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Effect of direct oral anticoagulants on dilute Russell´s viper venom time screen and confirm assays for lupus anticoagulant testing

Background: Direct oral anticoagulants (DOACs) strongly affect a wide variety of specialized coagulation assays. Among them, dilute Russell ´s viper venom time screen (dRVVTs) and confirm (dRVVTc) assays, key to the investigation of lupus anticoagulant (LA), are particularly sensitive to DOACs. Thus, results of LA testing could be misinterpreted, mostly due to its false positive identification, in patients treated with DOACs. Aim: The aim of this study was to investigate the impact of all three DOACs, dabigatran, rivaroxaban and apixaban, on both dRVVTs and dRVVTc assays for LA testing. Methods: The study included plasma samples from patients treated with dabigatran (N=57), rivaroxaban (N=58) and apixaban (N=28). Rivaroxaban and apixaban were determined using Innovance anti-FXa assay (Siemens Healthineers, Germany) with rivaroxaban and apixaban calibrators (Hyphen Biomed, France) and dabigatran was measured using Innovance DTI assay (Siemens Healthineers, Germany), funded as a part of Croatian Science Foundation research project IP-2016-06-8208. LA ratio was calculated from dRVVTs and dRVVTc assays (dRVVTs/dRVVTc) using LA1 screening and LA2 confirmation reagents (Siemens Healthineers, Germany). Cut-off for positive LA ratio is considered to be standard ratio greater than 1.37 according to the manufacturer recommendations for specific reagents used. All measurements were performed on BCSXP coagulation analyzer (Siemens Healthineers, Germany). All the data are described by basic statistical parameters: median with 95% confidence interval (95%CI) and interquartile range (IQR). Differences between groups were tested using the nonparametric Mann-Whitney rank sum test. A difference was considered statistically significant at P<0.05. Statistical analysis was done using MedCalc Statistical Software version 11.5.1 (MedCalc Software, Belgium). Results: All three DOACs led to a prolongation of both dRVVTs and dRVVTc assays (Table 1). LA ratio was significantly higher in patients treated with rivaroxaban compared to patients treated with dabigatran and apixaban (Table 1). Concentrations of all three DOACs were not significantly different among all patients investigated for LA (Table 1). Comparison of samples with positive and negative LA results for particular DOAC drug showed a large proportion of false positive (FP) LA results among all investigated patients. LA testing was positive in more than a half of all patients on dabigatran and rivaroxaban and in slightly lower proportion of patients taking apixaban (Table 2). Proportion of FP LA results was significantly higher in patients treated with rivaroxaban compared to patients taking apixaban (P=0.026), whereas proportions of FP results between patients taking dabigatran and rivaroxaban, as well as in those taking dabigatran and apixaban were not significantly different (P=0.307 and P=0.214). All three DOACs affected dRVVTs more than dRVVTc assay, although significant difference for dRVVTs assay between FP and true negative (TN) results of LA testing was obtained for dabigatran and rivaroxaban, but not for apixaban (Table 2). The results of dRVVTc assay showed significant difference between FP and TN for rivaroxaban only (Table 2). Conclusion: dRVVTs assay is the most sensitive test to the presence of all three DOACs. LA testing should not be performed in patients taking DOACs, as these drugs may cause false positive results in high proportion of patients.

dabigatran, rivaroxaban, apixaban, LA testing

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