Effect of dabigatran on a prothrombinase-based assay for detecting activated protein C resistance: an ex vivo and in vitro study in normal subjects and factor V Leiden carriers.

BACKGROUND: The aim of this study was to evaluate ex vivo and in vitro interference of a direct factor IIa inhibitor, dabigatran, on a prothrombinase-based assay to detect activated protein C resistance. MATERIALS AND METHODS: An ex vivo study was performed in six heterozygous factor V Leiden carriers and 12 normal subjects without the factor V Leiden mutation who were treated with dabigatran. An in vitro study was also performed considering 12 plasma samples (six from normal subjects and six from heterozygous factor V Leiden carriers) spiked with dabigatran. The dabigatran concentration was evaluated using a diluted thrombin time assay, activated protein C resistance was evaluated using a prothrombinase-based assay. RESULTS: In both the ex vivo and in vitro studies dabigatran interfered significantly with activated protein C resistance ratios observed in normal subjects and in factor V Leiden heterozygous carriers. DISCUSSION: The results reported in this paper seem to confirm that dabigatran is able to interfere with the Penthafarm prothrombinase-based assay used to study activated protein C resistance, significantly increasing observed ratios. This effect appears to be present already at low concentrations of dabigatran (6 ng/mL) and affects both normal subjects and heterozygous carriers of factor V Leiden. In this group of patients, dabigatran, at concentrations in the therapeutic range (100-200 ng/mL), could markedly increase the activated protein C resistance ratio, bringing it up to within the reference range for normal subjects, thus potentially leading to misclassification of patients.

Estimated glomerular filtration rate calculated using different creatinine and cystatin based formulas in prediction of trough plasma Dabigtran concentration.

BACKGROUND: In this paper we evaluated the relationship between trough DAB concentration with eGFR calculated using CRE and CYS based formulas. MATERIALS AND METHODS: We considered 100 patients. eGFR was calculated using CKD-EPIcreat, CG, MDRD, CKD-EPIcys and CKD-EPIcombined equations. DAB dosage was selected on the basis of CKD-EPIcreat and relationship between trough DAB concentration and eGFRs was evaluated. RESULTS: Trough DAB concentration roughly correlates with eGFR calculated using various formulas. CKD-EPIcreat eGFR was higher than CKD-EPIcys. In patients receiving a DAB dosage considered adequate using CKD-EPIcreat eGFR but considered excessive using CKD-EPIcys, we observed higher DAB trough concentration and an increased prevalence of subjects with drug concentration >200ng/mL. CONCLUSION: These results suggest that eGFR alone was unable to fully explain trough DAB plasma concentration. Therefore a drug's prescription schedule based on eGFR only should be inadequate. We observed a better correlation between trough DAB concentration and CKD-EPIcys rather than CKD-EPIcreat eGFR. Thus, in patients chronically treated with DAB for thromboprophylaxis in nonvalvular atrial fibrillation evaluation of eGFR using a cystatin base formula should be considered.