Factor VIIa analogue (V158D/E296V/M298Q‐FVIIa) normalises clot formation in whole blood from patients with severe haemophilia A

Abstract

Summary 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.

Citrate artificially masks the haemostatic effect of recombinant factor VIIa in dilutional coagulopathy

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Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives

“…19,20,25 An early study that used TEG to individualize therapy in 3 inhibitor patients led to identification of the lack of effect of rFVIIa in 1 patient (which the patient's mother had in fact suspected), while reducing the overall use of bypassing agents in 2 other patients led to more costeffective care without compromising efficacy. 20 This study also demonstrated the utility of TEG in assessing the effects of bypassing agents used in a combination for severe bleeds.…”

Diagnostic Performance and Therapeutic Consequence of Thromboelastometry Activated by Kaolin versus a Panel of Specific Reagents

“…Hyperfibrinolysis was generated adopting a setup previously used by our group in evaluation of clot stability. 22,23 Recombinant human single-chain tissuetype plasminogen activator (American Diagnostica Inc., Stamford, CT, final concentration 2 nM) was added to the WB sample immediately before processing the coagulation analysis. Heparin-induced Coagulopathy.…”