Intra-patient variability of thromboelastographic parameters following in vivo and ex vivo administration of recombinant activated factor VII in haemophilia patients. A multi-centre, randomised trial

Summary

Thromboelastography methods have been used to predict or monitor treatment of haemophilia patients with recombinant activated factor VII (rFVIIa). However, neither of the two thromboelastographic methods (ROTEM and TEG) has as yet been validated. This multi-centre, randomised trial compared both methods in terms of intra- and inter-patient variability following in vivo and ex vivo rFVIIa administration to haemophilia A and B patients with and without inhibitors. Patients (≥16 years old) received the same intravenous rFVIIa dose (45, 90 or 180 μg/kg) twice, 1–12 weeks apart. Blood samples were collected pre-dose and 15, 60, 120 and 240 minutes post-dose for ROTEM and TEG analysis. Pre-dose samples were also spiked ex vivo with rFVIIa (0.6, 1.2 or 2.4 μg/ml), to correspond to the three in vivo doses. Twenty-six haemophilia A and four haemophilia B patients were enrolled. A significant treatment effect was observed with in vivo rFVIIa (p<0.05) with more pronounced effects in inhibitor (n=14) versus non-inhibitor (n=16) patients. There was a strong positive correlation between ROTEM and TEG parameters. Intra- and inter-patient variation was large for all thromboelastography parameters at all time points and rFVIIa doses. Intra-patient variation was generally lower for non-inhibitor than inhibitor patients, and lower following ex vivo spiking versus in vivo rFVIIa administration. In conclusion, there was a clear effect of rFVIIa on all thromboelastography parameters, but the large intra- and inter-patient variability following in vivo rFVIIa administration renders the use of our method unsuitable for dose-response prediction for haemophilia patients in the clinical setting.

Keywords

Thromboelastography, recombinant activated factor VII, haemophilia, ROTEM, TEG

^# AB – Ferring Pharmaceuticals A/S

^† WW – YES Pharmaceutical Services GmbH, Friedrichsdorf, Germany

^‡ MK – Deutsche Klinik für Diagnostik, Hämostaseologie, Wiesbaden, Germany.

• References

• 1 Salooja N, Perry DJ. Thromboelastography. Blood Coagul Fibrinolysis 2001; 12: 327-337.
• 2 Rivard GE, Brummel-Ziedins KE, Mann KG. et al. Evaluation of the profile of thrombin generation during the process of whole blood clotting as assessed by thrombelastography. J Thromb Haemost 2005; 3: 2039-2043.
• 3 Luddington RJ. Thromboelastography/thromboelastometry. Clin Lab Haem 2005; 27: 81-90.
• 4 Koh MBC, Hunt BJ. The management of perioperative bleeding. Blood Rev 2003; 17: 179-185.
• 5 Sørensen B, Ingerslev J. Thromboelastography and recombinant factor VIIa – hemophilia and beyond. Semin Hematol 2004; 41 1 Suppl 1 140-144.
• 6 Carr JR ME, Martin EJ, Kuhn JG. et al. Monitoring of hemostatic status in four subjects being treated with recombinant factor VIIa. Clin Lab 2004; 50: 529-538.
• 7 Kawaguchi C, Takahashi Y, Hanesaka Y. et al. The in vitro analysis of the coagulation mechanism of activated factor VII using thrombelastogram. Thromb Haemost 2002; 88: 768-772.
• 8 Ingerslev J, Christiansen K, Calatzis A. et al. Management and monitoring of recombinant activated factor VII. Blood Coagul Fibrinolysis 2000; 11 (Suppl. 01) S25-S30.
• 9 DiMichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia 2002; 8: 280-287.
• 10 Barr RD, Saleh M, Furlong W. et al. Health status and health-related quality of life associated with hemophilia. Am J Hematol 2002; 71: 152-160.
• 11 Gabriel DA, Carr M, Roberts HR. Monitoring coagulation and the clinical effects of recombinant factor VIIa. Semin Hematol 2004; 41 (Suppl. 01) 20-24.
• 12 Key NS, Nelsestuen GL. Views on methods for monitoring recombinant factor VIIa in inhibitor patients. Semin Hematol 2004; 41 1 Suppl 1 51-54.
• 13 Sørensen B, Johansen P, Christiansen K. et al. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost 2003; 1: 551-558.
• 14 Young G, Blain R, Nakagawa P. et al. Individualization of bypassing agent treatment for haemophilic patients with inhibitors utilizing thromboelastography. Haemophilia 2006; 12: 598-604.
• 15 Sørensen B, Ingerslev J. Tailoring haemostatic treatment to patient requirements – an update on monitoring haemostatic response using thromboelastography. Haemophilia 2005; 11 (Suppl. 01) 1-6.
• 16 Sørensen B, Ingerslev J. Whole blood clot formation phenotypes on haemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa. J Thromb Haemost 2004; 2: 102-110.
• 17 ROTEM^® . Available at: http://www.rotem.de. Accessed March 24, 2009.
• 18 TEG^® . Available at: http://www.haemoscope.com. Accessed March 24, 2009.
• 19 Chitlur M, Warrier I, Rajpurkar M. et al. Thromboelastography in children with coagulation factor deficiencies. Br J Haematol 2008; 142: 250-256.
• 20 Nielsen VG. A comparison of the Thrombelastograph and the ROTEM. Blood Coagul Fibrinolysis 2007; 18: 247-252.
• 21 Young G, Ebbesen LS, Viuff D. et al. Evaluation of thromboelastography for monitoring recombinant activated factor VII ex vivo in haemophilia A and B patients with inhibitors: a multicentre trial. Blood Coagul Fibrinolysis 2008; 19: 276-282.