Monitoring of oral anticoagulant therapy in lupus anticoagulant positive patients with the anti‐phospholipid syndrome

Abstract

Introduction of the International Normalized Ratio (INR) has improved the standardization of laboratory control of oral anticoagulant therapy (OAT). However, it has been reported that misleading INR results can be obtained from OAT patients with lupus anticoagulant (LA). To investigate this claim, we studied 35 OAT patients, 14 of whom had anti‐phospholipid syndrome (APS) with a documented LA. Attainment of anticoagulation was confirmed by chromogenic assay of factor VII and factor X. Prothrombin times were performed using eight thromboplastins (five derived from rabbit brain, two recombinant human tissue factor and one made from human placenta) with an International Sensitivity Index (ISI) of <1.40. When using the thromboplastin manufacturers' ISI there was a significant difference (ANOVA, P<0.0001) between INR results obtained with the eight reagents for both APS (average CV = 12.4%) and non‐APS (average CV = 12.5%) patient groups. Variation using the eight thromboplastins was assessed by calculating the CV for each sample; these values were then pooled for each patient group to give the average CV for all samples with all reagents for the two patient groups. Results for both patient groups exhibited markedly reduced variation (APS group average CV = 6.5%, non‐APS group average CV = 5.8%) when locally assigned ISI values were employed in the calculation of INRs. Our data does not support the suggestion that the INR may not reflect the true level of anticoagulation in the long‐term warfarin‐treated patient, in whom lupus anticoagulant was detected. However, there was strong evidence that thromboplastin use should be restricted to those clot detection systems for which the reagent's manufacturer has assigned an ISI, or local ISI assignment must be undertaken. The inappropriate use of a generic (i.e. optical or mechanical clot detection system without regard to specific analyser type) ISI value can lead to ambiguous results.

Monitoring anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome

“…Measuring factor Xa activity with the CFX assay may therefore provide benefits to APS patients because the test results are not influenced by the presence of APL. To date, few studies have compared INR values and factor X activities in patients with and without APS [10][11][12][13][14]. The patient number in some studies was only small [12,13], and the results are conflicting.…”

Reticulated platelets in primary and reactive thrombocytosis

“…If the problems with the INR in patients with lupus anticoagulants on warfarin therapy are not taken into account, however, this study will potentially yield inconclusive results. In our recent paper (Lawrie et al, 1997) Valle et al (1996), who they say reported marked discrepancies in patients with LA on OAT, despite local determination of ISI. In fact, these workers used a different system, with diluted plasmas and Pro-IL complex, which is combined thromboplastin reagent and contains absorbed bovine plasma, which in theory could create artefacts or LA cofactor-like phenomena.…”

“…Lawrie et al (1997) reported that use of a locally assigned International Sensitivity Index (ISI) reduced the variation in International Normalized Ratio (INR) results obtained with different thromboplastins in patients with lupus anticoagulants on warfarin therapy. They also observed a similar decrease in variation for patients without lupus anticoagulants on warfarin therapy, and suggested that one problem with using the INR to monitor warfarin therapy in patients with lupus anticoagulants was related to the use of 'generic' ISI values (Lawrie et al, 1997). This suggestion does not explain the observations of Della- Valle et al (1996), however, who found marked INR discrepancies in patients with lupus anticoagulants on warfarin therapy, in spite of the use of locally determined ISIs.…”

Clinical utilization of the international normalized ratio (INR)

“…Della Valle and collaborators found INRs obtained with a recombinant thromboplastin (Recombiplastin, Ortho Laboratories) to be significantly higher in lupus anticoagulant (LA)-positive, than in LA-negative patients, using the manufacturer's instrumentcertified ISI, and questioned the validity of the INR system for monitoring OAT in LA-positive patients (158). Reagentdependent thromboplastin sensitivity to LA was also reported in three later studies (159)(160)(161). Laboratory and patient-specific determinations of the effect of LAs on thromboplastin sensitivity, and the avoidance of reagents that show an LA influence is one solution to this problem.…”