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.