title: Diluted thrombin time reliably measures low to intermediate plasma dabigatran concentrations.
abstract: BACKGROUND
  Direct oral anticoagulant dabigatran was first introduced as a fixed-dose drug without routine coagulation monitoring, but current recommendations suggest that diluted thrombin time can be used to estimate plasma drug level. The aim of this study was to assess a diluted thrombin time assay based on the same thrombin reagent already used for traditional thrombin time measurements that reliably measure low to intermediate plasma dabigatran levels.
  
  
  METHODS
  We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (23 patients) or 110 mg (21 patients) twice a day. Blood samples were collected at baseline (no dabigatran) and 2-4 weeks after the beginning of dabigatran therapy at trough and at peak. Plasma dabigatran levels were measured with diluted thrombin time and compared to liquid chromatography with tandem mass spectrometry as the reference method. The performance of the diluted thrombin time was compared to Hemoclot® Thrombin Inhibitor and Ecarin Chromogenic Assay.
  
  
  RESULTS
  In ex vivo plasma samples, diluted thrombin time highly correlated with the liquid chromatography with tandem mass spectrometry (Pearson's R = 0.9799). In the low to intermediate range (dabigatran concentration ≤ 100 µg/L) diluted thrombin time correlated significantly more closely to the liquid chromatography with tandem mass spectrometry (R = 0.964) than Hemoclot® Thrombin Inhibitor (R = 0.935, p = 0.05) or Ecarin Chromogenic Assay (R = 0.915, p < 0.01). It was also the only functional assay without any significant bias in the low to intermediate range. Both trough and peak diluted thrombin time values were similar to liquid chromatography with tandem mass spectrometry.
  
  
  CONCLUSIONS
  We conclude that the diluted thrombin time assay presented in this study reliably detects dabigatran and that it is superior to the Hemoclot® Thrombin Inhibitor assay in the low to intermediate range.
authors.affiliation: Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia mojca.bozic@kclj.si.
authors.forename: Mojca
authors.initials: M
authors.lastname: Božič-Mijovski
authors.affiliation: Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rickard E
authors.initials: RE
authors.lastname: Malmström
authors.affiliation: Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors.forename: Petra
authors.initials: P
authors.lastname: Malovrh
authors.affiliation: Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jovan P
authors.initials: JP
authors.lastname: Antovic
authors.affiliation: Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors.forename: Nina
authors.initials: N
authors.lastname: Vene
authors.affiliation: Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors.forename: Petra
authors.initials: P
authors.lastname: Šinigoj
authors.affiliation: Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors.forename: Alenka
authors.initials: A
authors.lastname: Mavri
mesh_terms: D000368:Aged; D000991:Antithrombins / Q000097:blood* / Q000494:pharmacology; D000069604:Dabigatran / Q000097:blood* / Q000494:pharmacology; D016903:Drug Monitoring; D006801:Humans; D057230:Limit of Detection; D015203:Reproducibility of Results; D013918:Thrombin Time
chemical_list: D000991:Antithrombins; D000069604:Dabigatran
keywords: Dabigatran; clinical laboratory techniques; thrombin time