title: Factor VIIa analog has marked effects on platelet function and clot kinetics in blood from patients with hemophilia A.
abstract: To evaluate the hemostatic effects of NN1731 and rFVIIa, an ex-vivo study in hemophilia patients used the Hemodyne Hemostasis Analysis System (HAS) to measure platelet contractile force (PCF), clot elastic modulus (CEM), and force onset time (FOT), and the Haemoscope Thrombelastograph (TEG) to measure reaction time (R), kinetics time (K), and maximum amplitude (MA). Blood samples from 10 healthy volunteers and 10 Factor VIII-deficient patients of varying severity (mild, moderate, severe), were spiked with rFVIIa and NN1731 (both 0.64 and 1.28 microg/ml, respectively) and analyzed to characterize platelet function and clot kinetics. There was wide variability in the rFVIIa response. NN1731 had greater and more consistent effects on PCF, CEM, FOT, R, and K relative to rFVIIa, in all hemophilia groups. The lowest NN1731 concentration (0.64 microg/ml) shortened R and FOT, and increased CEM and PCF more than rFVIIa 1.28 microg/ml. NN1731 normalized clotting parameters equivalent to values obtained in healthy volunteers. FOT and R were highly correlated (r = 0.96). No correlation was observed between CEM and MA. NN1731 produced less variable, more pronounced and predictable ex-vivo hemostatic effects on PCF, CEM, FOT, R and K than rFVIIa in all hemophilia groups. HAS and TEG assays provided similar estimates of FOT and R, however CEM appeared to be more sensitive than MA to changes in clot firmness.
authors.affiliation: School of Pharmacy, Coagulation Advancement Laboratory, Virginia Commonwealth University, Richmond, VA, USA. dbrophy@vcu.edu
authors.forename: Donald F
authors.initials: DF
authors.lastname: Brophy
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Martin
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Nolte
authors.forename: Janice G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: J Christian
authors.initials: JC
authors.lastname: Barrett
authors.forename: Mirella
authors.initials: M
authors.lastname: Ezban
mesh_terms: D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D016022:Case-Control Studies; D003018:Clot Retraction / Q000187:drug effects; D005167:Factor VII / Q000494:pharmacology*; D015942:Factor VIIa / Q000494:pharmacology; D006467:Hemophilia A / Q000097:blood* / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D013916:Thrombelastography; D055815:Young Adult
chemical_list: C519901:NN1731; D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa