Recombinant Activated Factor VII (rFVIIa): Characterization, Manufacturing, and Clinical Development

Abstract

Recombinant activated coagulation factor VII (rFVIIa) (NovoSeven) was developed for treatment of bleeding in hemophilia patients with inhibitors (antibodies) against factors VIII or IX. rFVIIa initiates the coagulation cascade by binding to tissue factor at the site of injury and causes the formation of sufficient amounts of thrombin to trigger coagulation. Patients with a variety of other coagulation deficiencies than hemophilia characterized by an impaired thrombin generation and life-threatening bleeding have been reported as successfully treated with rFVIIa. Data are now entered into clinical registries established to further monitor this experimental treatment with NovoSeven. rFVIIa is produced free of any added human protein. The amino acid sequence of rFVIIa is identical to plasma-derived FVIIa (pdFVIIa). Posttranslational modifications (i.e., gamma-carboxylations, N- and O-glycosylations) are qualitatively identical in pdFVIIa and rFVIIa although some quantitative differences exist. The activities of rFVIIa and pdFVIIa are indistinguishable. Manufacturing of rFVIIa involves expression in baby hamster kidney (BHK) cells followed by purification, including three ion-exchange and one immunoaffinity chromatography steps. The last anion-exchange chromatography step ensures completion of the autoactivation of recombinant factor VII (rFVII) to rFVIIa. This review describes the mechanism of action, characterization, manufacturing, and preclinical and current clinical evidence for the efficacy and safety of rFVIIa.

Acquired hemophilia A: A concise review

“…Prothrombin complex concentrates derived from plasma and containing activated vitamin K-dependent coagulation factors (factors VIIa, IXa, and Xa and thrombin) are able to promote hemostasis in the absence of factor VIII [46][47][48][49][50][51]. A major step toward the control of bleeding in acquired hemophilia has been achieved with a new hemostatic agent, recombinant activated factor VII (rFVIIa), which has been shown to be clinically safe and effective as both first-and second-line treatments for acute bleeding episodes [52][53][54][55][56][57][58][59][60][61]. A high response rate (88% after 8 hr and 92% after 24 hr) was observed by Hay and colleagues in a multicenter study [54].…”

Improved hemostasis with superactive analogs of factor VIIa in a mouse model of hemophilia A

“…[1][2][3][4] A small fraction of patients may be refractory to rFVIIa treatment 5 and could potentially benefit from genetically modified FVIIa molecules with increased potencies. To this end, FVIIa analogs with increased intrinsic activity have been generated that exhibit superior hemostatic profiles in vitro.…”

Aortic valve replacement in a patient with factor VII deficiency

“…Thus, it is devoid of other human proteins or human viruses, and this nullifies the possibility of transmission of HIV or hepatitis. [4] It initiates the coagulation cascade by binding with the tissue factor at the site of injury and causes the formation of sufficient amounts of thrombin to trigger coagulation. [4] The rationale behind the use of rFVIIA in FVII deficiency is self evident since it provides only the missing factor.…”