Recombinant Factor VIIa for the Treatment of Congenital Factor VII Deficiency

Hunault, Mathilde; Bauer, Kenneth A.

doi:10.1055/s-2000-8459

Cited by 56 publications

(35 citation statements)

References 24 publications

(28 reference statements)

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“…[26][27][28][29][30][31][32][33][52][53][54][55][56][57][58][59] It has primarily been used to treat hemophilia patients with acquired inhibitors. [28][29][30][31][32] The in vivo concentrations of factor VIIa for this treatment range from 3 to 20 nM 29,60-63 (based on 50 000 units/mg specific activity of recombinant factor VIIa 63 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of factor VIIa–dependent coagulation in hemophilia blood

Butenas

Brummel

Branda

et al. 2002

Blood

188

163

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The ability of factor VIIa to initiate thrombin generation and clot formation in blood from healthy donors, blood from patients with hemophilia A, and in anti-factor IX antibody-induced ("acquired") hemophilia B blood was investigated. In normal blood, both factor VIIa-tissue factor (TF) complex and factor VIIa alone initiated thrombin generation. The efficiency of factor VIIa was about 0.0001 that of the factor VIIa-TF complex. In congenital hemophilia A blood and "acquired" hemophilia B blood in vitro, addition of 10 to 50 nM factor VIIa (pharmacologic concentrations) corrected the clotting time at all TF concentrations tested (0-100 pM) but had little effect on thrombin generation. Fibrinopeptide release and insoluble clot formation were only marginally influenced by addition of factor VIIa. TF alone had a more pronounced effect on thrombin generation; an increase in TF from 0 to 100 pM increased the maximum thrombin level in "acquired" hemophilia B blood from 120 to 480 nM. Platelet activation was considerably enhanced by addition of factor VIIa to both hemophilia A blood and "acquired" hemophilia B blood. Thus, pharmacologic concentrations of factor VIIa cannot restore normal thrombin generation in hemophilia A and hemophilia B blood in vitro. The efficacy of factor VIIa (10-50 nM) in hemophilia blood is dependent on TF. IntroductionThe blood-coagulation cascade is initiated when cryptic tissue factor (TF) is expressed and exposed to circulating blood and binds plasma factor VIIa. The resulting factor VIIa-TF complex activates the serine protease zymogens factor IX and factor X. The factor Xa that is initially produced generates picomolar amounts of thrombin, which activates platelets and cleaves procofactors factors V and VIII. Factor VIIIa forms a complex on a membrane surface with serine protease factor IXa and activates factor X at a 50-to 100-fold higher rate than the factor VIIa-TF complex. The factor Xa produced, in complex with its cofactor, factor Va, and an appropriate membrane surface forms the prothrombinase complex, which is the primary activator of prothrombin. The thrombin produced amplifies its own generation by activating factor XI and completing the activation of platelets and procofactors. Thrombin cleaves fibrinogen and activates factor XIII to form the insoluble isopeptide cross-linked fibrin clot. The coagulation cascade is down-regulated by the stoichiometric inhibitors antithrombin III (AT-III) and tissue factor pathway inhibitor (TFPI) and by the dynamic protein C system. 1 Genetic and acquired deficiencies in coagulation proteins lead to hemorrhagic syndromes. [2][3][4][5][6] The most common bleeding disorders result from deficiencies of factor VIII (hemophilia A) or factor IX (hemophilia B) coagulant activity. In the past, the principal treatments for hemophilia relied on partially purified concentrates of coagulation factors. 7,8 These concentrates, however, have been associated with thromboembolic complications and viral infections. 9-11 During the past decade, plasma-derived, ...

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Section: Discussionmentioning

confidence: 99%

Mechanism of factor VIIa–dependent coagulation in hemophilia blood

Butenas

Brummel

Branda

et al. 2002

Blood

188

163

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“…As the presence of rVIIa is thought to be required when haemostasis is challenged, prophylaxis with rVIIa would seem unlikely to succeed because of its short half-life in blood. On-demand therapy with rVIIa for FVII deficiency has been described before in small studies and case reports (Bauer, 1996;Ingerslev et al, 1997;Mariani et al, 1999;Hunault & Bauer, 2000;Berrettini et al, 2001;Charpiat et al, 2002;Eskandari et al, 2002). Furthermore, rVIIa has been administered for many indications, such as haemophilia A and B with inhibitors, for which the product was originally developed, surgical procedures or trauma in otherwise healthy patients (Hedner, 2003).…”

Section: Patient 1 Patient 2 Patientmentioning

confidence: 99%

Prophylactic effect of recombinant factor VIIa in factor VII deficient patients

Mathijssen¹,

Masereeuw

Verbeek³

et al. 2004

Br J Haematol

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Summary Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder associated with a bleeding tendency. We describe three patients with congenital FVII deficiency who have been treated with activated recombinant factor VII (rVIIa). Two patients had novel mutations and were treated prophylactically with 1·2 mg rVIIa two to three times a week. Patients 1 and 2 had a severe bleeding tendency. The frequency and severity of bleeding decreased by treatment with rVIIa compared with similar treatment with plasma‐derived FVII. The third patient with a moderate bleeding phenotype was treated on demand and showed no change in the frequency of bleeding upon treatment with rVIIa or plasma products. The beneficial effect of rVIIa cannot be explained by the rVIIa half‐lives. Pharmacokinetical analysis showed rVIIa activity half‐lives of 35, 50 and 54 min for patients 1, 2 and 3, respectively. In conclusion, prophylactic treatment of FVII deficient patients with rVIIa appears to be applicable, safe and successful, although the mechanism of action remains to be elucidated.

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“…10 A rise of FVII activity .10% to 15% normal can achieve hemostasis in FVII-deficient patients. [11][12][13][14] Therefore, based on the current nonhuman primate data, 10 the translational potential of AAV-mediated gene therapy for FVII deficiency remains unclear. A further complication is the lack of data in large-animal models of FVII deficiency, in contrast to hemophilia, and the very limited use of species-specific FVII transgene(s).…”

Section: Introductionmentioning

confidence: 99%

Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII

Marcos‐Contreras

Smith

Bellinger³

et al. 2016

Blood

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• Dogs with an FVII G96E mutation (FVII-G96E) represent the most common human FVII mutation type and are ideal for testing new therapies.• cFVII gene delivery in FVII-G96E dogs via AAV at a dose effective in humans showed stable and clinically therapeutic FVII expression.Factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder treated by infusion of fresh-frozen plasma, plasma-derived FVII concentrates and low-dose recombinant activated FVII. Clinical data suggest that a mild elevation of plasma FVII levels (>10% normal) results in improved hemostasis. Research dogs with a G96E missense FVII mutation (FVII-G96E) have <1% FVII activity. By western blot, we show that they have undetectable plasmatic antigen, thus representing the most prevalent type of human FVII deficiency (low antigen/activity). In these dogs, we determine the feasibility of a gene therapy approach using liver-directed, adeno-associated viral (AAV) serotype 8 vector delivery of a canine FVII (cFVII) zymogen transgene. FVII-G96E dogs received escalating AAV doses (2E11 to 4.95E13 vector genomes [vg] per kg). Clinically therapeutic expression (15% normal) was attained with as low as 6E11 vg/kg of AAV and has been stable for >1 year (ongoing) without antibody formation to the cFVII transgene. Sustained and supraphysiological expression of 770% normal was observed using 4.95E13 vg/kg of AAV (2.6 years, ongoing). No evidence of pathological activation of coagulation or detrimental animal physiology was observed as platelet counts, D-dimer, fibrinogen levels, and serum chemistries remained normal in all dogs (cumulative 6.4 years). We observed a transient and noninhibitory immunoglobulin G class 2 response against cFVII only in the dog receiving the highest AAV dose. In conclusion, in the only largeanimal model representing the majority of FVII mutation types, our data are first to demonstrate the feasibility, safety, and long-term duration of AAV-mediated correction of FVII deficiency. (Blood. 2016;127(5):565-571)

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Recombinant Factor VIIa for the Treatment of Congenital Factor VII Deficiency

Cited by 56 publications

References 24 publications

Mechanism of factor VIIa–dependent coagulation in hemophilia blood

Mechanism of factor VIIa–dependent coagulation in hemophilia blood

Prophylactic effect of recombinant factor VIIa in factor VII deficient patients

Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII

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