title: Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban.
abstract: The new direct-acting anticoagulants such as dabigatran and rivaroxaban are usually not monitored but may be associated with haemorrhage, particularly where renal impairment occurs. They have no effective "antidotes". We studied 17 patients receiving dabigatran 150 mg twice daily for non-valvular atrial fibrillation and 15 patients receiving rivaroxaban 10 mg daily for the prevention of deep venous thrombosis after hip or knee replacement surgery. We assessed the effect of these drugs on commonly used laboratory tests and Calibrated Automated Thrombogram (CAT) using plasma samples. We also assessed effects in fresh whole blood citrated patient samples using thromboelastography on the TEG and the ROTEM. The efficacy of nonspecific haemostatic agents prothrombin complex concentrate (PCC), Factor VIII Inhibitor By-passing Activity (FEIBA) and recombinant activated factor VII (rVIIa) were tested by reversal of abnormal thrombin generation using the CAT. Concentrations added ex vivo were chosen to reflect doses normally given in vivo. Dabigatran significantly increased the dynamic parameters of the TEG and ROTEM and the lag time of the CAT. It significantly reduced the endogenous thrombin potential (ETP) and reduced the peak height of the CAT. Rivaroxaban did not affect the TEG and ROTEM parameters but did increase the lag time and reduce ETP and peak height of the CAT. For both drugs, these parameters were significantly and meaningfully corrected by PCC and FEIBA and to a lesser but still significant extent by rFVIIa. These results may be useful in devising a reversal strategy in patients but clinical experience will be needed to verify them.
authors.affiliation: Richard Herrmann, Department of Haematology, Royal Perth Hospital, Wellington Street, Perth, Australia, 6000, Tel.: +61 892243967, Fax +61 892243449, E-mail: richard.herrmann@health.wa.gov.au.
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.forename: James
authors.initials: J
authors.lastname: Thom
authors.forename: Alicia
authors.initials: A
authors.lastname: Wood
authors.forename: Michael
authors.initials: M
authors.lastname: Phillips
authors.forename: Shoaib
authors.initials: S
authors.lastname: Muhammad
authors.forename: Ross
authors.initials: R
authors.lastname: Baker
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology*; D019644:Arthroplasty, Replacement, Hip; D019645:Arthroplasty, Replacement, Knee; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy*; D057205:Automation, Laboratory; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000378:metabolism; D000069604:Dabigatran; D004864:Equipment and Supplies; D005167:Factor VII / Q000378:metabolism; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D009025:Morpholines / Q000009:adverse effects / Q000494:pharmacology; D011183:Postoperative Complications / Q000517:prevention & control*; D000069552:Rivaroxaban; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D013876:Thiophenes / Q000009:adverse effects / Q000494:pharmacology; D013916:Thrombelastography; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013918:Thrombin Time / Q000295:instrumentation / Q000379:methods*; D020246:Venous Thrombosis / Q000209:etiology / Q000517:prevention & control*; D028761:Withholding Treatment; D015091:beta-Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D001779:Blood Coagulation Factors; D009025:Morpholines; D013876:Thiophenes; D015091:beta-Alanine; C025667:prothrombin complex concentrates; D005167:Factor VII; D000069552:Rivaroxaban; C065655:anti-inhibitor coagulant complex; D013917:Thrombin; D000069604:Dabigatran
keywords: Anticoagulants; dabigatran; reversal; rivaroxaban; thrombin generation