title: Resistance to activated protein C (APC): mutation at Arg506 of coagulation factor V and vascular access thrombosis in haemodialysis patients.
abstract: BACKGROUND
  Vascular access thrombosis represents a serious problem in haemodialysis patients. Therefore identification of relevant thrombotic risk factors is clinically valuable. Resistance to activated protein C (APC) was recently identified as a new thrombophilic defect which is caused by a single point mutation in the factor V gene. Whether this mutation predisposes to vascular access thrombosis is unknown.
  
  
  METHODS
  The presence of factor V Leiden (mutation at nucleotide position 1691 of the factor V gene) was determined by polymerase chain reaction (PCR) analysis in 152 haemodialysis patients from all three haemodialysis units of the University Hospital of Vienna. In 61 patients (54 without mutation, 7 with heterozygous mutation) resistance to APC was evaluated. One hundred-seven individuals without renal failure (57 negative for factor V Leiden, 50 heterozygous subjects) served as controls. Haemodialysis patients with heterozygous factor V Leiden mutation were carefully investigated for thrombotic complications of vascular access, other thromboembolic events and additional putative thromboembolic risk factors.
  
  
  RESULTS
  Seven of 152 (4.6%) patients were heterozygous carriers of factor V Leiden. The mean APC resistance ration in heterozygous dialysis patients was 2.31; in the 50 heterozygous controls the ratio was 2.02. The mean APC ratio in haemodialysis patients without mutation was 3.53 in contrast to 2.95 in the control group. Not one of the seven heterozygous haemodialysis patients suffered from vascular access thrombosis of inexplicable origin. Three patients remained totally free of access thrombosis from onset of haemodialysis treatment. In four of seven patients nine events of thrombosis of the vascular access occurred, but were due to anatomical stenosis in each case. In six permanent central venous catheters no episode of occlusion or reduced blood flow requiring thrombolytic therapy was observed. Family history with regard to thrombotic events was negative in all seven patients. No thromboembolic complication occurred during 13 periods of immobilization, in the course of six pregnancies and during oral contraception.
  
  
  CONCLUSIONS
  The heterozygous carrier status for factor V Leiden does not appear to represent a risk factor for vascular access thrombosis in haemodialysis patients. This is possibly due to the fact that the functional APC activity is high and in heterozygous haemodialysis patients APC resistance ratios are very close to the normal range. However, it cannot be excluded that a homozygous factor V mutation represents an increased risk for shunt thrombosis. Therefore patients suffering from repeated and/or inexplicable shunt thrombosis should be tested for the factor V mutation to evaluate the effect of a homozygous mutation.
authors.affiliation: Abteilung für Molekularbiologie, Universität Wien, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Födinger
authors.forename: C
authors.initials: C
authors.lastname: Mannhalter
authors.forename: I
authors.initials: I
authors.lastname: Pabinger
authors.forename: D
authors.initials: D
authors.lastname: Koizar
authors.forename: C
authors.initials: C
authors.lastname: Rintelen
authors.forename: W H
authors.initials: WH
authors.lastname: Hörl
authors.forename: G
authors.initials: G
authors.lastname: Sunder-Plassmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D002408:Catheters, Indwelling / Q000009:adverse effects*; D015331:Cohort Studies; D004247:DNA / Q000032:analysis; D017931:DNA Primers / Q000737:chemistry; D005165:Factor V / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011486:Protein C / Q000235:genetics*; D006435:Renal Dialysis; D012307:Risk Factors; D013927:Thrombosis / Q000209:etiology / Q000235:genetics*; D014511:Uremia / Q000097:blood / Q000628:therapy
chemical_list: D017931:DNA Primers; D011486:Protein C; C095381:factor V Leiden; D005165:Factor V; D004247:DNA; D001120:Arginine