title: Monitoring rFVIIa 90 μg kg⁻¹ dosing in haemophiliacs: comparing laboratory response using various whole blood assays over 6 h.
abstract: Recombinant FVIIa is a haemostatic agent administered to patients with severe FVIII or FIX deficiency with inhibitors. Although rFVIIa is effective at stopping bleeding, a reliable assay to monitor its effect is lacking. To characterize the pharmacokinetics and global coagulation effects of rFVIIa for 6 h following a IV dose of 90 μg kg⁻¹. Ten non-bleeding subjects with severe FVIII or FIX deficiency were infused with a single-dose of rFVIIa 90 μg k⁻¹ body weight and blood was collected before and at 0.5, 1, 2, 4 and 6 h postdose. Global haemostasis was characterized throughout the study utilizing whole blood analyses (Hemodyne HAS, TEG, ROTEM). The clearance and half-life of factor FVII:C was estimated as 39.0 ± 8.8 mL h⁻¹ kg⁻¹ and 2.1 ± 0.2 h respectively. There was good inter-assay agreement with respect to clot initiation parameters (R, CT and FOT) and these parameters all fell to a mean of approximately 9 min following rFVIIa dosing. The platelet contractile force (PCF) and clot elastic modulus (CEM) were positively correlated to FVII:C (P < 0.0001), and these parameters were dynamic throughout the 6-h period. The MA and MCF did not correlate to FVII:C nor did they significantly change during the study. Prothrombin F1 + 2 significantly increased following rFVIIa dosing (P < 0.001), but remained steady throughout the study. There was no change in D-dimer concentrations over time. The FOT, R and CT characterized clot initiation following rFVIIa dosing. The PCF and CEM were correlated to FVII:C and characterized the dynamics of platelet function and clot strength over the rFVIIa dosing interval. The clinical significance of these findings needs additional study.
authors.affiliation: Coagulation Advancement Laboratory, Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University (VCU), Richmond, VA, USA. dbrophy@vcu.edu
authors.forename: D F
authors.initials: DF
authors.lastname: Brophy
authors.forename: E J
authors.initials: EJ
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Christian Barrett
authors.forename: M E
authors.initials: ME
authors.lastname: Nolte
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: P M
authors.initials: PM
authors.lastname: Gerk
authors.forename: M E
authors.initials: ME
authors.lastname: Carr
authors.forename: H
authors.initials: H
authors.lastname: Pelzer
authors.forename: H
authors.initials: H
authors.lastname: Agersø
authors.forename: M
authors.initials: M
authors.lastname: Ezban
authors.forename: U
authors.initials: U
authors.lastname: Hedner
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D001835:Body Weight; D003018:Clot Retraction / Q000187:drug effects; D004548:Elasticity / Q000187:drug effects; D015942:Factor VIIa / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood* / Q000188:drug therapy; D002836:Hemophilia B / Q000097:blood* / Q000188:drug therapy; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010979:Platelet Function Tests; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa