Possible Synergy between Recombinant Factor VIIa and Prothrombin Complex Concentrate in Hemophilia Therapy

Summary

Recombinant factor VIIa (rFVIIa; Novoseven™) is used for treatment of hemophilia patients with inhibitors. There are poorly defined differences in clinical responsiveness between individuals. Prior to licensure in the United States, rFVIIa was available through the compassionate use program, during which two patients described in this study demonstrated an excellent response. More recently, one of these individuals showed a sub-optimal response to rFVIIa. One possible explanation for different treatment outcomes was sequential therapy with prothrombin complex concentrates (PCC) followed by rFVIIa in the compassionate use program. In support of this, an in vitro test showed that this patient had an exceptionally strong response to rFVIIa when it was added to whole blood after the patient received PCC therapy. Results with other patients supported this hypothesis. With further evaluation, a therapeutic approach combining sequential PCC and rFVIIa may prove useful for treatment of bleeding refractory to either agent used alone.

Keywords

Factor VIIa - prothrombin complex concentrates - haemophilia

• References

• 1 Sultan Y, Loyer F. In vitro evaluation of factor VIII-bypassing activity of activated prothrombin complex concentrate, in the plasma of patients with factor VIII inhibitors: thrombin generation test in the presence of collagenactivated platelets. J Lab Clin Med 1993; 121: 444-52.
• 2 Teitel JM, Ni HY, Freedman JJ, Garvey MB. The endothelial cell and the factor VIII bypassing activty of prothrombin complex concentrates. Thromb Haemost 1988; 60: 226-9.
• 3 Hedner U. NovoSeven as a universal haemostatic agent. Blood Coagul Fibrinolysis 2000; 11 (Suppl. 01) S107-S111.
• 4 ten Cate H, Bauer KA, Levi M, Edgington TS, Sublett RD, Barzegar S, Kass BL, Rosenburg RD. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clinic Invest Inc 1993; 92: 1207-12.
• 5 Rao LVM, Rapaport SI. Cells and the activation of factor VII. Haemostas 1996; 26 (Suppl. 01) 1-5.
• 6 Monroe DM, Hoffman M, Oliver JA, Roberts HR. A possible mechanism of action of activated factor VII independent of tissue factor. Blood 1998; 09 (Suppl. 01) S15-S20.
• 7 Rao LVM, Rapaport SI. Factor VIIa-catalyzed activation of factor X independent of tissue factor: its possible significance for control of hemophilic bleeding by infused factor VIIa. Blood 1990; 75: 1069-73.
• 8 Lindley CM, Sawyer WT, Macik BG, Lusher J, Harrison JF, Baird-Cox K, Birch K, Glazer S, Roberts HR. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Therapeut 1994; 55: 638-48.
• 9 Aledort LM. Recombinant factor VIIa is a pan-hemostatic agent?. Thromb Haemost 2000; 83: 637-8.
• 10 Key NS, Aledort LM, Beardsley D, Cooper HA, Davignon G, Ewenstein BM, Gilchrist GS, Gill JC, Glader B, Hoots WK, Kisker CT, Lusher JM, Rosenfield CG, Shapiro AD, Smith H, Taft E. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912-8.
• 11 Sumner WT, Monroe DM, Hoffman M. Variability in platelet procoagulant activity in healthy volunteers. Thromb Res 1996; 81: 533-43.
• 12 Henderson N, Key NS, Christie B, Kisiel W, Foster W, Nelsestuen GL. Response of factor VIII and IX-deficient blood to recombinant wild type and high membrane-affinity mutants of factor VIIa in an in vitro whole blood clotting assay: Possible correlation to clinical outcome. Thromb Haemost 2002; 88: 98-103.
• 13 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237.
• 14 Verbryggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:c inhibitors: Improved specificity and reliability. Thromb Haemost 1995; 73: 247-51.
• 15 Santagostino E, Gringeri A, Mannucci PM. Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention. Brit J Haematol 1999; 104: 22-6.
• 16 Lusher JM. Recombinant activated factor VII for treatment of intramuscular haemorrhages: a comparison of early versus late treatment. Blood Coagul Fibrinol 1998; 09 (Suppl. 01) S111-S114.
• 17 Lusher JM. Acute hemarthroses: the benefits of early versus late treatment with recombinant activated factor VII. Blood Coagul Fibrinol 2000; 11 (Suppl. 01) S45-S49.
• 18 Lundblad RL, Bergstrom J, De Vreker R, Bray G, Gomperts E, Baker D, Kingdon HS, Mann KG, Hartshorn J, Jenny RJ. Measurement of active coagulation factors in Autoplex-T with colorimetric active site-specific assay technology. Thromb Haemost 1998; 80: 811-5.