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