Inhibitor Haemophilia A - Cases with Reduced Haemostatic Response to Wildtype rFVIIa Who Achieved a Normal Clotting Profile with a Novel Potent Analogue of rFVIIa.

Development of inhibitory antibodies to coagulation factor VIII represents a serious complication in patients with congenital or acquired haemophilia A. Recombinant factor VIIa (rFVIIa, NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) has proven efficacious in management of bleeding episodes in patients with inhibitors. Recently, a novel analogue of rFVIIa (NN1731, Novo Nordisk) has been developed. NN1731 has increased potency to generate factor Xa on the surface of activated platelets. We have developed a thrombelastographic (TEG) whole blood (WB) coagulation model, employing activation with minimal amounts of tissue factor. This global clotting assay reflects the clinical severity of haemophilia A and can be used to ex vivo assess the haemostatic capacity of rFVIIa and NN1731. Adopting the TEG model, we report on two cases where ex vivo addition of rFVIIa only induced minor improvements of the WB coagulation profile. However, ex vivo addition of NN1731 revealed a normalization of the WB coagulation signature. The first case was a 74 years old female with acquired haemophilia A (APTT=51 sec, FVIII:C = 0.08 IU/mL, Inhibitor = 3.6 BU/mL. The second case was a patient with congenital haemophilia A and inhibitors (APTT=101 sec, FVIII:C<0.01 IU/mL, Inhibitor=9 BU/mL). In both cases, the WB thrombelastographic analysis demonstrated a severely compromised haemostatic capacity. Ex vivo dose titration studies with rFVIIa induced minor improvements only of the suppressed WB clot formation profile. However, ex vivo addition of NN1731 at 2 μg/mL normalized the coagulation signature. The observations that the analogue NN1731 normalized the haemostatic WB clotting profiles in cases where rFVIIa induced minor changes stimulates further pre-clinical investigations.