Clinical Review & Education

JAMA Diagnostic Test Interpretation

Coagulation Test Interpretation in a Patient

Taking Direct Oral Anticoagulant Therapy
Michelle Sholzberg, MDCM, MSc; Yan Xu, MD

A 74-year-old man presented with spontaneous, acute onset of confusion and headache. He
had no preceding head trauma or falls. He had a history of atrial fibrillation with an annual stroke HOW DO YOU INTERPRET THESE
risk of 2.9% (based on points accrued for hypertension and age ⱖ65 years using the CHA2DS2- RESULTS?
VASc score1). He was being treated with rivaroxaban, 20 mg daily. He took his last dose 14 hours
prior to presentation. Other medications included ramipril and rosuvastatin. A. The patient’s hemostatic status
On physical examination, the patient’s blood pressure was 157/96 mm Hg, heart rate is appropriate for surgery because
was 72/min, and Glasgow Coma Scale score was 14 (range, 3-15 with 15 indicating best neu- aPTT is normal, which rules out anti-
rological status). Head computed tomogram (CT) showed a 2.5-cm left-sided acute subdu- coagulant effect from rivaroxaban.
ral hematoma with mass effect. He required urgent surgical evacuation and the neurosur-
gical team requested advice regarding his perioperative bleeding risk prior to surgery.
B. The patient’s hemostatic status is
Laboratory test results are shown in the Table.
not appropriate for surgery
because the abnormal PT
Table. Patient’s Laboratory Values
suggests anticoagulant effect
Laboratory Test Patient’s Value Reference Range from rivaroxaban.
Prothrombin time (PT), s 18.9 10-13
Activated partial thromboplastin time (aPTT), s 35 34-37
C. The patient’s hemostatic status
Hemoglobin, g/dL 14.0 13-17
3
Platelet count, ×10 /μL 176 140-400
cannot be assessed because the
Serum creatinine, mg/dL 1.04 0.5-1.3
thrombin clotting time is unknown.
Alanine aminotransferase, U/L 15 10-45
Total bilirubin, mg/dL 0.6 0-23 D. The patient’s hemostatic status
SI conversion factors: To convert creatinine to μmol/L, multiply values by 88.4; to convert alanine aminotransferase cannot be assessed because the
to μkat/L, multiply values by 0.0167; and to convert bilirubin to μmol/L, multiply values by 17.104. INR is unknown.

Answer sis. Based on pharmacokinetic studies, an elevated PT suggests the cir-

B. Thepatient’shemostaticstatusisnotappropriateforsurgerybecause
the abnormal PT suggests anticoagulant effect from rivaroxaban.
Test Characteristics
Prothrombin time (PT) and activated partial thromboplastin time
(aPTT) are clot-based tests that measure the length of time required
for thrombus formation in the presence of specific reagents. PT mea-
sures the activity of extrinsic (factor VII) and common (factors II, V, X)
coagulation pathways and was originally introduced for monitoring vi-
tamin K antagonist therapy (eg, warfarin).2 aPTT measures the activ-
ityofintrinsic(factorsVIII,IX,XI,andXII)andcommoncoagulationpath-
ways and was developed as a preoperative screen for hemophilia in
high-risk individuals, but later validated for monitoring therapy with
unfractionated heparin.3
Direct oral anticoagulants (DOACs) dabigatran, rivaroxaban,
apixaban, and edoxaban have reliable pharmacokinetics and are not
affected by vitamin K intake. Therefore, unlike warfarin, they do not
require coagulation test monitoring. Moreover, DOACs have short
half-lives (from 7 to 20 hours), which is an additional advantage rela-
tive to warfarin in emergency settings.
Measuring the anticoagulant effect of DOACs can be useful in cer-
tain circumstances (eg, major bleeding or need for emergency invasive
procedures) to inform the need for therapies to reestablish hemosta-
culating effect of a direct Xa inhibitor (agents approved by the Food
and Drug Administration [FDA] include rivaroxaban, apixaban, and
edoxaban), while an elevated aPTT suggests the effect of dabigatran,
adirectthrombininhibitor,inpatientsreceivingtherapy.4 However,sen-
sitivity of the PT to detect clinically relevant anticoagulant effect from
rivaroxaban is 74% (95% CI, 70%-78%) and for apixaban is 56% (95%
CI, 47%-64%).5 There is substantial variability in assay sensitivity de-
pending on the PT reagent used.4 aPTT has higher sensitivity for dabi-
gatran effect (sensitivity, 98% [95% CI, 89%-100%]),5 but is not help-
ful in detecting the effect of direct Xa inhibitors. While PT and aPTT can
helpqualitativelyassessthepresenceofDOACeffect,theseresultscan-
not be used to distinguish therapeutic vs supratherapeutic effects.
According to the Medicare fee schedule, PT costs $7.29 and aPTT
costs $11.13.
Application to This Patient
The elevated PT suggests anticoagulant effect from rivaroxaban at the
time of testing. The PT test result, combined with the patient’s clinical
presentation and need for urgent surgery, imply that he would benefit
fromcoagulationfactorsandantifibrinolytics,oraspecificreversalagent
torestorehemostasis.Althoughadministrationofprohemostaticagents
forcorrectingDOAC-associatedcoagulopathyarerecommendedforlife-
threatening or major bleeding,6 it is considered an off-label indication.

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 Clinical Review & Education JAMA Diagnostic Test Interpretation

Andexanet alfa was recently approved by the FDA for the reversal of di-
rect factor Xa inhibitors. Careful consideration of patient- and context-
specific variables, such as severity of bleeding and risk of thromboem-
bolism, is important to maximize its appropriate use.
The patient’s kidney and hepatic function were normal, which
is important because kidney and hepatic dysfunction can prolong
the elimination half-life of DOACs. Also, the patient is not taking any
medications that affect rivaroxaban metabolism. Specifically, inhibi-
tors of p-glycoprotein (eg, verapamil, dronedarone) and CYP3A4
(eg, ritonavir) can prolong elimination half-life.7
The timing of the last dose must also be considered in assess-
ing patients presenting with DOAC-associated bleeding; rivaroxa-
ban reaches peak plasma concentration 2 to 3 hours following in-
gestion based on pharmacokinetic studies.8 Therefore, coagulation
parameters can be falsely normal before complete systemic absorp-
tion has occurred, which is particularly important to consider in cases
of intentional or accidental overdose. This patient took his last dose
of rivaroxaban 14 hours prior to presentation, which is beyond the
9- to 12-hour window when plasma DOAC levels are expected to de-
cline meaningfully. Repeated coagulation testing, however, may be
indicated when timing of last ingestion is unclear, or to assess for a
continued anticoagulant effect due to redistribution of DOAC from
the extravascular space following drug reversal.
What Are Alternative Diagnostic Testing Approaches?
An anti-Xa assay using a drug-specific calibrator provides estimated
plasmalevelsofdirectXainhibitors.9 Inthistest,patientplasmaisadded
to a colorimetric commercial reagent in the presence of activated fac-
tor X, the target of direct Xa inhibitors. Similarly, the dilute thrombin
timeprovidesanestimationofplasmadruglevelfordabigatran.Where
available, these tests should be used in the setting of major bleeding
in patients taking a DOAC. In general, plasma drug levels of any DOAC
below 30 ng/mL derived by the anti-Xa assay or dilute thrombin time
suggest absence of a significant anticoagulant effect.6
If the dilute thrombin time is not available, the thrombin clotting
time, a common coagulation test that is highly sensitive (100%) to
dabigatran, can be used to exclude its effect. However, an elevated
thrombin clotting time cannot distinguish between clinically rel-
evant or insignificant dabigatran levels.10 Of note, while the throm-
bin clotting time is sensitive to direct thrombin inhibitors, it is not use-
ful for the detection of direct Xa inhibitor effect such as the effect of
rivaroxaban or apixaban.
Patient Outcomes
Anti-Xaassayforrivaroxabanwasobtainedandreportedat167.5ng/mL
(>30 ng/mL suggests rivaroxaban effect). A specific, on-label reversal
agent was not available. Therefore, the patient received prothrombin
complex concentrate at a dose of 2000 IU and tranexamic acid (an
antifibrinolytic agent) at 1 g given the severity of bleeding, timing
of last rivaroxaban dose, and need for urgent surgery. The surgeons
proceeded with an uncomplicated neurosurgical intervention. Post-
operative CT scan showed improvement of the subdural hematoma,
the patient’s symptoms resolved over the following few days, and he
was discharged home. His neurological status remained stable 1 month
later. Using a shared decision model, it was decided to continue with-
holding anticoagulation and reevaluate antithrombotic therapy at
a future appointment.
Clinical Bottom Line
• An elevated PT for anti-Xa inhibitors and an elevated aPTT for
dabigatran suggest clinically relevant drug effect at the time of testing.
• DOAC-specific coagulation tests such as anti-Xa assay and dilute
thrombin time may help guide clinical decisions in bleeding
patients or in those requiring urgent surgery.
• Up to 50% of people taking a direct Xa inhibitor with clinically
relevant anticoagulation effect can have a normal PT. Therefore,
normal PT results cannot be used to rule out the presence of
circulating rivaroxaban, apixaban, or edoxaban effect.
• Timing of last DOAC ingestion needs to be considered. Information
on the time of the last dose, dosage taken, and the half-life of the
drug are important in interpreting coagulation test results.
• Serial coagulation test results can be useful when evaluating
a patient with DOAC-associated bleeding, especially when the
timing of last dose is unknown or following drug reversal.

ARTICLE INFORMATION
Author Affiliations: Department of Medicine,
University of Toronto, Toronto, Ontario, Canada
(Sholzberg, Xu); Laboratory Medicine &
Pathobiology, University of Toronto, Toronto,
Ontario, Canada (Sholzberg); Li Ka Shing
Knowledge Institute, St. Michael’s Hospital,
Toronto, Ontario, Canada (Sholzberg).
Corresponding Author: Michelle Sholzberg, MD,
MSc, Coagulation Laboratory, St. Michael's Hospital,
30 Bond St, Toronto, ON M5B 1W8, Canada
(sholzbergm@smh.ca).
Section Editor: Mary McGrae McDermott, MD,
Senior Editor.
Published Online: September 14, 2018.
doi:10.1001/jama.2018.13998
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Additional Contributions: We thank the patient for
granting permission to publish this information.
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