For warfarin monitoring in patients with lupus inhibitors, review PT method
Wayne L. Chandler, MD
Oral anticoagulant monitoring in patients with lupus inhibitors
has been shown in a CAPSurvey to present problems for some laboratories.
The prothrombin time assay may be prolonged in patients with the antiphospholipid
antibody syndrome for several reasons. First, the antibodies produced
in this syndrome are directed toward phospholipid binding proteins,
including beta-2-glycoprotein I, protein S, protein C, and prothrombin.
If anti-prothrombin antibodies are formed, they may result in a reduced
half-life for prothrombin in the blood, lower prothrombin levels,
and an associated prolongation of the PT.1 This is not a test artifact;
it is due to a true reduction in prothrombin levels. Second, a lupus
inhibitor or anticoagulant interferes with the phospholipid in the
PT assay. The lupus inhibitor effect is more commonly seen in the
APTT assay, but it can be seen in the PT assay as well. As with other
lupus inhibitors, this does not represent inhibition of the coagulation
system in the patient, only an inhibition of the in vitro assay.
Patients with antiphospholipid antibody syndrome often develop venous
and arterial thrombi requiring treatment with antithrombotic agents
such as warfarin. While an INR of 2 to 3 is often used as a therapeutic
target in patients with antiphospholipid antibody syndrome, some patients
may require higher INRs to reach a therapeutic effect.2,3 If the PT
reagent used is sensitive to lupus inhibitors, then the patient’s
PT and INR will appear to be falsely high, leading to a potentially
inadequate warfarin dose.
In a recent CAP Survey (2002 CG2-B) a wildcard specimen was provided
from a patient with a history of antiphospholipid antibody syndrome,
deep venous thrombosis, and a lupus inhibitor on oral anticoagulant
therapy. Participants were asked to perform a PT with INR, APTT, and
factor II activity and factor X activity assays, and then to interpret
whether the patient was above, below, or at an appropriate therapeutic
level for oral anticoagulation.
There was a wide range of values for the APTT in this sample, depending
on the sensitivity of the reagent to lupus inhibitors and mild vitamin
K factor deficiency. APTT results ranged from 32 seconds to more than
245 seconds. The vast majority of labs (99.7 percent) rated the APTT
There was good agreement on the factor activity levels. The mean factor
II activity was 44 percent (SD eight percent), and the mean factor
X activity was 66 percent (SD nine percent). About eight to 10 percent
of participants indicated an inhibitor pattern was seen in the factor
assays. Both factor activity levels indicate the patient was below
therapeutic levels of anticoagulation, which would typically result
in vitamin K factor activities in the range of 15 percent to 30 percent.
Mean INRs for different reagent-instrument combinations ranged from
1.55 to 2.43. Overall the degree of anticoagulation was rated as below
therapeutic by 58 percent of participants, therapeutic by 31 percent,
and above therapeutic by 10 percent. While below therapeutic versus
therapeutic might be debated, the patient was clearly not above therapeutic.
Most, but not all, prothrombin reagents are not affected by lupus
inhibitors and work well for monitoring warfarin therapy.4 The wildcard
challenge indicates the need for laboratories to review their prothrombin
time methodology carefully with regard to warfarin monitoring in patients
with lupus inhibitors.
Dr. Chandler, a member of the CAPCoagulation Resource Committee,
is in the Department of Laboratory Medicine, University of Washington,
- Roubey RAS. Autoantibodies to phospholipid-binding
plasma proteins: a new view of lupus anticoagulants and other
“antiphospholipid” autoantibodies. Blood. 1994;84:2854–2867.
- Ansell J, Hirsh J, Dalen J, et al. Managing
oral anticoagulant therapy. Chest. 2001;119:22S–38S.
- Brunner HI, Chan WS, Ginsberg JS, et al. Longterm
anticoagulation is preferable for patients with antiphospholipid
antibody syndrome. Result of a decision analysis. Rheumatol.
- Tripodi A, Chantarangkul V, Clerici M, et al.
Laboratory control of oral anticoagulant treatment by the INR
system in patients with the antiphospholipid syndrome and lupus
anticoagulant. Results of a collaborative study involving nine
commercial thromboplastins. Br J Haematol. 2001; 115: 672–678.