title: Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis.
abstract: BACKGROUND
  Treatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known.
  
  
  OBJECTIVE
  We evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis.
  
  
  METHODS
  Thirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs.
  
  
  RESULTS
  Addition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001). The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma.
  
  
  CONCLUSIONS
  The anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis.
authors: Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Wilma
authors: W
authors: Potze
authors: Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Freeha
authors: F
authors: Arshad
authors: Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Jelle
authors: J
authors: Adelmeijer
authors: Department of Gastroenterology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Hans
authors: H
authors: Blokzijl
authors: Department of Gastroenterology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Arie P
authors: AP
authors: van den Berg
authors: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Joost C M
authors: JC
authors: Meijers
authors: Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Robert J
authors: RJ
authors: Porte
authors: Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands ; Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Ton
authors: T
authors: Lisman
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D001780:Blood Coagulation Tests / Q000379:methods; D000069604:Dabigatran; D005260:Female; D000077425:Fondaparinux; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000627:therapeutic use; D011134:Polysaccharides / Q000627:therapeutic use; D000069552:Rivaroxaban; D013876:Thiophenes / Q000627:therapeutic use; D013917:Thrombin / Q000378:metabolism*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D006495:Heparin, Low-Molecular-Weight; D009025:Morpholines; D011134:Polysaccharides; D013876:Thiophenes; D015091:beta-Alanine; D000069552:Rivaroxaban; D013917:Thrombin; D000069604:Dabigatran; D000077425:Fondaparinux