Factor VIIa analogue (V158D/E296V/M298Q-FVIIa) normalises clot formation in whole blood from patients with severe haemophilia A.
This study evaluated and compared the haemostatic potential of a recombinant factor VIIa (rFVIIa) analogue (V158D/E296V/M298Q-FVIIa, NN1731, Novo Nordisk, Denmark) with rFVIIa (NovoSeven, Novo Nordisk). In vitro studies were performed using freshly drawn whole blood (WB) from 14 patients with severe haemophilia A and two patients with inhibitory antibodies to FVIII, comparing NN1731 and rFVIIa against a buffer control. Fourteen healthy males served as controls. Dynamic WB coagulation profiles were recorded, quantitatively illustrating the initiation [clotting time = CT (s)], propagation [maximum velocity = MaxVel (mm*100/s)] and termination [maximum clot firmness = MCF (mm*100)] as determined by thromboelastography with minute amounts of tissue factor (TF, Innovin - final dilution 1:50 000, c. 0.12 pM) serving as activator. WB clot stability was assessed using a separate set-up including TF plus tissue plasminogen activator (final concentration 2 nmol/l), evaluating the MCF as well as the area under the elasticity curve (AUEC) after 60 min (mm*100*s). NN1731 shortened the CT more markedly than rFVIIa. At the dose tested, NN1731 even shortened CT in haemophilia below the value of healthy males. NN1731 accelerated MaxVel giving a value indistinguishable from that in healthy males. Furthermore, NN1731 increased clot stability more markedly than rFVIIa. Altogether, these in vitro studies on WB revealed a favourable haemostatic potential of NN1731 compared with rFVIIa in severe haemophilia A, both in the absence and presence of enhanced fibrinolytic activity.
Sørensen
Benny
B
Centre for Haemophilia and Thrombosis, Aarhus University Hospital, Skejby, Aarhus N, Denmark. benny.sorensen@ki.au.dk
Persson
Egon
E
Ingerslev
Jørgen
J
D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests / Q000379:methods; D003029:Coagulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005167:Factor VII / Q000494:pharmacology*; D015942:Factor VIIa; D005342:Fibrinolysis / Q000187:drug effects; D006467:Hemophilia A / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D013916:Thrombelastography
D003029:Coagulants; C519901:NN1731; D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa