Mechanism of action, development and clinical experience of recombinant FVIIa
Introduction
Patients with severe hemophilia need regular treatment with a hemostatically effective product in order to avoid the development of a chronic athropathy developing as a result of repeated joint bleedings. They also require immediate effective treatment of bleedings associated with trauma or essential surgery. Around 20% of patients with severe hemophilia A develop inhibitory antibodies against the coagulation factor they are missing. The administration of factor VIII (FVIII) or factor IX (FIX) concentrates is not effective in these patients, since the respective coagulation factor is neutralized by the antibodies. Much effort has, therefore, been focused on finding a treatment which is hemostatically effective independent of the presence of FVIII/FIX. Activated prothrombin complex concentrates (APCC) containing both activated coagulation proteins and zymogens are still widely used to achieve such a FVIII by-passing effect. A hemostatic effect of these concentrates averaging between 50 and 65% was reported (Lusher et al., 1983, Sjamsoedin et al., 1981). Also, side-effects in terms of thromboembolic events have been reported (Lusher, 1991). A dog model was used to identify some of the factors involved in the development of these side-effects (Hedner et al., 1979). Based on these studies, activated coagulation FVII (FVIIa) was identified as an attractive candidate for a hemostatic agent independent of FVIII/FIX, for use in hemophilia patients. Purified FVIIa was later shown to be free of such effects in a similar dog model (Hedner and Kisiel, 1983). Furthermore, purified plasma-derived FVIIa was shown to induce hemostasis in a few severe hemophilia patients (Hedner and Kisiel, 1983, Hedner et al., 1989). It was suggested at the time that pharmacological doses of FVIIa bind to tissue factor (TF) exposed at the site of injury, activating FX and provide thrombin locally at the site of injury (Hedner and Kisiel, 1983).
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Development of recombinant FVIIa
Based on the observed hemostatic effect of plasma-derived purified FVIIa in severe hemophilia patients, recombinant FVIIa (rFVIIa) was developed for use in the treatment of severe hemophilia complicated with inhibitors against FVIII/FIX (Thim et al., 1988, Hagen et al., 1986). The amino acid sequence and posttranslational modifications of rFVIIa from the culture medium of a transfected baby hamster kidney cell line was compared to human plasma FVIIa. The two molecules were identical as for
Preclinical development
The hemostatic effect of rFVIIa was demonstrated in hemophilia dogs (Brinkhous et al., 1989) as well as in warfarin treated rats (Diness et al., 1990). No systemic activation of the coagulation was found following the injection of rFVIIa into rabbits using a stasis model originally developed as a thrombosis model. For a comparison it was shown in the same model that the injection of activated prothrombin complex concentrate (FEIBA) did induce lowering of the platelet counts as well as of the
Clinical development
The first patient treated with rFVIIa underwent open surgical synovectomy in March 1988 without any complications and no per- or postoperative abnormal bleeding (Hedner et al., 1988). An efficacy rate of 90–100% was later confirmed in several series of severe hemophilia patients subjected to surgery including major orthopedic surgery (Ingerslev et al., 1996, Shapiro et al., 1998). A review of patients with severe hemophilia with antibodies including close to 500 subjects treated at around 1900
Normal hemostasis
According to current concept, hemostasis occurs on principally two types of surfaces, the tissue factor (TF) expressing cell and the thrombin activated platelet (Monroe et al., 2002). TF is expressed by a number of various cells localized in the deeper layers of the vessel wall and normally not exposed to the circulating blood. TF is a true receptor protein and FVII/FVIIa is its ligand. As a result of tissue injury, TF is exposed to the circulation and forms a complex with FVII or FVIIa on the
Clinical experience with rFVIIa in hemophilia patients with Inhibitors
Hemophilia patients lacking FVIII (hemophilia A) or FIX (hemophilia B) develop severe, spontaneous bleedings deep in the body, characterized by being essentially non-responding to local pressure and likely to recur several hours later. Thrombin formation is markedly impaired in hemophilia, underscoring the importance of full thrombin generation for optimal hemostasis. The administration of pharmacological doses of rFVIIa increasing the plasma level of FVII:C from the normal value of around 1
Clinical experience with rFVIIa in other situations with an impaired thrombin generation than hemophilia
The availability of platelet procoagulant phospholipids has been demonstrated to be rate limiting for thrombin generation and accordingly, an impaired thrombin generation was described in patients with thrombocytopenia in the 1950s by Biggs and MacFarlane (1962). In accordance with this, the dependence of thrombin generation on platelet counts in a cell-based in vitro model was shown (Kjalke et al., 1999, Kjalke et al., 2001). In the same cell-based model the addition of rFVIIa in
References (97)
- et al.
Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors
J. Thromb. Haemost.
(2004) - et al.
Recombinant factor VIIa for life-threatening post-partum haemorrhage
Br. J. Anaesth.
(2005) - et al.
Purification and characterization of TAFI, a thrombin activable fibrinolysis inhibitor
J. Biol. Chem.
(1995) - et al.
Factor IX is activated in vivo by the tissue factor mechanism
Blood
(1990) - et al.
Human plasma and recombinant factor VII: characterization of O-glysylation at serine 52 and 60 and effects of site directed mutagenesis of serine 52 to alanine
J. Biol. Chem.
(1991) Fibrinogen structure, activation, polymerization and fibrin gel structure
Thromb. Res.
(1994)- et al.
Native fibrin gel networks observed by 3D microscopy, permeation and turbidity
Biochim. Biophys. Acta
(1989) - et al.
Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma
Blood
(1996) - et al.
Mechanism of factor VIIa-dependent coagulation in hemophilia blood
Blood
(2002) - et al.
Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots
J. Biol. Chem.
(2003)
Recombinant human factor VIIa (rFVIIa) in a rabbit stasis model
Thromb. Res.
Effect of recombinant human FVIIa on warfarin-induced bleeding in rats
Thromb. Res.
Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial
Lancet
Recombinant factor VIIa (rFVIIa) and its use in severe bleeding in surgery and trauma: a review
Blood Rev.
The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX
J. Thromb. Haemost.
The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia
J. Thromb. Haemost.
Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy
Lancet
Inhibition of tissue factor limits the growth of venous thrombosis in the rabbit
J. Thromb. Haemost.
Treatment of traumatic bleeding with recombinant factor VIIa
Lancet
Analysis of the glycoforms of human recombinant factor VIIa by capillary electrophoresis and high-performance liquid chromatography
J. Chromatogr. A
Recombinant factor VIIa improves clot formation but not fibrinolytic potential in patients with cirrhosis and during liver transplantation
Hepatology
Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe haemophilia A
Blood
Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A
J. Thromb. Haemost.
Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count
J. Thromb. Haemost.
Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII
Blood
Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force
J. Thromb. Haemost.
Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation
Blood
Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation
J. Thromb. Haemost.
The P-selectin, tissue factor, coagulation triad
J. Thromb. Haemost.
Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey
J. Thromb. Haemost.
Recombinant factor VIIa reduces bleeding in severely thrombocytopenic rabbits
Thromb. Res.
Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa
Blood
Roles of factor XI, platelets and tissue factor-initiated blood coagulation
J. Thromb. Haemost.
A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor
J. Biol. Chem.
Characterization of glycopeptides from recombinant coagulation factor VIIa by high-performance liquid chromatography and capillary zone electrophoresis using ultraviolet and pulsed electrochemical detection
Anal. Biochem.
The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation
Blood Coagul. Fibrinolysis
Effect of varied procoagulant concentration on thrombin generation in a model system
Thromb. Haemost.
Antifibrinolytic treatment with epsilon-aminocaproic acid in connection with prostatectomy
Acta Chir. Scand.
Fibrinolysis: past and present, a reflection of fifty years
Semin. Thromb. Hemost.
Thrombin, fibrin and platelets a resonance loop in which von Willebrand factor plays an essential role
Thromb. Haemost.
Human Blood Coagulation and its Disorders
Activation of coagulation factor VII to VIIa
Res. Discl.
Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials
J. Trauma
Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease
Proc. Natl. Acad. Sci. U.S.A.
Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality
Stroke
Effect of fibrin structure on plasmin-mediated dissolution of plasma clots
Blood Coagul. Fibrinolysis
Size and density of fibrin fibers from turbidity
Macromolecules
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2023, Journal of Thrombosis and HaemostasisProduction of coagulation factor VII in human cell lines Sk-Hep-1 and HKB-11
2017, Protein Expression and PurificationCitation Excerpt :This study aimed to produce blood coagulation factor VII in human cell lines, which may be an advantage compared with other mammalian expression systems due to the ability to produce proteins most similar to those synthesized naturally in humans [18,27]. FVII is a clotting protein present in the blood at concentrations of 500 ng/mL; only 1% is in the active form [13,28]. Factor VII is a very unstable protein and any attempt at the large-scale production of FVII in significant quantities is challenging.
Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: Mode of its action
2017, Blood AdvancesCitation Excerpt :rFVIIa has been used widely for more than 2 decades to treat bleeding disorders in hemophilia patients with inhibitors and other groups of patients.9,10 Although a number of mechanisms have been proposed to explain the therapeutic effect of rFVIIa, either involving TF-dependent or platelet-dependent/TF-independent mechanisms,9,11-13 the mode of rFVIIa action in treating hemophilia is not entirely clear. We postulated earlier that FVIIa binding to EPCR might augment the hemostatic effect of rFVIIa in therapeutic conditions by effectively competing with protein C for limited EPCR on the endothelium and thus downregulating APC generation.1,5