title: Pro- and anticoagulant factors facilitate thrombin generation and balance the haemostatic response to FEIBA(®) in prophylactic therapy.
abstract: BACKGROUND
  FEIBA(®) consists of zymogens and traces of activated forms of procoagulant factors II, VII, IX, X, anticoagulants protein C and TFPI, and small amounts of cofactors FV, FVIII and protein S, in a balanced ratio. As shown previously, FII-FXa complex plays a key role in FEIBA's mode of action (MoA).
  
  
  METHODS
  Thrombin generation (TG) was measured by spiking coagulation factors, cofactors and inhibitors to high titer FVIII inhibitor plasma, and in plasma samples from patients in a phase 3 clinical study evaluating the safety and efficacy of FEIBA prophylaxis in haemophilia A patients with inhibitors.
  
  
  RESULTS
  Increasing the FXa/FII ratio improved TG, while adding coagulation enzyme components had a negligible effect. Adding FX, FIX, and FVII increased the peak thrombin and decreased the lag time. The presence of FV and phospholipids led to faster TG, while protein C and protein S reduced the amount of peak thrombin. TFPI appeared to have no effect. Patients on prophylaxis with FEIBA(®) showed higher peak thrombin and AUC with elevated FII, FX, FIX, FVIIa, and protein C levels, and experienced significantly less bleeding episodes than those receiving on-demand treatment.
  
  
  CONCLUSIONS
  These experiments showed that although the FII-FXa complex induced immediate thrombin formation on the activated platelet surface, other procoagulant components of FEIBA were necessary to achieve an optimal thrombin burst. The presence of the pro- and anti-coagulants in FEIBA provides a haemostatic balance, and is thus expected to prevent thrombotic events. Recent clinical data verified the postulated MoA of FEIBA in prophylaxis treatment.
authors.affiliation: Baxalta, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Varadi
authors.affiliation: Baxalta, Westlake Village, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tangada
authors.affiliation: Baxalta, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Loeschberger
authors.affiliation: Baxalta, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Montsch
authors.affiliation: Baxalta, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Schrenk
authors.affiliation: Baxalta, Westlake Village, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ewenstein
authors.affiliation: Baxalta, Vienna, Austria.
authors.forename: P L
authors.initials: PL
authors.lastname: Turecek
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood; D000925:Anticoagulants / Q000737:chemistry*; D001779:Blood Coagulation Factors / Q000378:metabolism*; D001780:Blood Coagulation Tests; D003029:Coagulants / Q000378:metabolism*; D006467:Hemophilia A / Q000097:blood / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D012720:Severity of Illness Index; D013917:Thrombin / Q000032:analysis* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000925:Anticoagulants; D001779:Blood Coagulation Factors; D003029:Coagulants; C065655:anti-inhibitor coagulant complex; D013917:Thrombin
keywords: FEIBA; haemophilia; inhibitors; prophylaxis; thrombin generation