Effect of recombinant factor VIIa variant (NN1731) on platelet function, clot structure and force onset time in whole blood from healthy volunteers and haemophilia patients.
NN1731 is a novel variant of recombinant factor VIIa (rFVIIa) that binds to activated platelets, but has greater enzymatic activity than rFVIIa in generating FXa and thrombin. The effect of NN1731 on clot structure and platelet function was characterized ex vivo in whole blood from healthy volunteers and haemophilic patients. Blood samples from six healthy volunteers, nine haemophilia A patients with and without inhibitors and one acquired haemophilia A patient, were spiked with increasing concentrations (0.32, 0.64 and 1.28 microg mL(-1)) of rFVIIa and NN1731. Platelet contractile force (PCF) or platelet function, clot elastic modulus (CEM) or clot structure, and force onset time (FOT) or the thrombin generation time (TGT) were determined using the Hemodyne Hemostasis Analysis System (HAS). Baseline PCF, CEM and FOT values in patients were abnormal compared to healthy volunteers' baseline values. Overall, haemophilia blood samples with or without inhibitors spiked with NN1731 had significantly greater PCF, CEM and shorter FOT values relative to samples spiked with corresponding doses of rFVIIa. The variability in response to treatment between patients was greater with rFVIIa compared to NN1731. At 1.28 microg mL(-1) (90 microg kg(-1)), NN1731 normalized PCF, CEM and FOT in nine of 10 patients, while rFVIIa normalized these parameters in four of 10 patients. Increasing in vitro concentrations of NN1731 normalized platelet function, clot structure and thrombin generation consistently in haemophilia blood with or without inhibitors. NN1731 may be a promising haemostatic agent for patients with bleeding disorders. These results should be confirmed in an in vivo study.
Brophy
D F
DF
Coagulation Special Studies Laboratory, Department of Pharmacy of Virginia Commonwealth University, Richmond, VA 23298, USA. dbrophy@vcu.edu
Martin
E J
EJ
Nolte
M E
ME
Kuhn
J G
JG
Carr
M E
ME
D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000502:physiology; D003018:Clot Retraction / Q000187:drug effects; D005167:Factor VII / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects*; D010976:Platelet Count
C519901:NN1731; D005167:Factor VII