Abstract
BACKGROUND: The presence of a lupus anticoagulant (LA) in a patient with a thromboembolic event often requires life-long oral anticoagulant. Yet, long-term oral anticoagulant therapy is not without risks. In addition, many individuals are discovered to have a LA but have not yet had a thromboembolic event. It is desirable to identify those at high risk of developing thromboembolic diseases and those unlikely to do so. Circulating monocytes are capable of generating functionally active tissue factor (TF) under many pathologic conditions. We hypothesize that patients with a lupus anticoagulant whose plasmas induce significant tissue factor activity on monocytes may be at higher risk of thrombosis than those whose plasmas do not.
METHOD: To test the hypothesis, we collected consecutive leftover plasma samples that tested positive for the presence of a lupus anticoagulant by the Dilute Russell’s Viper Venom Test from a clinical coagulation laboratory (DTL) over a four years period. These plasma samples were tested for their ability to induce TF activity in monocytes by recombining the test plasma samples with blood cells from freshly drawn blood, anticoagulated with Fragmin (heparin) and recalcified followed by incubation for 2 hrs at 37°C, a method previously described by Østerud et al (Blood Coagul Fibrinolysis1990; 1:41–6). Seventeen plasma samples from healthy donors were also tested as control. The test laboratory (BØ) did not know the clinical diagnosis of these patients at the time of testing. The test results were then matched with the corresponding patients’ clinical diagnosis.
RESULTS: A total of 112 patients’ plasma samples were tested, of which clinical information was available for 108 patients. The clinical data were used to divide the patients into two groups: those with thromboembolic diseases and those without at the time of testing. The results from TF activity induction data were also divided into two groups: those with significant TF induction activity and those without. The mean tissue factor activity detected with normal donors was 0.20 mU/106 monocytes, S.D= 0.20, range 0.02–0.5. A cut off value for positive tissue factor induction was chosen to be >1.0 (>4 S.D.). A contingency table was then constructed as follow:
Thrombosis TF Activity Induction No Yes Negative 28 15 Positive 22 43
A Fisher’s exact test analysis was carried out, which shows an Odd Ratio of 3.65 and a relative risk of 1.92, p=0.0017. In an additional on going study, IgGs were purified from 22 patients with significant thromboembolic diseases and of whom the plasmas were strongly positive for a lupus anticoagulant by the DRVVT test. Seventeen out of 22 of the IgG preparation induced significant TF activity on monocytes but failed to induce TF activity in neutrophils.
CONCLUSIONS:
Significant TF induction activity in a patient with a lupus anticoagulant is associated with an odd ratio of developing thrombosis of 3.6. IgGs from a majority, but not all, of patients with thromboembolic diseases and a lupus anticoagulant induce significant TF activity on monocytes.
We propose that measurement of TF induced on monocytes of whole blood by plasma from an individual with a lupus anticoagulant may provide a method to evaluate potential risk of thrombosis in that patient.
Measurement of tissue factor activity in extracellular vesicles from human plasma samples