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For warfarin monitoring in patients with lupus inhibitors, review PT method

January 2003
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 as abnormal.

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.

  1. Roubey RAS. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibodies. Blood. 1994;84:2854–2867.
  2. Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulant therapy. Chest. 2001;119:22S–38S.
  3. Brunner HI, Chan WS, Ginsberg JS, et al. Longterm anticoagulation is preferable for patients with antiphospholipid antibody syndrome. Result of a decision analysis. Rheumatol. 2002; 29:490–501.
  4. 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.
Dr. Chandler, a member of the CAPCoagulation Resource Committee, is in the Department of Laboratory Medicine, University of Washington, Seattle.