title: From laboratory to clinical practice: Dabigatran effects on thrombin generation and coagulation in patient samples.
abstract: BACKGROUND
  Dabigatran (Dabi) is not routinely monitored. However, in emergency cases quantitative assessment is required and laboratories must provide suitable tests at all hours. Little is known about Dabi effects on thrombin generation.
  
  
  METHODS
  Patient samples (n=241) were analyzed for functional Dabi concentrations (Dabi-TT) using a combination of the Hemoclot Thrombin Inhibitors assay (HTI®) and, for samples with low levels, undiluted thrombin time (TT). Results were compared to prothrombin time (PT) and activated partial thromboplastin time (APTT). In 49 samples Dabi effects were further investigated with Calibrated Automated Thrombogram (CAT®) for thrombin generation and with Russell's viper venom time (RVVT), prothrombinase-induced clotting time (PiCT®), chromogenic Anti-IIa® and ecarin clotting assay (ECA®). Fibrinogen and D dimer were assessed to reflect the coagulation status of the patient. A subset of these samples (n=21) were also analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  
  
  RESULTS
  Dabi-TT correlated with RVVT (R(2)=0.49), PiCT® (R(2)=0.73), ECA® (R(2)=0.89), Anti-IIa® (R(2)=0.90) and LC-MS/MS (R(2)=0.81). APTT correlated curvi-linearly with Dabi-TT (R(2)=0.71), but was normal in many cases (18/70) despite Dabi-TT>40ng/mL. There was no association between Dabi-TT and fibrinogen or D dimer levels. Increasing Dabi concentrations prolonged lag time (R(2)=0.54) and, surprisingly, elevated the ETP and Peak of CAT® (p<0.001).
  
  
  CONCLUSIONS
  Thrombin-specific tests measure Dabi accurately, whereas coagulation time based assays depend more on other factors. The enhanced thrombin generation in Dabi-treated patients may predict clinically relevant hypercoagulability and warrants further investigation.
authors.affiliation: Coagulation Disorders Unit, Clinical Chemistry, HUSLAB Laboratory Services, Helsinki University Central Hospital, POB 340, 00029, Helsinki, Finland. Electronic address: tuukka.helin@helsinki.fi.
authors.forename: Tuukka A
authors.initials: TA
authors.lastname: Helin
authors.affiliation: Coagulation Disorders Unit, Clinical Chemistry, HUSLAB Laboratory Services, Helsinki University Central Hospital, POB 340, 00029, Helsinki, Finland. Electronic address: marja.lemponen@hus.fi.
authors.forename: Marja
authors.initials: M
authors.lastname: Lemponen
authors.affiliation: Clinical Pharmacology Unit, Department of Medicine, Solna, Karolinska Institutet, and Karolinska University Hospital, 17176, Stockholm, Sweden. Electronic address: paul.hjemdahl@ki.se.
authors.forename: Paul
authors.initials: P
authors.lastname: Hjemdahl
authors.affiliation: Clinical Pharmacology Unit, Karolinska University Hospital, 17176, Stockholm, Sweden. Electronic address: yuko.ronquist@karolinska.se.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Rönquist-Nii
authors.affiliation: Coagulation Disorders Unit, Hematology and Cancer Center and Clinical Chemistry (HUSLAB Laboratory Services), University of Helsinki, Helsinki University Central Hospital, POB 340, 00029, Helsinki, Finland. Electronic address: riitta.lassila@hus.fi.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lassila
authors.affiliation: Coagulation Disorders Unit, Clinical Chemistry, HUSLAB Laboratory Services, Helsinki University Central Hospital, POB 340, 00029, Helsinki, Finland. Electronic address: lotta.joutsi-korhonen@hus.fi.
authors.forename: Lotta
authors.initials: L
authors.lastname: Joutsi-Korhonen
mesh_terms: D000991:Antithrombins / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D000069604:Dabigatran / Q000494:pharmacology*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D053719:Tandem Mass Spectrometry; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013918:Thrombin Time
chemical_list: D000991:Antithrombins; D013917:Thrombin; D000069604:Dabigatran
keywords: Anticoagulants; Blood Coagulation Tests; Dabigatran Etexilate; Drug Monitoring; Thrombin Generation