title: Bleeding risk in warfarinized patients with a therapeutic international normalized ratio: the effect of low factor IX levels.
abstract: OBJECTIVE
  Bleeding is the main complication of warfarin therapy, even patients with an international normalized ratio (INR) in the target range can suffer bleeding, suggesting that INR does not perfectly reflect the therapeutic effect of warfarin. We hypothesized the INR might underestimate the level of anticoagulation in a subject with a lower factor (F) IX level than average.
  
  
  RESULTS
  We modeled warfarin anticoagulation in our in vitro thrombin generation (TG) model by adjusting the levels of vitamin K-dependent factors to those of patients with an INR of 2-3. Variation in FIX had a marked effect on TG but had no effect on the prothrombin time (PT)-INR. A prospective observational, cross-sectional clinical study including 341 consecutive patients admitted to the emergency department with an INR between 2 and 3, showed a statistically lower FIX activity in bleeders (P = 0.004) compared with others. No correlation was found between TG capacity and PT-INR results (P = 0.36). However, in patients, presenting with a warfarin-related hemorrhage, TG was significantly lower (P < 0.001) than others. A correlation on the boundary of significance was observed between TG capacity and FIX levels (P = 0.09).
  
  
  CONCLUSIONS
  These data demonstrates that patients who bleed when their PT-INR is in the target range 2-3 might have defective TG related to a lower level of FIX than expected.
authors.affiliation: Unite d'Hemostase Clinique, Hopital Edouard Herriot, Universite Lyon 1, Lyon, France. ydargaud@univ-lyon1.fr
authors.forename: Y
authors.initials: Y
authors.lastname: Dargaud
authors.forename: M
authors.initials: M
authors.lastname: Hoffman
authors.forename: L
authors.initials: L
authors.lastname: Lefrapper
authors.forename: F-C
authors.initials: FC
authors.lastname: Lin
authors.forename: A
authors.initials: A
authors.lastname: Genty
authors.forename: B
authors.initials: B
authors.lastname: Chatard
authors.forename: S
authors.initials: S
authors.lastname: Marin
authors.forename: C
authors.initials: C
authors.lastname: Négrier
authors.forename: D M
authors.initials: DM
authors.lastname: Monroe
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000737:chemistry / Q000627:therapeutic use*; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000166:cytology; D003430:Cross-Sectional Studies; D005164:Factor IX / Q000378:metabolism*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000188:drug therapy; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D011446:Prospective Studies; D011516:Prothrombin / Q000737:chemistry; D012306:Risk; D013917:Thrombin / Q000737:chemistry; D014812:Vitamin K / Q000737:chemistry; D014859:Warfarin / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D011516:Prothrombin; D005164:Factor IX; D013917:Thrombin
keywords: bleeding and blood coagulation tests; factor IX; international normalized ratio; warfarin