RESUMEN

BACKGROUND AND OBJECTIVE: Prolonged anticoagulation aiming at International Normalized Ratio (INR) values > 3.0 has been recommended for patients with thrombosis and the antiphospholipid-antibody syndrome. We evaluated the influence of anticoagulant antibodies in two different prothrombin time (PT) assays carried out on plasma from lupus anticoagulant patients on oral anticoagulation. DESIGN AND METHODS: INR values obtained with a combined (final test plasma dilution 1:20) and a recombinant (final test plasma dilution 1:3) thromboplastin were compared in 17 patients with persistent lupus anticoagulants (LA) receiving oral anticoagulant treatment and monitored for 69.8 patient-years. Doses of anticoagulant drugs were always assigned based on the results obtained with the combined thromboplastin, aiming at a target INR of 2.5 or 3.0 for patients with venous or arterial thromboembolic disease. Paired determinations with both reagents were also obtained throughout the study period in 150 patients on stable oral anticoagulation but free of antiphospholipid antibodies. Total IgG fractions were purified from selected patients to evaluate effect in the two PT assay systems. RESULTS: No patient experienced recurrence of thrombosis or major bleeding complications (95% confidence interval: 0.1-6.5 per 100 patient-years). INR values with the recombinant reagent were significantly higher than with the combined reagent in 8 LA patients (mean DINR ranging from 0.17 to 0.54) of the degree of anticoagulation was overestimated in all but one LA patients with the recombinant reagent when compared to the DINR observed in non-LA patients (-0.64 +/- 0.42). The anti-cardiolipin IgG titer (r(2) = 0.43, p = 0.004) and the anti-b(2)GPI IgG titer (r(2) = 0.30, p = 0.023) were positively associated with the mean deltaINR observed in LA patients. When added to plasmas with different levels of vitamin K-dependent factors, total IgG fractions from 6 LA patients with significant overestimation of the INR with the recombinant reagent (mean DINR ranging from 0.17 to 0.54, group 1) and from 7 LA patients with mean deltaINR < or = 0.0 (ranging from -0.25 to 0.04, group 2) reproduced the effects observed ex vivo in the two assay systems. However, when total IgG fractions were tested at the same final concentration in the two PT assay systems, there was no difference in the clotting times determined with total IgG fractions from group 1 and group 2 LA patients. Addition of negatively charged liposomes (0.4 and 0.8 mg/mL final concentrations) to platelet free plasma from LA-free patients on stable oral anticoagulation caused a 20% to 48% prolongation of the prothrombin time determined with the recombinant reagent. In contrast, no significant prolongation of the prothrombin time determined with the recombinant reagent was observed upon addition of negatively charged liposomes to plasma from group 1 LA patients. INTERPRETATION AND CONCLUSIONS: These results confirm previous suggestions of assay-dependency of INR values in LA patients on oral anticoagulation. For these patients, accurate INR values may be obtained using combined thromboplastin reagents that permit testing at high plasma dilution.

Asunto(s)

RESUMEN

Patients with antiphospholipid antibody syndrome (APS) experience a higher rate of recurrence of thrombosis than the general population of patients with thrombotic disease. Based on a retrospective analysis, it has been suggested that patients with APS should be kept on prolonged anticoagulation aiming at international normalised ratio (INR) values > 3.0. To evaluate whether the requirement for more intense anticoagulation depends on the variable sensitivity of thromboplastin reagents to the influence of aPLA, we monitored oral anticoagulant treatment in 10 patients with persistent lupus anticoagulants (LA) and venous thromboembolic disease using two thromboplastin reagents: Pro-IL-Complex (Instrumentation Laboratory, combined) and Recombiplastin (Ortho, recombinant). Acenocoumarol dosage was always assigned based on INR values obtained with the combined thromboplastin using diluted (1:20) test plasma, aiming at an INR interval of 2.0 to 3.0. Single INR determinations with both reagents were obtained throughout the study period for 110 aPLA-free patients on stable oral anticoagulation. Using the manufacturer's instrument-certified international sensitivity index (ISI) values, INR obtained with the recombinant reagent were significantly higher than those obtained with the combined reagent in LA-positive patients, but they were lower in LA-negative patients. After correction for local ISI calibration in LA-negative patients, INR values of 3.1 and 4.6 with Recombiplastin corresponded, respectively, to INR values of 2.0 and 3.0 with Pro-IL-Complex. These results indicate the thromboplastin-dependency of INR values in patients with LA, thereby questioning the validity of the INR system for the monitoring of oral anticoagulant treatment in these patients.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

The changes in plasma levels of the vitamin K-dependent natural anticoagulants protein C (PC) and protein S (PS) and procoagulant factors II, IX and X were evaluated in 8 adult patients during treatment with L-asparaginase (L-ase i.v. 120,000 U/m2 over 10 days). PC anticoagulant activity and factor IX, X and II coagulant activity decreased proportionally to their half-lives to a nadir of 50-60% of pretreatment values after 2-5 L-ase infusions, suggesting that inhibition of protein synthesis rather than consumption is the main mechanism responsible for the observed changes. Free PS antigen levels declined at a rate similar to total PS antigen, reaching a nadir of 56% of pretreatment values after 3 L-ase infusions; however due to C4b-binding protein levels higher than total PS levels (p less than 0.05), they were constantly lower than the corresponding total PS antigen levels (0.05 less than p less than 0.001). This implicates that total PS antigen levels cannot be taken as an indicator of PS activity. No differences between the antigenic levels and the anticoagulant activities of PC and free PS could be observed suggesting that L-ase does not affect the mechanisms of vitamin K-dependent carboxylation of Gla-residues. The faster rate of decline of PC and PS activities relative to that of factor II may be responsible for the onset of an hypercoagulable state during the early phase of L-ase treatment.

Asunto(s)