title: Factor VIII inhibitor-bypassing agents act by inducing thrombin generation and can be monitored by a thrombin generation assay.
abstract: Factor VIII (FVIII)-bypassing agents have complex modes of action but all control bleeding in inhibitor patients by triggering the generation of thrombin. No routine test is available for monitoring this therapy in patients with inhibitors against FVIII. We present an assay that records FEIBA- or FVIIa-mediated changes in thrombin generation (TG) in FVIII inhibitor plasma samples. In plasma samples spiked with FEIBA TG was normalized above 0.4 U/ml, while for recombinant FVIIa (rFVIIa) more than 12.5 microg/ml were required to induce TG in the absence of tissue factor (TF). Addition of TF increased the TG potential of rFVIIa in vitro. This assay seems suitable for monitoring the pharmacokinetics of inhibitor bypassing agents during treatment and possibly for predicting responses to treatment.
authors.affiliation: Baxter BioScience, Vienna, Austria. peter_turecek@baxter.com
authors.forename: P L
authors.initials: PL
authors.lastname: Turecek
authors.forename: K
authors.initials: K
authors.lastname: Váradi
authors.forename: B
authors.initials: B
authors.lastname: Keil
authors.forename: C
authors.initials: C
authors.lastname: Negrier
authors.forename: E
authors.initials: E
authors.lastname: Berntorp
authors.forename: J
authors.initials: J
authors.lastname: Astermark
authors.forename: J-C
authors.initials: JC
authors.lastname: Bordet
authors.forename: M
authors.initials: M
authors.lastname: Morfini
authors.forename: S
authors.initials: S
authors.lastname: Linari
authors.forename: H P
authors.initials: HP
authors.lastname: Schwarz
mesh_terms: D001323:Autoantibodies / Q000276:immunology*; D001779:Blood Coagulation Factors / Q000032:analysis / Q000494:pharmacology*; D003199:Computer Systems; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000494:pharmacology*; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000627:therapeutic use; D015942:Factor VIIa; D006467:Hemophilia A / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D008954:Models, Biological; D011994:Recombinant Proteins / Q000097:blood / Q000494:pharmacology*; D013917:Thrombin / Q000032:analysis / Q000096:biosynthesis*; D013925:Thromboplastin / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D001779:Blood Coagulation Factors; D007518:Isoantibodies; D011994:Recombinant Proteins; D005167:Factor VII; D005169:Factor VIII; D013925:Thromboplastin; C103587:recombinant FVIIa; C065655:anti-inhibitor coagulant complex; D015942:Factor VIIa; D013917:Thrombin