title: Genetic variations of phenprocoumon metabolism in patients with ventricular assist devices.
abstract: OBJECTIVE
  Anticoagulation in patients with ventricular assist device (VAD) support is crucial and to date, no alternative to vitamin K antagonists (VKAs) can be safely used. Genetic variances of cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC) have been recently connected with variation of VKA maintenance as well as loading doses. In this retrospective study, we assessed the incidence of genetic variations and the influence of different genotypes of CYP2C9 and VKORC1 in VAD patients.
  
  
  METHODS
  A total of 161 patients received a VAD implant in our institution between January 2006 and July 2014. Of these, 63 consented to genetic analysis and completed an interview with standardized questions on phenprocoumon (PC) dosage, international normalized ratio and anticoagulation-related complications. Determination of VKORC (-1639 G > A; -1173 C > T) and of CYP2C9 (*2, 430 C > T; *3, 1075 A > C) polymorphisms was performed by polymerase chain reaction and restriction analysis.
  
  
  RESULTS
  The most common VKORC-1639 allele combination was wild-type GG (41%) followed by GA (32%) and AA (27%). Patients with VKORC1 polymorphisms AA and GA needed less PC in the maintenance phase of anticoagulation (P < 0.001) compared with wild-type GG patients. In contrast, CYP2C9 polymorphisms showed no effect on PC doses. Similar findings were observed in the initiation phase of PC therapy. High complications rates under PC therapy were observed particularly at the beginning.
  
  
  CONCLUSIONS
  VKORC polymorphism affects PC dosage in the initiation as well as the maintenance phase. High rates of bleeding complications and thromboembolic events were found at the beginning of PC therapy in VAD patients. Therefore, a genotype-guided dosage algorithm might be useful in VAD patients.
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Freiburg - Bad Krozingen, Freiburg, Germany kerstin.brehm@universitaets-herzzentrum.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brehm
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Freiburg - Bad Krozingen, Freiburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Krumnau
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Freiburg - Bad Krozingen, Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Heilmann
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Freiburg - Bad Krozingen, Freiburg, Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Beyersdorf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D001777:Blood Coagulation / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006333:Heart Failure / Q000097:blood / Q000601:surgery*; D006353:Heart-Assist Devices; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010644:Phenprocoumon / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D013923:Thromboembolism / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D004247:DNA; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D010644:Phenprocoumon
keywords: Anticoagulation; CYP2C9; Phenprocoumon; VAD; VKORC1