitoring, there are two situations when coagulation testing and DOACs collide: (i) When clinicians require information about the anticoagulant activity of a DOAC in order to make management decisions, and (ii) When screening (PT, aPTT) and diagnostic coagulation tests, are ordered while a patient is taking a DOAC potentially causing spurious results, which may lead to inaccurate diagnoses.

Laboratory Assessment of Direct Oral Anticoagulants

  1. Top of page
  2. Summary
  3. Case Presentation
  4. Direct Oral Anticoagulants
  5. Laboratory Assessment of Direct Oral Anticoagulants
  6. Coagulation Test Interference from DOACs
  7. Conclusions
  8. References

Despite more predictable pharmacokinetics compared with warfarin, there are patient situations where DOAC anticoagulant activity or drug concentration information could be useful including: (i) Assessment of bleeding potential prior to high-risk invasive procedures (neurosurgery) or medical interventions (thrombolytic therapy for acute ischemic stroke), (ii) Assessment of risk and benefits of dialysis and rescue procoagulant factor concentrates during acute, severe bleeding [7], (iii) Concern for poor compliance particularly when a thrombo-embolic event occurs, and (iv) Concern for excessive bleeding risk due to worsening renal insufficiency, frailty, drug interactions, and overdoses. For most clinical situations, qualitative information is sufficient because clinicians are concerned about extremely high- or low-DOAC levels, relying on published peak and trough ranges from clinical trials for guidance in the absence of definitive ‘therapeutic ranges’. It is also essential to know time elapsed between last dose and blood collection to interpret laboratory results.

Results of studies revaluating the effects of DOACs on screening coagulation tests are generally consistent. Both PT and aPTT show a positive dose response to increasing DOAC concentrations, however, responsiveness varies based on the screening test and reagent. aPTT reagents are more sensitive to dabigatran than PT reagents [8], while the opposite is generally true for rivaroxaban [9], except for Owren PT reagents which are minimally sensitive to DFXaI [10]. aPTT dose-response curves are curvilinear, steeper at low dabigatran [11] and rivaroxaban [9] concentrations then flattening out a high concentrations, (typically greater than 200 ng/mL), while PT dose-response curves are linear [9, 11, 12]. Thromboplastin sensitivity to DOACs varies considerably among reagent brands [8, 9] and is not predictable based on thromboplastin source. For example, recombinant human Innovin is relatively unresponsive to rivaroxaban and apixaban while Recombiplastin is one of the more responsive thromboplastins [13]. While the conversion of PT ratios to INRs based on thromboplastin-specific ISI calibration is an effective way to harmonize prolonged PT results for warfarin monitoring, it fails when DFXaI are present in plasma [13]. It is possible to calculate ISI exponents for responsiveness to DFXaI [14], but wide adoption is unlikely. Diluting PT thromboplastins increases sensitivity to DOACs [11, 15], but does not reduce between brand variability. The prothombinase-induced clotting time (PiCT) combines patient plasma with phospholipid, FXa, and a FV activator [16]. Increasing concentrations of dabigatran and rivaroxaban produce a sensitive and nonlinear prolongation of a one stage PiCT [9, 11]. A common way to express coagulation reagent sensitivity to DOACs is to determine the in vitro drug concentration required to double baseline values for pooled normal plasma [11, 13]. Coagulation laboratories can provide this information for routine screening tests, such as PT and aPTT, to clinicians by comparing their instrument/reagents to commercial DOAC calibrators, as shown in Figure 1 for rivaroxaban. Thrombin time reagents are exquisitely sensitive to dabigatran, making this test useful to ‘rule out’ a clinically meaningful concentration of dabigatran when TT is within the reference range [17]. Some thromboplastin reagents may be sensitive enough to exclude a clinically relevant anticoagulation effect of rivaroxaban when the PT is within the reference range [18]. However, this is based on expert opinion and not good-quality evidence. Similarly, chromogenic [13] and clot-based (Heptest®) [16] anti-Xa assays are reasonably sensitive screening tests for the presence of rivaroxaban and apixaban. While nonspecific clotting and chromogenic tests provide qualitative information about DOAC anticoagulant activities, they are vulnerable to many variables that affect these endpoints (coagulopathies, elevated Factor VIII, lupus anticoagulants, presence of heparin), in addition to reagent and instrument-dependent variation.

Measuring DOAC concentration can be done directly via high-performance liquid chromatography-mass spectrometry in a pharmaceutical or reference laboratory [19, 20] or indirectly by calibrating a functional assay with DOAC standards. In the United States, laboratories must perform extensive validation before offering these tests for patient care since the FDA has not cleared any commercial assay to measure a DOAC concentration. Several coagulation methods to measure DOACs are sufficiently sensitive and provide a linear dose response over a wide concentration range. Two quantitative methods apply to dabigatran: (i) Using a commercial kit [17], or an in-house method [21], to predilute plasma before performing a thrombin time calibrated with dabigatran standards, and (ii) Chromogenic [11] or clot-based [17] ecarin methods. Ecarin, derived from the venom of the Indian saw-scaled viper, Echis carinatus, converts prothrombin to an active intermediate, meizothrombin, which converts fibrinogen to fibrin (clotting method) or hydrolyzes a peptide substrate with an attached chromophobe (chromogenic method). As dabigatran also inhibits meizothrombin, comparing patient plasma results from either assay to dabigatran standards provides quantitative results. Chromogenic anti-Xa methods are ideal for quantifying DFXaI activities [13]. Several studies have validated measuring plasma rivaroxaban levels using a chromogenic anti-FXa method calibrated with rivaroxaban standards [19, 22, 23]. Except for one DFXaI-specific commercial method [24], anti-FXa methods are sensitive to heparin, LMWH, and fondaparinux, which would confound measurement of a DFXaI if they are present in plasma. Calibration with either LMWH or apixaban produces excellent linear correlations to apixaban concentrations [25]. Therefore, an in-house calibration of a chromogenic anti-FXa assay output(IU/ml) to DFXaI concentration (ng/ml) would provide clinicians with useful information in some clinical situations (Figure 1). However, there are two caveats for in vitro spiking studies. First, the therapeutic ranges for LMWH (IU/mL) must not be used to adjust apixaban or rivaroxaban doses because there is no evidence supporting similar in vivo anticoagulant activity. Second, results of coagulation tests performed on pooled plasma spiked with a DTI or DFXaI will show less variation compared with results from different patients taking these medicines, and therefore must be used only as approximations.

Coagulation Test Interference from DOACs

  1. Top of page
  2. Summary
  3. Case Presentation
  4. Direct Oral Anticoagulants
  5. Laboratory Assessment of Direct Oral Anticoagulants
  6. Coagulation Test Interference from DOACs
  7. Conclusions
  8. References

As DOAC prescribing becomes more frequent, so will the frequency of these drugs in blood collected for screening and diagnostic coagulation testing. This can produce inaccurate and biased results, which can cause diagnosis and treatment errors. Coagulation experts must minimize this patient safety risk by:

  • Educating clinicians about DOAC related coagulation test artifacts and how to minimize them by timing phlebotomy to coincide with expected trough concentrations
  • Knowing how their coagulation test methods are affected by DOACs
  • Screening for DOAC ‘contaminants’ in plasma samples, and canceling tests when appropriate
  • Providing comments or interpretations with selected test results warning clinicians of these risks.

Some interferences are specific to the type of DOAC, the test method, or selected commercial reagents, and the DOAC concentration threshold to affect results also vary widely. Table 1 is a summary of currently recognized DOAC interferences. Some artifacts are predictable. When evaluating a prolonged PT or aPTT, both oral DTI and DFXaI can produce inhibitor patterns due to incomplete correction of a 50 : 50 mix with normal pooled plasma. Both classes of DOACs can cause underestimates of specific factor activities, with or without demonstrating an inhibitor pattern on serial dilutions. Thrombophilia testing is particularly vulnerable to interference from DOACs. Prolonged clotting times due to DOAC contamination can cause positive biases for protein S, protein C, and activated protein C resistance testing, and the potential of reporting false negative results, while also causing false positive lupus anticoagulant results. Chromogenic antithrombin activities are falsely elevated by dabigatran interference if the substrate is thrombin, or falsely elevated by rivaroxaban interference if the substrate is factor Xa. The impact of DOACs on clot-based fibrinogen determinations is variable. Dabigatran contamination produces a concentration-dependent negative bias in fibrinogen-Clauss methods with low thrombin concentrations but does not affect methods using high thrombin concentrations [26]. Very high concentrations of rivaroxaban cause an unexplained approximately 10% negative bias in selected fibrinogen-Clauss methods [10]. Despite using different thrombin generation methods, investigators have shown both dabigatran and rivaroxaban have more impact on lag time than on endogenous thrombin potential [11, 23].

Table 1. Interference patterns of direct oral anticoagulants on screening and diagnostic coagulation tests (↑- potential positive bias, ↓ -potential negative bias, ↔ -no or minimal bias, empty-no information available, numbers refer to references)
TestDabigatranRivaroxabanApixaban
PT[8, 11, 30][9, 22, 33][13]
dPT[11][16][16]
PiCT[11][9, 22] 
aPTT[8, 11, 26][9, 10]
TT 
Fibrinogen-Clauss↓/↔[8, 30][10, 33] 
PT/aPTT 1 : 1 mixing studies[32]  
Extrinsic pathway factor activities-clot based[30, 32][31, 33] 
Intrinsic pathway factor activities-clot based[30, 32][31, 33] 
Chromogenic factor VIII activity[32][31] 
Chromogenic heparin activity [9, 13][13, 25]
Clot-based heparin activity-Heptest↑[[16]; Unpub-lished][16][16]
Lupus anticoagulant-aPTT [23] 
Lupus anticoagulant-DRVVT↑(false positive)[30]↑(false positive)[23] 
Antithrombin chromogenic-FXa[26][10] 
Antithrombin chromogenic-FIIa[11, 26, 32][10] 
Protein C activity-clot based[32]  
Protein S activity-clot based[32][33] 
APC resistance-aPTT based[11, 26][10] 

Direct oral anticoagulants can affect whole blood clotting tests as well, although published evaluations are limited. Dabigatran prolongs activated clotting time [11] and Hemachron Jr Signature + INR [27] results. Thromboelastography may or may not be [28, 29] sensitive to DOACs depending upon the instrument and test methods.

Fortunately, some coagulation tests are not affected by DOACs [30-33]: Reptilase time, immunoturbidity methods (D-dimer, free protein S antigen, von Willebrand factor antigen), chromogenic methods not involving FXa or FIIa (protein C activity, plasminogen activity), von Willebrand factor ristocetin cofactor assay, and molecular methods (Factor V Leiden). To date, there are no comprehensive reports describing the impact of DOACs on platelet function testing methods.

Conclusions

  1. Top of page
  2. Summary
  3. Case Presentation
  4. Direct Oral Anticoagulants
  5. Laboratory Assessment of Direct Oral Anticoagulants
  6. Coagulation Test Interference from DOACs
  7. Conclusions
  8. References

Direct oral anticoagulants have freed clinical management of many arterial and venous thromboembolic conditions from routine therapeutic drug monitoring. However, a pharmacologic revolution also disrupts established practice routines, and both clinicians and laboratory directors must adapt to these new conditions, while being alert to additional clinical evidence and diagnostic tools which will be forthcoming. The following is a summary of key points:

  • Peak and trough concentration ranges from DOAC clinical trials are not therapeutic ranges and they should not be used to make dose adjustments.
  • Therapeutic ranges for monitoring warfarin (PT/INR), heparin (aPTT, anti-Xa activity) or LMWH (anti-Xa activity) must not be applied to DOACs.
  • Coagulation laboratory directors should be familiar with the sensitivity of PT and aPTT reagents in their laboratories to oral direct thrombin and direct FXa inhibitors and should share that information with clinicians.
  • Most concerns about DOACs deal with extremely high- or low-anticoagulant activities and can be addressed with screening coagulation tests (PT, aPTT, TT) when combined with time from last oral dose, renal function, and other clinical information.
  • Some specialized coagulation laboratories may validate methods to measure dabigatran, rivaroxaban, apixaban, and future licensed DOACs concentrations. However, these tests are expensive, not rapidly completed, and, currently, lack robust evidence to guide their use in managing patients.
  • Coagulation laboratories must protect patients from inaccurate test results due to DOAC interference by educating clinicians, screening plasma (thrombin time for dabigatran, possibly anti-FXa assays for rivaroxaban/apixaban) prior to selected tests and providing interpretive comments warning of possible confounding of results due to the presence of DOACs.

References

  1. Top of page
  2. Summary
  3. Case Presentation
  4. Direct Oral Anticoagulants
  5. Laboratory Assessment of Direct Oral Anticoagulants
  6. Coagulation Test Interference from DOACs
  7. Conclusions
  8. References
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