title: Dabigatran is Less Effective Than Warfarin at Attenuating Mechanical Heart Valve-Induced Thrombin Generation.
abstract: BACKGROUND
  Patients with mechanical heart valves (MHV) require warfarin to prevent thromboembolism. Although dabigatran was as effective as warfarin for stroke prevention in atrial fibrillation when compared with warfarin in patients with MHV, the study was stopped early because of more strokes and bleeding with dabigatran. To determine why dabigatran was less effective than warfarin, we compared their effects on thrombin generation induced by MHV.
  
  
  RESULTS
  Thrombin generation in the absence or presence of valve leaflets or sewing ring segments (SRS) was quantified. Studies were done in control plasma, plasma depleted of factors (F) XII, XI, or VII, plasma containing varying concentrations of dabigatran, or plasma from patients on dabigatran or warfarin with varying dabigatran concentrations or international normalized ratio (INR) values. Mean endogenous thrombin potential (ETP) increased 1.2-, 1.5-, and 1.8-fold in the presence of leaflets, Teflon SRS, and Dacron SRS, respectively. Whereas ETP in FVII-depleted and control plasma was similar, ETP was reduced to background levels in FXII-depleted plasma and abrogated in FXI-depleted plasma. Dabigatran had little effect on ETP at concentrations below 400 ng/mL, whereas in plasma from warfarin-treated patients, ETP was suppressed with INR values over 1.5.
  
  
  CONCLUSIONS
  MHV induce thrombin generation via the intrinsic pathway and generate sufficient thrombin to overwhelm clinically relevant dabigatran concentrations. In contrast, warfarin is more effective than dabigatran at suppressing MHV-induced thrombin generation. These data explain why dabigatran failed in MHV patients and suggest that strategies targeting FXII or FXI may suppress the root cause of thrombosis in such patients.
authors: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada (I.H.J., A.R.S., J.C.F., J.I.W.) Department of Surgery, McMaster University, Hamilton, Ontario, Canada (I.H.J., R.P.W.) Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada (I.H.J., J.I.W.).
authors: Iqbal H
authors: IH
authors: Jaffer
authors: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada (I.H.J., A.R.S., J.C.F., J.I.W.) Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.R.S., J.C.F., J.I.W.).
authors: Alan R
authors: AR
authors: Stafford
authors: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada (I.H.J., A.R.S., J.C.F., J.I.W.) Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.R.S., J.C.F., J.I.W.).
authors: James C
authors: JC
authors: Fredenburgh
authors: Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (R.P.W., N.C.C.) Department of Surgery, McMaster University, Hamilton, Ontario, Canada (I.H.J., R.P.W.).
authors: Richard P
authors: RP
authors: Whitlock
authors: Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (R.P.W., N.C.C.).
authors: Noel C
authors: NC
authors: Chan
authors: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada (I.H.J., A.R.S., J.C.F., J.I.W.) Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada (I.H.J., J.I.W.) Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.R.S., J.C.F., J.I.W.) Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (J.I.W.).
authors: Jeffrey I
authors: JI
authors: Weitz
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000991:Antithrombins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000069604:Dabigatran / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006350:Heart Valve Prosthesis / Q000009:adverse effects*; D019918:Heart Valve Prosthesis Implantation / Q000009:adverse effects* / Q000295:instrumentation; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D019934:International Normalized Ratio; D007700:Kinetics; D011474:Prosthesis Design; D013917:Thrombin / Q000378:metabolism*; D013923:Thromboembolism / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D016896:Treatment Outcome; D014859:Warfarin / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D014859:Warfarin; D013917:Thrombin; D000069604:Dabigatran
keywords: anticoagulants; coagulation; thrombin; valves