title: Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX.
abstract: OBJECTIVE
  The key complication of treatment with vitamin K antagonists (VKAs) is bleeding. The major determinant of VKA-induced bleeding is the intensity of anticoagulation. Individual patient characteristics may also influence bleeding risk. In addition, soluble thrombomodulin (s-TM) levels and mutations in the propeptide of factor (F)IX are important candidate risk factors in this respect.
  
  
  METHODS
  A matched case-control study was designed to search for risk factors that predict bleeding during VKA treatment. We selected cases that had experienced major bleeding during treatment with VKA and matched controls without bleeding complications from the databases of two Thrombosis Services. The controls were matched for indication of treatment, age, gender, type of anticoagulant used and whether or not treatment with VKA was stopped. DNA and plasma were stored of all cases and controls.
  
  
  CONCLUSIONS
  In total 110 patients and 220 controls consented to participate. The results indicate that s-TM levels, measured by ELISA, may be a risk indicator for bleeding [crude odds ratio 3.25 for the highest quartile vs. the lowest quartile (95% confidence interval 1.40, 7.51)]. Three novel mutations, determined by direct sequencing, in the gene portion encoding the propeptide of FIX were identified that do not seem to play an important role in bleeding risk during treatment with VKAs.
authors.affiliation: Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands. j_f.vanderheijden@amc.uva.nl
authors.forename: J F
authors.initials: JF
authors.lastname: van der Heijden
authors.forename: B
authors.initials: B
authors.lastname: Rekké
authors.forename: B A
authors.initials: BA
authors.lastname: Hutten
authors.forename: F J M
authors.initials: FJ
authors.lastname: van der Meer
authors.forename: M G H
authors.initials: MG
authors.lastname: Remkes
authors.forename: M
authors.initials: M
authors.lastname: Vermeulen
authors.forename: H R
authors.initials: HR
authors.lastname: Büller
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
mesh_terms: D000074:Acenocoumarol; D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D003625:Data Collection; D005164:Factor IX / Q000235:genetics*; D005260:Female; D006470:Hemorrhage / Q000209:etiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010644:Phenprocoumon; D015995:Prevalence; D012307:Risk Factors; D018180:Thrombomodulin / Q000097:blood*; D014812:Vitamin K / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D018180:Thrombomodulin; D014812:Vitamin K; D005164:Factor IX; D000074:Acenocoumarol; D010644:Phenprocoumon