Monitoring low dose recombinant factor VIIa therapy in patients with severe factor XI deficiency undergoing surgery

Summary

Although factor XI (FXI) concentrate is an effective replacement therapy in severe FXI deficiency without inhibitors, some patients are unwilling to receive it because it is plasma-derived. We report on the use and monitoring of low dose, recombinant factor VIIa (rFVIIa, NovoSeven^®), to cover surgery (caesarean section, cholecystectomy and abdominoplasty) in four female patients (FXI:C 2–4 IU/dl, aged 32–51 years) who wished to avoid exposure to plasma. None of our patients had inhibitors to FXI. Our aim was to find the optimal dose of rFVIIa by in vitro spiking of patient samples and to correlate this with the response to rFVIIa in vivo. Prior to surgery, venous blood was collected into sodium citrate with corn trypsin inhibitor and spiked with 0.25–1.0 μg/ml rFVIIa in vitro, equivalent to a 15–70 μg/kg dose of rFVIIa in vivo. Analysis using thromboelastometry and thrombin generation assays, triggered with tissue factor, showed that the thrombin generation assay was insufficiently sensitive to the haemostatic defect in these patients. A concentration of 0.5 μg/ml was as effective as 1.0 μg/ml FVIIa in normalising thromboelastometry in vitro in all four patients. Therefore, patients received 15–30 μg/kg rFVIIa at 2–4 hourly intervals with tranexamic acid 1g every six hours. Post treatment samples were taken at 10–240 minutes and showed initial normalisation of thromboelastometry with gradual return to baseline after 2–4 hours. In conclusion, low-dose rFVIIa therapy was successfully used in four patients with severe FXI deficiency undergoing surgery to prevent bleeding and can be monitored using thromboelastometry.

keywords

Factor XI deficiency - recombinant factor VIIa - thromboelastometry - thrombin generation

• References

• 1 Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia 2008; 14: 1183-1189.
• 2 Hedner U. Factor VIIa in the treatment of haemophilia. Blood Coagul Fibrinolysis 1990; 1: 307-317.
• 3 Kenet G, Lubetsky A, Luboshitz J. et al. Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors. Haemophilia 2009; 15: 1065-1073.
• 4 Livnat T, Tamarin I, Mor Y. et al. Recombinant activated factor VII and tranexamic acid are haemostatically effective during major surgery in factor XI-deficient patients with inhibitor antibodies. Thromb Haemost 2009; 102: 487-492.
• 5 O’Connell NM, Riddell AF, Pascoe G. et al. Recombinant factor VIIa to prevent surgical bleeding in factor XI deficiency. Haemophilia 2008; 14: 775-781.
• 6 Santagostino E, Morfini M, Rocino A. et al. Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors. Thromb Haemost 2001; 86: 954-958.
• 7 Othman M, Powell S, Hopman WM. et al. Variability of thromboelastographic responses following the administration of rFVIIa to haemophilia A dogs supports the individualization of therapy with a global test of haemostasis. Haemophilia 2010; 6: 919-925.
• 8 Viuff D, Andersen S, Sorensen BB. et al. Optimizing thrombelastography (TEG) assay conditions to monitor rFVIIa (NovoSeven) therapy in haemophilia A patients. Thromb Res 2010; 126: 144-149.
• 9 Rugeri L, Quelin F, Chatard B. et al. Thrombin generation in patients with factor XI deficiency and clinical bleeding risk. Haemophilia 2010; 16: 771-777.