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November / December  1999

RECOMBINANT FACTOR VIIa:  A New Product for Factor VIII and IX Inhibitors

Margaret V. Ragni, M.D., Medical Director, M.P.H., Director, Hemophilia Center of Western Pennsylvania Patient Transfusion Services


INTRODUCTION

Recombinant coagulation factor VIIa (rFVIIa) (Novoseven), is a Vitamin K-dependent glycoprotein recently licensed by the FDA for treatment of bleeding in individuals with hemophilia A and B inhibitors, acquired inhibitors (e.g. anti-VIII), and congenital factor VII deficiency.

BACKGROUND

Produced in baby hamster kidney (BHK) cells transfected with the FVII gene, secreted rFVII is rapidly activated in cell culture to its active form, rFVIIa during chromatographic purification. Because the culture medium contains newborn calf serum, the final product contains trace mouse IgG and BHK protein. The observed half-life of the product in pharmacokinetic studies is 2-3 hours. The site of action of rFVIIa is the extrinsic coagulation cascade, specifically complexing to tissue factor, with which promotes activation of factor X to Xa, factor IX to IXa, and factor II (prothrombin) to IIa (thrombin). The clot promoting activity of this product through the extrinsic pathway, bypassing the intrinsic pathway (factors VIII and FIX), makes it potentially beneficial in patients with acquired inhibitors to factor VIII or IX, who no longer respond to factor VIII or IX concentrates, and patients with congenital factor VII deficiency. Factor VIIa efficacy demonstrated in the Wessler rabbit stasis model have shown that FVIIa promotes clot formation and hemostasis at the site of injury with no evidence of activation of the coagulation system, e.g. decreased in platelets, fibrin split products, or fibrin monomer.

CLINICAL STUDIES

rFVIIa has been shown to be safe and effective for acute bleeding, life and limb-threatening hemorrhage, and in the surgical setting. In a study by Lusher et al carried out in 78 hemophilia A and B patients with severe or moderately severe disease, with FVIII:C or IX:C < 0.02 U/ml, 66 with inhibitors, the product was found to be safe and effective during treatment for 179 hemorrhages. The clinical response to the higher of two tested treatment doses, 70 vs.35 m g/kg, was somewhat higher, 69% vs. 53%. Only mild adverse events were reported in 22%.

SAFETY ISSUES

rFVIIa has been evaluated in nearly 300 patients for 2,000 hemorrhages and appears to be safer and more effective than currently available treatment for patients with inhibitors (plasma-derived FEIBA, Autoplex) or congenital factor VII deficiency (plasma). Specifically, rFVIIa avoids the major risk associated with FEIBA and Autoplex, thrombosis, and it avoids the major risk associated with plasma, e.g. blood-borne virus transmission and other pathogens, as well as plasma-derived product shortages. There has been no evidence of allergic reaction or activation of coagulation, thrombocytopenia, or disseminated intravascular coagulation. A drawback is the short half-life of rFVII, which requires frequent dosing and results in high cost. Continuous infusion may be a potential approach, although local thrombophlebitis is a major complication, possibly related to the high concentration of rVIIa in peripheral veins. Until more information is available on rFVIIa stability and local thrombophlebitis, continuous infusion is not recommended.

CLINICAL MONITORING

The major effect of rFVIIa is to shorten the prothrombin time (PT), that is, the time from vessel injury to clot formation via the tissue factor pathway. The extent of PT shortening, however, does not specifically correlate with clinical efficacy of rFVIIa. Thus, patients treated with rFVIIa should be monitored for blood loss, transfusion requirement, and hemoglobin.

DOSING GUIDELINES

The initial recommended dose of rFVIIa is 90 m g/kg, continued every 2-3 hours, and once bleeding and hemoglobin have stabilized, tapered to every 6-8 hours, then every 12-24 hours, and stopped. Dosing in children may differ from that in adults, given the shorter half-life observed in pharacokinetic studies of pediatric patients.

Coagulation Cascade

REFERENCES

1. Lusher JM, Roberts HR, Davignon G, Joist JH, Smith H, Shapiro A, Laurian Y, Kasper CK, Mannucci PM.  A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle, and mucocutaneous hemorrhages in persons with haemophilia A and B, with and without inhibitors. Haemophilia 1998; 4:790-8.

2. Hay CRM, Negrier C, Ludlam CA. The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: a multi-center study. Thromb Hemostas 1997; 78: 1463-7.

3. Hedner U, Ingerslev J. Clinical use of recombinant factor VIIa (rFVIIa). Transfus Sci 1998;19: 163-76.

4. Hedner U, Kristensen H, Berntorp E, Ljung R, Petrini P, Tengborn L. Pharmacokinetics of rFVIIa in children. Haemophilia 1998; 4: 244 (355) abstract.

5.Scharrer I. Recombinant factor VIIa for serious bleeding episodes or bleeding during surgery in patients with inhibitors to factors VIII or IX, or with FVII deficiency. Haemophilia 1998; 4: 239 (335) abstract. 


Copyright 2000, Institute For Transfusion Medicine


For questions regarding rFVIIa, please contact Margaret A. Ragni, M.D. at 
(412) 209-7288 or by e-mail: ragni@msx.dept-med.pitt.edu

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