title: Mechanical heart valve recipients: anticoagulation in patients with genetic variations of phenprocoumon metabolism.
abstract: OBJECTIVE
  Oral anticoagulation in mechanical heart valve recipients remains crucial, and vitamin K antagonists (VKA) are still the gold standard. Polymorphisms of vitamin K epoxide oxidase reductase (VKORC) and cytochrome p450 (CYP2C9) were recently found to influence VKA metabolism. We retrospectively investigated the prevalence of these genotypes and associated anticoagulation-related complications in our patients.
  
  
  METHODS
  Between August 1998 and August 2008, 563 patients received mechanical heart valve replacement in our institution. Of these, 179 completed a questionnaire on anticoagulation-related complications and consented to genetic analysis. We analysed polymorphisms of VKORC (-1639 G>A; 1173 C>T) and of CYP2C9 (*2, 144 C>T; *3, 359 A>C) by PCR and restriction analysis.
  
  
  RESULTS
  For VKORC-1639/1173 alleles, there were 62 (35%) patients with the combination GG/CC, 91 (51%) with GA/CT, 25 (14%) with AA/TT and 1 (1%) with AA/CT. Phenprocoumon (PC) dosage was related to VKORC polymorphism (P < 0.001) with lower doses required for AA/TT patients. Overall, there were 27 severe bleedings and 11 thromboembolic events. For GG/CC, the incidence of major bleeding events and thromboembolic events was 13 and 6%, respectively, and for AA/TT, it was 27 and 12%, respectively. Variation in international normalized ratio (INR) >1.5 was associated with severe bleeding complications (P = 0.025) and GA/CT patients were predisposed to INR variations >1.5 (P = 0.028). No influence of CYP2C9 polymorphism on PC dosage and anticoagulation-related complications was found.
  
  
  CONCLUSIONS
  VKORC polymorphism affects PC dosage and anticoagulation-related complication rates in mechanical heart valve recipients. Genotyping may help to identify patients at particular risk of anticoagulation-related complications.
authors: Department of Cardiovascular Surgery, University Heart Center Freiburg-Bad Krozingen, Freiburg, Germany. kerstin.brehm@universitaets-herzzentrum.de
authors: Kerstin
authors: K
authors: Brehm
authors: Jenny
authors: J
authors: Schack
authors: Claudia
authors: C
authors: Heilmann
authors: Philipp
authors: P
authors: Blanke
authors: Hans Joachim
authors: HJ
authors: Geissler
authors: Friedhelm
authors: F
authors: Beyersdorf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation / Q000379:methods*; D006470:Hemorrhage / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010644:Phenprocoumon / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D012189:Retrospective Studies; D013923:Thromboembolism / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D064417:Vitamin K Epoxide Reductases; D010644:Phenprocoumon
keywords: CYP2C9; Mechanical heart valve; Phenprocoumon; VKORC1