title: Effect of warfarin treatment on thrombin activatable fibrinolysis inhibitor (TAFI) activation and TAFI-mediated inhibition of fibrinolysis.
abstract: BACKGROUND
  Severe clotting deficiencies are associated with enhanced in vitro fibrinolysis due to insufficient thrombin activatable fibrinolysis inhibitor (TAFI) activation. Because oral anticoagulant therapy (OAT) with warfarin causes a partial deficiency of vitamin K-dependent factors, its effect on clot lysability remains unclear.
  
  
  OBJECTIVE
  To evaluate plasma and blood fibrinolytic capacity in patients under stable OAT (n = 221) as compared with controls (n = 132).
  
  
  METHODS
  Fibrinolysis resistance of plasma (turbidimetry) and blood (thromboelastography) clots was calculated as the lysis time of tissue factor-induced clots exposed to 30 and 100 ng mL(-1) t-PA, respectively.
  
  
  RESULTS
  Plasma PAI-1 was similar in the two groups, whereas TAFI was slightly lower in patients. OAT plasma clots lysed faster than controls (P = 0.001). The addition of the TAFIa inhibitor PTCI reduced lysis time by 14% in OAT and 34% in controls, and the difference between the groups disappeared. Similar data were obtained with blood clots. Thrombin and TAFIa generation in OAT plasma amounted to roughly 50% of controls, supporting a reduced thrombin-dependent TAFI activation. Clot resistance of OAT plasma was normalized by Ba-citrate plasma eluate or prothrombin but not by BaSO(4) serum eluate, rFVIIa or FX. Surprisingly, circulating levels of TAFIa and its inactive derivative TAFIai were higher in warfarin patients (P < 0.0001) and correlated with plasmin-antiplasmin (P = 0.0001) but not with prothrombin F(1) (+) (2) .
  
  
  CONCLUSIONS
  OAT enhances both plasma and blood fibrinolysis by reducing thrombin-dependent TAFI activation, a phenomenon largely determined by low prothrombin levels. At variance with in vitro data, 'basal' in vivo TAFIa/ai levels seem related to plasmin rather than thrombin generation.
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Incampo
authors.forename: C
authors.initials: C
authors.lastname: Carrieri
authors.forename: R
authors.initials: R
authors.lastname: Galasso
authors.forename: F A
authors.initials: FA
authors.lastname: Scaraggi
authors.forename: F
authors.initials: F
authors.lastname: Di Serio
authors.forename: B
authors.initials: B
authors.lastname: Woodhams
authors.forename: N
authors.initials: N
authors.lastname: Semeraro
authors.forename: M
authors.initials: M
authors.lastname: Colucci
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000925:Anticoagulants / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D025901:Carboxypeptidase B2 / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D063285:Fibrin Clot Lysis Time; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009391:Nephelometry and Turbidimetry; D010446:Peptide Fragments / Q000097:blood; D011237:Predictive Value of Tests; D011516:Prothrombin; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism*; D014859:Warfarin / Q000008:administration & dosage*; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; D010446:Peptide Fragments; D000979:alpha-2-Antiplasmin; C037742:plasmin-plasmin inhibitor complex; C045879:prothrombin fragment 1.2; D014859:Warfarin; D011516:Prothrombin; D025901:Carboxypeptidase B2; D013917:Thrombin; D005341:Fibrinolysin